203Pb-labeled alpha-melanocyte-stimulating hormone peptide as an imaging probe for melanoma detection.

Peptide-targeted alpha-therapy with 7.4 MBq of (212)Pb-[1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid]-ReO-[Cys(3,4,10),d-Phe(7),Arg(11)]alpha-MSH(3-13) ((212)Pb-DOTA-Re(Arg(11))CCMSH) cured 45% of B16/F1 murine melanoma-bearing C57 mice in a 120-d study, highlighting its melanoma treatment potential. However, there is a need to develop an imaging surrogate for patient-specific dosimetry and to monitor the tumor response to (212)Pb-DOTA-Re(Arg(11))CCMSH therapy. The purpose of this study was to evaluate the potential of (203)Pb-DOTA-Re(Arg(11))CCMSH as a matched-pair SPECT agent for (212)Pb-DOTA-Re(Arg(11))CCMSH. METHODS: DOTA-Re(Arg(11))CCMSH was labeled with (203)Pb in 0.5 M NH(4)OAc buffer at pH 5.4. The internalization and efflux of (203)Pb-DOTA-Re(Arg(11))CCMSH were determined in B16/F1 melanoma cells. The pharmacokinetics of (203)Pb-DOTA-Re(Arg(11))CCMSH was examined in B16/F1 melanoma-bearing C57 mice. A micro-SPECT/CT study was performed with (203)Pb-DOTA-Re(Arg(11))CCMSH in a B16/F1 melanoma-bearing C57 mouse at 2 h after injection. RESULTS: (203)Pb-DOTA-Re(Arg(11))CCMSH was easily prepared in NH(4)OAc buffer and completely separated from the excess nonradiolabeled peptide by reversed-phase high-performance liquid chromatography (RP-HPLC). (203)Pb-DOTA-Re(Arg(11))CCMSH displayed fast internalization and extended retention in B16/F1 cells. Approximately 73% of (203)Pb-DOTA-Re(Arg(11))CCMSH activity internalized after a 20-min incubation at 25 degrees C. After incubation of the cells in culture medium for 20 min, 78% of internalized activity remained in the cells. (203)Pb-DOTA-Re(Arg(11))CCMSH exhibited a biodistribution pattern similar to that of (212)Pb-DOTA-Re(Arg(11))CCMSH in B16/F1 melanoma-bearing mice. (203)Pb-DOTA-Re(Arg(11))CCMSH exhibited a peak tumor uptake of 12.00+/-3.20 percentage injected dose per gram (%ID/g) at 1 h after injection. The tumor uptake gradually decreased to 3.43+/-1.12 %ID/g at 48 h after injection. (203)Pb-DOTA-Re(Arg(11))CCMSH exhibited a peak tumor-to-kidney uptake ratio of 1.53 at 2 h after injection. The absorbed doses to the tumor and kidneys were 4.32 and 4.35 Gy, respectively, per 37 MBq. Whole-body clearance of (203)Pb-DOTA-Re(Arg(11))CCMSH was fast, with approximately 89% of the injected activity cleared through the urinary system by 2 h after injection. (203)Pb showed 1.6-mm SPECT resolution, which was comparable to (99m)Tc. Melanoma lesions were visualized through SPECT/CT images of (203)Pb-DOTA-Re(Arg(11))CCMSH at 2 h after injection. CONCLUSION: (203)Pb-DOTA-Re(Arg(11))CCMSH exhibited favorable pharmacokinetic and tumor imaging properties, highlighting its potential as a matched-pair SPECT agent for (212)Pb-DOTA-Re(Arg(11))CCMSH melanoma treatment.     

Progressive myoclonic ataxia with intrathecal immune activation in six patients

In six patients with slowly progressive sporadic cerebellar ataxia and cortical multifocal action myoclonus, cerebrospinal fluid (CSF) IgG index was persistently very high (1.2–6.7) and numerous oligoclonal bands were detected. Progressive cognitive impairment and MRI cerebellar and cerebral atrophy were observed. No serum antibodies were found. Various degenerative, metabolic, inflammatory and systemic diseases were excluded. The cerebellum may be the main target of a degenerative or immune process and releases antigens that, enhancing a compartmentalised (auto)immune response, as suggested by the persistent intrathecal activation, could lead to further cerebellar damage. As the frequency of CSF oligoclonal banding in myoclonic ataxia is unknown, our patients’ disease might represent a hitherto unreported entity or a subset of progressive myoclonic ataxia.

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Sommario Descriviamo sei pazienti con atassia cerebellare sporadica e mioclono corticale d’azione multifocale, nel cui liquor i valori dell’indice IgG si mantenevano persistentemente elevati ed erano presenti numerose bande oligoclonali. I pazienti manifestavano un progressivo declino cognitivo e la RM mostrava atrofia cerebellare e cerebrale. In assenza di anticorpi identificabili non era possibile formulare una diagnosi di malattia nota. Suggeriamo che il cervelletto possa essere il principale bersaglio di un processo degenerativo o immuno-mediato e che gli antigeni liberati inducano la produzione di anticorpi che ulteriormente provocano danno cerebrale. Poiché non è nota la frequenza delle bande oligoclonali nel liquor di pazienti con atassia mioclonica, non sappiamo se la malattia qui descritta sia una entità nuova o un sottogruppo delle atassie miocloniche.

     

Torasemide, a new loop diuretic, in patients with chronic renal failure

Torasemide, a new loop diuretic, was administered in 9 hospitalized patients with chronic renal failure to treat both arterial hypertension and peripheral edema. The urine of 5 patients was collected over 12-hour periods to assess the long-lasting diuretic activity of torasemide. Torasemide induced a significant decrease in blood pressure and reversion of peripheral edema in all patients without adverse effects. Torasemide is a high-ceiling loop diuretic, useful in correcting extracellular fluid volume expansion in patients with chronic renal failure.     

Cerebral MR findings in tuberous sclerosis

Cerebral magnetic resonance (MR) and CT findings of two sisters affected by clinically defined tuberous sclerosis are reported. Magnetic resonance showed a greater number of lesions than did CT. In addition, MR depiction of the abnormalities better corresponded to the pathological findings usually described in this disease.     

Skeletonized bilateral internal mammary arteries for non-elective surgical revascularization in unstable angina.

OBJECTIVE: The aim of this study was to evaluate the feasibility, safety and outcome of skeletonized bilateral internal mammary arteries (BIMA) in patients with unstable angina (UA) undergoing non-elective myocardial revascularization. METHODS: Between January 1997 and December 2003, 758 patients, mean age 62+/-12 years, underwent non-elective coronary artery bypass grafting (CABG) for unstable angina. Two hundred and five (27%) were operated emergently and 503 (73%) urgently. BIMA were employed in 320 (42%) patients (Group B) and isolated left IMA and/or saphenous vein grafts in the remaining 438 (58%) patients (Group M). RESULTS: In-hospital mortality (B = 5.9% and M = 5.3%), and perioperative myocardial infarction (B = 2.2%; M = 1.96%) were similar between the two groups (P = ns). Actuarial survival at 1, 3 and 7 years was 98.7, 97.5 and 96.2% in B and 99, 94.3 and 88.4% in M (P < 0.05 at 7 years follow-up). At 7 years follow-up, the event-free cardiac survival (92 vs. 87%, P = 0.021), angina-free survival (98.6 vs. 94%, P = 0.039), reoperation-free cardiac survival (98 vs. 95%, P = 0.04) and infarct-free cardiac survival (98.7 vs. 96%, P = 0.05) were better in Group B. Multivariate analysis identified age > 65 years (P = 0.02), LVEF < 35% (P = 0.01), > 1 ischemic irreversible area (P = 0.03) as independent predictors for late deaths, while the use of the LIMA (P=0.006) and both mammary arteries (P=0.001) decreased the risk of late deaths. CONCLUSIONS: The use of BIMA in non-elective CABG for UA is safe and effective. Mid-term outcome, however, are superior with improved freedom from cardiac death, from coronary reintervention and from myocardial infarction.     

Diffusion-weighted imaging study of patients with essential tremor.

The pathophysiology of essential tremor (ET) is unknown. PET and fMRI studies have revealed bilateral activation and (1)H-MRS studies metabolic abnormalities in the cerebellum and other functionally related brain structures in ET. Diffusion-weighted imaging (DWI) was used to search for evidence of tissue integrity abnormalities in these areas in ET patients and 10 matched controls by calculating water apparent diffusion coefficients (ADCs). Regions of interest included the left and right cerebellum, red nucleus, thalamus, caudate, putamen, pallidum, and frontal white matter. Histograms of ADCs were generated for all pixels in the infratentorial compartment and manually segmented areas corresponding to brainstem, vermis, and cerebellar hemispheres. ADC values were similar in all brain areas in patients and controls. Our study did not detect changes affecting the investigated brain regions in ET patients. These findings argue against major structural damage in the ET brain, although more subtle neurodegenerative changes cannot be ruled out.     

A comparison of technetium-99m-thiodiglycolic acid and iodine-123-hippuran in the evaluation of equivocal upper urinary tract obstruction

In a comparative trial, 21 patients (mean age 43 (range 19-66) years) with dilated upper urinary tracts underwent diuresis renography with both 123I-hippuran and the experimental agent. 99Tcm-thiodiglycolic acid (TDG). Deconvolution analysis of the derived renograms was also performed and the transit times were calculated. Excellent agreement was found between results with the two radiopharmaceuticals. There was complete agreement in interpretation of the response to diuresis with both agents and 84% agreement in the transit time estimations. Good images were produced with both agents and 99Tcm-TDG is considered to be a useful alternative to 123I-hippuran.     

Effects of antihypertensive medications on vitality and well-being

The effects of captopril, methyldopa, and propranolol were assessed for sense of well-being and vitality among 626 men with mild to moderate hypertension in a multicenter, randomized, double-blind clinical trial. After a 24-week treatment period, patients taking captopril, compared with patients taking methyldopa and propranolol, scored significantly higher on measures of well-being and vitality. In addition, patients on captopril had more favorable results in being able to keep up with their work and in not feeling tired or sleepy at work. The effects of each of the drugs manifested themselves at different periods. For example, the negative effects of methyldopa on vitality were evident by week 8, whereas the negative effects did not become manifest for propranolol until week 24. On the other hand, a steady progressive improvement in vitality scores was evident at week 8 and at week 24 for patients on captopril. The findings of the study also suggest that the effects of the treatment drugs were most marked in patients who had had previous antihypertensive medications and who were on single-drug therapy during the course of the clinical trial. Further, the differences between patients taking captopril and those on methyldopa and propranolol appear to be obscured by the addition of a diuretic. The findings of the study may guide the physician in orienting his or her patient and in planning and implementing a therapeutic regimen.     

The radiosensitivity of populations of murine hemopoietic colony-forming cells that respond to combinations of growth factors

Combinations of murine recombinant interleukin 3 (IL-3), purified murine macrophage colony-stimulating factor (M-CSF), and human recombinant interleukin 1 alpha (IL-1 alpha) were used to determine the effects of growth factors on the measured radiosensitivity of different populations of murine colony-forming cells (CFC). The data showed that combinations of growth factors resulted in different values of CFC radiosensitivity, being less than values observed when colony growth was stimulated using a single factor. For various combinations of growth factors, Do values ranged from 106 +/- 8 to 175 +/- 24 cGy for progenitor cells in normal bone marrow; 74 +/- 3 to 171 +/- 18 cGy for primitive multipotent CFC enriched using fluorescence-activated cell sorting; and from 46 +/- 4 to 131 +/- 10 cGy for more mature granulocyte-macrophage CFC, enriched by counterflow centrifugal elutriation. Only combinations of three factors produced the high values of Do reported in experiments using unpurified conditioned medium as a stimulus for colony formation.