Poly(methyl methacrylate) particles for local drug delivery using shock wave lithotripsy: In vitro proof of concept experiment.

To leverage current local drug delivery systems methodology, there is vast use of polymeric particles serving as drug carriers to assure minimal invasive therapy with little systemic distribution of the released drug. There is an increasing interest in poly(methyl methacrylate) (PMMA) serving as carriers in drug delivery. The study aims to develop PMMA carriers for localized drug delivery and release system, combining innovative biomaterial technology and shock wave lithotripsy (SWL), and to study the effect of SWL on various concentrations of PMMA particles. We prepared PMMA particles that contain horseradish peroxidase (HRP) using a double emulsion technique, and investigated the mechanism of in vitro drug release from the carriers following exposure to SWL. We investigated the correlation between production method modifications, concentrations of the carriers subjected to SWL, and shock wave patterns. We successfully produced PMMA particles as drug carriers and stimulated the release of their contents by SWL; their polymeric shell can be shattered externally by SWL treatment, leading to release of the encapsulated drug. HRP enzyme activity was maintained following the encapsulation process and exposure to high dose of SWL pulses. Increased shock wave number results in increased shattering and greater fragmentation of PMMA particles. The results demonstrate a dose-response release of HRP; quantitation of the encapsulated HRP from the carriers rises with the number of SWL. Moreover, increased concentration of particles subjected to the same dose of SWL results in a significant increase of the total HRP release. Our research offers novel technique and insights into new, site-specific drug delivery and release systems.

Physical exercise enhances hepatic insulin signaling and inhibits phosphoenolpyruvate carboxykinase activity in diabetes-prone Psammomys obesus.

We have shown that physical exercise enhances insulin sensitivity of skeletal muscle in diabetes-prone Psammomys-obesus. In this study, we examined the effect of physical exercise on the liver of these animals. Three groups of animals were exposed to a 4-week protocol; high-energy diet (CH), high-energy diet and exercising (EH), and low-energy diet (CL). Different groups were studied either in a fed state or after an overnight fast, 30 minutes after intraperitoneal (IP) injection of 1 U insulin. Hepatic phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) activity was measured. Insulin signaling response was examined after insulin injection in the fast state by analyzing tyrosine phosphorylation of insulin receptor (IR) and the association between insulin receptor substrate-1 (IRS-1) and IRS-2 with phosphatidylinositol 3 kinase (PI3-K). After 4 weeks, none of the EH animals became diabetic, whereas all the CH animals became diabetic. PEPCK activity in the fed state was higher in the CH group compared with the CL and EH groups (480 +/- 28 nmol/min/mg protein, 280 +/- 30 nmol/min/mg protein, and 208 +/- 13 nmol/min/mg protein, respectively) (P < .02). G6Pase activity was higher in the CH and EH groups compared with the CL group (261 +/- 54 nmol/min/mg protein, 251 +/- 34 nmol/min/mg protein, and 75 +/- 32 nmol/min/mg protein, respectively) (P < .01). After insulin administration in the fast state, tyrosine phosphorylation of IR and association of IRS-2 with PI3-K were higher in the EH and CL groups than in the CH group. We conclude that exercise improves in vivo hepatic insulin sensitivity in diabetes-prone Psammomys-obesus.

The "golden hour" for heatstroke treatment.

Exertional heatstroke is a life-threatening event. It occurs mainly among the young healthy populations of athletes and soldiers. The severity of exertional heatstroke is directly correlated to the area under the temperature duration curve. Therefore, rapid cooling in the field has an enormous effect on prognosis. Four cases of exertional heatstroke are presented which differ in their outcome. We argue that there is a "window time period" within which simple and effective cooling techniques can determine prognosis.

Liver transplantation in exertional heat stroke: a medical dilemma.

BACKGROUND: Exertional heat stroke (EHS) is a life-threatening condition caused by an extreme elevation in core body temperature. Hepatic involvement is one of the hallmarks of heat stroke, affecting nearly all heat stroke patients. It is usually manifested by increased serum levels of liver enzymes, but acute liver failure has also been reported. Liver transplantation has been proposed as a potential treatment in cases of severe liver failure, but there are no unanimous criteria pointing to the right stage in which to conduct the transplantation. CASE PRESENTATION: We report a case of an 18-year old patient who suffered heat-induced liver failure. The patient was referred for orthotopic liver transplantation (OLT) but spontaneously recovered completely with conservative treatment. CONCLUSIONS: This case demonstrates the complexity of the decision for liver transplantation in EHS. The various prognostic criteria of acute hepatic failure and their relevance to EHS are critically reviewed, with an aim to assess their application for such a condition.

Hydration status measurement by radio frequency absorptiometry in young athletes--a new method and preliminary results.

A new method for non-invasive measurement of the human state of hydration is presented. This method is based on frequency-dependent absorptiometry of radio-waves passing through tissues. A device utilizing this method was constructed and applied to 12 young (24 +/- 1) male volunteers, who were dehydrated for 1-2.5% of their weight by performance of a physical effort (two 30 min bouts of treadmill walking/running at 2, 3, 4, 5, 6 and 7 mph, 5 min at each speed, separated by 10 min rest), under moderate heat stress (40 degrees C, 40% RH). Hypohydration level was determined by body weight measurements taken before each session, after 30 min and at the end of each session. Concomitantly, measurements of radio frequency (RF) absorption were taken. Each volunteer underwent the heat stress exercise twice: one in which no drinking was permitted, and another with free drinking. A correlation (R2 = 0.734) between weight loss and a change in the radio-waves absorption pattern was observed in most of the volunteers, in both hypo and euhydration sessions. Further work to establish the reproducibility and validity of the RF methodology in larger and different populations, i.e., females, other age groups and different health conditions, is already being researched.

Physical exercise enhances protein kinase C delta activity and insulin receptor tyrosine phosphorylation in diabetes-prone psammomys obesus.

We recently reported that physical exercise prevents the progression of type 2 diabetes mellitus in Psammomys obesus, an animal model of nutritionally induced type 2 diabetes mellitus. In the present study we characterized the effect of physical exercise on protein kinase C delta (PKC delta) activity, as a mediator of the insulin-signaling cascade in vivo. Three groups of Psammomys obesus were exposed to a 4-week protocol: high-energy diet (HE/C), high-energy diet and exercise (HE/EX), or low-energy diet (LE/C). None of the animals in the HE/EX group became diabetic, whereas all the animals in the HE/C group became diabetic. After overnight fast, intraperitoneal (IP) insulin (1U) caused a greater reduction in blood glucose levels in the HE/EX and LE/C groups compared to the HE/C group. Tyrosine phosphorylation of insulin receptor (IR), insulin receptor substrate-1 (IRS-1), and phosphatidylinositol 3 kinase (PI3 kinase) was significantly higher in the HE/EX and LE/C groups compared with the HE/C group. Finally, IR-associated PKC delta was higher in the HE/EX and LE/C groups compared to the HE/C group. Coprecipitation of PKC delta with IR was higher in the HE/EX and LE/C groups compared to the HE/C group. Thus, we suggest that 4 weeks of physical exercise results in improved insulin-signaling response in Psammomys obesus accompanied by a direct connection between PKC delta and IR. We conclude that this mechanism may be involved in the preventive effect of exercise on type 2 diabetes mellitus in Psammomys obesus.

Plasma antioxidant status and cell injury after severe physical exercise.

Strenuous exercise leads to an increase in metabolic rate, increased production of reactive oxygen species, and compromised antioxidant defense systems. To study the effects of oxidative stress during strenuous exercise, a homogeneous group of 31 male subjects participated in a 6-month, 5 days/week training schedule involving two extreme marches of 50 km and 80 km at sea level, separated by 2 weeks of regular training. Each participant carried 35 kg of extra weight. Blood samples were drawn immediately before and after each march. Twenty-nine subjects completed the 50-km march, and only 16 completed the 80-km march. Plasma levels of reduced ascorbic acid, total ascorbate, and dehydroascorbate did not undergo significant changes during either march. However, the 50- and 80-km marches led to 25% and 37% increases, respectively, in plasma levels of uric acid; due presumably to increases in the metabolic rate and consequent pyrimidine nucleotide metabolism. Both marches led to an approximately 10-fold increase leakage of creatine phosphokinase into the plasma. Likewise, plasma levels of aspartate transaminase, a characteristic marker of liver injury, increased approximately 4-fold. Plasma levels of bilirubin, creatine, urea, and glucose also increased. Plasma protein carbonyl content, a marker of protein oxidative damage, decreased significantly during each march. These results are discussed with respect to the consideration that elevation of the respiration rate during exercise leads to production of more reactive oxygen species than the antioxidant systems can scavenge. Plausible explanations for leakage of molecules into the plasma are discussed.

Hypothermia and local cold injuries in combat and non-combat situations--the Israeli experience.

INTRODUCTION: Cold weather has been recognized in the Israel Defense Forces (IDF) as a potential medical and operational threat to the soldier. Although regulations have been issued to cope with this situation, every year about 20 cases of hypothermia (T(core) < 35 degrees C) and peripheral cold injuries are reported. METHODS: This study was aimed at following cold weather injuries (CI) in the IDF in the period 1994-2001. 136 cases were reported to our institute during this period. All patients were from the general population of young (20 +/- 2 yr), male soldiers in the IDF. All were classified a priori as healthy, active subjects. RESULTS: Of these patients, 51% were diagnosed with mild hypothermia and 49% with peripheral CI. Among those soldiers who suffered from peripheral CI, less than 5% were diagnosed with frostbite. Most of the cases (76%) occurred in the winter months; however, 10% occurred in the spring, 13% in autumn, and 2 cases (1%) were reported in the summer. The majority of all CI cases occurred during routine scheduled training (51%), and 15% occurred during routine duties. Of the cases, 34% occurred during combat operations (mainly ambushing and surveillance). DISCUSSION: The present study provides data on CI cases in an army where the awareness of the hazards involved in hostile environments is extensive, and in which detailed regulations aimed to prevent these injuries are common practice. The Israeli experience indicates that CI is preventable in most instances by following a few simple regulations and providing proper education to the soldiers and their commanding officers.

[Multi-organ failure in a young soldier: a clinical-pathological meeting].

This clinical-pathological conference took place at the Sourasky Medical Center, Tel Aviv, on February 21, 2001. We present the case of a young and previously healthy soldier who developed multi-organ failure with predominant liver dysfunction following exertional heatstroke. The patient's clinical course consisted of an early phase of transient encephalopathy, associated with hyperthermia, hypophosphatemia, mild laboratory indications of renal failure, rhabdomyolysis and consumption coagulopathy. Following an intermediate convalescing phase that lasted a single day the patient deteriorated into a catastrophic course with hemodynamic instability, fulminant hepatic failure, respiratory distress, kidney failure, rhabdomyolysis, coagulopathy and coma. He died 4 days later. In this article we elaborate on the association of heatstroke with multiple organ dysfunction syndrome in general, and fulminant liver failure in particular. The nature of hypophosphatemia and the possible role of additional injury from acetaminophen are discussed.

Physical exercise prevents the development of type 2 diabetes mellitus in Psammomys obesus.

We hypothesized that exercise training might prevent diabetes mellitus in Psammomys obesus. Animals were assigned to three groups: high-energy diet (CH), high-energy diet and exercise (EH), and low-energy diet (CL). The EH group ran on a treadmill 5 days/wk, twice a day. After 4 wk, 93% of the CH group were diabetic compared with only 20% of the EH group. There was no difference in weight gain among the groups. Both EH and CH groups were hyperinsulinemic. Epididymal fat (% of body weight) was higher in the CH group than in either the EH and or the CL group. Protein kinase C (PKC)-delta activity and serine phosphorylation were higher in the EH group. No differences were found in tyrosine phosphorylation of the insulin receptor, insulin receptor substrate-1, and phosphatidylinositol 3-kinase among the groups. We demonstrate for the first time that exercise training effectively prevents the progression of diabetes mellitus type 2 in Psammomys obesus. PKC-delta may be involved in the adaptive effects of exercise in skeletal muscles that lead to the prevention of type 2 diabetes mellitus.