Role of [18F]-FDG-PET/MDCT in evaluating early response in patients with Hodgkin's lymphoma.

PURPOSE: The authors evaluated the prognostic role of 18-fluoro-fluorodeoxyglucose positron emission tomography/multidetector computed tomography ([(18)F]-FDG PET/MDCT) in treating patients with Hodgkin's lymphoma (HL). MATERIALS AND METHODS: We retrospectively evaluated 132 patients with HL studied with PET/MDCT before the start of chemotherapy (CTX) for staging purposes and again after two CTX cycles with [doxorubicin (Adriblastin), bleomycin, vinblastine, dacarbazine (ABVD_] (interim PET/MDCT), at least 30 days after the end of the last CTX cycle and/or 3 months after the end of radiotherapy, if delivered (final PET-MDCT). RESULTS: Interim PET-MDCT was negative in 104/132 patients (79%), and their final PET-MDCT showed complete remission in 102/104 (98%) of cases, with disease recurrence/persistence in two (2%). In the remaining 28 (21%) patients, interim PET-MDCT revealed an early response in 68% of cases and chemoresistance with disease progression in 32% of cases; in these 28 patients, final PET-MDCT showed a lack of response to treatment in 43% of cases (43%) and complete remission in 57% of cases. Statistical analysis of these data showed that interim PET-MDCT had a negative predictive value of 98% and a positive predictive value of 42%, with values of sensitivity, specificity and diagnostic accuracy of 85.7%, 86.4% and 86.4%, respectively. CONCLUSIONS: Interim PET-MDCT has a reliable prognostic role in diagnosis and treatment of patients with HL, as it helps predict which patients are more likely to achieve a complete response at the end of treatment. PET/MDCT may also lead to a change in treatment, with reduced treatment-related toxic effects and significantly reduced total costs.

Portal vein thrombosis after radiofrequency ablation of HCC.

The authors describe an unusual complication after radiofrequency ablation of hepatocellular carcinoma (HCC). An 84-year old man, already operated of right hepatectomy for HCC, underwent radiofrequency ablation (RFA) of a new focal hepatic lesion in IV segment, under ultrasound (US) and computed tomography (CT) guidance. The procedure was carried out without any special difficulties or complications. Seven days later, the patient suddenly complained epigastric pain, progressive jaundice and sleepiness and an increase in cholestasis sierological parameters. A CT scan revealed thrombosis of the left side branch of the portal vein, with moderate bile ducts distension. The case described demonstrates how RFA may cause thermally mediated damage of the surrounding structures, due to unpredictable radio-frequency propagation. The interest of this case report is due to the fact that portal vein thrombosis did not occur immediately after the procedure, it happened without direct vessel injury by the needle and involved a vessel greater than 3 mm.

Accuracy of early and delayed FDG PET-CT and of contrast-enhanced CT in the evaluation of lung nodules: a preliminary study on 30 patients.

PURPOSE: The aim of our prospective study was to compare the diagnostic accuracy of early, delayed and dual-time-point positron emission tomography (PET) acquisition with contrast enhanced computed tomography (CT) within a PET-CT examination in the evaluation of pulmonary solitary nodules (SPNs). MATERIALS AND METHODS: Thirty patients were enrolled in the study. All the patients underwent a dual-time-point PET-CT examination. Whole-body PET images were acquired at 50 min after fluorine18-fluorodeoxyglucose ((18)F-FDG) administration (early), followed by a chest acquisition (delayed). Lung nodules with maximum standardised uptake value SUVmax > or =2.5 were considered malignant. SUVmax was calculated on early and delayed images; SUV increasing > or =10% (Delta SUVmax) was considered suggestive of malignancy. Absence of significant lung nodule enhancement (<15 Delta HU) at CT was considered strongly predictive of benignity. For the CT morphological assessment, the irregularity of the shape of each lesion was rated. PET-CT results were related to histological assays and clinical records. Diagnostic accuracy was assessed by area under the receiveroperarting characteristic (ROC) curves analysis. RESULTS: Early and delayed SUVmax of malignant nodules were significantly higher than those of benign disease. Early SUVmax sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were 77%, 91%, 79.5% and 66.7%; delayed SUVmax corresponding values were 77%, 66%, 74% and 66%; dual-time-point SUVmax values were 83%, 67%, 75% and 74%; DeltaHU values were 94%, 34%, 67%, 96%; CT morphologic evaluation values were 61%, 46%, 60%, 47%. Area under the curve (AUC) for early SUVmax was 0.79, for delayed SUVmax 0.80, for dual-time-point SUVmax 0.85, for DeltaHU 0.63 and for CT morphologic assessment 0.58. CONCLUSIONS: In our small series of patients, early and delayed SUVmax showed comparable accuracies, whereas morphological and contrast enhanced CT evaluations showed the lowest accuracies. Dual-time-point SUVmax showed the largest AUC. However, dual-time-point SUVmax was most sensitive, whereas single-time-point SUVmax was most specific.

FEM analysis of RF breast ablation: multiprobe versus cool-tip electrode.

BACKGROUND: Radio-frequency ablation (RFA) has recently received much attention as an effective minimally invasive strategy for the local treatment of tumors. The purpose of this study was to evaluate the efficacy of single-needle cool-tip RF breast ablation in terms of temperature distribution and duration of the procedure as compared to multiprobe RF breast ablation. MATERIALS AND METHODS: Two different commercially available radiofrequency ablation needle electrodes were compared. Finite-element method (FEM) models were developed to simulate the thermoablation procedures. A series of ex vivo radiofrequency thermal lesions were induced to check the response of the FEM calculations. RESULTS: Data obtained from FEM models and from ex vivo procedures showed that cool-tip RF breast ablation assures better performances than multiprobe RF breast ablation in terms of temperature distribution and duration of the procedure. Histopathological analysis of the cool-tip RF thermoablated specimens showed successful induction of coagulation necrosis in the thermoablated specimens. CONCLUSION: Data obtained from FEM models and from ex vivo procedures suggest that the proposed cool-tip RF breast ablation may kill more tumor cells in vivo with a single application than the multiprobe RF breast ablation.

Real-time ultrasound elastography for assessment of response to brentuximab vedotin treatment in relapsed and refractory Hodgkin lymphoma.

OBJECTIVE: To evaluate the application of ultrasound elastography (ES) in monitoring treatment response to brentuximab vedotin (Seattle Genetics, Seattle, WA, USA). PATIENTS AND METHODS: Patients were selected when suffering from relapsed and refractory Hodgkin Lymphoma (HL). Our research investigated if the interim of ultrasound ES is a predictive value for treatment outcome in patients treated with brentuximab vedotin. RESULTS: 30 patients with refractory HL were enrolled. After treatment with brentuximab vedotin, 14 patients were classified as responders and 16 were classified as non-responders. At baseline, there was no difference between the groups both in the strain ratio (z = 1.1, p = 0.3) and in the volume (z = -0.3, p = 0.8). While after treatment there was a difference between the groups both in the strain ratio (z = -2.09, p < 0.05) and in the volume (z = 4.1, p < 0.001). CONCLUSIONS: Real-time elastosonography could be a reliable tool for the assessment of refractory Hodgkin lymphoma response to brentuximab vedotin treatment and help to identify patient with improved clinical outcome early during treatment. Results indicate that changes in ultrasound elastosonography parameters are correlated with the clinical and pathologic response of patients. These findings could pave the way for establishing protocols for the clinical applications of ultrasound elastography techniques in therapy response monitoring.

Pyrrolobenzoxazepinone derivatives as non-nucleoside HIV-1 RT inhibitors: further structure-activity relationship studies and identification of more potent broad-spectrum HIV-1 RT inhibitors with antiviral activity.

Pyrrolobenzoxazepinone (PBO) derivatives represent a new class of human immunodeficiency virus type 1 (HIV-1) non-nucleoside reverse transcriptase (RT) inhibitors (NNRTs) whose prototype is (+/-)-6-ethyl-6-phenylpyrrolo[2,1-d][1,5]benzoxazepin-7(6H)- one (6). Docking studies based on the three-dimensional structure of RT prompted the synthesis and biological evaluation of novel derivatives and analogues of 6 featuring a meta-substituted phenyl or a 2-thienyl ring at C-6 and a pyridine system in place of the fused-benzene ring to yield pyrrolopyridooxazepinones (PPOs). Compared with the lead 6 and nevirapine, several of the synthesized compounds (PBOs 13a-d and PPOs 13i-k) displayed higher inhibitory activity against wild-type RT and clinically relevant mutant RTs containing the single amino acid substitutions L100I, K103N, V106A, Y181I, and Y188L. The most potent inhibitors were further evaluated for in vitro antiviral activity on lymphocytes and monocyte-macrophages, for cytotoxicity on a panel of cell lines, and for potential synergistic antiviral activity with AZT. Pharmacokinetic studies performed on 13b, 13c, and 13i showed that these compounds achieve high concentrations in the brain. The results of the biological and pharmacokinetic experiments suggest a potential clinical utility of analogues such as 13b-d, 13i, and 13j, in combination with nucleoside RT inhibitors, against strains of HIV-1 bearing those mutations that confer resistance to known NNRTI.

Quinoxalinylethylpyridylthioureas (QXPTs) as potent non-nucleoside HIV-1 reverse transcriptase (RT) inhibitors. Further SAR studies and identification of a novel orally bioavailable hydrazine-based antiviral agent.

Quinoxalinylethylpyridylthioureas (QXPTs) represent a new class of human immunodeficiency virus type 1 (HIV-1) non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs) whose prototype is 6-FQXPT (6). Docking studies based on the three-dimensional structure of RT prompted the synthesis of novel heteroarylethylpyridylthioureas which were tested as anti-HIV agents. Several compounds proved to be potent broad-spectrum enzyme inhibitors and significantly inhibited HIV-1 replication in vitro. Their potency depends on the substituents and the nature of the heterocyclic skeleton linked to the ethyl spacer, and structure-activity relationships are discussed in terms of the possible interaction with the RT binding site. Although the new QXPTs analogues show potent antiviral activity, none of the compounds tested overcome the pharmacokinetic disadvantages inherent to ethylpyridylthioureidic antiviral agents, which in general have very low oral bioavailability. Through an integrated effort involving synthesis, docking studies, and biological and pharmacokinetic evaluation, we investigated the structural dependence of the poor bioavailability and rapid clearance within the thioureidic series of antivirals. Replacing the ethylthioureidic moiety with a hydrazine linker led to a new antiviral lead, offering promising pharmacological and pharmacokinetic properties in terms of antiviral activity and oral bioavailability.

Effect of differentiation on hydrolysis and association of Leu-enkephalin to K562(S) cells.

Hydrolysis of Leu-enkephalin and association to cells of the peptide-radioactive label have been studied on the K562(S) erythroleukemic cell subline. Data obtained indicate that in the presence of these cells, Leu-enkephalin is hydrolyzed, that the peptide's radioactive label is partially associated to cells, and that these phenomena are related. Hydrolysis and association are inversely modified by the cells' differentiation: hydrolysis is increased and association is decreased in differentiated compared with nondifferentiated cells. Moreover, the ratio of hydrolysis by-products is dissimilar between differentiated and nondifferentiated cells as a result of a significant modification of the soluble enzymes' release. The alterations induced by differentiation on all parameters investigated seem to indicate significant changes in the membrane structures responsible for the mechanisms controlling these phenomena.

Non-nucleoside HIV-1 reverse transcriptase inhibitors: synthesis and biological evaluation of novel quinoxalinylethylpyridylthioureas as potent antiviral agents.

New heterocyclic derivatives of ethylpyridylthiourea, quinoxalinylethylpyridylthiourea (QXPT) and analogues, inhibited human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) activity and prevented HIV-1 cytopathogenicity in T4 lymphocytes. Several of these novel non-nucleoside RT inhibitors, with a substituted pyrroloquinoxalinone heteroaromatic skeleton, showed inhibitory activity against wild-type RT as well as against mutant RTs containing the single amino acid substitutions L1001, K103N, V106A, Y1811 and Y188L that was much greater than other non-nucleoside inhibitors such as nevirapine. Maximum potency in enzymatic assays was achieved with a fluoropyrroloquinoxaline skeleton linked to the ethylpyridylthiourea moiety (FQXPT). In cell-based assays on different cell lines and on human monocyte-macrophages, 6-FQXPT exhibited EC50 values in the nanomolar range, with a promising selectivity index. Moreover, 6-FQXPT showed synergistic antiviral activity with zidovudine.

Stress-induced increase in brain neuroactive steroids: antagonism by abecarnil.

Acute foot shock stress elicits a selective and time-dependent increase of neuroactive steroid (pregnenolone, progesterone, allotetrahydrodeoxycorticosterone) concentrations in rat brain cortex, accompanied by a marked increase of plasma corticosterone. The brain cortical neuroactive steroid levels peaked between 10 and 30 min poststress and returned to control values by 2 h. Abecarnil (0.3 mg/kg), i.p.), a beta-carboline derivative with anxiolytic properties, completely antagonized the effect of foot shock on brain cortical neuroactive steroids. A single administration of the anxiogenic beta-carboline FG 7142 (15 mg/kg, i.p.), in contrast, mimicked the effect of foot shock. These data support the hypothesis for the existence of a functional relationship between brain neuroactive steroid concentrations and GABAA receptor function/emotional state of the animal.

The role of second-look ultrasound of BIRADS-3 mammary lesions detected by breast MR imaging.

OBJECTIVE: To asses the value of second-look ultrasound (US) for identifying BIRADS 3 (Breast Imaging Reporting Data System) mammary lesions detected by breast Magnetic Resonance imaging (MRI). MATERIALS AND METHODS: From April 2008 to May 2009 330 breast MRI were performed of which 60 patients are classified as BIRADS 3. 84 lesions underwent second-look US and percutaneous vacuum biopsy Vacora system US-guided. STATISTICAL ANALYSIS: lesions were stratified into two groups: visible on US (Group 1) and not visible on US (Group 2). The clinical impact of second-look US was studied in terms of negative predictive value (NPV). RESULTS: The positive predictive value (PPV) of category 3 BIRADS MRI was found to be 89%. Second look-US results detected lesions in 51% of the MRI enhancing lesions. The second look-US showed a NPV of 97%. The NPV of second look-US was significantly greater than the NPV of MRI BIRADS 3 (97% vs 89%, p<0.05). The logistic regression analysis showed a higher number of malignant lesions in group 1 than in group 2 (7vs 2, OR 3.7, p<0.05). CONCLUSIONS: The second-look US permitted the correct management of subcentimetric MRI BIRADS 3 lesions not visible with conventional imaging tecniques.

Cost-effectiveness analysis of two vacuum-assisted breast biopsy systems: Mammotome and Vacora.

PURPOSE: This study was undertaken to compare the cost effectiveness of two vacuum-assisted breast biopsy devices, the Mammotome and Vacora systems. MATERIALS AND METHODS: Between January and June 2006, 238 vacuum-assisted breast biopsies were performed at our radiology department. Five out of 238 lesions were excluded because of inadequate sampling. The Mammotome system was used in 108/233 lesions and the Vacora system in 125/233. Fifty-eight lesions underwent ultrasound-guided breast biopsy, and 50 lesions underwent mammography-guided biopsy with both Mammotome and Vacora devices. Magnetic-resonance-guided biopsy was possible with the Vacora system only (17/125 lesions). RESULTS: All procedures were successfully completed. No significant differences were found between the results of the Mammotome and Vacora biopsies in terms of effectiveness: sensitivity was 84.4% and 86.2%, respectively, and specificity 100%. In terms of cost, the Mammotome system has higher costs per procedure compared with the Vacora. CONCLUSIONS: Our clinical results confirm the diagnostic accuracy of both the Mammotome and Vacora systems, whereas our cost analysis shows that there is a considerable difference, mostly related to the initial investment.

In vivo, high-field, 3-Tesla 1H MR spectroscopic assessment of liver fibrosis in HCV-correlated chronic liver disease.

PURPOSE: Histology is the gold standard by which to diagnose and score hepatic fibrosis. Recently, it has been proposed that hepatic magnetic resonance spectroscopy (MRS) could provide an accurate representation of the disease process. The aim of this study was to correlate the in vivo high-field (3-Tesla) (1)H MRS features of noncirrhotic chronic hepatitis C patients stratified according to the histopathological stages of fibrosis. MATERIALS AND METHOD: Six healthy controls and 23 patients with biopsy-proven precirrhotic hepatitic C virus (HCV)-related liver disease were included. The subdivision of patients into the histopathological stages of fibrosis was based on the Ishak fibrosis (F) scoring system: mild hepatitis (0< or =F< or =1), moderate (2< or =F< or =3) and severe hepatitis (4< or =F< or =5). For correlation analysis, the Spearman nonparametric test was used. Differences between groups were calculated with the nonparametric Mann-Whitney U test. A p value <0.05 was considered significant. The particular metabolite content was evaluated in relative units (RU), according to the pattern metabolite/H(2)O=area of the metabolite x1,000/area of nonsuppressed water. RESULT: A significant statistical difference was observed between control vs. mild and moderate vs. severe disease severity in choline-containing compounds (CCC)/H(2)O ratios (p=0.0379 and p=0.0003) and in glutamine/glutamate (Glx)/H(2)O ratios (p=0.004 and p<0.0001), whereas a statistically significant difference in the lipid/H(2)O ratios was achieved only between control vs. moderate and between moderate vs. severe stages of disease (p=0.011 and p=0.0030). CONCLUSION: High-field (1)H MRS successfully differentiates between mild/moderate vs. severe stages of chronic hepatitis and can be considered a complement to most standard imaging protocols in the liver.

MR breast imaging: a comparative analysis of conventional and parallel imaging acquisition.

PURPOSE: The objective of this study was to compare conventional breast magnetic resonance imaging (MRI) with breast MRI acquired with the sensitivity-encoding (SENSE) technique on a 1.5-T MRI scanner in the same patient, on the basis of image quality and kinetics analysis. MATERIALS AND METHODS: Thirty-one patients with suspicious mammography and US findings were included in the study. Conventional breast MRI consisted of the following sequences: T1 (matrix, 288 x 512); T2 (matrix 225 x 512); short tau inversion recovery (STIR) (matrix 320 x 224) and dynamic T1 [2D fast-field echo (FFE)] (matrix 256 x 512; temporal resolution

MR imaging-guided 10-gauge vacuum-assisted breast biopsy: histological characterisation.

PURPOSE: The aim of this study was to evaluate a handheld vacuum-assisted device for magnetic resonance imaging (MRI)-guided breast biopsy. MATERIALS AND METHODS: In 47 patients, a total of 47 suspicious breast lesions (mean maximum diameter 9 mm) seen with MRI (no suspicious changes on breast ultrasound or mammography) were sampled using a 10-gauge vacuum-assisted breast biopsy (VAB) device under MRI guidance. Histology of biopsy specimens was compared with final histology after surgery or with follow-up in benign lesions. RESULTS: Technical success was achieved in all biopsies. Histological results from VAB revealed malignancy in 15 lesions (32%), atypical ductal hyperplasia in four lesions (8%) and benign findings in 28 lesions (60%). One of four lesions with atypical ductal hyperplasia was upgraded to ductal carcinoma in situ after surgery. One of seven lesions showing ductal carcinoma was upgraded to invasive carcinoma after surgery. Two lesions diagnosed as infiltrating carcinoma by VAB were not validated at excisional biopsy due to complete removal of the lesion during the procedure. During the follow-up (mean 18 months) of histologically benign lesions, we observed no cases of breast cancer development. Because of morphological changes on follow-up MRI scans, two lesions underwent surgical excision, which confirmed their benign nature. Besides minor complications (massive bleeding, n = 1) requiring no further therapeutic intervention, no complications occurred. CONCLUSIONS: MRI-guided biopsy of breast lesions using a handheld vacuum-assisted device is a safe and effective method for the workup of suspicious lesions seen on breast MRI alone.

Sixty-four-section CT cerebral perfusion evaluation in patients with carotid artery stenosis before and after stenting with a cerebral protection device.

BACKGROUND AND PURPOSE: Brain tissue viability depends on cerebral blood flow (CBF) that has to be kept within a narrow range to avoid the risk of developing ischemia. The aim of the study was to evaluate by 64-section CT (VCT) the cerebral perfusion modifications in patients with severe carotid stenosis before and after undergoing carotid artery stent placement (CAS) with a cerebral protection system. MATERIALS AND METHODS: Fifteen patients with unilateral internal carotid stenosis (>or=70%) underwent brain perfusional VCT (PVCT) 5 days before and 1 week after the stent-placement procedure. CBF and mean transit time (MTT) values were measured. RESULTS: Decreased CBF and increased MTT values were observed in the cerebral areas supplied by the stenotic artery as compared with the areas supplied by the contralateral patent artery (P < .001). A significant normalization of the perfusion parameters was observed after the stent-placement procedure (mean pretreatment MTT value, 5.3 +/- 0.2; mean posttreatment MTT value, 4.3 +/- 0.18, P < .001; mean pretreatment CBF value, 41.2 mL/s +/- 2.1; mean posttreatment CBF value, 47.9 mL/s +/- 2.9, P < .001). CONCLUSIONS: PVCT is a useful technique for the assessment of the hemodynamic modifications in patients with severe carotid stenosis. The quantitative evaluation of cerebral perfusion makes it a reliable tool for the follow-up of patients who undergo CAS.

Increased hepatitis C virus (HCV)-specific CD4+CD25+ regulatory T lymphocytes and reduced HCV-specific CD4+ T cell response in HCV-infected patients with normal versus abnormal alanine aminotransferase levels.

CD4+CD25+ T regulatory cells may play a role in the different clinical presentations of chronic hepatitis C virus (HCV) infection by suppressing CD4+ T cell responses. Peripheral CD4+CD25+ T cells from chronic HCV carriers with normal and abnormal alanine aminotransferase (ALT) were analysed for specificity and effect on HCV-specific CD4+ T cell reactivity by flow cytometry for intracellular cytokine production and proliferation assay. HCV-specific CD4+CD25(+high) T cells consistently produced transforming growth factor (TGF)-beta but only limited amounts of interleukin (IL)-10 and no IL-2 and interferon (IFN)-gamma. The HCV-specific TGF-beta response by CD4+CD25(+high) T cells was significantly greater in patients with normal ALT compared to patients with elevated ALT. In addition, a significant inverse correlation was found between the HCV-specific TGF-beta response by CD4+CD25(+high) T cells and liver inflammation. In peripheral blood mononuclear cells (PBMC), both HCV antigen-induced IFN-gamma production and proliferation of CD4+ T cells were greater in patients with elevated ALT compared with patients with normal ALT. Depletion of CD4+CD25+ cells from PBMC resulted in an increase of both IFN-gamma production and proliferation of HCV-specific CD4+ T cells that was significantly greater in patients with normal ALT levels compared with patients with elevated ALT. In addition, CD4+CD25+ T cells from patients with normal ALT levels proved to be significantly more potent to suppress CD4+ T cell reactivity with respect to those from patients with elevated ALT. In conclusion, these data support the hypothesis that CD4+CD25+ cells may play a role in controlling chronic inflammatory response and hepatic damage in chronic HCV carriers.

Enzymes and inhibitors in leu-enkephalin in metabolism in human plasma.

The enzymes degrading leucine enkephalin in human plasma and the inhibitors active on these enzymes were studied by kinetic and chromatographic techniques. Data obtained evidence the existence of complex kinetics of leu-enkephalin hydrolysis and of formation of its hydrolysis by-products. These appear to originate from the combined effect of further hydrolysis of the enkephalin's fragments after their release and of competition between the different enzymes present in plasma. Chromatographic separation of plasma proteolysis inhibitors indicates the existence of several pools of substances acting on all three enzyme groups that degrade leu-enkephalin. The partial specificity of these substances induces competition effects: consequently, the actual protection over leu-enkephalin is considerably lower that the total inhibitory activity. That notwithstanding, plasma inhibitors control enkephalin hydrolysis to a relevant extent, while they modify only slightly the ratio of hydrolysis between the different enzymes. This latter parameter--and specifically the large prevalence of aminopeptidases over dipeptidylaminopeptidases and dipeptidylcarboxypeptidases--appears controlled mainly by kinetic factors.

Enkephalin-degrading dipeptidylcarboxypeptidases in human and Cavia porcellus plasma.

1. The dipeptidylcarboxypeptidases that degrade leucine enkephalin in human and guinea pig plasma were studied by kinetic and chromatographic techniques. 2. The extremely rapid degradation of enkephalins in Cavia plasma seems to be caused by both increased activity of enzymes and reduced role of inhibitors. 3. The increased role of dipeptidylcarboxypeptidases in Cavia as compared to Homo appears prevalently caused by the presence in the former species of a considerable number of very active enzymes. 4. The sum of these data indicates the existence of noticeable intraspecific differences either in peptide-degrading enzymes present in plasma, or in plasma peptides, or in both.

Role of enzymes and inhibitors in leu-enkephalin metabolism in rabbit and human plasma.

The hydrolysis of leucine enkephalin by the proteolytic enzymes present in human and rabbit plasma has been studied by kinetic and chromatographic techniques. Data obtained indicate the existence of noticeable intraspecific differences in the kinetics of leu-enkephalin degradation, and of formation of its hydrolysis by-products. The separation of the enzymes active on the substrate and of the inhibitors active on these enzymes evidences the existence of a species specific distribution of both groups of substances. Yet, the dissimilar kinetics of the substrate hydrolysis and of formation of its hydrolysis by-products appear to arise more from diversities in the competition between the enzymes present in plasma and in the role of inhibitors than from the differences in the enkephalin-degrading enzymes. It is suggested that differences observed may be related to the existence of species specific populations of the information-carrying plasma peptides.