Lactate turnover in rat glioma measured by in vivo nuclear magnetic resonance spectroscopy

Elevated tissue lactate concentrations typically found in tumors can be measured by in vivo nuclear magnetic resonance (NMR) spectroscopy. In this study, lactate turnover in rat C6 glioma was determined from in vivo 1H NMR measurements of [3-13C]lactate buildup during steady-state hyperglycemia with [1-13C]glucose. With this tumor model, a narrow range of values was observed for the first-order rate constant that describes lactate efflux, k2 = 0.043 +/- 0.007 (n = 12) SD min-1. For individual animals, the standard error in k2 was small (< 18%), which indicated that the NMR data fit the kinetic model well. Lactate measurements before and after infusing [1-13C]glucose showed that the majority of the tumor lactate pool was metabolically active. Signals from 13C-labeled glutamate in tumors were at least 10-fold smaller than the [3-13C]lactate signal, whereas spectra of the contralateral hemispheres revealed the expected labeling of [4-13C]glutamate, as well as [2-13C] and [3-13C]glutamate, which indicates that label cycled through the tricarboxylic acid cycle in the brain tissue. Lack of significant 13C labeling of glutamate was consistent with low respiratory metabolism in this glioma. It is concluded that lactate in rat C6 glioma is actively turning over and that the kinetics of lactate efflux can be quantified noninvasively by 1H NMR detection of 13C label. This noninvasive NMR approach may offer a valuable tool to help evaluate tumor growth and metabolic responsiveness to therapies.     

Attachment staining: a novel method for flow cytometric quantitation of protein expression in limited numbers of adherent cells

Malignant tumors are known to exhibit high rates of glycolytic activity leading to high production of lactic acid. Hence, neoplastic cells have elevated activity of enzymes responsible for glycolysis. Echitamine chloride, an indole alkaloid extracted from the bark of Alstonia scholaris, has been reported to have a highly promising anticancer activity against fibrosarcoma in rats. In the present study, the effect of echitamine chloride on energy metabolism of S-180 cells is investigated to have a better understanding on the mode of action of echitamine chloride. The effect of echitamine chloride on the mitochondrial and cellular respiration of S-180 cells was studied. Also, the effects on glucose utilization, pyruvate utilization and lactate formation were studied on whole S-180 cells and S-180 cell-free homogenate. The levels of glycolytic enzymes such as hexokinase and lactate dehydrogenase were estimated in which particular emphasis has been laid on hexokinase which occurs both in cytosolic and particulate forms in neoplastic cells. Hence the differential effect of echitamine chloride on the levels of total, cytosolic and particulate hexokinase has been investigated. In conclusion, echitamine chloride affects both cellular and mitochondrial respiration, leading to reduction of the cellular energy pool and thereby resulting in the loss of viability of S-180 cells.     

Lymphoma of the skin. A comparative clinico-pathologic study of 50 cases including mycosis fungoides and primary and secondary cutaneous lymphoma

A clinico-pathologic study of lymphomas of the skin included 14 cases of mycosis fungoides, 14 of primary lymphoma and 22 of secondary lymphoma. Mycosis fungoides has clinical and histopathologic features which allow for separation from the other groups. In this study, patients with mycosis fungoides had a longer duration of history and presented with papules, plaques, erythroderma or generalized dermatitis but not with tumor nodules ab initio. A confident histologic diagnosis required the presence of the mycosis cell, which was usually present in association with a mixed inflammatory cell infiltrate. Another important histologic feature was the presence of invasion of the epidermis by the mycosis cells singly and/or in nests (Pautrier microabscesses). Primary and secondary lymphomas of the skin presented clinically as multiple tumor nodules and histologically as a monomorphic infiltrate of neoplastic cells confined to the dermis and subcutis. A feature which has not been adequately documented in a large series was the presence of an associated prominent epithelioid cell reaction in several cases from all three groups.     

Papillary and follicular thyroid carcinomas with an insular component

BACKGROUND: Papillary (PC) and follicular (FC) thyroid carcinomas may have a focal or predominant insular component (IC). This study correlates histologic behavior with the extent of the IC of these tumors. METHODS: Forty-one thyroid carcinomas (17 follicular variants [FV] of PC, 24 FC) with focal or predominant IC were reviewed. The tumors were stained with carcinoembryonic antigen, thyroglobulin, and calcitonin. DNA ploidy analysis was done on 18 tumors on paraffin-embedded tissue. The IC was correlated with age, stage of disease, follow-up, and ploidy analysis by Fisher's exact two-tailed test. RESULTS: No tumor was purely insular. IC was minor (10-40% tumor area) in 16 and predominant (50-90%) in 25. Nuclear features in IC included typical FC nuclei in 14, FVPC nuclei in 16, and intermediate-type nuclei in 16 tumors. Vascular invasion was seen in 22, necrosis in 10, and sclerotic stroma in all. Fourteen tumors were confined to the thyroid, 13 showed regional spread, and 9 had distant metastases; five patients are dead of disease and six are alive with disease. Thirteen tumors were diploid, three tetraploid, and two hyperdiploid aneuploid. There was no correlation of quantity of IC with tumor stage, follow-up status, or ploidy. CONCLUSION: IC within PC and FC does not adversely affect prognosis.     

Multivoxel proton MR spectroscopy and hemodynamic MR imaging of childhood brain tumors: preliminary observations

PURPOSE: To assess multivoxel proton MR spectroscopy combined with MR imaging and hemodynamic MR imaging in the evaluation of brain tumors in children and young adults. METHODS: Fifteen patients with brain tumors and 10 healthy children underwent MR imaging and MR spectroscopy on a 1.5-T system. Ten patients with tumors had both MR spectroscopy and hemodynamic MR imaging. MR spectroscopy data sets with 1 cm3 to 3.4 cm3 resolution were acquired within 8.5 minutes by using a point-resolved spectroscopic, chemical-shift imaging technique in two dimensions with volume preselection. MR imaging was performed using fast spin-echo techniques. Hemodynamic MR imaging data were acquired every 2.5 seconds at one anatomic level using a spoiled gradient-echo sequence during intravenous bolus administration of contrast material. RESULTS: Assessment with multivoxel MR spectroscopy and hemodynamic MR imaging added about 30 minutes to the total MR examination time. Normal tissue exhibited spectral peaks from biologically significant compounds such as N-acetylaspartate (NAA), choline-containing compounds (Cho), and total creatine (tCr). Twelve biopsy-proved tumors exhibited prominent Cho, reduced NAA, variable tCr, and/or lactate or lipids, and two showed increased hemodynamic parameters. Three of the tumors treated with radiation did not reveal prominent levels of Cho. Tissue necrosis had no Cho, NAA, or tCr, and reduced hemodynamics. CONCLUSIONS: Preliminary findings by MR spectroscopy combined with MR imaging and hemodynamic MR imaging suggest that regions of active tumor may be differentiated from areas of normal tissue and areas of necrosis. These findings may enable metabolic and hemodynamic characterization of childhood brain tumors as well as suggest their response to therapy.     

Interleukin (IL)-1beta increases glucose uptake and induces glycolysis in aerobically cultured rat ovarian cells: evidence that IL-1beta may mediate the gonadotropin-induced midcycle metabolic shift

This communication explores the possibility that interleukin (IL)-1beta, a putative intermediary in the ovulatory process, may take part in the gonadotropin-driven midcycle diversion of ovarian carbohydrate metabolism toward glycolysis. We examined the effect of treatment with IL-1beta on glucose metabolism in aerobically cultured whole ovarian dispersates from immature rats. Treatment with IL-1beta increased cellular glucose consumption/uptake, stimulated extracellular lactate accumulation and media acidification, and decreased extracellular pyruvate accumulation in a receptor-mediated, time-, dose- and cell density-dependent manner. Endogenous IL-1beta-like bioactivity was shown to mediate the ability of gonadotropins to exert these same metabolic effects. The IL-1beta effect was also (1) apparent over a broad range of glucose concentrations, inclusive of the putative physiological window; (2) relatively specific, because tumor necrosis factor-alpha and insulin were inactive; (3) contingent upon cell-cell cooperation (4) and reliant on de novo protein synthesis. Comparison of the molar ratios of lactate accumulation to glucose consumption in IL-1beta-replete vs. IL-1beta-deplete cultures suggests that IL-beta promotes the conversion of all available glucose to lactate but that other substrates for lactate production may also exist. However, no lactate was generated by cells grown under glucose-free conditions. Taken together, our data suggest that IL-1beta may act as a metabolic hormone in the ovary. Subject to the limitations of the in vitro paradigm, our data also suggest that IL-1beta may mediate the gonadotropin-associated midcycle shift in ovarian carbohydrate metabolism. By converting the somatic ovarian cells into a glucose-consuming glycolytic machinery, IL-1beta may establish glycolysis as the main energy source of the relatively hypoxic preovulatory follicle and the resultant cumulus-oocyte complex. The consequent oxygen sparing may conserve the limited supply of oxygen needed for vital biosynthetic processes such as steroidogenesis. This adaptational response may also provide the glycolytically incompetent oocyte with the obligatory tricarboxylic cycle precursors it depends on to meet the increased energy demands imposed upon it by the resumption of meiosis.     

Symmetric cutaneous necrosis of the hind feet and multicentric follicular lymphoma in a cat

A 7-year-old castrated male domestic shorthair cat was admitted to the veterinary teaching hospital for evaluation of symmetric necrosis of the skin of its hind feet and high liver enzyme activities. Lymphoma was diagnosed on cytologic examination of a fine needle aspirate of the liver. The owner declined treatment for the lymphoma. On postmortem histologic examination, lymphoma was found in the liver, stomach, and multiple lymph nodes. Immunohistochemical staining revealed the neoplasm to have a mixed B- and T-cell follicular arrangement, and a diagnosis of multicentric follicular lymphoma was made. The distal portion of the feet were necrotic, but a neoplastic infiltrate was not seen on histologic examination. After thrombosis and vasculitis were excluded as causes, the ischemic necrosis of the feet of the cat in this report was considered a paraneoplastic syndrome, as can be seen in people with lymphoma or other internal malignancies.     

31P magnetic resonance spectroscopy as predictor of clinical response in human extremity sarcomas treated by single dose TNF-alpha + melphalan isolated limb perfusion

Irresectable extremity sarcomas are large (grade II/III) tumors requiring amputation of the limb for local control. Limb salvage can be achieved by isolated limb perfusion (ILP) with tumor necrosis factor alpha (TNF-alpha), interferon-gamma and melphalan. To obtain insight into the effects of single dose ILP on extremity tumors, phosphate metabolism was monitored by 31P magnetic resonance spectroscopy (MRS) using the chemical shift imaging (CSI) technique. 2D CSI was used in combination with a slice select gradient in the third dimension to obtain true 3D localization. Spectral maps obtained prior to ILP revealed reductions in phosphocreatine (PCr) level and increases in phosphomonoester (PME) and phosphodiester (PDE) in tumor compared with muscle tissue. ILP treated tumors showed highly divergent changes in Pi while PME decreased in all cases (n = 11). Tumor volume, unchanged on day 8 after ILP, was decreased by 58 +/- 29% (mean +/- SD) at 2 months. Linear regression analysis revealed correlation between the changes in tumor metabolites measured on day 8, with percent volume decrease (Pi: r = -0.88, p < 0.001) and percent necrosis at resection (PME: r = -0.79, p -0.01). Correlation between pretreatment spectra and effectiveness of ILP treatment was not found. It is concluded that a single ILP with TNF-alpha + melphalan induced changes in tumor metabolite levels (measured on day 8) that reflect treatment efficacy. 31P MRS can thus provide information facilitating the decision as to when to remove tumor (residue) and, in the case where tumor remains inoperable, whether or not to apply additional therapy.     

Impairment of muscle energy metabolism in patients with sleep apnoea syndrome

Impairment of muscle energy metabolism has been demonstrated in normal subjects with chronic hypoxaemia (altitude chronic respiratory failure). The purpose of this study was to verify the hypothesis that a comparable condition could develop in patients with sleep apnoea syndrome (SAS), considering that they are exposed to prolonged and repeated hypoxaemia periods. Muscle metabolism was assessed in 11 patients with SAS performing a maximal effort on cycloergometer. In comparison with normal subjects, SAS patients reached lower maximal loads [144 +/- 7 vs. 182 +/- 10 W (P < 0.005)] and lower peak oxygen uptakes [26.4 +/- 1.2 vs 33.2 +/- 1.4 ml kg-1 min-1 (P < 0.005)]. Abnormal metabolic features were found: maximal blood lactate concentration was significantly lower than in normal subjects [0.034 +/- 0.004 vs. 0.044 +/- 0.002 mmol l-1 W-1 (P < 0.05)]; and lactate elimination rate, calculated during a 30-min recovery period, was reduced [0.127 +/- 0.017 vs, 0.175 +/- 0.014 mmol l-1 min-1 (P < 0.025)]. The extent of these anomalies correlated with the severity of SAS. The patients also showed higher maximal diastolic blood pressures than normal subjects [104 +/- 5 vs. 92 +/- 4 mmHg (P < 0.05)]. These results can be interpreted as indications of an impairment of muscle energy metabolism in patients with SAS. Decrease in maximum blood lactate concentration suggests an impairment of glycolytic metabolism, while decrease in the rate of lactate elimination indicates a defect in oxidative metabolism. Since no respiratory pathology apart from SAS was found in this group of patients, it seems legitimate to link the genesis of these impairments to repeated bouts of nocturnal hypoxaemia.     

The role of magnetic resonance spectroscopy in the investigation of lactic acidosis and inborn errors of energy metabolism

Magnetic resonance spectroscopy (MRS) provides a non-invasive method of investigating disordered energy metabolism in vivo. Here, we briefly outline some MRS studies of skeletal muscle and brain metabolism that have been carried out in patients with inborn errors of energy metabolism. We concentrate in particular on the use of 1H MRS for the detection of elevated brain lactate in these patients.     

Contribution of glycogen and exogenous glucose to glucose metabolism during ischemia in the hypertrophied rat heart

Although hypertrophied hearts have increased rates of glycolysis under aerobic conditions, it is controversial as to whether glucose metabolism during ischemia is altered in the hypertrophied heart. Because endogenous glycogen stores are a key source of glucose during ischemia, we developed a protocol to label the glycogen pool in hearts with either [3H]glucose or [14C]glucose, allowing for direct measurement of both glycogen and exogenous glucose metabolism during ischemia. Cardiac hypertrophy was produced in rats by banding the abdominal aorta for an 8-week period. Isolated hearts from aortic-banded and sham-operated rats were initially perfused under substrate-free conditions to decrease glycogen content to 40% of the initial pool size. Resynthesis and radiolabeling of the glycogen pool with [3H]glucose or [14C]glucose were accomplished in working hearts by perfusion for a 60-minute period with 11 mmol/L [3H]glucose or [14C]glucose, 0.5 mmol/L lactate, 1.2 mmol/L palmitate, and 100 mumol/mL insulin. Although glycolytic rates during the aerobic perfusion were significantly greater in hypertrophied hearts compared with control hearts, glycolytic rates from exogenous glucose were not different during low-flow ischemia. The contribution of glucose from glycogen was also not different in hypertrophied hearts compared with control hearts during ischemia (1314 +/- 665 versus 776 +/- 310 nmol.min-1.g dry wt-1, respectively). Glucose oxidation rates decreased during ischemia but were not different between the two groups. However, in both hypertrophied and control hearts, the ratio of glucose oxidation to glycolysis was greater for glucose originating from glycogen than from exogenous glucose. Our data demonstrate that glycogen is a significant source of glucose during low-flow ischemia, but the data do not differ between hypertrophied and control hearts.     

Changes of sex hormone levels in patients with hepatitis B virus-related postnecrotic cirrhosis: relationship to the severity of portal hypertension

The purpose of this study was to develop a model in which the regional pharmacokinetics of a drug in tumor and nontumorous tissue could be evaluated under a variety of physiological conditions. To this effect, the growth of a human choriocarcinoma cell line (JAR) was evaluated in pigs immunosuppressed with 25 mg cyclosporine/kg every 24 h. During an initial study, we demonstrated that suspensions containing approximately 3 million JAR cells with and without 1 million normal human fibroblasts injected s.c. into the inguinal region of pigs resulted in the growth of tumors consisting primarily of polygonal neoplastic cells. Multinucleate tumor cells, inflammatory cells, necrotic debris, and vascular endothelial cells were also present. Maximal tumor size was noted on day 12, after which time tumor regression occurred. The coinoculation of fibroblasts resulted in significantly larger tumors. Two single pedicle, axial pattern tubed flaps were created in the inguinal area of 4 pigs. JAR cells and fibroblasts were transplanted to one flap to allow for tumor formation. The other flap served as a nontumorous control. Both flaps were removed for perfusion with a physiological solution 11 days later. Glucose utilization, lactate concentrations, lactate dehydrogenase activities, and microscopic evaluation of skin samples were used to assess flap viability. All flaps remained viable for 8 h of perfusion. The only differences detected between nontumorous and tumor flaps was the initial perfusion pressure which was significantly lower in tumor flaps (P < 0.05). The isolated perfused tumor and skin flap is unique in that it consists of a tumor surrounded by normal tissue with an intact microvascular system and can be utilized to design regional pharmacokinetic studies describing drug distribution in tumor tissue.     

Lactate release and uptake in hepatoma 7288CTC perfused in situ with L-[(U)-14C]lactate or D-[(U)-14C]glucose

Arteriovenous differences (AVD) for glucose and lactic acid measured across tissue-isolated rat tumors in vivo have shown that individual tumors with similar rates of glucose consumption may either release or utilize lactic acid. The experiments described here investigated the relationships among arterial blood lactate concentrations and tumor lactate and glucose balances. AVDs for lactate, pyruvate, glucose, 14CO2, PO2, PCO2, pH, and lactate specific activities were measured across 17 tissue-isolated 7288CTC hepatomas perfused in situ with arterial blood containing 2.5 to 14.4 mmol/L lactate and either L-[(U)-14C]lactic acid or D-[(U)-14C]glucose. Measurements were made over a range of blood flow rates from 60% to 200% of the mean in vivo rate, 0.11 mL/min. Data collected during steady states were compared by regression analysis. Tumor lactate balance and the arterial blood lactate concentration were directly related (r = .895, n = 22, P < .01). Net negative and positive balances occurred below and above approximately 6.5 mmol/L arterial blood lactate, respectively. The mean intratumor lactate concentration for all tumors was 6.9 +/- 1.0 mmol/L (mean +/- SD, n = 13). Rates of 14C-lactate oxidation to 14CO2 (r = .716, n = 18, P < .01) and tumor venous/arterial blood 14C-lactate specific activity ratios (r = .845, n = 19, P < .01) were low during lactate release and were increased during lactate uptake. Total arterial blood lactate removal estimated from chemical and isotopic analyses was 23.1% +/- 11% and 43.0% +/- 16% (P < .05), respectively, for six lactate-utilizing tumors. Perfusions performed with 14C-glucose showed that approximately 50% of the glucose consumed during net negative lactate balance was released as 14C-lactate to the tumor venous blood, whereas only 5% was released as 14C-lactate during net positive lactate balance. The data support the following conclusions: Arterial blood lactate controls net lactate balance in solid tumors; high concentrations increase uptake. Lactate uptake inhibits lactate formation from glucose without changing the glucose balance. Lactate is release during net lactate uptake. Since lactate uptake may exceed glucose uptake, arterial blood lactate can be a substrate for tumor energy metabolism and growth.     

Lactate is released and taken up by isolated rabbit vagus nerve during aerobic metabolism

To determine if lactate is produced during aerobic metabolism in peripheral nerve, we incubated pieces of rabbit vagus nerve in oxygenated solution containing D-[U-14C]glucose while stimulating electrically. After 30 min, nearly all the radioactivity in metabolites in the nerve was in lactate, glucose 6-phosphate, glutamate, and aspartate. Much lactate was released to the bath: 8.2 pmol (microg dry wt)(-1) from the exogenous glucose and 14.2 pmol (microg dry wt)(-1) from endogenous substrates. Lactate release was not increased when bath PO2 was decreased, indicating that it did not come from anoxic tissue. When the bath contained [U-14C]lactate at a total concentration of 2.13 mM and 1 mM glucose, 14C was incorporated in CO2 and glutamate. The initial rate of formation of CO2 from bath lactate was more rapid than its formation from bath glucose. The results are most readily explained by the hypothesis that has been proposed for brain tissue in which glial cells supply lactate to neurons.     

Sequential observations of brain edema with proton magnetic resonance imaging and spectroscopy

The purpose of this study was to assess the relationship between morphological and metabolic changes in brain edema using proton magnetic resonance systems. The serial changes during the first 24 hours in the cold-injury trauma rat brain model were investigated by proton magnetic resonance imaging (1H MRI) and high-resolution proton MR spectroscopy (1H MRS). We also analyzed the efficacy of AVS 1,2-bis (nicotinamide)-propane which can scavenge free radicals to the edema in this experiment. The edema was developing extensively via the corpus callosum in ipsi- and contralateral hemispheres as shown by gradually increased signal intensity on 1H MRI. 1H MRS initially showed accumulation of acetate and lactate, and transient increasing of glutamine. After 24 hours, the increased glutamine decreased below the control, alanine increased, and N-acetyl asparatate decreased with the edema development. AVS-treatment significantly suppressed edema development, increases of lactate and alanine and decreases of N-acetyl asparatate. We suggest that the cold-induced lesion contains anaerobic glycolysis deterioration and results in severe brain tissue breakdown. AVS is proved valuable for the treatment of this edema lesion. Clinical 1H MRS showed prolonged lactate elevation and significant decreases of other metabolites in human ischemic stroke edema. In peritumoral edema, decreased N-acetyl asparatate gradually improved, and slightly elevated lactate disappeared after tumor removal. 1H MRS feasibly characterizes the ischemic and peritumoral edema and makes a quantitative analysis in human brain metabolism. We believe the combined 1H MRI and MRS study is a practical method to monitor the brain conditions and will make it easy and possible to find new therapeutic agents to some brain disorders.     

Requirement of glycolytic substrate for metabolic recovery during moderate low flow ischemia

Low flow ischemia with stable hemodynamic function can result in partial metabolic recovery characterized by an increase in phosphocreatine (PCr). Prior data suggest that glycolytic production of adenosine triphosphate (ATP) may be critical for this recovery and that the ATP produced by oxidative phosphorylation alone may be insufficient. This study tested the hypotheses that, during moderate low flow ischemia, (a) metabolic recovery is dependent on glycolytic production of ATP, and, therefore, (b) a mitochondrial substrate such as pyruvate alone is inadequate to allow metabolic recovery. High energy phosphates, pH, and lactate release were measured during 2 h of moderate low flow ischemia. Hearts were perfused with either a glycolytic plus mitochondrial substrate (glucose, insulin and pyruvate) or a mitochondrial substrate alone (pyruvate). Flow reductions required to reduce PCr by approximately 8% resulted in stable and equal reductions of rate-pressure product in each group. PCr recovered fully during the ischemic period in control hearts with glycolytic substrate, associated with preservation of normal end-diastolic pressure, and increased lactate release during the first hour of ischemia. Reperfusion of these hearts restored hemodynamic function and increased PCr above baseline values. In contrast, the use of pyruvate alone as a substrate resulted in a progressive fall of PCr during ischemia, increased end-diastolic pressure, and no significant increase in lactate release. Reperfusion in these hearts restored hemodynamic function, but did not result in normalization of PCr. Both groups had significant reductions in ATP during ischemia. Recovery of PCr during ongoing moderate low flow ischemia is observed in the presence of mixed glycolytic and mitochondrial substrates (glucose, insulin and pyruvate) but is not observed with pyruvate as a sole mitochondrial substrate. These data support a critical role for glycolytic flux under these conditions, suggesting that ATP generated solely by oxidative phosphorylation is not sufficient to promote metabolic recovery or maintain diastolic function during moderate low flow ischemia.     

Threshold increases in plasma growth hormone in relation to plasma catecholamine and blood lactate concentrations during progressive exercise in endurance-trained athletes

Plasma human growth hormone ([HGH]), adrenaline ([A]), noradrenaline ([NA]) and blood lactate ([La-](b)) concentrations were measured during progressive, multistage exercise on a cycle ergometer in 12 endurance-trained athletes [aged 32.0 (SEM 2.0) years]. Exercise intensities (3 min each) were increased by 50 W until the subjects felt exhausted. Venous blood samples were taken after each intensity. The [HGH] and catecholamine concentrations increased negligibly during exercise of low to moderate intensities revealing an abrupt rise at the load corresponding to the lactate threshold ([La-]-T). Close correlations (P <0.001) were found between [La-]b and plasma [HGH] (r = 0.64), [A] (r = 0.71) and [NA] (r = 0.81). The mean threshold exercise intensities for [HGH], [A] and [NA], detected by log-log transformation, [154 (SEM 19) W, 162 (SEM 15) W and 160 (SEM 17) W, respectively] were not significantly different from the [La-]-T [161 (SEM 12) W]. The results indicated that the threshold rise in plasma [HGH] followed the patterns of plasma catecholamine and blood lactate accumulation during progressive exercise in the endurance-trained athletes.     

Spontaneous tumors and common diseases in two colonies of Syrian hamsters. I. Incidence and sites

Syrian hamsters from two colonies [Eppley colony (EC); Hannover colony (HC)] were examined for spontaneous neoplastic and noneoplastic diseases. Significant differences were found in tumor incidence (30%, EC' 42%, HC), occurrence of malignant neoplasms (15%, EC; 32%, HC), appearance of multiple primary tumors in different organs (42%, EC; 30%, HC), average survival rates of tumor-bearing animals, organ distribution and histologic types, and average survival rates of all animals. The frequencies of nonneoplastic diseases also varied between the two colonies. The findings indicated a need for precise histologic evaluation to generate information for comparative purposes regarding the use of hamsters in experimental pathology and carcinogenesis studies.     

Metalloproteinase inhibitors and wound healing: a novel enhancer of wound strength

BACKGROUND: Wound strength is a balance between collagen synthesis and degradation. The role of collagen breakdown in wound healing is still not well understood. We investigated the role of collagenases (metalloproteinases [MMPs]) in wound healing in using GM6001, a novel inhibitor of MMPs. METHODS: We used the dorsal skin incision model with implantation of polyvinyl alcohol sponges. Twenty male Sprague-Dawley rats were randomly assigned to receive either GM6001 (10 mg/kg body weight) or 2 mL saline subcutaneously. Ten days after operation the animals were killed and fresh wound breaking strength, scar and sponge hydroxyproline content, and collagen type I gene expression in sponges were assayed. In addition, the inflammatory response and the wound fluid cytokine (tumor necrosis factor-alpha [TNF-alpha] and transforming growth factor-beta 1 [TGF-beta 1]) profile were studied. RESULTS: GM6001 significantly increased wound strength (422 +/- 59 vs 302 +/- 33 g, P < .05), whereas scar collagen content did not differ. In the sponge granulomas the inflammatory infiltrate, the collagen content, and the collagen type I gene expression were all significantly decreased by GM6001. CONCLUSIONS: Inhibition of MMP activity during acute wound healing enhances wound strength even though new collagen synthesis and the inflammatory response are significantly decreased. This could be achieved by decreasing collagen turnover or increasing collagen maturation and crosslinking, or both.     

Clinical value of proton magnetic resonance spectroscopy for differentiating recurrent or residual brain tumor from delayed cerebral necrosis

PURPOSE: Delayed cerebral necrosis (DN) is a significant risk for brain tumor patients treated with high-dose irradiation. Although differentiating DN from tumor progression is an important clinical question, the distinction cannot be made reliably by conventional imaging techniques. We undertook a pilot study to assess the ability of proton magnetic resonance spectroscopy (1H MRS) to differentiate prospectively between DN or recurrent/residual tumor in a series of children treated for primary brain tumors with high-dose irradiation. METHODS AND MATERIALS: Twelve children (ages 3-16 years), who had clinical and MR imaging (MRI) changes that suggested a diagnosis of either DN or progressive/recurrent brain tumor, underwent localized 1H MRS prior to planned biopsy, resection, or other confirmatory histological procedure. Prospective 1H MRS interpretations were based on comparison of spectral peak patterns and quantitative peak area values from normalized spectra: a marked depression of the intracellular metabolite peaks from choline, creatine, and N-acetyl compounds was hypothesized to indicate DN, and median-to-high choline with easily visible creatine metabolite peaks was labeled progressive/recurrent tumor. Subsequent histological studies identified the brain lesion as DN or recurrent/residual tumor. RESULTS: The patient series included five cases of DN and seven recurrent/residual tumor cases, based on histology. The MRS criteria prospectively identified five out of seven patients with active tumor, and four out of five patients with histologically proven DN correctly. Discriminant analysis suggested that the primary diagnostic information for differentiating DN from tumor lay in the normalized MRS peak areas for choline and creatine compounds. CONCLUSIONS: Magnetic resonance spectroscopy shows promising sensitivity and selectivity for differentiating DN from recurrent/progressive brain tumor. A novel diagnostic index based on peak areas for choline and creatine compounds may provide a simple discriminant for differentiating DN from recurrent or residual primary brain tumors.