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Adenoma miss rates in colonoscopy are unacceptably high, especially for sessile serrated adenomas / polyps (SSA/Ps) and in high-risk populations, such as patients with Lynch syndrome. Detection rates may be improved by fluorescence molecular endoscopy (FME), which allows morphological visualization of lesions with high-definition white-light imaging as well as fluorescence-guided identification of lesions with a specific molecular marker. In a clinical proof-of-principal study, we investigated FME for colorectal adenoma detection, using a fluorescently labelled antibody (bevacizumab-800CW) against vascular endothelial growth factor A (VEGFA), which is highly upregulated in colorectal adenomas. Methods: Patients with familial adenomatous polyposis (n = 17), received an intravenous injection with 4.5, 10 or 25 mg of bevacizumab-800CW. Three days later, they received NIR-FME. Results: VEGFA-targeted NIR-FME detected colorectal adenomas at all doses. Best results were achieved in the highest (25 mg) cohort, which even detected small adenomas (<3 mm). Spectroscopy analyses of freshly excised specimen demonstrated the highest adenoma-to-normal ratio of 1.84 for the 25 mg cohort, with a calculated median tracer concentration in adenomas of 6.43 nmol/mL. Ex vivo signal analyses demonstrated NIR fluorescence within the dysplastic areas of the adenomas. Conclusion: These results suggest that NIR-FME is clinically feasible as a real-time, red-flag technique for detection of colorectal adenomas., Competing Interests: Competing Interests: G.M.v.D. and W.B.N. received an unrestricted research grant made available to the institution for the development of optical molecular imaging from SurgVision BV ('t Harde, the Netherlands). G.M.v.D. and V.N. are members of the scientific advisory board of SurgVision BV. Other authors declare no competing financial interests.

The femoral head-neck alpha angle is used to quantify the degree of femoral head asphericity in patients suspected of cam-type femoroacetabular impingement. The measurement was first performed using magnetic resonance imaging and, more recently, three-dimensional computed tomography (CT). We set out to determine whether the alpha angle could be reliably measured using ultrasound. Patients were recruited from a cohort presenting for CT of the hip. Alpha angles were calculated following the departmental protocol by institutionally accredited radiographers. After the CT, patients were imaged with ultrasound and the alpha angle calculated from the ultrasound image by a sonographer blinded to the CT result. Statistical comparison of the two methods was performed with the Bland-Altman test using SPSS (version 21.0, Chicago, USA), and a p < 0.05 afforded significance. Twenty-eight patients were recruited. Eleven patients were bilateral examinations, providing 39 hips for analysis. There were 15 females and 13 males, with 21 right and 18 left hips examined. Average patient age (±standard deviation) was 40 y (±13.9 y). Mean (±standard deviation) measurements for CT and ultrasound were 62.5° (±14.2°) and 64.5° (±12.6°), respectively. The mean absolute difference between the two methods was 10.5° (95% confidence interval 6.9°-14.0°). Sensitivity of each individual ultrasound measurement was 91.3%. The specificity of ultrasound was 43.75%. The positive predictive value was 0.7, and the negative predictive value was 0.78. Overall accuracy of the ultrasound-derived alpha angle was calculated at 0.718. Ultrasound demonstrates good sensitivity and good negative predictive value in calculation of the femoral head-neck alpha angle compared with CT; however, specificity is low. Ultrasound measurement of the alpha angle can provide objective evidence of cam-type femoroacetabular impingement in symptomatic patients and can direct patients to more established imaging techniques where appropriate., (Copyright © 2018 World Federation for Ultrasound in Medicine and Biology. All rights reserved.)

Millipedes (Diplopoda) are well known for their toxic or repellent defensive secretions. As part of a larger investigation, we describe the chemical constituents of 14 species of Tasmanian millipedes in seven genera. Six species in the genus Gasterogramma were found to produce acyclic ketones, including the pungent unsaturated ketones 1, 2, and 6, and the novel (rel-3R,5S,7S)-3,5,7-trimethyl-2,8-decanedione (7b), for which the stereoconfiguration was established by stereoselective syntheses of pairs of isomers. These compounds have not been detected before in millipede defensive secretions. This report is the first on species of the suborder Dalodesmidea (Polydesmida), a dominant component of the soil and litter fauna of the temperate regions of the Southern Hemisphere.

Objectives/hypothesis: To compare the effectiveness of massed versus interval training when teaching otolaryngology residents microvascular suturing on a validated microsurgical model., Study Design: Otolaryngology residents were placed into interval (n = 7) or massed (n = 7) training groups. The interval group performed three separate 30-minute practice sessions separated by at least 1 week, and the massed group performed a single 90-minute practice session. Both groups viewed a video demonstration and recorded a pretest prior to the first training session. A post-test was administered following the last practice session., Methods: At an academic medical center, 14 otolaryngology residents were assigned using stratified randomization to interval or massed training. Blinded evaluators graded performance using a validated microvascular Objective Structured Assessment of Technical Skill tool. The tool is comprised of two major components: task-specific score (TSS) and global rating scale (GRS). Participants also received pre- and poststudy surveys to compare subjective confidence in multiple aspects of microvascular skill acquisition., Results: Overall, all residents showed increased TSS and GRS on post- versus pretest. After completion of training, the interval group had a statistically significant increase in both TSS and GRS, whereas the massed group's increase was not significant. Residents in both groups reported significantly increased levels of confidence after completion of the study., Conclusions: Self-directed learning using a chicken thigh artery model may benefit microsurgical skills, competence, and confidence for resident surgeons. Interval training results in significant improvement in early development of microvascular anastomosis skills, whereas massed training does not., Level of Evidence: NA. Laryngoscope, 127:2490-2494, 2017., (© 2017 The American Laryngological, Rhinological and Otological Society, Inc.)

Providing timely and effective care in the emergency department (ED) requires the management of individual patients as well as the flow and demands of the entire department. Strategic changes to work processes, such as adding a flow coordination nurse or a physician in triage, have demonstrated improvements in throughput times. However, such global strategic changes do not address the real-time, often opportunistic workflow decisions of individual clinicians in the ED. We believe that real-time representation of the status of the entire emergency department and each patient within it through information visualizations will better support clinical decision-making in-the-moment and provide for rapid intervention to improve ED flow. This notion is based on previous work where we found that clinicians' workflow decisions were often based on an in-the-moment local perspective, rather than a global perspective. Here, we discuss the challenges of designing and implementing visualizations for ED through a discussion of the development of our prototype Throughput Dashboard and the potential it holds for supporting real-time decision-making., (Copyright © 2017. Published by Elsevier Inc.)

Importance: Hypocalcemia is the most common complication after total thyroidectomy and can result in prolonged hospital admissions and increased hospital charges., Objective: To determine the effectiveness of preoperative calcium and calcitriol supplementation in reducing hypocalcemia following total thyroidectomy., Design, Setting, and Participants: A retrospective cohort study was conducted at a tertiary care center in 65 patients undergoing total thyroidectomy by a single surgeon. Patients were divided into 2 groups: those receiving preoperative as well as postoperative supplementation with calcium carbonate, 1000 to 1500 mg, 3 times daily and calcitriol, 0.25 to 0.5 µg, twice daily, and those receiving only postoperative supplementation with those agents at the same dosages. Data on patients who underwent surgery between January 1, 2008, and December 31, 2011, were acquired, and data analyses were conducted from March through June 2012, and from October through December 2016., Interventions: Calcium and calcitriol therapy., Main Outcomes and Measures: Postoperative serum calcium levels and development of postoperative hypocalcemia., Results: Of the 65 patients who underwent total thyroidectomy 27 (42%) were men; mean (SD) age was 49.7 (16.7) years. Thirty-three patients received preoperative calcium and calcitriol supplementation, and 32 patients received only postoperative therapy. In the preoperative supplementation group, 15 of 33 (45%) patients underwent complete central compartment neck dissection and 11 of 33 (33%) had lateral neck dissection, compared with 16 of 32 (50%) and 12 of 32 (38%), respectively, patients without preoperative supplementation. The mean measured serum calcium level in those without preoperative supplementation vs those with supplementation are as follows: preoperative, 9.6 vs 9.4 mg/dL (absolute difference, 0.16; 95% CI, -0.12 to 0.49 mg/dL); 12 hours postoperative, 8.3 vs 8.6 mg/dL (absolute difference, -0.30; 95% CI,  -0.63 to 0.02 mg/dL); and 24 hours postoperative, 8.4 vs 8.5 mg/dL (absolute difference, -0.13; 95% CI, -0.43 to 0.16 mg/dL). In patients not receiving preoperative supplementation, 5 of 32 (16%) individuals became symptomatically hypocalcemic vs 2 of 33 (6%) in the preoperative supplementation group; an absolute difference of 10% (95% CI, -6.6% to 26.3%). Compared with the group not receiving preoperative supplementation, the mean [SD] length of stay was significantly shorter in the preoperative supplementation group (3.8 [1.8] vs 2.9 [1.4] days; absolute difference, -0.9; 95% CI, -1.70 to -0.105 days). Preoperative supplementation resulted in an estimated $2819 savings in charges per patient undergoing total thyroidectomy., Conclusions and Relevance: Preoperative calcium and calcitriol supplementation, in addition to routine postoperative supplementation, was associated with a reduced incidence of symptomatic hypocalcemia, length of hospital stay, and overall charges following total thyroidectomy.

Early detection of adverse local tissue reaction (ALTR) to prosthetic hip wear debris is vital to improve the success of revision surgery. Magnetic resonance imaging with metal artefact reduction sequencing (MARS MRI) is considered the modality of choice to provide cross-sectional imaging of the soft tissues. The areas adjacent to the prosthesis are, however, not readily imaged using these protocols. Ultrasound has also been recommended as an imaging modality in the follow-up of hip replacement surgery. We decided to characterise the typical ultrasound findings in a group of patients undergoing routine biennial review of arthroplastic hips with particular reference to the hip capsule, femoral neck and iliopsoas bursa and tendon adjacent to the implant. Fifty-two patients with a mean (±SD) age of 60.4 (±12) y were prospectively recruited. Twelve patients had bilateral hip prostheses, giving 64 hips for analysis. Mean (±SD) age of the prosthesis in situ was 8.2 (±3.3) y. Data were grouped on the basis of the shape of the iliofemoral ligament. The median (range) maximal anteroposterior synovial thickness was 5 (2-8) mm in the normal concave iliofemoral ligament group and 7 (4-56) mm in the abnormal straight/convex iliofemoral ligament group (p = 0.001). The anteroposterior iliopsoas tendon measurement was 5 (3-8) mm in the normal group and 5 (4-8) mm in the abnormal group (p = 0.065). ALTR development in asymptomatic well-functioning prostheses may be recognised earlier using ultrasound rather than MARS MRI by carefully assessing the shape of the iliofemoral ligament. Ultrasound findings of an abnormal straight or convex ligament may be suggestive of early ALTR and warrant streaming of patients to a more frequent surveillance program., (Copyright © 2017 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Photodynamic therapy (PDT) is a clinically approved cancer therapy, based on a photochemical reaction between a light activatable molecule or photosensitizer, light, and molecular oxygen. When these three harmless components are present together, reactive oxygen species are formed. These can directly damage cells and/or vasculature, and induce inflammatory and immune responses. PDT is a two-stage procedure, which starts with photosensitizer administration followed by a locally directed light exposure, with the aim of confined tumor destruction. Since its regulatory approval, over 30 years ago, PDT has been the subject of numerous studies and has proven to be an effective form of cancer therapy. This review provides an overview of the clinical trials conducted over the last 10 years, illustrating how PDT is applied in the clinic today. Furthermore, examples from ongoing clinical trials and the most recent preclinical studies are presented, to show the directions, in which PDT is headed, in the near and distant future. Despite the clinical success reported, PDT is still currently underutilized in the clinic. We also discuss the factors that hamper the exploration of this effective therapy and what should be changed to render it a more effective and more widely available option for patients.

Endoscopic ultrasound-guided fine needle aspirations (EUS-FNA) of pancreatic masses suffer from sample errors and low-negative predictive values. Fiber-optic spectroscopy in the visible to near-infrared wavelength spectrum can noninvasively extract physiological parameters from tissue and has the potential to guide the sampling process and reduce sample errors. We assessed the feasibility of single fiber (SF) reflectance spectroscopy measurements during EUS-FNA of pancreatic masses and its ability to distinguish benign from malignant pancreatic tissue. A single optical fiber was placed inside a 19-gauge biopsy needle during EUS-FNA and at least three reflectance measurements were taken prior to FNA. Spectroscopy measurements did not cause any related adverse events and prolonged procedure time with ? 5 ?? min . An accurate correlation between spectroscopy measurements and cytology could be made in nine patients (three benign and six malignant). The oxygen saturation and bilirubin concentration were significantly higher in benign tissue compared with malignant tissue (55% versus 21%, p = 0.038 ; 166 ?? ? mol / L versus 17 ?? ? mol / L , p = 0.039 , respectively). To conclude, incorporation of SF spectroscopy during EUS-FNA was feasible, safe, and relatively quick to perform. The optical properties of benign and malignant pancreatic tissue are different, implying that SF spectroscopy can potentially guide the FNA sampling.

Epidermal keratinocytes migrate through the epidermis up to the granular layer where, on terminal differentiation, they progressively lose organelles and convert into anucleate cells or corneocytes. Our report explores the role of autophagy in ensuring epidermal function providing the first comprehensive profile of autophagy marker expression in developing epidermis. We show that autophagy is constitutively active in the epidermal granular layer where by electron microscopy we identified double-membrane autophagosomes. We demonstrate that differentiating keratinocytes undergo a selective form of nucleophagy characterized by accumulation of microtubule-associated protein light chain 3/lysosomal-associated membrane protein 2/p62 positive autolysosomes. These perinuclear vesicles displayed positivity for histone interacting protein, heterochromatin protein 1α, and localize in proximity with Lamin A and B1 accumulation, whereas in newborn mice and adult human skin, we report LC3 puncta coincident with misshaped nuclei within the granular layer. This process relies on autophagy integrity as confirmed by lack of nucleophagy in differentiating keratinocytes depleted from WD repeat domain phosphoinositide interacting 1 or Unc-51 like autophagy activating kinase 1. Final validation into a skin disease model showed that impaired autophagy contributes to the pathogenesis of psoriasis. Lack of LC3 expression in psoriatic skin lesions correlates with parakeratosis and deregulated expression or location of most of the autophagic markers. Our findings may have implications and improve treatment options for patients with epidermal barrier defects., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Photodynamic therapy (PDT) induces cell death through local light activation of a photosensitizer (PS) and has been used to treat head and neck cancers. Yet, common PS lack tumor specificity, which leads to collateral damage to normal tissues. Targeted delivery of PS via antibodies has pre-clinically improved tumor selectivity. However, antibodies have long half-lives and relatively poor tissue penetration, which could limit therapeutic efficacy and lead to long photosensitivity. Here, in this feasibility study, we evaluate at the pre-clinical level a recently introduced format of targeted PDT, which employs nanobodies as targeting agents and a water-soluble PS (IRDye700DX) that is traceable through optical imaging. In vitro, the PS solely binds to cells and induces phototoxicity on cells overexpressing the epidermal growth factor receptor (EGFR), when conjugated to the EGFR targeted nanobodies. To investigate whether this new format of targeted PDT is capable of inducing selective tumor cell death in vivo, PDT was applied on an orthotopic mouse tumor model with illumination at 1h post-injection of the nanobody-PS conjugates, as selected from quantitative fluorescence spectroscopy measurements. In parallel, and as a reference, PDT was applied with an antibody-PS conjugate, with illumination performed 24h post-injection. Importantly, EGFR targeted nanobody-PS conjugates led to extensive tumor necrosis (approx. 90%) and almost no toxicity in healthy tissues, as observed through histology 24h after PDT. Overall, results show that these EGFR targeted nanobody-PS conjugates are selective and able to induce tumor cell death in vivo. Additional studies are now needed to assess the full potential of this approach to improving PDT., (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Light fractionation significantly increases the efficacy of 5-aminolevulinic acid (ALA) based photodynamic therapy (PDT) using the nano-emulsion based gel formulation BF-200. PDT using BF-200 ALA has recently been clinically approved and is under investigation in several phase III trials for the treatment of actinic keratosis. This study is the first to compare BF-200 ALA with ALA in preclinical models., Results: In hairless mouse skin there is no difference in the temporal and spatial distribution of protoporphyrin IX determined by superficial imaging and fluorescence microscopy in frozen sections. In the skin-fold chamber model, BF-200 ALA leads to more PpIX fluorescence at depth in the skin compared to ALA suggesting an enhanced penetration of BF-200 ALA. Light fractionated PDT after BF-200 ALA application results in significantly more visual skin damage following PDT compared to a single illumination. Both ALA formulations show the same visual skin damage, rate of photobleaching and change in vascular volume immediately after PDT. Fluorescence immunohistochemical imaging shows loss of VE-cadherin in the vasculature at day 1 post PDT which is greater after BF-200 ALA compared to ALA and more profound after light fractionation compared to a single illumination., Discussion: The present study illustrates the clinical potential of light fractionated PDT using BF-200 ALA for enhancing PDT efficacy in (pre-) malignant skin conditions such as basal cell carcinoma and vulval intraepithelial neoplasia and its application in other lesion such as cervical intraepithelial neoplasia and oral squamous cell carcinoma where current approaches have limited efficacy.

We derive a new flavor symmetry relation for the determination of the weak phase β=ϕ&#95;{1} from time-dependent CP asymmetries and B→J/ψP decay rates. In this relation, the contributions to sin2β proportional to V&#95;{ub} are parametrically suppressed compared to the contributions in the B→J/ψK^{0} time-dependent CP asymmetry alone. This relation uses only SU(3) flavor symmetry, and does not require further diagrammatic assumptions. The current data either fluctuate at the 2σ level from expectations, or may hint at effects of unexpected magnitude from contributions proportional to V&#95;{ub} or from isospin breaking.

We present a fully perturbative mechanism that naturally generates mass hierarchies for the standard model (SM) fermions in a flavor-blind sector. The dynamics generating the mass hierarchies can therefore be independent from the source of flavor violation, and hence this dynamics may operate at a much lower scale. This mechanism works by dynamically enforcing simultaneous diagonalization--alignment--among a set of flavor-breaking spurions, as well as generating highly singular spectra for them. It also has general applications in model building beyond the SM, wherever alignment between exotic and SM sources of flavor violation is desired.

Objective: Self-sample human papillomavirus (HPV) testing in public emergency departments (EDs) may be a viable strategy to opportunistically screen women who otherwise do not attend for regular Papanicolaou test-based cervical cancer screening. We describe the acceptability of self-sample HPV testing among women presenting to two high-volume, urban EDs that primarily care for the medically underserved., Methods: In 2014, a total of 210 women 21 years of age and older were recruited from two public ED waiting areas following a two-stage cluster sampling design. Questionnaire items inquired about demographics, healthcare access and utilization, history of cervical cancer screening, and acceptability of self-sample HPV testing. Descriptive analyses were performed., Results: Overall, 34.8% of participants were considered screening non-attendees based on their adherence to the current guidelines for Pap testing every three years. Acceptability of self-sample HPV testing was high, with over 85% of participants reporting that they would be willing to use the test if available. A smaller proportion (58%) was deemed likely to accept self-sample HPV testing in a public ED restroom setting. Primary concerns expressed by women were that the sampling may not be done correctly (64%) and that they may not know how to perform the sampling (39%)., Conclusions: Opportunistic self-sample HPV testing is acceptable to women seeking care at a high-volume, urban emergency care center. The use of this intervention potentially offers a unique strategy to improve cervical cancer screening among high-risk women who otherwise do not attend for regular screening., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background and Objective: Fluorescence measurements in the skin are very much affected by absorption and scattering but existing methods to correct for this are not applicable to superficial skin measurements., Study Design/materials and Methods: The first use of multiple-diameter single fiber reflectance (MDSFR) and single fiber fluorescence (SFF) spectroscopy in human skin was investigated. MDSFR spectroscopy allows a quantification of the full optical properties in superficial skin (μa, μs' and γ), which can next be used to retrieve the corrected - intrinsic - fluorescence of a fluorophore Qμa,x(f). Our goal was to investigate the importance of such correction for individual patients. We studied this in 22 patients undergoing photodynamic therapy (PDT) for actinic keratosis., Results: The magnitude of correction of fluorescence was around 4 (for both autofluorescence and protoporphyrin IX). Moreover, it was variable between patients, but also within patients over the course of fractionated aminolevulinic acid PDT (range 2.7-7.5). Patients also varied in the amount of protoporphyrin IX synthesis, photobleaching percentages and resynthesis (>100× difference between the lowest and highest PpIX synthesis). The autofluorescence was lower in actinic keratosis than contralateral normal skin (0.0032 versus 0.0052; P<0.0005)., Conclusions: Our results clearly demonstrate the importance of correcting the measured fluorescence for optical properties, because these vary considerably between individual patients and also during PDT. Protoporphyrin IX synthesis and photobleaching kinetics allow monitoring clinical PDT which facilitates individual-based PDT dosing and improvement of clinical treatment protocols. Furthermore, the skin autofluorescence can be relevant for diagnostic use in the skin, but it may also be interesting because of its association with several internal diseases., (Copyright © 2015 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.)

Recently, a multidiameter single-fiber reflectance and fluorescence spectroscopy device has been developed that enabled us to extract the autofluorescence of tissue that is corrected for the optical properties. Such a system has been incorporated in the population-based Rotterdam Study to investigate the autofluorescence of the skin. Since the device will be used by different operators over many years, it is essential that the results are comparable between users. It is, however, unclear how different methods of handling the probe might influence the outcome. Variability of blood oxygen saturation, blood volume fraction and vessel diameter, average gamma, reduced scattering coefficient at 800 nm, and integrated intrinsic fluorescence measured in three volunteers were assessed within and between eight untrained users. A variability of less than one standard deviation from the group mean was defined as an acceptable limit. Three mature volunteers were also included to assess the intrauser variability of mature skin. The variation in the measured parameters suggests that variation is dominated by tissue heterogeneity. Most users measured within one standard deviation of the group mean. Notably, corrected intrinsic fluorescence showed low intra- and interuser variability. These results strongly suggest that variability is mostly caused by tissue heterogeneity and is not user induced.

Photodynamic therapy (PDT) is an established treatment modality, used mainly for anticancer therapy that relies on the interaction of photosensitizer, light and oxygen. For the treatment of pathologies in certain anatomical sites, improved targeting of the photosensitizer is necessary to prevent damage to healthy tissue. We report on a novel dual approach of targeted PDT (vascular and cellular targeting) utilizing the expression of neuropeptide somatostatin receptor (sst2) on tumor and neovascular-endothelial cells. We synthesized two conjugates containing the somatostatin analogue [Tyr3]-octreotate and Chlorin e6 (Ce6): Ce6-K3-[Tyr3]-octreotate (1) and Ce6-[Tyr3]-octreotate-K3-[Tyr3]-octreotate (2). Investigation of the uptake and photodynamic activity of conjugates in-vitro in human erythroleukemic K562 cells showed that conjugation of [Tyr3]-octreotate with Ce6 in conjugate 1 enhances uptake (by a factor 2) in cells over-expressing sst2 compared to wild-type cells. Co-treatment with excess free Octreotide abrogated the phototoxicity of conjugate 1 indicative of a specific sst2-mediated effect. In contrast conjugate 2 showed no receptor-mediated effect due to its high hydrophobicity. When compared with un-conjugated Ce6, the PDT activity of conjugate 1 was lower. However, it showed higher photostability which may compensate for its lower phototoxicity. Intra-vital fluorescence pharmacokinetic studies of conjugate 1 in rat skin-fold observation chambers transplanted with sst2+ AR42J acinar pancreas tumors showed significantly different uptake profiles compared to free Ce6. Co-treatment with free Octreotide significantly reduced conjugate uptake in tumor tissue (by a factor 4) as well as in the chamber neo-vasculature. These results show that conjugate 1 might have potential as an in-vivo sst2 targeting photosensitizer conjugate.

Different distributions of hexyl aminolevulinate (HAL), aminolevulinic acid (ALA) and methyl aminolevulinate (MAL) in the superficial vasculature are not well studied but they are hypothesized to play an important role in topical photodynamic therapy (PDT). The colocalization of fluorescent CD31 and protoporphyrin IX (PpIX) was calculated using confocal microscopy of mouse skin sections to investigate the vascular distribution after topical application. Vascular damage leads to disruption of the normal endothelial adherens junction complex, of which CD144 is an integral component. Therefore, normal CD31 combined with loss of normal fluorescent CD144 staining was visually scored to assess vascular damage. Both the vascular PpIX concentration and the vascular damage were highest for HAL, then ALA and then MAL. Vascular damage in MAL was not different from normal contralateral control skin. This pattern is consistent with literature data on vasoconstriction after PDT, and with the hypothesis that the vasculature plays a role in light fractionation that increases efficacy for HAL and ALA-PDT but not for MAL. These findings indicate that endothelial cells of superficial blood vessels synthesize biologically relevant PpIX concentrations, leading to vascular damage. Such vascular effects are expected to influence the oxygenation of tissue after PDT which can be important for treatment efficacy., (© 2014 The American Society of Photobiology.)

Background: In a previous study it is shown that for topically applied ALA-PDT, PpIX concentration correlates with vascular changes including vasoconstriction and/or vascular leakage of small vessels and arterioles in the mouse epidermis and dermis. In this study we report on vascular responses induced by ALA-PDT for different fluence rates, including both changes in vessel diameter and dynamics in RBC velocity in arterioles, imaged using intra-vital confocal microscopy in skinfold chambers in hairless mice. Our interest is in the dynamics of vascular changes in the early stages of illumination., Methods: We have determined the total PDT dose to be relatively low, 13 J cm(-2), and fluence rates of 26, 65 and 130 mW cm(-2) were investigated. Local vascular effects occurred very soon after the start of the therapeutic illumination in ALA-PDT., Results: In this study, we did not find a significant difference between fluence rates. Arterioles were particularly sensitive to vasoconstriction during low dose PDT, often resulting in complete vasoconstriction. When we observed complete vasoconstriction, this coincided with changes in RBC velocity., Conclusion: Since the therapeutic effects of PDT are dependent on a fine balance between the need for oxygen during illumination and disruption of the vasculature, the results of the present study add to our understanding of acute vascular effects during ALA-PDT and aid our efforts to optimize PDT using porphyrin pre-cursors., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The detailed mechanisms associated with the influence of scattering and absorption properties on the fluorescence intensity sampled by a single optical fiber have recently been elucidated based on Monte Carlo simulated data. Here we develop an experimental single fiber fluorescence (SFF) spectroscopy setup and validate the Monte Carlo data and semi-empirical model equation that describes the SFF signal as a function of scattering. We present a calibration procedure that corrects the SFF signal for all system-related, wavelength dependent transmission efficiencies to yield an absolute value of intrinsic fluorescence. The validity of the Monte Carlo data and semi-empirical model is demonstrated using a set of fluorescent phantoms with varying concentrations of Intralipid to vary the scattering properties, yielding a wide range of reduced scattering coefficients (μ's = 0-7 mm (-1)). We also introduce a small modification to the model to account for the case of μ's = 0 mm (-1) and show its relation to the experimental, simulated and theoretically calculated value of SFF intensity in the absence of scattering. Finally, we show that our method is also accurate in the presence of absorbers by performing measurements on phantoms containing red blood cells and correcting for their absorption properties.

Background and Objective: The effect of photodynamic therapy (PDT) is dependent on the localization of photosensitizer in the treatment volume at the time of illumination. Investigation of photosensitizer pharmacokinetics in and around the treatment volume aids in determining the optimal drug light interval for PDT., Materials and Methods: In this paper we have investigated the distribution of the photosensitizers chlorin e6 and Bremachlorin in the oral squamous cell carcinoma cell-line OSC19-Luc-Gfp in a tongue tumor, tumor boundary, invasive tumor boundary, and normal tongue tissue by the use of confocal microscopy of frozen sections. Tongues were harvested at t = [3, 4.5, 6, 24, 48] hours after injection., Results: Both photosensitizers showed a decreasing fluorescence with increasing incubation time, and at all time points higher fluorescence was measured in tumor boundary than in tumor itself. For short incubation times, a higher fluorescence intensity was observed in the invasive tumor border and normal tissue compared to tumor tissue. Bremachlorin showed a small increase in tumor to normal ratio at 24 and 48 hours incubation time. Ce6 was undetectable at 48 hours. We did not find a correlation between photosensitizer localization and the presence of vasculature., Conclusion: The modest tumor/tumor boundary to normal selectivity of between 1.2 and 2.5 exhibited by Bremachlorin 24 and 48 hours after administration may allow selective targeting of tongue tumors. Further studies investigating the relationship between Bremachlorin concentration and therapeutic efficacy PDT with long incubation times are warranted., (© 2014 Wiley Periodicals, Inc.)

Cancer patients could benefit from a surgical procedure that helps the surgeon to determine adequate tumor resection margins. Systemic injection of tumor-specific fluorescence agents with subsequent intraoperative optical imaging can guide the surgeon in this process. However, tumor heterogeneity hampers tumor-specific targeting. In addition, determination of adequate resection margins can be very challenging due to invasive tumor strands that are difficult to resolve and because of the confounding effect of variations in tissue optical properties in the surgical margin. We provide an overview of the "classic approach" of imaging tumor-specific targets or tumor-associated pathophysiological processes, and explain the limitations of these targeting strategies. It is proposed that problems of tumor heterogeneity can theoretically be circumvented by shifting focus of tumor targeting towards the follicle-stimulating hormone receptor (FSHR). Furthermore, we discuss why objective determination of resection margins is required to improve resection of the invasive strands, a goal that may be achieved by targeting the FSHR. When invasive strands would nevertheless extend beyond such a standardized resection margin, we suggest that adjuvant photodynamic therapy would be a very suitable therapeutic regimen. Finally, we describe how point optical spectroscopy can be used to scrutinize suspect tissue that is difficult to differentiate from normal tissue by measuring the local tissue optical properties to recover a local intrinsic fluorescence measurement.

Quantification of fluorescence in vivo is complicated by the influence of tissue optical properties on the collected fluorescence signal. When tissue optical properties in the measurement volume are quantified, one can obtain the intrinsic fluorescence, which equals the product of fluorophore absorption coefficient and quantum yield. We applied this method to in vivo single-fiber fluorescence spectroscopy measurements on mouse tongue, skin, liver, and oral squamous cell carcinoma, where we detected intrinsic fluorescence spectra of the photosensitizers chlorin e6 and Bremachlorin at t=[3,4.5,6,24,48]  h incubation time. We observed a tissue-dependent maximum of 35% variation in the total correction factor over the visible wavelength range. Significant differences in spectral shape over time between sensitizers were observed. Although the wavelength position of the fluorescence intensity maximum for ce6 shifted to the red, Bremachlorin showed a blue shift. Furthermore, the Bremachlorin peak appeared to be broader than the ce6 fluorescence peak. Intrinsic fluorescence intensity, which can be related to photosensitizer concentration, was decreasing for all time points but showed significantly more Bremachlorin present compared to ce6 at long incubation times. Results from this study can be used to define an optimal treatment protocol for Bremachlorin-based photodynamic therapy.

Background: Light fractionation with a 2-h dark interval increases the efficacy of topical aminolevulinic acid (ALA) photodynamic therapy (PDT). Hexyl-aminolevulinate (HAL) is the hexyl ester of ALA. Both HAL and ALA lead to protoporphyrin IX (PpIX) accumulation in endothelial cells and to vascular effects, which are important for light fractionation. We investigated light fractionation for HAL-PDT in a mouse skin model and compared this with ALA., Methods: Three illumination schemes were studied: (a) 100 J cm(-2) in a single illumination; (b) 50+50 J cm(-2) in a twofold illumination; (c) a small first light fraction until 50% of PpIX was photobleached (ca. 3 J cm(-2)), followed by 97 J cm(-2) 2h later. PpIX fluorescence was measured continuously during illumination. Efficacy was evaluated by daily visual skin damage scoring up to 7 days after PDT., Results: Light fractionation showed a trend towards increased efficacy for HAL-PDT. Both the initial PpIX synthesis and the PpIX resynthesis during the dark interval were higher for ALA, but these were not correlated with efficacy. Single HAL-PDT was more effective than single ALA-PDT. Photobleaching rates of HAL and ALA were similar indicating similar biodistributions at depth., Conclusion: Our results provide evidence to support that light fractionation may be beneficial for HAL-PDT. We are cautious because we found only a non-significant increase in response. However, combining our results with literature data suggest that the illumination scheme may be further optimized for HAL-PDT to potentially enhance the effect of light fractionation., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background and Objective: Foslip and Fospeg are liposomal formulations of the photosensitizer mTHPC (Foscan), which is used for photodynamic therapy (PDT) of malignancies. Literature suggests that liposomal mTHPC formulations have better properties and increased tumor uptake compared to Foscan. To investigate this, we used the 4NQO-induced carcinogen model to compare the localization of the different mTHPC formulations within normal, precancerous, and cancerous tissue. In contrast to xenograft models, the 4NQO model closely mimics the carcinogenesis of human oral dysplasia., Materials and Methods: Fifty-four rats drank water with the carcinogen 4NQO. When oral examination revealed tumor, the rats received 0.15 mg/kg mTHPC (Foscan, Foslip, or Fospeg). At 2, 4, 8, 24, 48, or 96 hours after injection the rats were sacrificed. Oral tissue was sectioned for HE slides and for fluorescence confocal microscopy. The HE slides were scored on the severity of dysplasia by the epithelial atypia index (EAI). The calibrated fluorescence intensity per formulation or time point was correlated to EAI., Results: Fospeg showed higher mTHPC fluorescence in normal and tumor tissue compared to both Foscan and Foslip. Significant differences in fluorescence between tumor and normal tissue were found for all formulations. However, at 4, 8, and 24 hours only Fospeg showed a significant difference. The Pearson's correlation between EAI and mTHPC fluorescence proved weak for all formulations., Conclusion: In our induced carcinogenesis model, Fospeg exhibited a tendency for higher fluorescence in normal and tumor tissue compared to Foslip and Foscan. In contrast to Foscan and Foslip, Fospeg showed significantly higher fluorescence in tumor versus normal tissue at earlier time points, suggesting a possible clinical benefit compared to Foscan. Low correlation between grade of dysplasia and mTHPC fluorescence was found., (© 2013 Wiley Periodicals, Inc.)

We have recently demonstrated a means for quantifying the absorption and scattering properties of biological tissue through multidiameter single-fiber reflectance (MDSFR) spectroscopy. These measurements can be used to correct single-fiber fluorescence (SFF) spectra for the influence of optical properties, enabling quantification of intrinsic fluorescence. In our previous work, we have used a series of pinholes to show that selective illumination and light collection using a coherent fiber bundle can simulate a single solid-core optical fiber with variable diameter for the purposes of MDSFR spectroscopy. Here, we describe the construction and validation of a clinical MDSFR/SFF spectroscopy system that avoids the limitations encountered with pinholes and free-space optics. During one measurement, the new system acquires reflectance spectra at the effective diameters of 200, 600, and 1000 μm, and a fluorescence spectrum at an effective diameter of 1000 μm. From these spectra, we measure the absolute absorption coefficient, μ(a), reduced scattering coefficient, μ'(s'), phase function parameter, γ, and intrinsic fluorescence, Qμ(a,x)(f), across the measured spectrum. We validate the system using Intralipid- and polystyrene sphere-based scattering phantoms, with and without the addition of the absorber Evans Blue. Finally, we demonstrate the combined MDSFR/SFF of phantoms with varying concentrations of Intralipid and fluorescein, wherein the scattering properties are measured by MDSFR and used to correct the SFF spectrum for accurate quantification of Qμ(a,x)(f).

Vascular responses to photodynamic therapy (PDT) may influence the availability of oxygen during PDT and the extent of tumor destruction after PDT. However, for topical PDT vascular effects are largely unknown. Arteriole and venule diameters were measured before and after hexylaminolevulinate (HAL) and aminolevulinic acid (ALA) PDT and related to the protoporphyrin IX (PpIX) concentration in the vessel wall. A mouse skin fold chamber model and an intravital confocal microscope allowed direct imaging of the subcutaneous vessels underlying the treated area. In both HAL and ALA groups over 60% of arterioles constricted completely, while venules generally did not respond, except for two larger veins that constricted partially. Arteriole vasoconstriction strongly correlated with PpIX fluorescence intensity in the arteriole wall. Total PpIX fluorescence intensity was significantly higher for HAL than ALA for the whole area that was imaged but not for the arteriole walls. In conclusion, complete arteriole vasoconstriction occurs frequently in both HAL and ALA based topical PDT, especially when relatively high PpIX concentrations in arteriole walls are reached. Vasoconstriction will likely influence PDT effect and should be considered in studies on topical HAL and ALA-PDT. Also, our results may redefine the vasculature as a potential secondary target for topical PDT., (Copyright © 2013 Elsevier B.V. All rights reserved.)

The purpose of this integrative review is to identify the effectiveness of using triage protocols to decrease ED length of stay. The review method described by Ganong was used to guide the review process. Data sources included CINAHL (Cumulative Index to Nursing and Allied Health Literature), Medline, the Cochrane Library, Mosby's Nursing Consult, and the National Guideline Clearinghouse. In addition, reference lists of all articles were reviewed, 3 authors of previous articles were contacted for more current or updated work, and a hand search of the Journal of Emergency Nursing was conducted. The search generated 56 articles, 8 of which met inclusion criteria. Data were interpreted and evaluated by use of a data summary sheet. Key conclusions drawn from the appraisals included that a decrease in length of stay was related to protocol use and nurses were able to initiate diagnostic testing and treatments appropriately. These conclusions apply to acuity levels 3 and 4, which require either little or no testing or require testing to facilitate a disposition decision. The implications for nursing are that appraisals of evidence lead to better practice decisions, protocols can provide greater nursing autonomy and satisfaction, and protocols are able to increase the facilitation of patient care in the emergency department., (Copyright © 2013 Emergency Nurses Association. Published by Mosby, Inc. All rights reserved.)

Multi diameter single fiber reflectance (MDSFR) spectroscopy is a non-invasive optical technique based on using multiple fibers of different diameters to determine both the reduced scattering coefficient (μs') and a parameter γ that is related to the angular distribution of scattering, where γ = (1-g2)/(1-g1) and g1 and g2 the first and second moment of the phase function, respectively. Here we present the first in vivo MDSFR measurements of μs'(λ) and γ(λ) and their wavelength dependence. MDSFR is performed on nineteen mice in four tissue types including skin, liver, normal tongue and in an orthotopic oral squamous cell carcinoma. The wavelength-dependent slope of μs'(λ) (scattering power) is significantly higher for tongue and skin than for oral cancer and liver. The reduced scattering coefficient at 800 nm of oral cancer is significantly higher than of normal tongue and liver. Gamma generally increases with increasing wavelength; for tumor it increases monotonically with wavelength, while for skin, liver and tongue γ(λ) reaches a plateau or even decreases for longer wavelengths. The mean γ(λ) in the wavelength range 400-850 nm is highest for liver (1.87 ± 0.07) and lowest for skin (1.37 ± 0.14). Gamma of tumor and normal tongue falls in between these values where tumor exhibits a higher average γ(λ) (1.72 ± 0.09) than normal tongue (1.58 ± 0.07). This study shows the potential of using light scattering spectroscopy to optically characterize tissue in vivo.

Light fractionation, with a long dark interval, significantly increases the response to ALA-PDT in pre-clinical models and in non-melanoma skin cancer. We investigated if this increase in efficacy can be replicated in PAM 212 cells in vitro. The results show a significant decrease in cell survival after light fractionation which is dependent on the PpIX concentration and light dose of the first light fraction. This study supports the hypothesis that an underlying cellular mechanism is involved in the response to light fractionation in which a first light fraction leads to sub-lethally damaged cells that are sensitised to a second light fraction 2 hours later. The current study reveals the in vitro circumstances under which we can investigate the cellular pathways involved.

Photodynamic therapy (PDT) using topical porphyrin-precursors is a promising treatment for superficial basal cell carcinoma (sBCC), but it needs further optimization. The aim of this study was to compare 5-year lesion (complete) response rates of sBCC treated with topical aminolaevulinic acid (ALA)-PDT using a single illumination vs. ALA-PDT using a 2-fold illumination scheme. A prospective, randomized study was performed, in which 91 patients with 299 lesions were treated with a 2-fold illumination scheme with 2 light fractions of 20 and 80 J/cm2 delivered 4 and 6 h after a single application of 20% ALA, and 106 patients with 274 lesions were treated with a single illumination of 75 J/cm2 4 h after a single application of 20% ALA. All lesions were treated at a fluence rate of 50 mW/cm2. An interim time to event analysis of complete response (CR) rates at 12 months showed encouraging results, and therefore lesions were followed for 5 years post-therapy. A third group of 50 patients with 172 lesions treated with 2-fold illumination were included after the initial period and analysed separately. The CR rate was significantly greater following the 2-fold illumination than the single illumination (p = 0.0002, log-rank test). Five years after therapy the CR rate after 2-fold illumination was 88%, whereas the CR rate after single illumination was 75%. The CR rate in the third group of lesions, treated with 2-fold illumination was 97% and 88% at 12 months and 5 years after therapy, respectively. Long-term follow-up indicates superior efficacy in sBCC of ALA-PDT with 2-fold illumination compared with ALA-PDT with single illumination.

Introduction: we aimed to investigate on the potential relationship between vitamin D and orthostatic hypotension (OH) in a case-control model in older adults., Methods: all participants were community-dwelling adults who were not taking vitamin D supplements. Cases were subjects aged 64 or older who were diagnosed with OH at a Falls and Blackout Unit. Controls were age- (within 5 years) and gender-matched subjects who had no history of blackouts, falls or orthostatic dizziness in the preceding year. OH was defined according to standard criteria and was diagnosed with an active stand test. Serum vitamin D [25(OH)D] was measured by radioimmunoassay., Results: seventy-six subjects were included in the analysis (38 controls and 38 cases). Twenty-four in each group were female and mean age was between 78 and 79 years. Subjects with OH had lower serum 25(OH)D compared to controls (mean difference = 20.6 nmol/l, P = 0.0002). Lower vitamin D status was associated with an increased risk of OH after adjustment for season, body mass index, presence of stroke, diabetes and angina (P = 0.035) but not with impaired orthostatic haemodynamics., Discussion: findings suggest that vitamin D may play a role in the aetiology of OH. Further studies will be required to explore on this relationship.

Background and Objective: Anal cancer and preneoplastic anal lesions (anal intraepithelial neoplasia, AIN) rising especially in men having sex with men (MSM). There are no widely accepted treatment standards for AIN. Photodynamic therapy (PDT) using the systemic sensitizer meta-tetrahydroxyphenylchlorin (mTHPC) has the potential to treat the anal area even when the exact borders of the preneoplastic anal lesion cannot easily be visualized., Study Design/materials and Methods: In this prospective intervention study, 15 HIV-positive MSM with AIN 3 were treated in 25 PDT-sessions using mTHPC intravenously administered at drug doses of 0.075-0.15 mg ml(-1) and illumination at 48  hours. The illumination was performed using a custom made applicator using either red light (652 nm) to a measured intended fluence of 10 and 20 J cm(-2) and green light (532 nm) to a measured intended fluence of 105, 210, and 340 J cm(-2) . Red and green illuminations were performed at a (green) equivalent fluence rate of 105 mW cm(-2) ., Results: Initial complete response was seen in 7/25 (28%) of treatments and another 4/25 (16%) initial partial responses. After an average 8 months, recurrences were detected in 7/11 (64%) of sessions that initially showed response. A total 4/25 (16%) showed persistent complete response 6-15 months after green light illumination. Red light illuminations caused more significant side effects combined with no persistent complete response. Reported side effects were intense pain, bloody and purulent rectal discharge, and anal stricture formation, in one patient., Conclusion: The results show that the use of systemic mTHPC is partially effective for the treatment of AIN 3., (Copyright © 2012 Wiley Periodicals, Inc.)

Multi-diameter single fiber reflectance (MDSFR) spectroscopy enables quantitative measurement of tissue optical properties, including the reduced scattering coefficient and the phase function parameter γ. However, the accuracy and speed of the procedure are currently limited by the need for co-localized measurements using multiple fiber optic probes with different fiber diameters. This study demonstrates the use of a coherent fiber bundle acting as a single fiber with a variable diameter for the purposes of MDSFR spectroscopy. Using Intralipid optical phantoms with reduced scattering coefficients between 0.24 and 3 mm(-1), we find that the spectral reflectance and effective path lengths measured by the fiber bundle (NA = 0.40) are equivalent to those measured by single solid-core fibers (NA = 0.22) for fiber diameters between 0.4 and 1.0 mm (r ≥ 0.997). This one-to-one correlation may hold for a 0.2 mm fiber diameter as well (r = 0.816); however, the experimental system used in this study suffers from a low signal-to-noise for small dimensionless reduced scattering coefficients due to spurious back reflections within the experimental system. Based on these results, the coherent fiber bundle is suitable for use as a variable-diameter fiber in clinical MDSFR quantification of tissue optical properties.

Multidiameter single fiber reflectance (MDSFR) spectroscopy is a method that allows the quantification of μs' and the phase-function-dependent parameter γ of a turbid medium by utilizing multiple fibers with different diameters. We have previously introduced the theory behind MDSFR and its limitations, and here we present an experimental validation of this method based on phantoms containing a fractal distribution of polystyrene spheres both in the absence and presence of the absorber Evans Blue.

In vivo measurement of photosensitizer concentrations may optimize clinical photodynamic therapy (PDT). Fluorescence differential path-length spectroscopy (FDPS) is a non-invasive optical technique that has been shown to accurately quantify the concentration of Foscan® in rat liver. As a next step towards clinical translation, the effect of two liposomal formulations of mTHPC, Fospeg® and Foslip®, on FDPS response was investigated. Furthermore, FDPS was evaluated in target organs for head-and-neck PDT. Fifty-four healthy rats were intravenously injected with one of the three formulations of mTHPC at 0.15 mg kg(-1). FDPS was performed on liver, tongue, and lip. The mTHPC concentrations estimated using FDPS were correlated with the results of the subsequent harvested and chemically extracted organs. An excellent goodness of fit (R(2)) between FDPS and extraction was found for all formulations in the liver (R(2)=0.79). A much lower R(2) between FDPS and extraction was found in lip (R(2)=0.46) and tongue (R(2)=0.10). The lower performance in lip and in particular tongue was mainly attributed to the more layered anatomical structure, which influences scattering properties and photosensitizer distribution.

Reflectance spectra measured in Intralipid (IL) close to the source are sensitive to wavelength-dependent changes in reduced scattering coefficient ([Formula: see text]) and scattering phase function (PF). Experiments and simulations were performed using device designs with either single or separate optical fibers for delivery and collection of light in varying concentrations of IL. Spectral reflectance is not consistently linear with varying IL concentration, with PF-dependent effects observed for single fiber devices with diameters smaller than ten transport lengths and for separate source-detector devices that collected light at less than half of a transport length from the source. Similar effects are thought to be seen in tissue, limiting the ability to quantitatively compare spectra from different devices without compensation.

This study utilizes Monte Carlo simulations of single fiber fluorescence to develop an empirical model that corrects for the influence of scattering and absorption on fluorescence intensity (F(SF)). The model expresses F(SF) in terms of the reduced scattering coefficient (μs') and absorption coefficient (μ(a)), each determined independently at excitation and emission wavelengths (λ(x) and λ(m)), and the fiber diameter (d(f)). This model returns accurate descriptions (mean residual <6%) of F(SF) across a biologically relevant range of μs' and μ(a) values and is insensitive to the form of the scattering phase function., (© 2012 Optical Society of America)

Quantitative determination of fluorophore content from fluorescence measurements in turbid media, such as tissue, is complicated by the influence of scattering properties on the collected signal. This study utilizes a Monte Carlo model to characterize the relationship between the fluorescence intensity collected by a single fiber optic probe (F(SF)) and the scattering properties. Simulations investigate a wide range of biologically relevant scattering properties specified independently at excitation (λ(x)) and emission (λ(m)) wavelengths, including reduced scattering coefficients in the range μ'(s)(λ(x)) ∈ [0.1 - 8]mm(-1) and μ'(s)(λ(m)) ∈ [0.25 - 1] × μ'(s)(λ(x)). Investigated scattering phase functions (P(θ)) include both Henyey-Greenstein and Modified Henyey-Greenstein forms, and a wide range of fiber diameters (d(f) ∈ [0.2 - 1.0] mm) was simulated. A semi-empirical model is developed to estimate the collected F(SF) as the product of an effective sampling volume, and the effective excitation fluence and the effective escape probability within the effective sampling volume. The model accurately estimates F(SF) intensities (r=0.999) over the investigated range of μ'(s)(λ(x)) and μ'(s)(λ(m)), is insensitive to the form of the P(θ), and provides novel insight into a dimensionless relationship linking F(SF) measured by different d(f)., (2011 Optical Society of America)

Multiple diameter single fiber reflectance (MDSFR) measurements of turbid media can be used to determine the reduced scattering coefficient (μ'(s)) and a parameter that characterizes the phase function (γ). The MDSFR method utilizes a semi-empirical model that expresses the collected single fiber reflectance intensity as a function of fiber diameter (d(fiber)), μ'(s), and γ. This study investigated the sensitivity of the MDSFR estimates of μ'(s) and γ to the choice of fiber diameters and spectral information incorporated into the fitting procedure. The fit algorithm was tested using Monte Carlo simulations of single fiber reflectance intensities that investigated biologically relevant ranges of scattering properties (μ'(s) ∈ [0.4 - 4]mm(-1)) and phase functions (γ ∈ [1.4 - 1.9]) and for multiple fiber diameters (d(fiber) ∈ [0.2 - 1.5] mm). MDSFR analysis yielded accurate estimates of μ'(s) and γ over the wide range of scattering combinations; parameter accuracy was shown to be sensitive to the range of fiber diameters included in the analysis, but not to the number of intermediate fibers. Moreover, accurate parameter estimates were obtained without a priori knowledge about the spectral shape of γ. Observations were used to develop heuristic guidelines for the design of clinically applicable MDSFR probes.

A major challenge in biomedical optics is the accurate quantification of in vivo fluorescence images. Fluorescence imaging is often used to determine the pharmacokinetics of photosensitizers used for photodynamic therapy. Often, however, this type of imaging does not take into account differences in and changes to tissue volume and optical properties of the tissue under interrogation. To address this problem, a ratiometric quantification method was developed and applied to monitor photosensitizer meso-tetra(hydroxyphenyl) chlorin (mTHPC) pharmacokinetics in the rat skin-fold observation chamber. The method employs a combination of dual-wavelength excitation and dual-wavelength detection. Excitation and detection wavelengths were selected in the NIR region. One excitation wavelength was chosen to be at the Q band of mTHPC, whereas the second excitation wavelength was close to its absorption minimum. Two fluorescence emission bands were used; one at the secondary fluorescence maximum of mTHPC centered on 720 nm, and one in a region of tissue autofluorescence. The first excitation wavelength was used to excite the mTHPC and autofluorescence and the second to excite only autofluorescence, so that this could be subtracted. Subsequently, the autofluorescence-corrected mTHPC image was divided by the autofluorescence signal to correct for variations in tissue optical properties. This correction algorithm in principle results in a linear relation between the corrected fluorescence and photosensitizer concentration. The limitations of the presented method and comparison with previously published and validated techniques are discussed.

We report the discovery of a new (S)-3-aminopyrrolidine series of CCR2 antagonists. Structure-activity relationship studies on this new series led to the identification of 17 (INCB8761/PF-4136309) that exhibited potent CCR2 antagonistic activity, high selectivity, weak hERG activity, and an excellent in vitro and in vivo ADMET profile. INCB8761/PF-4136309 has entered human clinical trials.

The objective quantitative monitoring of light, oxygen, and photosensitizer is challenging in clinical photodynamic therapy settings. We have previously developed fluorescence differential path-length spectroscopy (FDPS), a technique that utilizes reflectance spectroscopy to monitor microvascular oxygen saturation, blood volume fraction, and vessel diameter, and fluorescence spectroscopy to monitor photosensitizer concentration. In this paper the clinical feasibility of the technique is tested on eight healthy volunteers and on three patients undergoing PDT of oral cavity cancers. Model-based analysis of the measured spectra provide quantitative tissue parameters that are corrected for background tissue absorption, autofluorescence, and the transmission of the optical system; this method allows comparison of intra- and inter-subject parameters. The FDPS correctly estimated the absence of m-THPC in volunteers and detected photobleaching in the areas receiving treatment light in patients undergoing PDT treatment. This study demonstrates the feasibility of monitoring clinical photodynamic therapy treatments using optical spectroscopy., (Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Optically monitoring the vascular physiology during photodynamic therapy (PDT) may help understand patient-specific treatment outcome. However, diffuse optical techniques have failed to observe changes herein, probably by optically sampling too deep. Therefore, we investigated using differential path-length spectroscopy (DPS) to obtain superficial measurements of vascular physiology in actinic keratosis (AK) skin. The AK-specific DPS interrogation depth was chosen up to 400 microns in depth, based on the thickness of AK histology samples. During light fractionated aminolevulinic acid-PDT, reflectance spectra were analyzed to yield quantitative estimates of blood volume and saturation. Blood volume showed significant lesion-specific changes during PDT without a general trend for all lesions and saturation remained high during PDT. This study shows that DPS allows optically monitoring the superficial blood volume and saturation during skin PDT. The patient-specific variability supports the need for dosimetric measurements. In DPS, the lesion-specific optimal interrogation depth can be varied based on lesion thickness., (Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Introduction: The posterior circumflex humeral artery (PCHA) travels together with the axillary nerve through the quadrilateral space of the shoulder. Angiographic occlusion of this artery upon abduction and external rotation (ABER) of the arm has been accepted as evidence of mechanical compression of the axillary nerve and thus considered pathognomonic of quadrilateral space syndrome (QSS). The specificity of this sign for QSS has however been called into question as there are, to date, limited data on the incidence of axillary neurovascular compression during ABER in a normal population. We set out to determine the rate of stenosis or occlusion of the PCHA on ABER in healthy volunteers using ultrasound., Methods: Healthy volunteers asymptomatic for shoulder complaints were recruited from patients attending the clinic for ultrasound imaging not related to the shoulder, as well as volunteers among staff. Doppler sampling of the PCHA of both shoulders of participants was conducted in neutral and abduction and externally rotated positions. Each shoulder was treated as a separate entity., Results: Results showed that 15/93 (16%) of shoulders demonstrated Doppler ultrasound evidence of occlusion or significant stenosis in the absence of shoulder complaints., Conclusion: Occlusion or stenosis of the PCHA on ABER is an uncommon finding in an asymptomatic population. Axillary neurovascular compression is unlikely if colour Doppler ultrasound does not show PCHA compromise during ABER., (© 2011 The Authors. Journal of Medical Imaging and Radiation Oncology © 2011 The Royal Australian and New Zealand College of Radiologists.)