The timing of antibiotic treatment relative to hypotension is closely associated with survival in this murine model of septic shock. Delay in antibiotic treatment results in the persistence of inflammatory/stress markers even after antibiotic treatment is initiated.

Abstract-Persistent vasodilation characteristic of septic shock may result from overproduction of nitric oxide and can lead to pressor-refractory hypotension and death. To evaluate the significance of cytokine-inducible nitric oxide synthase (iNOS) in the pathogenesis of sepsis, we used a clinically relevant mouse model of sepsis and compared mortality and microvascular reactivity in wild-type (WT) mice and transgenic mice deficient in iNOS. WT C57BL/6 and iNOS-deficient mice were made septic by cecal ligation and puncture. Treated mice were given fluids and antibiotics every 6 hours. Microvascular vasoconstriction in response to topical norepinephrine was measured in cremasteric arterioles (15 to 30 m) by videomicroscopy. Mortality at 48 hours was significantly lower in treated septic iNOS-deficient mice (45%) than in treated septic WT mice (76%), untreated septic iNOS-deficient mice (87%), or untreated WT mice (100%) (PϽ0.01). Norepinephrine-induced vasoconstriction was decreased in WT septic mice (EC 50 200Ϯ56 nmol/L) compared with WT and iNOS-deficient shams (16Ϯ4 and 13Ϯ6 nmol/L), and vasoconstriction was significantly improved in septic iNOS-deficient mice (35Ϯ13 nmol/L, PϽ0.01). Microvascular catecholamine responsiveness and survival were improved in iNOS-deficient mice in a clinically relevant model of sepsis, suggesting that iNOS plays an important, but not exclusive, role in refractory vasodilation in patients with septic shock. (Circ Res. 2000;86:774-779.)Key Words: sepsis Ⅲ vascular reactivity Ⅲ nitric oxide Ⅲ inducible nitric oxide synthase Ⅲ videomicroscopy T he characteristic hemodynamic abnormality in septic shock is persistent vasodilation with a normal or high cardiac output, which results in hypotension, hypoperfusion, and a high mortality. This vasodilation is often refractory to vasopressor therapy with catecholamines. Nitric oxide (NO), a potent endogenous vasodilator, has been implicated in vascular relaxation and hypotension in sepsis. 1 NO is synthesized from L-arginine by the enzyme NO synthase (NOS), which has constitutive and inducible isoforms encoded by distinct genes. 2 The inducible NOS isoform (iNOS) is present in macrophages, hepatocytes, and vascular smooth muscle cells; is regulated at the transcriptional level; and releases large amounts of NO in a sustained fashion after stimulation with mediators associated with sepsis, such as endotoxin, tumor necrosis factor, interleukin-1, interleukin-2, and interferon-␥. 2 Overproduction of NO by activation of iNOS has been well documented both in animal models of sepsis and in septic patients. [3][4][5][6] The vasodilatory effects of NO have been implicated in both the vascular relaxation associated with hypotension in sepsis 1,7 and in refractoriness to vasopressor catecholamines. 8,9 The major determinant of vascular resistance in the systemic circulation is the tone of resistance arterioles, as the principal pressure drop in the vascular tree occurs at the level of the microvasculature. 10 Previous studies in our laboratory have u...

We present our experience of fine-needle aspiration (FNA) cytology of the thyroid in a community hospital setting and discuss the cancer probability of the indeterminate FNA results. There were 1,621 FNAs, 401 of which have follow-up thyroidectomies during a 10-yr period. The initial FNA diagnoses of these 401 cases were benign non-neoplastic (BNN) 159, malignant 34, atypical 33, suspicious 19, follicular neoplasm (FN) 88, follicular lesion (FL) 51, and inadequate 17. There were no false-positive cases. Cancer was found in 11 cases diagnosed as BNN (7%), 6 cases were due to sampling errors (incidental microcarcinomas), and 5 cases were due to failure to identify focal atypia in the smears of a follicular variant of papillary carcinoma. The false-negative rate was 3%, with the exclusion of cases of incidental microcarcinomas. Among the indeterminate FNA results, the follow-up operations revealed malignant tumors in 16 of 33 (48%) cases of atypical, 13 of 19 (68%) cases of suspicious, 29 of 88 (33%) cases of FN, and 7 of 51 (14%) cases of FL. Malignant tumors were also found in 2 of 17 (12%) of inadequate specimens with follow-up. When compared to the cancer rate (3%) for FNA diagnosis of BNN, the likelihood of finding cancer in the thyroidectomy is 5 times more for a FL, 11 times more for a FN, 16 times more for atypical, and 23 times more for suspicious. The sensitivity and specificity are 87 and 100%, respectively.