Optical properties of Intralipid: a phantom medium for light propagation studies.

Intralipid is an intravenous nutrient consisting of an emulsion of phospholipid micelles and water. Because Intralipid is turbid and has no strong absorption bands in the visible region of the electromagnetic spectrum, and is readily available and relatively inexpensive, it is often used as a tissue simulating phantom medium in light dosimetry experiments. In order to assist investigators requiring a controllable medium that over a finite range of wavelengths is optically equivalent to tissue, we have compiled previously published values of the optical interaction coefficients of Intralipid, most of which were measured at a wavelength of 633 nm. We have extended the measurements of the absorption and reduced scattering coefficients from 460 to 690 nm and the total attenuation coefficient from 500 to 890 nm. These measurements show that, for stock 10% Intralipid, the absorption coefficient varies from 0.015 to 0.001 cm-1 between 460 and 690 nm, the reduced scattering coefficient varies from 92 to 50 cm-1 between 460 and 690 nm, the total attenuation coefficient varies from 575 to 150 cm-1 between 500 and 890 nm, and the average cosine of scatter varies from 0.87 to 0.82 between 460 and 690 nm. With these data, we discuss the design of an optically tissue-equivalent phantom consisting of Intralipid and black India ink.     

Statins, neuromuscular degenerative disease and an amyotrophic lateral sclerosis-like syndrome: an analysis of individual case safety reports from vigibase.

BACKGROUND: The WHO Foundation Collaborating Centre for International Drug Monitoring (Uppsala Monitoring Centre [UMC]) has received many individual case safety reports (ICSRs) associating HMG-CoA reductase inhibitor drug (statin) use with the occurrence of muscle damage, including rhabdomyolysis, and also peripheral neuropathy. A new signal has now appeared of disproportionally high reporting of upper motor neurone lesions. AIM AND SCOPE: The aim of this paper is to present the upper motor neurone lesion cases, with other evidence, as a signal of a relationship between statins and an amyotrophic lateral sclerosis (ALS)-like syndrome. The paper also presents some arguments for considering that a spectrum of severe neuromuscular damage may be associated with statin use, albeit rarely. The paper does not do more than raise the signal for further work and analysis of what must be regarded as a potentially very serious and perhaps avoidable or reversible adverse reaction, though it also suggests action to be taken if an ALS-like syndrome should occur in a patient using statins. METHODS: The 43 reports accounting for the disproportional reports in Vigibase (the database of the WHO Programme for International Drug Monitoring) are summarised and analysed for the diagnosis of an ALS-like syndrome. The issues of data quality and potential reporting bias are considered. RESULTS: 'Upper motor neurone lesion' is a rare adverse event reported in relationship to drugs in Vigibase (a database containing nearly 4 million ICSRs). Of the total of 172 ICSRs on this reported term, 43 were related to statins, of which 40 were considered further: all but one case was reported as ALS. In 34/40 reports a statin was the sole reported suspected drug. The diagnostic criteria were variable, and seven of the statin cases also had features of peripheral neuropathy. Of a total of 5534 ICSRs of peripheral neuropathy related to any drug in Vigibase, 547 were on statins. The disproportional reporting of statins and upper motor neurone lesion persisted after age stratification, and such disproportionality was not seen for statins and Parkinson's disease, Alzheimer's disease, extrapyramidal disorders, or multiple sclerosis-like syndromes. DISCUSSION: Because the cases were sometimes atypical we propose the use of the term 'ALS-like syndrome' and speculate whether this is part of a spectrum of rare neuromuscular damage. The diagnosis of ALS is often problematic, and the insidiousness and chronicity of the disease make causality with a drug difficult to assess. The disproportionally high reporting makes this an important signal nevertheless, since ALS is serious clinically and statins are so widely used. Wide use of the statins also makes a chance finding more probable, but is unlikely to cause disproportional reporting when there are no obvious biases identified. CONCLUSION: We emphasise the rarity of this possible association, and also the need for further study to establish whether a causal relationship exists. We do advocate that trial discontinuation of a statin should be considered in patients with serious neuromuscular disease such as the ALS-like syndrome, given the poor prognosis and a possibility that progression of the disease may be halted or even reversed.     

Real-time imaging of Rab3a and Rab5a reveals differential roles in presynaptic function

We investigated the roles of two Rab-family proteins, Rab3a and Rab5a, in hippocampal synaptic transmission using real-time fluorescence imaging. During synaptic activity, Rab3a dissociated from synaptic vesicles and dispersed into neighbouring axonal regions. Dispersion required calcium-dependent exocytosis and was complete before the entire vesicle pool turned over. In contrast, even prolonged synaptic activity produced limited dispersion of Rab5a. A GTPase-deficient mutant, Rab3a (Q81L), dispersed more slowly than wild-type Rab3a, and decreased the rate of exocytosis and the size of the recycling pool of vesicles. While overexpression of Rab3a did not affect vesicle recycling, overexpression of Rab5a reduced the recycling pool size by 50%. We propose that while Rab3a preferentially associates with recycling synaptic vesicles and modulates their trafficking, Rab5a is largely excluded from recycling vesicles.     

The Hospital Frailty Risk Score is Not an Accurate Predictor of Treatment Costs for Total Joint Replacement Patients in a Medicare Bundled Payment Population

BackgroundMedically complex patients require more resources and experience higher costs within total joint arthroplasty (TJA) bundled payment models. While risk adjustment would be beneficial for such patients, no tool currently exists which can reliably identify these patients preoperatively. The purpose of this study is to determine if the Hospital Frailty Risk Score (HFRS) is a valid predictor of high-TJA treatment costs.MethodsRetrospective analysis was performed on patients who underwent primary TJA between 2015 and 2020 from a single large orthopedic practice. ICD-10 codes from an institutional database were used to calculate HFRS. Cost data including inpatient, postacute, and episode of care (EOC) costs were collected. Charlson comorbidity index, demographics, readmissions, and complications were analyzed.Results4936 patients had a calculable HFRS and those with intermediate and high scores experienced more frequent readmissions/complications after TJA, as well as higher EOC costs. However, HFRS did not reliably predict EOC costs, yielding a sensitivity of 49% and specificity of 66%. Multivariate analysis revealed that both patient age and sex are superior individual cost predictors when compared with HFRS. Secondary analyses indicated that HFRS more effectively predicts TJA complications and readmissions but is still nonideal for clinical applications.ConclusionHFRS has poor sensitivity as a predictor of high-EOC costs for TJA patients but has adequate specificity for predicting postoperative readmissions and complications. Further research is needed to develop a scale that can appropriately predict orthopedic cost outcomes.     

Construction,quality assurance and calibration of spherical isotropic fibre optic light diffusers

Spherical isotropic fibre optic light diffusers are used in photodynamic therapy either as a light source or as a light detector. The construction of light diffusers using different materials is described, viz. an optical method involving local polymerization of a dental fissure sealant, which is referred to as the Henderson method, and a second method using plastic or ceramic pre-fabricated spheres. Quality tests necessary for reliable clinical use are presented for the mechanical strength, output power and isotropy. The maximum pull-off force and blow-off output power for the different kinds of diffusers were determined. The calibration procedures are given for measurement of the output power and wavelength of the light emitted by a diffuser and for measurement of the fluence rate by a light-detecting diffuser, using a compact integrating sphere device. With all types of diffusers described, an isotropy can be obtained of better than ± 20% measured over a 320° angle for spheres as small as 1 mm. Larger ceramic diffusers are particularly suitable for delivering high output powers. A 3-mm-diameter ceramic diffuser mounted on a 600-m-core fibre can emit up to 5 W of continuous wave (CW) visible light in air. Diffusers used for light detection can measure the light fluence rate in tissue with 15% accuracy or better if calibration factors are determined for each individual probe.     

Comparison between isotropic and nonisotropic dosimetry systems during intraperitoneal photodynamic therapy

BACKGROUND AND OBJECTIVE: On-line monitoring of light fluence during intraperitoneal photodynamic therapy (IP PDT) is crucial for safe light delivery. A flat photodiode-based dosimetry system is compared with an isotropic detector-based system in patients undergoing IP PDT. STUDY DESIGN/MATERIALS AND METHODS: Flat photodiodes and spherical detectors were placed side by side in the abdomen, for simultaneous light dosimetry in 19 patients. Tissue phantom experiments were performed to provide a preliminary estimate of the tissue optical properties of the peritoneum. RESULTS: The conversion factor between systems for 630-nm light was found to be 1.7 +/- 0.12. The mu(eff) of the tissues in the abdomen is estimated to vary between 0.5 cm(-1) to 1.4 cm(-1) assuming a mu(s)' = 7 cm(-1). CONCLUSIONS: The measured conversion factor should allow for comparison of light fluences with future clinical protocols that use an isotropic-based detector system. Differences in the optical properties of the underlying tissues may contribute to the variability in light measurements.     

Alpha-melanocyte-stimulating hormone reduces endotoxin-induced liver inflammation.

Alpha-Melanocyte-stimulating hormone (MSH) is a potent anti-inflammatory agent in many models of inflammation, suggesting that it inhibits a critical step common to different forms of inflammation. We showed previously that alpha-MSH inhibits nitric oxide (NO) production in cultured macro-phages. To determine how alpha-MSH acts in vivo, we induced acute hepatic inflammation by administering endotoxin (LPS) to mice pretreated with Corynebacterium parvum, alpha-MSH prevented liver inflammation even when given 30 min after LPS administration. To determine the mechanisms of action of alpha-MSH, we tested its influence on NO, infiltrating inflammatory cells, cytokines, and chemokines. Alpha-MSH inhibited systemic NO production, hepatic neutrophil infiltration, and increased hepatic mRNA abundance for TNF alpha, and the neutrophil and monocyte chemokines (KC/IL-8 and MCP-1). We conclude that alpha-MSH prevents LPS-induced hepatic inflammation by inhibiting production of chemoattractant chemokines which then modulate infiltration of inflammatory cells. Thus, alpha-MSH has an effect very early in the inflammatory cascade.     

Participatory inquiry with a colleague: an innovative faculty development process

Clinical evaluation is central to the aims of nursing education; however, little has been written about the actual evaluative practices of nurse educators and the sources of influence on those practices. In this article, we describe our experience as co-investigators into the evaluation practices of one of us (J.A.J.) and overview some of the challenges and opportunities of participatory inquiry. We describe how J.A.J.'s involvement in this research project encouraged her to explore her evaluative practices in a meaningful way, which moved her to a place of deeper understanding about her work and transformed her as a nurse educator. As a result of this study, we are convinced of the necessity for a faculty development process whereby colleagues commit to a critical inquiry process focused on identifying each other's evaluative practices and sources of influence on those practices. In addition, schools of nursing can encourage faculty participation in peer development by adopting an expanded view of scholarship in which the disciplined examination of one's evaluative practices is accepted as evidence of the scholarship of teaching.     

Bone morphogenic protein-9 stimulates endothelin-1 release from human pulmonary microvascular endothelial cells: A potential mechanism for elevated ET-1 levels in pulmonary arterial hypertension

Abnormalities of signalling for the transforming growth factor beta (TGFβ) family of peptides, including bone morphogenic proteins (BMP), have been described in heritable pulmonary arterial hypertension (PAH). TGFβ can modulate synthesis of the vasoconstrictor and mitogen, endothelin-1 (ET-1), a mediator that contributes to the pathogenesis of PAH. BMP-9 is a circulating peptide recently recognized to affect endothelial function. The stimuli for increased microvascular endothelial production of ET-1 in PAH are unknown. We therefore studied the effects of BMP-9 on ET-1 production by human lung blood microvascular endothelial cells (HMVEC-LBl) in vitro. In vitro, BMP-9 increased ET-1 production by HMVEC-LBl. The effect was identical to TGFβ-1, but BMP-9 and TGFβ-1 combined further increased ET-1 levels by 29%. As compared to TGFβ-1, BMP-9 induced more potent and rapid phosphorylation of Smad 1/5, the downstream signalling molecules of the activin-like kinase 1 (ALK-1) receptor. Moreover, as has been previously shown for endothelial cells of other origin, BMP-9 also induced Smad 2 phosphorylation in HMVEC-LBl. In conclusion, BMP-9 stimulates ET-1 production by HMVEC-LBl in vitro. BMP-9 signals via several Smad pathways. These studies provide novel mechanisms for the potentiation of PAH.     

Granulocyte colony-stimulating factor attenuates early ventricular expansion after experimental myocardial infarction

OBJECTIVE: In the early phase after transmural myocardial infarction (MI), the infarcted myocardium undergoes replacement by scar tissue, which is essential for preserving the structural integrity of the infarcted tissue. Transforming growth factor (TGF)-beta1, which is known as a fibrotic cytokine, plays a pivotal role in the reparative fibrosis after MI. It is reported that granulocyte colony-stimulating factor (G-CSF) can accelerate wound healing. The aim of our study was to investigate the effect of G-CSF on early ventricular expansion after MI. METHODS: MI was induced by ligation of the left coronary artery in male Wistar rats. G-CSF (20 microg/kg/day, MI-GCSF) or saline (MI-saline) was injected subcutaneously 3 h after MI and every 24 h thereafter for 7 days. Hemodynamic and echocardiographic studies were performed at 14 days. Expression of TGF-beta1 and procollagen type I and type III mRNA in both the infarcted and noninfarcted areas was studied by quantitative RT-PCR at 1, 3, 7, and 14 days after MI. Histological studies were performed at 7 days. RESULTS: MI-GCSF had higher LV max dP/dt, lower LV end-diastolic pressure, and smaller LV end-diastolic and end-systolic dimensions compared to MI-saline. Infarct size was not different between MI-GCSF and MI-saline. Expression of TGF-beta1 mRNA in the infarcted area at 3 days was significantly higher in MI-GCSF than in MI-saline. Expression of procollagen type I and type III mRNA in the infarcted area at 3 days was higher in MI-GCSF compared to MI-saline, and the peak mRNA levels were earlier in MI-GCSF. In the noninfarcted area, there was no difference in TGF-beta1 mRNA expression between MI-GCSF and MI-saline. Histologically, collagen accumulation in the infarcted area at 7 days was more prominent in MI-GCSF than in MI-saline. CONCLUSION: G-CSF treatment improves early post-infarct ventricular expansion through promotion of reparative collagen synthesis in the infarcted area, suggesting some beneficial effect of G-CSF on the infarct healing process.