Muscle necrosis in the extremities: evaluation with Tc-99m pyrophosphate scanning--a retrospective review

A retrospective review was done of 34 extremities studied between 1981 and 1985 with technetium-99m pyrophosphate scanning; 22 were subsequently amputated. Results of detailed pathologic examination or immediate postoperative examination of the resected extremity were available in 16 cases. In these cases, scanning had allowed correct prediction of the level of amputation and of the specific areas of muscle infarction in 13 cases. In the one case in which amputation was performed for infection rather than muscle necrosis, the lack of necrosis was correctly predicted with the scan. The limited results of this study indicate that the Tc-99m pyrophosphate scan allows the location of necrotic muscle to be predicted accurately and may therefore be a useful adjunct in determining the best level for ultimate amputation. Special caution is required in those cases in which muscle necrosis is due to acute causes (e.g., traumatic thrombosis) rather than chronic vascular disease.     

Impairment of chemoattractant-stimulated hexose uptake in neonatal neutrophils

Neonatal neutrophils (polymorphonuclear leukocytes [PMN]) exhibit a well-documented deficiency in chemotaxis, the nature of which has not been fully elucidated. To determine whether impaired ability of neonatal PMN to increase hexose uptake in response to chemoattractants could contribute to this defect, we compared uptake of 2-deoxy-D- glucose (2-DOG) in stimulated versus resting PMN from neonates (cord blood) and healthy adults. Compared with unstimulated values; N-formyl- methionyl-leucyl-phenylalanine (fMLP) (optimal at 10 nmol/L) caused a threefold to fourfold increase in 2-DOG uptake by adult PMN. Unstimulated 2-DOG uptake by neonatal PMN was slightly higher than that for adult cells, but fMLP caused only a minimal (less than twofold) increase, and optimally stimulated uptake was significantly lower than for adult PMN (P < .01 for adult versus neonatal stimulated uptake; n = 6). Findings were similar when ionomycin or C5a was used as a stimulus. Optimal fMLP stimulation of adult PMN was associated with a marked decrease in the Km for 2-DOG uptake, from 0.74 +/- 0.11 to 0.23 +/- 0.03 mmol/L (delta Km = -0.51 +/- 0.12 mmol/L; n = 6). In contrast, there was relatively little fMLP-induced change in the Km for uptake of 2-DOG by neonatal PMN (from 0.44 +/- 0.04 mmol/L to 0.32 +/- 0.019 mmol/L n = 6); delta Km = -0.12 +/- 0.04 mmol/L; P = .011 for adult versus neonatal delta Km. Stimulation with fMLP was not accompanied by a significant change in the Vmax for 2-DOG uptake with either adult or neonatal PMN, and the respective values for Vmax were similar. We conclude that the chemoattractant-induced increase in hexose uptake by PMN is deficient in neonates compared with adults and that this deficiency involves mechanisms that determine the Km for this process. This impairment may contribute to defective chemotaxis in neonatal PMN.     

Genetic polymorphisms and drug interactions modulating CYP2D6 and CYP3A activities have a major effect on oxycodone analgesic efficacy and safety

Background and purpose:

Thrombus formation is commonly associated with pulmonary arterial hypertension (PAH). Thrombin may thus play an important role in the pathogenesis and pathophysiology of PAH. Hence, we investigated the contractile effects of thrombin and its mechanism in pulmonary artery.

Experimental approach:

The cytosolic Ca²⁺ concentrations ([Ca²⁺]_i), 20 kDa myosin light chain (MLC20) phosphorylation and tension development were evaluated using the isolated porcine pulmonary artery.

Key results:

Thrombin induced a sustained contraction in endothelium-denuded strips obtained from different sites of a pulmonary artery, ranging from the main pulmonary artery to the intrapulmonary artery. In the presence of endothelium, thrombin induced a transient relaxation. The contractile effect of thrombin was abolished by either a protease inhibitor or a proteinase-activated receptor 1 (PAR₁) antagonist, while it was mimicked by PAR₁-activating peptide (PAR₁AP), but not PAR₄AP. The thrombin-induced contraction was associated with a small elevation of [Ca²⁺]_i and an increase in MLC20 phosphorylation. Thrombin and PAR₁AP induced a greater increase in tension for a given [Ca²⁺]_i elevation than that obtained with high K⁺-depolarization. They also induced a contraction at a fixed Ca²⁺ concentration in α-toxin-permeabilized preparations.

Conclusions and implications:

The present study revealed a unique property of the pulmonary artery. In contrast to normal arteries of the systemic circulation, thrombin induces a sustained contraction in the normal pulmonary artery, by activating PAR₁ and thereby increasing the sensitivity of the myofilament to Ca²⁺. This responsiveness of the pulmonary artery to thrombin may therefore contribute to the pathogenesis and pathophysiology of PAH.     

Optimizing pH-responsive Polymeric Micelles for Drug Delivery in a Cancer Photodynamic Therapy Model

Different pH-sensitive, randomly- and terminally-alkylated N -isopropylacrylamide (NIPAM) copolymers were synthesized and used to prepare pH-responsive polymeric micelles (PM). These copolymers were modified from previously-studied copolymers by incorporating an additional hydrophilic monomer, N- vinyl-2-pyrrolidone (VP) to decrease uptake by the mononuclear phagocyte system (MPS) and improve localization in tumors. VP lowered the phase transition pH of the copolymers but did not affect the onset of micellization. The in vitro cytotoxicity of the copolymers was evaluated on EMT-6 mouse mammary tumor cells in comparison to Cremophor EL (CRM). The anticancer photosensitizer aluminum chloride phthalocyanine (AlClPc) was loaded into the PM with a standard dialysis procedure. Biodistribution and in vivo photodynamic activity were then evaluated in Balb/c mice bearing intradermal EMT-6 tumors. All NIPAM copolymers demonstrated substantially lower cell cytotoxicity than the control surfactant CRM. In vivo, similar AlClPc tumor uptake was observed for the PM and CRM formulations. However, the PM appeared to exhibit greater activity in vivo than CRM formulation at an AlClPc subtherapeutic dose. Therefore, NIPAM-based copolymers containing VP units represent promising alternatives for the formulation of poorly water-soluble phthalocyanines.     

Attenuation correction and gating synergistically improve the diagnostic accuracy of myocardial perfusion SPECT

BACKGROUND: The diagnostic accuracy of myocardial perfusion single photon emission computed tomography is limited by soft tissue attenuation. Artifacts may be reduced by attenuation correction (AC) or compensated for by assessment of wall motion in gated images. We studied the benefit of gating and AC, both separately and combined, in improving accuracy. METHODS AND RESULTS: Sixty-six subjects (27 with > or =50% angiographic stenosis, 5 with <50% stenosis, and 34 Bayesian normal volunteers) underwent gated AC single photon emission computed tomography. Images were reconstructed and independently viewed in 4 ways: static with motion correction (MC) only, gated with MC only, static with MC plus blur correction plus AC (referred to as combined corrections [CC]), and gated with CC. Images were interpreted by 2 blinded observers for overall presence of coronary disease and for vascular territory (left anterior descending [LAD], left circumflex [LCx], and right coronary artery [RCA]). Statistical analysis of sensitivity and normalcy was done by means of the Cochran Q test. Overall diagnostic accuracy showed statistically significant improvement (P =.05 for sensitivity, P <.001 for normalcy), progressing from static MC to gated MC to static CC to gated CC (sensitivity/normalcy = 85%/54%, 78%/62%, 93%/77%, and 96%/85%, respectively, for the 4 reconstruction and viewing approaches). Sensitivity was highest in all 3 vascular territories for the combination of gating and CC; normalcy was also highest with the same combination for the LAD and RCA territories; sensitivity/normalcy with this combination was 85%/87% for the LAD, 69%/87% for the LCx, and 89%/87% for the RCA territory. CONCLUSIONS: The combination of gating and CC provides the highest diagnostic accuracy, and gating and AC should thus be considered complementary and synergistic.