We propose a method for quantitative assessment of pain, by analyzing hemodynamic patterns with a non-invasive sensor measuring the dynamic light scattering from the skin. The results corresponded to changes in pain reported by subjects.

ABSTRACT The quantitative determination of the level of pain is one of the most challenging clinical problems. This article proposes a method for quantitative assessment of both acute and chronic levels of pain, based on the analysis of hemodynamic patterns measured using a non-invasive sensor. Hemodynamic characteristics were taken from the finger using a sensor measuring the dynamic scattering of light from the skin surface. Changes in hemodynamic parameters in patients with chronic pain were studied. One group of patients with chronic back pain required epidural injection for pain relief. The second group of patients had a Spinal Cord Stimulator implant which was switched off one hour before arriving at the clinic. Optical signals were collected before and after pain relief, either by epidural injection or by turning on the stimulator. Both groups reported their pain level using a standard numerical rating scale. Processing of the results showed that the changes in measured hemodynamic parameters corresponded in most cases to the changes in pain reported by patients following medical intervention. The results suggest that this new non-invasive measurement of pain can be used both for physiological studies and for monitoring various categories of patients suffering from pain.

Currently there is no accurate objective measure for monitoring pain during the state of drug-induced unconsciousness (such as during surgical anesthesia). Moreover, the absence of an objective measure for detecting pain hampers the physician's ability to provide an optimal dose of analgesics. We have developed a novel method for detecting pain by quantifying skin blood flow dynamics using a miniaturized dynamic light scattering (mDLS) sensor placed on the skin. Healthy awake volunteers were studied with mDLS sensors placed on both index fingers while being subjected to a series of cutaneous painful stimuli (electric shock and heat), randomly applied in a range between the subjects’ pain threshold and tolerance. Power spectrum analysis of the recorded signal was performed with a focus on two frequency bands, representing relative blood flow of non-pulsatile vessels and larger pulsatile arterioles. Relative blood flow of pulsatile vessels decreased while flow of non-pulsatile vessels increased in response to painful stimulation, with a high correlation between the responses obtained on the right and left index fingers. The changes in hemodynamics that occur during painful stimulation suggest a redistribution of blood flow between pulsatile and non-pulsatile vessels, probably related to central activation of the sympathetic system combined with local dynamic autoregulatory responses. Thus, optical parameters of skin blood flow can detect nociceptive stimuli and consequently can serve as objective biomarkers of pain.

Self-measurement of blood pressure (BP) is important for monitoring treatment of hypertension, but current instruments are cumbersome and at times also impractical, especially for the older population. Current optical solutions, such as PPG-based technologies that were developed for improving convenience, provide derived measurements that are often inaccurate, particularly for diastolic values. Alternatively, by using dynamic light scattering (DLS) we are able to measure the direct hemodynamic response. We propose a simple physical model that explains the relation between arterial pressure values and the hemodynamic response which is measured from the finger root following changes in externally applied pressure. Based on this model we have developed a small-scaled, optical, mobile device that measures BP at the finger using dynamic light scattering. The apparatus is positioned at the base of the index finger and contains a ring with an inflatable cuff with two miniaturized dynamic light scattering (mDLS) sensors situated distal to the cuff. The cuff is inflated to above systolic pressure, and changes in blood flow (hemodynamics) are measured during cuff deflation. BP measurement is carried out using specially designed algorithms based on hemodynamic indexes and waveform analysis which capture systolic and diastolic points in real-time. Using this apparatus, we measured BP from 69 patients visiting a hypertension outpatient clinic, and a control group of 15 healthy subjects. BP readings were compared with measurements recorded at the arm location with an Omron device used in the clinic. The mean absolute error (MAE) for systolic and diastolic blood pressure was 7.8 and 9 mmHg, respectively at all ranges of BP measured. In conclusion, using Elfi-Tech's innovative technology, it is possible to measure BP accurately at the finger location using a compact, convenient mDLS-based device with high accuracy.

The physiological characteristics of skin blood flow can be described in terms of the hemodynamic indices (HI). The HI is derived from the laser speckle characteristics, which are governed by the cutaneous blood flow. A miniaturized dynamic light-scattering sensor was used to measure the speckle pattern from the finger root. Three groups of subjects from 15 to 25 years of age were tested. The first group included subjects who are actively engaged in sport activities; the second group included subjects with low level of physical activity; and the third group included healthy controls with moderate physical activity. The HI parameters were measured prior to and after the performance of a determined physical load. As a marker of cardiovascular fitness (CVF), we used the postload decay rate of HI. We found that the hemodynamic response to the physical load provides a statistically significant correlation with the postload heart rate decay. It was also found that postocclusion increase of the arterial HI is more prominent in the group with higher physical activity. These results indicate that hemodynamic indices can be used as an additional marker for cardiovascular fitness level.

It is widely recognized that effective stress management could have a dramatic impact on health care and preventive medicine. In order to meet this need, efficient and seamless sensing and analytic tools for the non-invasive stress monitoring during daily life are required. The existing sensors still do not meet the needs in terms of specificity and robustness. We utilized a miniaturized dynamic light scattering sensor (mDLS) which is specially adjusted to measure skin blood flow fluctuations and provides multi-parametric capabilities. Based on the measured dynamic light scattering signal from the red blood cells flowing in skin, a new concept of hemodynamic indexes (HI) and oscillatory hemodynamic indexes (OHI) have been developed. This approach was utilized for stress level assessment for a few usecase scenario. The new stress index was generated through the HI and OHI parameters. In order to validate this new non-invasive stress index, a group of 19 healthy volunteers was studied by measuring the mDLS sensor located on the wrist. Mental stress was induced by using the cognitive dissonance test of Stroop. We found that OHIs indexes have high sensitivity to the mental stress response for most of the tested subjects. In addition, we examined the capability of using this new stress index for the individual monitoring of the diurnal stress level. We found that the new stress index exhibits similar trends as reported for to the well-known diurnal behavior of cortisol levels. Finally, we demonstrated that this new marker provides good sensitivity and specificity to the stress response to sound and musical emotional arousal.

Specific cancer cell targeting is a pre-requisite for efficient drug delivery as well as for high-resolution imaging and still represents a major technical challenge. Tumor-associated enzyme-assisted targeting is a new concept that takes advantage of the presence of a specific activity in the tumor entity. MMP-9 is a protease found to be upregulated in virtually all malignant tumors. Consequently, we hypothesized that its presence can provide a de-shielding activity for targeted delivery of drugs by nanoparticles (NPs) in pancreatic cancer. Here, we describe synthesis and characterization of an optimized MMP-9-cleavable linker mediating specific removal of a PEG shield from a PLGA-b-PEG-based polymeric nanocarrier (Magh@PNPs-PEG-RegaCP-PEG) leading to specific uptake of the smaller PNPs with their cargo into cells. The specific MMP-9-cleavable linker was designed based on the degradation efficiency of peptides derived from the collagen type II sequence. MMP-9-dependent uptake of the Magh@PNPs-PEG-RegaCP-PEG was demonstrated in pancreatic cancer cells in vitro. Accumulation of the Magh@PNPs-PEG-RegaCP-PEG in pancreatic tissues in the clinically relevant KPC mouse model of pancreatic cancer, as a proof-of-concept, was tumor-specific and MMP-9-dependent, indicating that MMP-9 has a strong potential as a specific mediator of PNP de-shielding for tumor-specific uptake. Pre-treatment of mice with Magh@PNPs-PEG-RegaCP-PEG led to reduction of liver metastasis and drastically decreased average colony size. In conclusion, the increased tumor-specific presence and activity of MMP-9 can be exploited to deliver an MMP-9-activatable NP to pancreatic tumors specifically, effectively, and safely.

The need for test systems for nanoparticle biocompatibility, toxicity, and inflammatory or adaptive immunological responses is paramount. Nanoparticles should be free of microbiological and chemical contaminants, and devoid of toxicity. Nevertheless, in the absence of contamination, these particles may still induce undesired immunological effects in vivo, such as enhanced autoimmunity, hypersensitivity reactions, and fibrosis. Here we show that artificial particles of specific sizes affect immune cell recruitment as tested in a dermal air pouch model in mice. In addition, we demonstrate that the composition of nanoparticles may influence immune cell recruitment in vivo. Aside from biophysical characterizations in terms of hydrodynamic diameter, zeta potential, concentration, and atomic concentration of metals, we show that - after first-line in vitro assays - characterization of cellular and molecular effects by dermal air pouch analysis is straightforward and should be included in the quality control of nanoparticles. We demonstrate this for innate immunological effects such as neutrophil recruitment and the production of immune-modulating matrix metalloproteases such as MMP-9; we propose the use of air pouch leukocytosis analysis as a future standard assay.

We have conducted a study on a large group of healthy and sick subjects and have demonstrated that a new index of coagulativety (SKF), based on measurement of the laser speckle signal from the finger root, correlates with chronological age ranging from 1 to 85 years old. The kinds of non-invasive measurements were obtained during two measurement sessions: one with the application of over-systolic occlusion and another without application of the occlusion. The very significant correlation with age was noted both during the stasis stage and during the non-occluding stage. We observed a higher SKF index in sick subjects, correlating directly with severity of illness. We speculated that the observed phenomena are caused by temporarily fluctuations in local blood viscosity associated with interactions of the Red Blood Cells and endothelial cells.

We conducted a study on 861 healthy and sick subjects and demonstrated that some calculated parameters based on measurement of the dynamic light scattering (DLS) signal from the finger correlate highly with chronological age ranging from 1.5 to 85 years old. Measurements of DLS signals were obtained during both occlusion and nonocclusion of blood flow in the finger. For the nonocclusion case we found that the low-frequency component of the DLS signal significantly correlates with the biological age while the high-frequency component of the DLS signal resembles the arterial pulse-wave and does correlate with age. However, the most prominent correlation between the DLS characteristics and age was noted with the stasis stage measurements. We propose that the observed age-related phenomena are caused by alterations in local blood viscosity and interactions of the endothelial cells with erythrocytes. Further, a new noninvasive index based on the age-related optical characteristics was introduced. This noninvasive index may be used as a research and diagnostic tool to examine the endothelial and thrombolytic properties of the vascular system.

We present a new non-invasive method for assessing hemostasis in vivo. This method is based on the analysis of the movement characteristics of red blood cells (RBCs) during blood stasis condition. Stasis is intermittently induced by occlusion of arterial blood flow at the finger root. We assumed that under zero flow conditions, RBC movement is driven mostly by Brownian motion, and we characterized the RBC movement by utilizing the dynamic light scattering (DLS) technique in vivo. We found that during the stasis the RBCs diffusion coefficient in plasma decreases. We speculate that the RBC diffusion coefficient is most strongly related to endothelial and hemostatic activity. This assumption is supported by our findings that RBC movement, being expressed through the characteristics of the measured DLS signal, is correlative to the biological age and also is related to the coagulation factors. This new method can serve as a new diagnostic and research tool for the assessment of hemostasis and vascular function.

Background: Cultural differences have been discussed as a potential factor influencing students' perception and motivation towards their studies. At the Sackler Faculty of Medicine, Tel-Aviv University, two separate programs coexist for American and Israeli medical students. Both are taught at the same sites and by the same faculty, thus enabling cultural comparisons. Our aim was to examine the differences of two medical student groups, American and Israeli, regarding their satisfaction with studies, view of the educational workload, and their perceptions of physician characteristics. Methods: During the academic year 2007-2008 we administered an anonymous questionnaire to the two groups immediately after their first clinical clerkship in internal medicine. The response rate was 82% (90 out of 110) for the Israelis and 93% (53 out of 57) for the Americans. Results : Americans, compared to the Israelis, are significantly more satisfied with their medical studies, consider fewer alternatives to future careers in clinical medicine, feel less of a workload, and hold a more positive opinion of physician characteristics. Conclusions: Cultural differences affect students' perception of their studies, mentors and future careers. Medical educators should be sensitive to the effects of students' background which influence academic and professional attitudes and find ways to strengthen their commitment to the profession.

Patients with hypothyroidism often have increased creatine kinase (CK) levels. It is possible that there is increased production of CK, but other mechanisms, such as an increased cell membrane permeability or decreased enzyme clearance were also proposed. Recently, troponins T and I have been extensively studied because of their cardiac specificity. Cardiac troponins are sensitive and specific markers of cardiac injury. The objective of the study was to measure cardiac troponin T (cTnT) levels in patients with hypothyroidism. Twenty-five patients with primary hypothyroidism were evaluated (thyroid-stimulating hormone (TSH) >30 mU/L and low FT(4)). In all patients thyrotropin (TSH), free thyroxine (FT(4)), CK, CK-MB and cTnT were measured.There were 3 men and 22 women with a mean age of 47.5 +/- 12.4 years. TSH levels ranged from 31 to 75 mIU/L and mean FT(4) levels were 4.5 +/- 1.9 pmol/L. CK was normal in 11 patients and increased in 14. CK levels ranged between 86 and 1221 U/L (normal levels <170 in women, <195 in men) with a mean of 322 U/L +/- 279. CK-MB was increased in 4 patients (16%) and normal in 21. All 25 patients had normal cTnT levels, < 0.01 ng/mL (normal levels 0-0.1 microg/L). Increase in CK and its MB fraction are common in patients with hypothyroidism but cTnT levels are not, even in patients with increased CK-MB. Therefore, cTnT is a reliable marker of cardiac injury even in the hypothyroid patient.

Behçet's disease is a multisystem disorder of probable autoinflammatory etiology with manifestations that can affect many organ systems.We present a patient with the unusual presentation of splenic infarction and pseudoaneurysm of the iliac artery.Behçet's disease should be included in the differential diagnosis of pseudoaneurysms if they are accompanied by other classic features of this interesting disease.