Matrix metalloproteinase-9 (MMP-9) as an activator of nanosystems for targeted drug delivery in pancreatic cancer.

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.

Intradermal air pouch leukocytosis as an in vivo test for nanoparticles.

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.

New noninvasive index for evaluation of the vascular age of healthy and sick people.

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.

The P. CEZANNE Project: innovative approaches to continuous glucose Monitoring.

Our EC-funded project, (FP6 contract No. 031867), "Development of an Implanted Biosensor for Continuous Care and Monitoring System of Diabetic Patients", addresses the pressing needs for the improvement of Blood Glucose monitoring and management through the development of an implanted sensor. This reagentless device integrates a novel nanobiotechnological glucose-sensing array at the heart of a ground-breaking fluorimetric detector, itself using an innovative hydrogel waveguide technology. The implant will wirelessly feed a sustained stream of Glucose values into a networked telemedicine system that will be able to support thousands of diabetic patients, and is planned to eventually integrate an insulin pump, thus fulfilling the ultimate goal of devising a cybernetic, externally supervised "artificial pancreas".

Prevalence and evaluation of B12 deficiency in patients with autoimmune thyroid disease.

BACKGROUND: Patients with autoimmune thyroid disease (AITD) have a higher prevalence of pernicious anemia compared with the general population. Clinical signs of B12 deficiency may be subtle and missed, particularly in patients with known autoimmune disease. We assessed the prevalence of vitamin B12 deficiency in patients with AITD and whether their evaluation may be simplified by measuring fasting gastrin levels. METHODS: Serum B12 levels was measured in 115 patients with AITD (7 men and 108 women), with a mean age of 47 +/- 15 years. In patients with low serum B12 levels (< or =133 pmol/L), fasting serum gastrin and parietal cell antibodies (PCA) were measured. RESULTS: Thirty-two patients (28%) with AITD had low B12 levels. Fasting serum gastrin was measured in 26 and was higher than normal in 8 patients. PCA were also measured in 27 patients with B12 deficiency and were positive in 8 patients. Five patients with high gastrin levels underwent gastroscopy with biopsy, and atrophic gastritis was diagnosed in all. The prevalence of pernicious anemia as assessed by high serum gastrin levels in patients with low B12 was 31%. CONCLUSIONS: Patients with AITD have a high prevalence of B12 deficiency and particularly of pernicious anemia. The evaluation of B12 deficiency can be simplified by measuring fasting serum gastrin and, if elevated, referring the patient for gastroscopy.

Comparing the distress of American and Israeli medical students studying in Israel during a period of terror.

INTRODUCTION: Medical school is a very stressful environment with multiple sources of stress, including academic, social and other issues. International medical students are exposed to additional stressors such as homesickness and culture shock. METHODS: In order to assess the influence of cultural background on the level of perceived distress, we examined Israeli and American students studying at the same university during a period of terror. RESULTS: We found clear differences between the 2 groups of students, with Americans reporting a higher level of anxiety and a poorer level of social functioning than the Israelis. Although there was no significant difference between the 2 groups in terms of their sense of safety, the American students reported a higher level of fear and more change in their daily activities to a greater extent than did the Israelis. CONCLUSIONS: These findings underscore the effect of culture on students' responses to the same stressful stimuli and to a perceived dangerous environment. Faculty needs to be aware that cultural factors may affect students' adjustment to the medical school environment.

Cultural perception of harassment in two groups of medical students: American and Israeli.

The aims of this study were to determine whether harassment occurs in the authors' school, the Sackler Faculty of Medicine at Tel Aviv University, and to address the possible influence of cultural background on the perception of harassment. The unique makeup of the school was utilized, with two separate programs for American and Israeli students trained at the same sites and by the same faculty. A two-part questionnaire was developed that included students' reports on the occurrence of harassment, at what stage of their studies, by whom and its nature as well as demographic data. In the second part, students reported on their perception of harassment. Seven common scenarios were presented, and they were asked to indicate (on a four-point scale plus a non-applicable option) to what extent each scenario constituted harassment. A total of 115 Israeli and 81 American students in their clinical years responded during 2000-2001. About 50% experienced harassment, mainly in the clinical years. Significant differences were identified between the Israeli and the American students in their: (1) reporting of the amount (Israeli 59% vs. American 38%) and nature of harassment, and (2) perception of harassment (differed in six out of the seven scenarios), that can be related to their different cultures. These findings suggest that medical school faculty should be made aware of cultural differences in students' perception of harassment, thus enabling them to adapt their approach towards the students and take action to prevent its occurrence.

Is the treatment of hyperlipidemia as secondary prevention adequate in different age groups in Israel?

BACKGROUND: Treatment of hyperlipidemia is important for secondary prevention in patients suffering from coronary heart disease. It has been proven that "young elderly" (patients aged 65-75 years) can benefit from the treatment at least as much as younger patients. OBJECTIVE: To assess the adequacy of treatment as part of secondary prevention in "young elderly" and younger patients. METHODS: In this prospective study, 389 patients discharged from the hospital with the diagnosis of coronary heart disease were divided according to age groups. Data were collected regarding lipid profile examinations, dietary and drug therapy, and results of lipid profiles. RESULTS: Less than one-third of the patients achieved target low density lipoprotein levels. More patients in the older age group achieved the treatment goals. The goals were achieved despite the fact that the percentage of patients treated with lipid-lowering drugs was lower in the older age group. CONCLUSION: The percentage of patients treated for hyperlipidemia as part of a secondary prevention plan in Israel is similar to that in other developed countries. The fact that more "young elderly" patients achieve adequate lipid profiles compared to younger patients indicates that there is no age discrimination towards this patient group. The finding that less than one-third of the patients reach the treatment goals should prompt physicians to treat hyperlipidemia more aggressively.

Overnight dexamethasone suppression test: a reliable screen for Cushing's syndrome in the obese.

OBJECTIVE: Reevaluation of the validity of the 1-mg overnight dexamethasone suppression test (ODST) as a screening test for Cushing's syndrome in obese patients. RESEARCH METHODS AND PROCEDURES: Eighty-six obese patients (body mass index, 30 to 53 kg/m(2)) that were referred to a general endocrine outpatient clinic for evaluation of simple obesity, diabetes mellitus, hypertension, polycystic ovary disease, or pituitary tumor. One milligram dexamethasone was administered orally at 11:00 PM, and serum cortisol levels were measured the following morning between 8:00 AM and 9:00 AM. Suppression of serum cortisol to <80 nM (3 micro g/dL) was chosen as the cut-off point for normal suppression. Patients with serum cortisol levels > or =80 nM were evaluated for Cushing's syndrome. RESULTS: Suppression of morning cortisol levels to <80 nM occurred in 79 of the 86 obese patients. Seven patients had serum cortisol levels higher than 80 nM; five were eventually diagnosed with Cushing's syndrome and two were considered false positive results in view of normal 24-hour free urinary cortisol and normal suppression on a low dose dexamethasone suppression test (0.5 mg of dexamethasone every 6 hours for 2 days). We found a false positive rate of 2.3% for the ODST using a cut-off serum cortisol of 80 nM. DISCUSSION: The ODST is a valid screening test for Cushing's syndrome in the obese population. The false positive rate was 2.3%, even when using a strict cut-off serum cortisol of 80 nM. Abnormal cortisol suppression in obese patients should be investigated and not be considered false positive results.

A tale of two exposures: a comparison of two approaches to early clinical exposure.

PURPOSE: Early Clinical Exposure (ECE) programs are an increasingly widespread component of undergraduate medical education. Little systematic research exists on the topic. This report compares the approach and cost/benefits of two parallel ECE programs at the Sackler School of Medicine, Tel Aviv University. METHOD: The two ECE programs were compared using student questionnaires, faculty questionnaires, focus groups and participant-observations. RESULTS: ECE for American medical students in Israel was based upon a semi-structured mentoring relationship with a hospital-based specialist, in which students were able to practice interviewing skills. ECE for Israeli students emphasized structured exposure to a wide variety of primary care settings and informal patient contact. Both ECEs were supplemented by campus-based small group discussion. Students, preceptors and group leaders in both ECEs all reported very high levels of satisfaction and perceived impact on medical training. CONCLUSION: There appears to be no "best" way to conduct ECE. The ECE should be tailored to the specific needs and goals of the student population. Further research and international comparison is needed.

The effects of coffee consumption on sleep and melatonin secretion.

BACKGROUND: In this study we examined the effects of caffeine on sleep quality and melatonin secretion. Melatonin is the principal hormone responsible for synchronization of sleep. Melatonin secretion is controlled by neurotransmitters that can be affected by caffeine. METHODS: In the first part of the study, six volunteers drank either decaffeinated or regular coffee in a double-blind fashion on one day, and the alternate beverage 7 days later. Sleep parameters were assessed by actigraphy. In the second part of the study, the subjects again drank either decaffeinated or regular coffee, and they then collected urine every 3h for quantitation of 6-sulphoxymelatonin (6-SMT), the main metabolite of melatonin in the urine. RESULTS: We found that drinking regular caffeinated coffee, compared to decaffeinated coffee, caused a decrease in the total amount of sleep and quality of sleep, and an increase in the length of time of sleep induction. Caffeinated coffee caused a decrease in 6-SMT excretion throughout the following night. CONCLUSIONS: The results of our study confirm the widely held belief that coffee consumption interferes with sleep quantity and quality. In addition, we found that the consumption of caffeine decreases 6-SMT excretion. Individuals who suffer from sleep abnormalities should avoid caffeinated coffee during the evening hours.