Rayleigh backscattered radiation produced by an arbitrary incident mode in multimode optical fibers.

The recently developed diffraction technique of analytical investigation of the Rayleigh backscattering produced by an incident fundamental mode in a multimode optical fiber with an arbitrary refractive index profile is generalized to admit an arbitrary incident mode, either radial or azimuthal. The relative powers of all backscattered modes are determined with explicit formulas via the properly normalized transverse distributions of the incident and backscattered mode fields within the fiber cross section. The regularities conditioned by azimuthal indices are expressed via a universal set of coefficients, and dependences on the radial mode indices are estimated numerically. Excitation coefficients are shown to be symmetrical for any pair of incident and backscattered modes.

Influence of a variable Rayleigh scattering-loss coefficient on the light backscattering in multimode optical fibers.

The recently developed diffraction technique of analytical investigation of the Rayleigh backscattering produced by an incident fundamental mode in a multimode optical fiber with an arbitrary refractive index profile is supplemented by taking into account the Rayleigh scattering-loss coefficient, which could be variable within the fiber cross section. The relative changes in various radial and azimuthal modes' excitation levels, due to some typical radial dependences of this coefficient, are computed for the quadratic- and step-index fibers. It is stated that the excitation efficiency could either rise or decay for different modes. The effect of the variable Rayleigh scattering-loss coefficient is shown to be more noticeable in the fibers with a quadratic refractive index profile, whereas it is negligible in actual multimode step-index fibers.

Rayleigh backscattering from the fundamental mode in step-index multimode optical fibers.

The Rayleigh backscattering produced by an incident fundamental mode in a multimode step-index optical fiber was analyzed using a recently developed diffraction technique. The complete set of backward propagating modes, both radial and azimuthal, was determined and regarded. For this type of fiber, normalized mode functions were constructed in an explicit form, thus providing a unified power scale to characterize the relationships between various excited modes. The dependencies of the mode excitation efficiencies on the technical parameters of the fiber and the frequency of the launched radiation were studied. A comparison of the mode excitation efficiencies was performed with those in the fiber with quadratic refractive index profiles.

Rayleigh backscattering from the fundamental mode in multimode optical fibers.

Rayleigh backscattering produced by an incident fundamental mode in a multimode optical fiber is analyzed using a diffraction technique, with a full set of backward-propagating modes being taken into consideration. Explicit formulas are derived for mode excitation efficiency via radial distributions of the mode fields, and it is proved that only half-azimuthal modes are backscattered by the incident wave of a fixed polarization. Advanced analytical expressions are developed for fibers with a quadratic refractive-index profile, and mode groups of even numbers, composed of modes with equal propagation constants, are stated to be excited with equal efficiencies.

The effect of losartan therapy on ventricular function in Marfan patients with haploinsufficient or dominant negative FBN1 mutations.

BACKGROUND: Mild biventricular dysfunction is often present in patients with Marfan syndrome. Losartan has been shown to reduce aortic dilatation in patients with Marfan syndrome. This study assesses the effect of losartan on ventricular volume and function in genetically classified subgroups of asymptomatic Marfan patients without significant valvular regurgitation. METHODS: In this predefined substudy of the COMPARE study, Marfan patients were classified based on the effect of their FBN1 mutation on fibrillin-1 protein, categorised as haploinsufficient or dominant negative. Patients were randomised to a daily dose of losartan 100 mg or no additional treatment. Ventricular volumes and function were measured by magnetic resonance imaging at baseline and after 3 years of follow-up. RESULTS: Changes in biventricular dimensions were assessed in 163 Marfan patients (48 % female; mean age 38 ± 13 years). In patients with a haploinsufficient FBN1 mutation (n = 43), losartan therapy (n = 19) increased both biventricular end diastolic volume (EDV) and stroke volume (SV) when compared with no additional losartan (n = 24): left ventricular EDV: 9 ± 26 ml vs. -8 ± 24 ml, p = 0.035 and right ventricular EDV 12 ± 23 ml vs. -18 ± 24 ml; p < 0.001 and for left ventricle SV: 6 ± 16 ml vs. -8 ± 17 ml; p = 0.009 and right ventricle SV: 8 ± 16 ml vs. -7 ± 19 ml; p = 0.009, respectively. No effect was observed in patients with a dominant negative FBN1 mutation (n = 92), or without an FBN1 mutation (n = 28). CONCLUSION: Losartan therapy in haploinsufficient Marfan patients increases biventricular end diastolic volume and stroke volume, furthermore, losartan also appears to ameliorate biventricular filling properties.

The revised role of TGF-ß in aortic aneurysms in Marfan syndrome.

BACKGROUND: Recently, we demonstrated that losartan reduced the aortic root dilatation rate (AoDR) in adults with Marfan syndrome (MFS); however, responsiveness was diverse. The aim was to determine the role of transforming growth factor-ß (TGF-ß) as therapeutic biomarker for effectiveness of losartan on AoDR. METHODS: Baseline plasma TGF-ß levels of 22 healthy controls and 99 MFS patients, and TGF-ß levels after 1 month of losartan treatment in 42 MFS patients were measured. AoDR was assessed by magnetic resonance imaging at baseline and after 3 years of follow-up. RESULTS: Patients with MFS had higher TGF-ß levels compared with healthy controls (121 pg/ml versus 54 pg/mL, p = 0.006). After 1 month of therapy, losartan normalised the TGF-ß level in 15 patients (36%); the other 27 patients (64%) showed a significant increase of TGF-ß. After 3 years of losartan therapy, patients with a decrease in TGF-ß had significantly higher AoDR compared with patients with increased TGF-ß (1.5 mm/3 years versus 0.5 mm/3 years, p = 0.04). Patients showing a decrease in TGF-ß after losartan therapy had significantly elevated baseline TGF-ß levels compared with patients with increased TGF-ß (189 pg/ml versus 94 pg/ml, p = 0.05). CONCLUSION: Patients responding to losartan therapy with a reduction of the plasma TGF-ß level had higher baseline TGF-ß levels and a higher AoDR. Most likely, TGF-ß levels may be considered to be a readout of the disease state of the aorta. We propose that increased angiotensin II is the initiator of aorta dilatation and is responsible for increased TGF-ß levels in MFS. The concept of TGF-ß as initiator of aortic dilatation in MFS patients should be nuanced.

Delay to carotid endarterectomy in patients with symptomatic carotid artery stenosis.

OBJECTIVE: In patients with recently symptomatic carotid artery stenosis, guidelines recommend carotid revascularization within 2 weeks of the index event. The "index event" may be defined as either the first or the most recent event. The delay between the index event and carotid endarterectomy (CEA) over a period of 6 years in a single centre was evaluated and the effect of defining the index event as either the first or the most recent event was assessed. DESIGN: Observational study. METHODS: 555 consecutive patients with symptomatic carotid stenosis ≥ 50% treated with CEA between 2007 and 2012 were assessed. In 2010, changes to the in-hospital process of care to reduce delays in referral and CEA were introduced. These changes included, for example, improving access to physicians, imaging, and operating rooms. The delay from symptoms to surgery was expressed in days. RESULTS: The median time between the first event and surgery was reduced from 53 days (interquartile range [IQR] 30-78) in 2007 to 21 days (IQR 12-45) in 2012, and between the most recent event and CEA from 45 days (IQR 28-67) to 17 days (IQR 9-28). Patients referred directly by their general practitioner more often underwent CEA within 2 weeks than patients referred by specialists from other hospitals. Compared to patients with transient ischaemic attack or ocular symptoms, patients with ischaemic stroke more often underwent CEA within 2 weeks. CONCLUSIONS: A small change in the process of care significantly reduced the delay from the index event to CEA, but in 2012 it still exceeded 14 days in the majority of patients. The definition of the "index event" has a large impact on the total duration of delay, and should therefore be uniform across studies.

Current status of clinical magnetic resonance imaging for plaque characterisation in patients with carotid artery stenosis.

OBJECTIVE: The article aims to provide an overview of the literature that assessed the agreement between magnetic resonance imaging (MRI) and histology for specific carotid plaque characteristics associated with vulnerability in terms of sensitivity and specificity. METHODS: A systematic search strategy was conducted in MEDLINE and EMBASE databases resulting in 1084 articles. Finally, we included 17 papers. Due to variation in presentation, especially in MRI and histology methods, a pooled analysis could not be performed. RESULTS: Two studies were performed on a 3.0-T MRI scanner; all other studies were performed on a 1.5-T scanner. Most performed sequences were two-dimensional (2D) and three-dimensional (3D) T1-weighted and all histology protocols varied slightly. Our results indicate that calcification, fibrous cap, intraplaque haemorrhage and lipid-rich necrotic cores can be identified with moderate-to-good sensitivity and specificity. CONCLUSIONS: Based on current literature, it appears premature for routine application of MRI as an imaging modality to assess carotid plaque characteristics associated with plaque vulnerability. Although MRI still holds promise, clinical application for plaque characterisation would require consensus regarding MRI settings and confirmation by histology. Predefined protocols for histology and MR imaging need to be established.

Asymptomatic carotid artery stenosis: identification of subgroups with different underlying plaque characteristics.

OBJECTIVES: Optimal surgical treatment of patients with asymptomatic carotid artery stenosis (ACAS) remains a matter of debate. Established definitions of ACAS include: (1) patients who never suffered from ipsilateral cerebrovascular events (group 1) or (2) patients who suffered from ipsilateral cerebrovascular events more than 6 months prior to revascularisation (group 2). Cerebrovascular symptoms are closely related to underlying carotid plaque composition and therefore we investigated potential plaque differences between these definition-based subgroups. DESIGN: Cross-sectional analysis of a longitudinal prospective biobank study. MATERIAL AND METHODS: Carotid atherosclerotic plaques from 264 asymptomatic patients were harvested during endarterectomy, and subjected to histopathological examination. Patients were divided into two groups: group 1: truly asymptomatic (n = 182), and group 2: patients with ipsilateral events more than 6 months before carotid endarterectomy (CEA) (n = 82). RESULTS: Patients in group 1 had relatively more stable plaque characteristics as compared with patients in group 2, with a higher median plaque smooth muscle cell content (2.1 (0.0-18.7) vs. 1.6 (0.0-14.4); P = 0.036), a higher proportion of heavily calcified plaques (67.7% (123/182) vs. 48.8% (40/82); P = 0.005) and less frequently intraplaque haemorrhages (11.5% (21/182) vs. 30.5% (25/82); P = 0.001). CONCLUSION: Different plaque characteristics within subgroups of ACAS patients can be identified based on reported past ipsilateral events, which might result in adjusted future treatment strategies.

Radiation-induced carotid stenotic lesions have a more stable phenotype than de novo atherosclerotic plaques.

OBJECTIVE: To identify plaque characteristics of carotid artery radiation-induced stenosis. MATERIALS AND METHODS: Nineteen carotid plaques were obtained during carotid endarterectomy (CEA) in 17 consecutive patients with prior cervical radiation therapy (XRT) (median interval 10 years) and compared with 95 matched control carotid plaques of patients without a history of XRT. The following histopathological factors were assessed: calcification, collagen, macrophages, smooth muscle cells, atheroma, microvessels and intraplaque haemorrhage. Association of individual histological parameters with XRT plaque was analysed through a multivariable regression model. RESULTS: Less infiltration of macrophages (6/19 versus 60/95, adjusted p = 0.003) and a smaller lipid core size (Atheroma >10%: 10/19 versus 80/95, adjusted p = 0.006) were independently associated with XRT plaque, compared to non-XRT plaques. CONCLUSIONS: Carotid stenotic lesions in patients with previous cervical radiation are less inflammatory and more fibrotic than carotid atherosclerotic lesions in non-radiated patients.

Prevalence and clinical consequences of carotid artery residual defects following endarterectomy: a prospective CT angiography evaluation study.

OBJECTIVES: It is still unclear whether residual defects seen after carotid endarterectomy (CEA) have clinical consequences. We investigated prevalence of residual defects in the carotid artery and their possible impact on clinical and Duplex ultrasound (DUS) follow-up. MATERIALS AND METHODS: Sixty-five patients who had undergone CEA were prospectively examined with 1-3 month postoperative computed tomographic angiography (CTA), clinical and DUS follow-up. Defects in common (CCA), external (ECA) and internal carotid artery (ICA) were scored as clamp marks, intimal step or flap, mural thrombus, kink, microdehiscence suture or residual stenosis. RESULTS: Fifty-eight patients (89.2%) had residual defects in CCA, ECA or ICA (143 defects). Intimal steps (n = 39) and residual stenosis (n = 17) were most noted defects. Only residual defects in ECA were significantly associated with significant higher PSV values both at short-term and long-term follow-up (1990 vs. 1400 mm s(-1) at 1 year and 2000 vs. 1230 mm s(-1) at 2 years, P-values 0.031 and 0.016). CONCLUSION: Carotid artery residual defects on CTA after CEA are very common, simple fingerprints of the operative procedure, have no clear consequence. When CTA is performed clinically after CEA, knowledge of high prevalence and type of defects detected on CTA may be of importance for radiologists and clinicians.

Development of a self-limiting model of methotrexate-induced mucositis reinforces butyrate as a potential therapy.

Gastrointestinal mucositis is a complication of anticancer treatment, with few validated in vitro systems suitable to study the complex mechanisms of mucosal injury. Therefore, we aimed to develop and characterize a chemotherapeutic-induced model of mucositis using 3D intestinal organoids. Organoids derived from mouse ileum were grown for 7 days and incubated with different concentrations of the chemotherapeutic agent methotrexate (MTX). Metabolic activity, citrulline levels and cytokine/chemokine production were measured to determine the optimal dosage and incubation time. The protective effects of folinic acid on the toxicity of MTX were investigated by pre-treating organoids with (0.0005-50 µg/mL) folinic acid. The impact of microbial-derived short-chain fatty acids was evaluated by supplementation with butyrate in the organoid model. MTX caused a dose-dependent reduction in cell metabolic activity and citrulline production that was salvaged by folinic acid treatment. Overall, MTX causes significant organoid damage, which can be reversed upon removal of MTX. The protective effect of folinic acid suggest that the organoids respond in a clinical relevant manner. By using the model for intervention, it was found that prophylactic treatment with butyrate might be a valuable strategy for prophylactic mucositis prevention.

Antimicrobial activity of vanadium chloroperoxidase on planktonic Streptococcus mutans cells and Streptococcus mutans biofilms.

The aim of this study was to investigate the antimicrobial activity of vanadium chloroperoxidase (VCPO) reaction products on planktonic and biofilm cells of Streptococcus mutans C180-2. Planktonic and biofilm cells were incubated in a buffered reaction mixture containing VCPO, halide (either chloride or bromide) and hydrogen peroxide, and the killing efficacy was assessed by CFU counts. The enzymatic products formed by VCPO significantly reduced the viability of planktonic and biofilm cells compared to their negative controls and the effect on the biofilm cells was more effective than a 0.2% chlorhexidine digluconate treatment. We conclude that VCPO and its reaction products form a potent antimicrobial system against S. mutans.

Degeneration, inflammation, regeneration, and pain/disability in dogs following destabilization or articular cartilage grooving of the stifle joint.

OBJECTIVE: The most used model for joint instability is the canine anterior cruciate ligament transection (ACLT)-model. The ACLT-model can be extended with a medial meniscectomy (MX) (i.e., ACLT-MX-model) to avoid unintentional, and with that variable, meniscal damage. The present study compares the ACLT-MX-model with the more recently introduced Groove-model on longitudinal measurements of osteophyte formation and gait as a surrogate marker of pain and disability, in addition to structural endpoint parameters. METHODS: Degenerative joint damage was induced Labrador dogs according to the ACLT-MX-model (n=7) or Groove-model (n=7). Every 4 weeks radiographs were taken to analyze osteophyte formation. Every 2 weeks gait was recorded using force-plate analysis. Joints were analyzed for features of degeneration 12 weeks after surgery. RESULTS: Both models showed similar osteophyte formation and gait changes for both experimental and contra-lateral control joints, although more pronounced for the ACLT-MX-model. This was supported by the structural endpoint measurements. Cartilage integrity, chondrocyte activity and synovial inflammation revealed similar characteristics of degenerative joint disease in both groups, again more pronounced in the ACLT-MX-model. CONCLUSIONS: The ACLT-MX-model demonstrates characteristics of joint degeneration that are related to moderate to severe osteoarthritis with clear synovial inflammatory activity. The Groove-model is a less painful and a significantly milder model of joint degeneration. The latter model might be more suitable to study subtle changes as a result of intervention than the more robust ACLT-MX-model.

Improved health-related quality of life, participation, and autonomy in patients with treatment-resistant chronic pain after an intensive social cognitive intervention with the participation of support partners.

Despite the availability of various specific treatments, most patients with chronic pain (CP) consider their pain problem as undertreated. Recently, multiple sclerosis (MS) patients who were given an intensive 3-day social cognitive treatment with the participation of support partners experienced lasting improvements in health-related quality of life (HRQoL) and self-efficacy. In this study, a similar intervention was given to treatment-resistant CP patients with stressors, relational problems with support partner, and distress, anxiety or depression. Before and 1, 3, and 6 months after the intervention, patients completed the Euro-Qol 5 Dimensions 5 Levels (EQ-5D-5L) and Impact on Participation and Autonomy (IPA) questionnaires (primary outcomes), and the Survey Of Pain Attitudes (SOPA), the Four-Dimensional Symptom Questionnaire (4DSQ) (distress, depression, anxiety, and somatization), and Visual Analog Scale for pain intensity, whereas the support partners completed the Caregiver Strain Index (CSI) questionnaire. Differences between baseline and post-treatment were tested via paired t-tests (significance level 0.05). Of the 39 patients who were included, 34 (87.2%) completed the 3-day treatment. At 1, 3, and 6 months, improvements were seen in EQ-5D-5L-Index (+40.6%; +22.4%; +31.7%), Health Today (+61.8%; +36.3%; +46.8%), Control attitude (+45.8%; not significant [NS]; +55.0%) and decreases in IPA-Problems (-14.8%; NS; -20.4%), Harm attitude (-18.9%; -15.0%; -17.7%), Distress (-17.7%; -31.8%; -37.1%), and Depression (-37.4%; -31.4%; -35.7%) scores. The CSI score had decreased by -29.0%, -21.4%, and -25.9%, respectively. In conclusion, after an intensive 3-day social cognitive intervention, treatment-resistant CP patients experienced substantial and lasting improvements in HRQoL and in problematic limitations to participation and autonomy, in association with improvements in pain attitudes, depression, and distress. To assess whether this innovative approach may be an effective treatment for this subgroup of CP patients, future randomized controlled studies are needed.

Transformation capacities of the papillary renal cell carcinoma-associated PRCCTFE3 and TFE3PRCC fusion genes.

A recurrent chromosomal abnormality associated with a subset of papillary renal cell carcinomas is t(X;1)(p11;q21). This translocation leads to the formation of two fusion genes, TFE3PRCC and the reciprocal product PRCCTFE3. Both fusion genes are expressed in t(X;1)-positive renal cell carcinomas and contain major parts of the coding regions of the parental transcription factor PRCC and TFE3 genes, respectively. To find out whether these fusion genes possess transforming capacity, we transfected NIH3T3 and rat-1 cells with the fusion products, either separately or combined. When using soft agar assays, we observed colony formation in all cases. NIH3T3 cells transfected with PRCCTFE3 or PRCCTFE3 together with TFE3PRCC yielded the highest colony forming capacities. Examination of other characteristics associated with malignant transformation, i.e., growth under low-serum conditions and formation of tumors in athymic nude mice, revealed that cells transfected with PRCCTFE3 exhibited all these transformation-associated characteristics. Upon transfection of the fusion products into conditionally immortalized kidney cells, derived from the proximal tubules of an H-2Kb-tsA58 transgenic mouse, and consecutive incubation under non-permissive conditions, growth arrest was observed, followed by differentiation except for those cells transfected with PRCCTFE3. Therefore, we conclude that PRCCTFE3 may be the t(X;1)-associated fusion product that is most critical for the development of papillary renal cell carcinomas.

Dissociation-reconstitution experiments support the presence of two catalytic beta-subunits in mitochondrial F1.

Mitochondrial F1, inactivated to various extents with 4-chloro-7-nitrobenzo-2-oxa-1,3-diazole (NBD-Cl), was dissociated with LiCl and reconstituted after removal of the salt. This procedure resulted in a reactivation that corresponded with a reactivation theoretically expected on the basis of the assumption that the reassociation of beta-subunits into native F1 molecules is random and that two out of the three beta-subunits are directly involved in catalysis. Repeated inactivation of such reactivated F1, followed by the same dissociation-association procedure, resulted in similar data. After inactivation of F1 by covalent binding of 2-N-AT(D)P to one catalytic site, no reactivation upon dissociation-reassociation was obtained due to the fact that such modified F1 did not dissociate under the experimental conditions used.

Photoaffinity labelling of the 2-oxoglutarate binding site of prolyl 4-hydroxylase with 5-azidopyridine-2-carboxylic acid.

The synthesis of the photoaffinity label 5-azidopyridine-2-carboxylic acid is described. The 2-oxoglutarate analogue photoaffinity label is a competitive inhibitor with respect to 2-oxoglutarate with a Ki value of 9 X 10(-3) M. Upon ultraviolet irradiation, 5-azidopyridine-2-carboxylic acid inactivated prolyl 4-hydroxylase irreversibly by up to 50%. The extent of inactivation depended on the 5-azidopyridine-2-carboxylic acid concentration and the irradiation time. Inactivation was prevented in the presence of an excess of 2-oxoglutarate. It is concluded that the 5-azidopyridine-2-carboxylic acid became covalently bound to the alpha subunit of prolyl 4-hydroxylase, as the alpha subunit of the photoaffinity labelled enzyme had a decreased electrophoretic mobility in polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulphate.

Inhibition of mitochondrial F1-ATPase activity by binding of (2-azido-) ADP to a slowly exchangeable non-catalytic nucleotide binding site.

F1-ATPase was treated so that it contained three tightly bound nucleotides per molecule. One of these was bound at a catalytic site and was rapidly exchangeable, the two remaining nucleotides were nonexchangeable. Incubation of this preparation with ADP in the presence of Mg2+ results in 40-45% inhibition of the ATPase activity. With 2-azido-ADP instead of ADP, the ligand was covalently bound to F1 by illumination, in the presence or absence of turnover of the enzyme, and the site of binding was determined. In this way, one site could be identified, which induces the inhibition. The attachment of the covalently bound 2-nitreno-ADP is at Tyr-368 of a beta-subunit, characterized in the literature as a non-catalytic site. A second, non-catalytic site also binds 2-azido-ADP, but this binding is partially reversed by the addition of ATP and does not cause further inhibition of the ATPase activity. It is concluded that the slowly exchangeable non-catalytic site is the site of inhibition by ADP.

Identification of an exchangeable non-catalytic site on mitochondrial F1-ATPase which is involved in the negative cooperativity of ATP hydrolysis.

Labeling of mitochondrial F1-ATPase with 8-azido-ATP or 8-azido-ADP under turnover conditions with Mg(2+)-ATP resulted in the identification of one exchangeable non-catalytic site whose occupation with a ligand does not influence the ATPase activity of F1 when measured at Vmax. With 8-azido-ADP two exchangeable non-catalytic sites could be labeled, but at one of them the bound ligand exchanges, at least partly, during the illumination under turnover conditions. After labeling an exchangeable non-catalytic site under turnover conditions with 8-azido-ATP or with 8-azido-ADP, F1-ATPase kept the ability to bind NAP3-2N3ADP at the slowly exchangeable noncatalytic site, thereby inhibiting the ATPase activity by 45%, as recently described (Edel et al. (1992) Biochim. Biophys. Acta 1101, 329-338). Covalent modification of the low-affinity non-catalytic site with 8-nitreno-AT(D)P increased the Km of ATP and abolished the negative cooperativity of ATP hydrolysis. This site can therefore be marked as a regulatory site, whose occupation with a nucleotide decreases the affinity of the catalytic sites for ATP.