Immunotherapy and whole-body hyperthermia as combined modality treatment of a subcutaneous murine sarcoma

Interleukin–2 and hyperthermia have been used individually to treat a variety of tumors in both experimental and human trials. Combined adoptive immunotherapy and hyperthermia is an exciting new line of investigation. Previous work in our laboratory has shown that combined local hyperthermia and rIL-2 therapy can significantly decrease the rate of tumor growth. In this study, we investigated the effect of combined whole-body hyperthermia (WBHT) and rIL-2 on the growth of subcutaneous MCA-105 murine tumors in C57BL/6 mice. Treatment of both microscopic (day 3) and macroscopic (day 10) tumors was evaluated. In the treatment of microscopic tumors, animals received either no treatment; rIL-2 (3 × 10⁵ IU ip tid) on days 3–7; plus WBHT(41°C for 30 min) on days 3, 5, and 7; or WBHT only on days 3, 5, and 7. In treating macroscopic tumors, animals received either no treatment; rIL-2 on days 10–14; plus WBHT on days 10, 12, and 14; or WBHT only on days 10, 12, and 14. While combined treatment and WBHT alone had no significant effect on the growth of microscopic tumors, combined IL-2 and WBHT significantly reduced the rate of tumor growth of macroscopic tumors. These results suggest that the tumor microenvironment plays a critical role in combined WBHT and rIL-2 therapy, and may be due to effects of WBHT on the tumor vasculature. © 1993 Wiley-Liss, Inc.     

Central opioid receptors differentially regulate the nalmefene-induced suppression of ethanol- and saccharin-reinforced behaviors in alcohol-preferring (P) rats.

The exact opioid-sensitive receptors participating in EtOH-seeking behaviors remains unclear. Previous studies have reported higher densities of micro-opioid receptor binding in the nucleus accumbens (NACC) of P relative to NP rats; however, no differences were seen in delta-receptor binding. In contrast to the NACC, substantially lower levels of micro-receptor binding have been observed in the ventral tegmental area (VTA) of both P and NP rats, albeit no line differences have been observed. In the present study, opioid receptors in the NACC, VTA, and hippocampus were evaluated for their capacity to regulate both EtOH- and saccharin-motivated behaviors in the genetically selected alcohol-preferring (P) rat. To accomplish this, nalmefene, an opiate antagonist with preferential binding affinity for the micro-opioid receptor was unilaterally or bilaterally infused during concurrent availability of 1 h daily EtOH (10% v/v) and saccharin (0.025 or 0.050% w/v) solutions. Rats performed under a two-lever fixed ratio (FR) schedule in which four responses on one lever produced the EtOH solution, and four on a second lever produced the saccharin solution. The results demonstrated that when responding maintained by both EtOH and saccharin are matched at basal levels, unilateral (1-60 microg) or bilateral (0.5-10 microg) microinjections of nalmefene into the NACC produced selective dose-dependent reductions on responding maintained by EtOH. Unilateral (40, 60 microg) and bilateral (10 microg) VTA infusions were also observed to selectively reduced EtOH responding; however, greater nalmefene doses were required and the magnitude of suppression on EtOH responding was markedly less compared with the NACC. The greater sensitivity of nalmefene to suppress EtOH responding in the NACC is likely due to the greater number of opioid receptors in the NACC relative to the VTA. Only bilateral infusion of the 40 microg dose in the NACC and VTA suppressed responding maintained by both EtOH and saccharin. In contrast, intrahippocampal infusions dose dependently suppressed EtOH- and saccharin-maintained responding over a range of doses (1-20 microg). The present study provides evidence that nalmefene suppresses EtOH-motivated behaviors via blockade of opioid receptors within the NACC and VTA, and under various dose conditions both reinforcer and neuroanatomical specificity can be observed.     

Crosslinking of fibrinogen and fibronectin by free radicals: a possible initial step in adhesion formation in osteoarthritis of the temporomandibular joint.

PURPOSE: Adhesion formation in osteoarthritis (OA) of the temporomandibular joint (TMJ) typically results in a sustained limitation of joint movement. We propose the hypothesis that free-radical-mediated crosslinking of proteins underlies this adhesion formation in affected joints. Free radicals may cause oxidative modification of proteins, creating an opportunity for the formation of intramolecular and intermolecular crosslinks via covalent bonds. This may stabilize protein aggregates, rendering them more resistant to degradation. In this study, the free-radical-mediated crosslinking of model proteins (fibrinogen and fibronectin) was investigated to test our hypothesis that free radicals contribute to adhesion formation via this mechanism in OA of the TMJ. MATERIALS AND METHODS: Physiological clot formation of fibrinogen by thrombin and free-radical-induced crosslinking of fibrinogen and of fibronectin were analyzed using spectrophotometric turbidity measurements, light-scattering techniques, polyacrylamide gel electrophoresis (PAGE), and rotary shadowing. RESULTS: Fibrinogen was shown to aggregate after free radical treatment, as detected using turbidity measurements and light-scattering techniques. Using PAGE, fibrinogen as well as fibronectin was shown to degrade under low oxidative stress. Under high oxidative stress, however, fragments from both proteins were found to be covalently crosslinked, resulting in high-molecular-weight protein aggregates. The aggregation was shown to be at random with rotary shadowing. CONCLUSION: The study shows that high oxidative stress contributes to the formation of crosslinked proteins that may serve as an initial scaffolding for the development of adhesions frequently seen in OA of the TMJ.     

Phenotype of endomyocardial biopsy-derived T-lymphocyte cultures and chronic rejection after heart transplantation

Chronic rejection (CR) is a major problem in long-term survival in heart transplantation. We analysed whether the occurrence of CR correlates with the incidence of acute rejections (AR) or with characteristics of endomyocardial biopsy-derived cell cultures. CR was diagnosed by annual angiography and defined as all coronary vascular changes. One year after transplantation 24 of the 63 patients had CR (38%). The incidence of AR in CR + and CR — patients was comparable. The patients in both groups had similar individual median percentages of EMB-yielding cell cultures. During the first year the CR — patients had more cultures in which at least 60% of the cells were CD4 + T cells (50% vs 37%, P = 0.05), due to a stronger CD4 predominance in the first 6 months. In the second year the CD4 predominance in the patients diagnosed as CR + after 1 year tended to be higher (P = 0.08). The patients had comparable percentages of cultures predominated by CD8 + T cells, γδ T cells or NK cells, irrespective of the time interval. These results might indicate that CD4 + T lymphocytes play a dual role in the aetiology of CR.     

Treatment of congenital cystic adenomatoid malformation-does resection in the early postnatal period increase surgical risk?

OBJECTIVE: The recent development of fetal ultrasonography has allowed for an increasing number of prenatal diagnoses for congenital cystic adenomatoid malformation (CCAM). However, the appropriate surgical timing of these patients has not been studied as of yet. The aim of this study is to suggest a safe strategy for the treatment of CCAM by identifying the relationship between the timing of surgery and postoperative outcome. METHODS: Between 1987 and 2003, 40 patients (28 males, 12 females) underwent surgical resection for CCAM. The mean age was 38.6+/-9.1 (2 days-13 years) months. CCAM was diagnosed by prenatal ultrasonography in eight patients. Early operations were performed in four out of the eight. Operation was deferred until 2-12 months of age for the remaining four patients. RESULTS: Type I CCAM was found in 20 patients, type II in 20 and no patient exhibited type III. Five patients had associated pectus excavatum anomaly. There were no cases of operative mortality. Seventeen minor postoperative complications developed in 16 patients (40.0%): prolonged chest tube drain in 10, wound infection in 4, and 1 case of pneumonia, empyema and pleural space, respectively. The average hospital stay was 11.8 (6-29) days. During the mean follow-up period of 67.5 months, one patient died of accidental aspiration 7 months after operation during the postoperative recovery course of Ravich operation for pectus excavatum. The remaining patients reported doing well with normal physical activity. All five patients who underwent surgery at the age of under 1 month did not exhibit increased postoperative morbidity. CONCLUSIONS: We concluded that surgery for CCAM could be safely performed in all age groups with satisfactory long-term outcomes. It is suggested that early elective surgical correction can be recommended for a patient whose diagnosis was made in utero.     

Safety of thrombolysis during cardiopulmonary resuscitation.

The prognosis is generally poor for patients who experience a cardiac arrest. The most common causes of sudden cardiac arrest are massive pulmonary embolism (PE) and acute myocardial infarction (MI). While thrombolysis is a first-line treatment option in massive PE and acute MI, cardiopulmonary resuscitation (CPR) has been regarded as a relative contraindication for thrombolysis because of the anticipated bleeding risk caused by traumatic cardiocompressions. However, an increasing number of case reports and clinical studies on thrombolysis during and after CPR highlight an increased frequency of the return of spontaneous circulation and a better neurological outcome of surviving patients. These effects are mainly due to the thrombolysis of macroscopic blood clots and the amelioration of microcirculatory reperfusion.This article reviews case reports and clinical studies of thrombolysis during and shortly after CPR in order to estimate the risk of severe bleeding events caused by CPR in association with thrombolysis compared with CPR without thrombolysis.Although thrombolysis per se can cause severe and potentially fatal haemorrhage, there is no evidence that severe bleeding events occur more often when thrombolysis is combined with cardiocompressions. In addition, by far the majority of bleeding complications can be treated effectively. Thus, in many cases, the possible benefit of thrombolysis during CPR seems to outweigh the potential risks. However, there may be a publication bias in some case reports and studies towards reporting successful rather than unsuccessful CPRs. In addition, not enough controlled clinical trials have yet been conducted. Therefore, data from large randomised, multicentre studies are needed to definitely answer the question of the relationship between safety and efficacy of this promising treatment option.We conclude that the currently available data do not indicate that thrombolysis contributes to a significant increase in bleeding complications when administered during CPR.     

123I-MIBG myocardial scintigraphy as a noninvasive screen for the diagnosis of coronary artery spasm

Background  It has been suggested that the sympathetic nervous system might play an important role in the development of coronary artery spasm. However, no cardiac imaging modality has been able to demonstrate abnormal sympathetic innervation in patients with coronary artery spasm. The purpose of this study was to assess the presence and location of abnormal sympathetic innervation using iodine 123-metaiodobenzylguanidine (¹²³I-MIBG) single photon emission computed tomography (SPECT) and to evaluate the clinical efficacy of ¹²³I-MIBG SPECT as a noninvasive screening test in patients with coronary artery spasm. Methods and Results  Coronary arteriography and a provocative test with intravenous administration of ergonovine maleate were performed in 26 patients (20 men, 6 women, mean age 48.2±12.0 years, range 20 to 67 years) who were suspected of having a coronary artery spasm. The subjects were divided into 2 groups: group 1 (n=18) comprised subjects with negative provocative provocative test result, and group 2 (n=8) comprised subjects with negative provocative test results. Ten healthy subjects served as controls. No abnormal MIBG uptake was observed in the control subjects. Abnormal sympathetic nervous innervation using ¹²³I-MIBG SPECT was observed either as a reduced uptake or a defective pattern in the perfused areas in 13 of the 18 regions supplied by vessels of ergonovine-induced vasospasm. Normal sympathetic innervation, as evidenced by normal ¹²³I-MIBG uptake, was noted in all of the 60 segments of normal vessel territories. Reduced uptake of ¹²³I-MIBG was not detected in the perfused areas of 5 vasospasm-induced vessels (perfusion territory of left anterior descending coronary artery [LAD] and the right coronary artery [RCA] in 2 and 3 patients, respectively). The sensitivity and specificity of ¹²³I-MIBG for detection of coronary artery spasm were 72.2% (95% confidence interval, [CI] 55% to 89%) and 100%, respectively. The positive predictive and negative predictive values were 100% and 92.3% (95% CI 91% to 93%), respectively. Conclusion   ¹²³I-MIBG SPECT is a feasible method to evaluate noninvasively and localize the territories of coronary arteries with spasm. Invasive diagnostic coronary arteriography with ergonovine provocation test may be unnecessary for diagnosis of coronary artery spasm in patients with typical resting pain, negative exercise test or normal thallium perfusion scan results, but showing abnormalities in ¹²³I-MIBG SPECT. Presented in part at the European Association of Nuclear Medicine Congress, September 1996, Copenhagen, Denmark.     

Effects of Fiber, Phytic Acid, and Oxalic Acid in the Diet on Mineral Bioavailability

Studies on effects of fiber, phytic acid, and oxalic acid on mineral bioavailability are reviewed. It is difficult to separate the effects of fiber and phytic acid when cereal products are fed, because they occur together in these foods. However, even the combination of fiber and phytic acid does not appear to affect mineral balances unless unrefined cereal intakes are high and mineral intakes are low. Also, the body may be able to adjust to the decreased availability by increased absorption of the available mineral. Oxalic acid may result in decreases in mineral bioavailability if consumed with a high fiber diet, but the decrease may also be transient.