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Background— The American Heart Association 2010 resuscitation guidelines recommended adding a fifth link (multidisciplinary postresuscitation care in a regional center) to the previous 4 in the chain of survival concept for out-of-hospital cardiac arrest. Our study aimed to determine the effectiveness of this fifth link. Methods and Results— This multicenter prospective cohort study involved all eligible out-of-hospital cardiac arrest patients in the Aizu region (n=1482, suburban/rural, Fukushima, Japan). Proportions of favorable neurological outcomes were evaluated before (January 2006–April 2008) and after (January 2009–December 2010) the implementation of the fifth link. After implementation, all patients were transported directly from the field to the tertiary-level hospital or secondarily from an outlying hospital to the tertiary-level hospital after restoration of circulation. The tertiary hospital provided intensive postresuscitation care, including appropriate hemodynamic and respiratory management, therapeutic hypothermia, and percutaneous coronary intervention. One-month survival with a favorable neurological outcome among all patients treated by emergency medical services providers improved significantly after implementation (4 of 770 [0.5%] versus 21 of 712 [3.0%]; P Conclusion— The proportion of out-of-hospital cardiac arrest patients with a favorable neurological outcome improved significantly after the implementation of the fifth link, which may be an independent predictor of outcome. Clinical Trial Registration— URL: http://www.apps.who.int/trialsearch . Unique identifier: UMIN000001607.

We would like to thank Mark and colleagues for their thoughtful comments on our study. 1 About their first concern, we agree with the concept that the rate of intensive care unit admission correlates with the patients’ favorable outcome. However, we did not include intensive care unit admission as a predictor variable in the multivariable analysis because the purpose and intervention of the current study was to evaluate the effectiveness of the “fifth link,” a multidisciplinary postresuscitation care bundle that cannot be performed without intensive care unit admission. Therefore, it is not surprising that the intensive care unit admission rate increased as a result of the intervention. We also appreciate their letter for giving us the opportunity to provide …

In order to clarify the role of the kallikrein-kinin system in the hypotensive mechanisms of converting-enzyme inhibition, captopril was administered in a single oral dose of 50 mg to 17 hypertensive patients, of whom 14 had essential hypertension, one had chronic renal failure, one had primary aldosteronism, and one had glucocorticoid responsive hyperaldosteronism. Captopril lowered blood pressure remarkably in either low-renin or normal-, and high-renin hypertensives, however, there was no significant relationship between the fall in blood pressure and pretreatment levels of plasma renin activity (PRA) in any of the patients any time after the administration. PRA was significantly increased in normal- and high-renin hypertensives but not in low-renin patients. Plasma aldosterone concentration (PAC) was decreased significantly in normal- and high-renin patients, while no significant change in PAC was observed in patients with low-renin activity. Captopril elevated plasma bradykinin concentration (PBK) from a control value of 12.5 +/- 4.1 (mean +/- s.d.) to 20.3 +/- 7.7 pg/ml (p less than 0.001) at 30 min, and there was a significant correlation between changes in PBK and changes in mean blood pressure 120 min after the administration in all the patients (r = 0.741, p less than 0.01, n = 17). In one patient with primary aldosteronism, PBK increased from a baseline of 10.0 to a maximum value of 19.0 pg/ml, corresponding to the rapid fall in blood pressure. Also, in one patient with glucocorticoid responsive hyperaldosteronism, captopril increased PBK from a control of 14.1 to 27.9 pg/ml at 30 min, corresponding to the marked fall in blood pressure from 170/106 to 136/90 mmHg. From these findings, it is suggested that the accumulation of kinins following captopril administration plays a major role in the short-term reduction of blood pressure in hypertensive patients, especially in those with low renin-angiotensin activity.

In low-renin hypertensive patients, the acute effect of the angiotensin I-converting enzyme inhibitor, captopril, was evaluated in relation to the response of plasma bradykinin (PBK) levels as a parameter of its inhibitory effect on kininase II. Captopril significantly lowered the blood pressure and increased PBK levels. While there was no significant relationship between the reduction of blood pressure and pretreatment plasma renin activity, a significant correlation was observed between the antihypertensive effect of captopril and changes in PBK (r = -0.834, p less than 0.01, n = 10). Furthermore, in a patient with primary aldosteronism and, also, in a patient with glucocorticoid responsive hyperaldosteronism, captopril increased plasma PBK with reduction of the blood pressure. It is likely, therefore, that in low-renin hypertension, the vasodepressor effect of acute converting enzyme inhibition is due mainly to kinin accumulation rather than inhibition of angiotensin II formation.

Angiotensin-converting enzyme activity in six areas of the brain (cerebral cortex, midbrain, thalamus, hypothalamus, striatum, and cerebellum) and subcellular fractions of the aorta (homogenate, mitochondria, microsomes, and supernatant) was determined in both normotensive and renal hypertensive rats [Goldblatt one-clip, one-kidney (1-c, 1-k) and one-clip, two-kidney (1-c, 2-k) hypertensive, and two-clip, two-kidney (2-c, 2-k) hypertensive rats]. Converting-enzyme activity was relatively high in the thalamus and relatively low in the cerebellum in normotensive and renal hypertensive rats. The enzyme activity in the hypothalamus of Goldblatt 1-c, 2-k rats was significantly higher than that of normotensive and other renal hypertensive rats. However, there was no significant difference in the enzyme activity in each brain area among normotensive, Goldblatt 1-c, 1-k hypertensive and 2-c, 2-k hypertensive rats. The enzyme activity of the supernatant from aortic subcellular fractions was extremely high in normotensive and renal hypertensive rats. However, the enzyme activity in all aortic fractions from Goldblatt 1-c, 2-k rats was significantly higher than that of normotensive and other renal hypertensive rats. There was no significant difference in the enzyme activity among normotensive, Goldblatt 1-c, 1-k hypertensive and 2-c, 2-k hypertensive rats. Therefore, it is likely that increased angiotensin-converting enzyme activity in the brain and the aorta may play a role in the initiation or the maintenance of hypertension in Goldblatt 1-c, 2-k hypertensive rats.

Suppressor T cell function induced by concanavalin A (con A) was evaluated in patients with Graves' disease and Hashimoto's thyroiditis. Patients with Graves' disease were divided into the following two groups: (1) untreated, and (2) euthyroid during antithyroid drug (methylmercaptoimidazole) therapy. T cells (2 X 10(5)), activated by con A for 48 hours, were added to preincubated responder cells (2 X 10(5)) and re-incubated for 7 days in the presence of pokeweed mitogen (PWM). IgG produced in the culture medium was measured by radioimmunoassay and then % suppressions (IgG) were calculated. Thyroid stimulating activity (TSA) in serum was measured by McKenzie's method by means of normal human thyroid slices, and % suppressions (c-AMP) were calculated. IgG produced in lymphocyte culture medium was suppressed by added con A-activated cells in untreated and euthyroid groups of Graves' disease, Hashimoto's thyroiditis and normal controls. The value of % suppression (IgG) was reduced in each group of Graves' disease compared to normal controls. No significant relation was observed between TSA in serum and % suppression (IgG), but three cases with high serum TSA showed low % suppressions (IgG). In 12 cases of Graves' disease, % suppression (IgG) had a positive relation with % suppression (c-AMP) in same medium. The amount of c-AMP produced in thyroid slices incubated in medium, in which responder cells (8 X 10(5)), was elevated in all 7 untreated cases of Graves' disease, while not elevated in 7 euthyroid cases. The value of % suppression (c-AMP) in euthyroid cases with Graves' disease was significantly higher than that in untreated cases. The value of % suppression (IgG) was reduced and had a significant negative relation with logarithm of serum antimicrosomal antibody titer in patients with Hashimoto's thyroiditis. These results indicate that low activity of suppressor T cell had a role on antibody production, including thyroid stimulating antibody, and pathogenesis of autoimmune thyroid diseases.

The angiotensin I-converting enzyme in normal human urine was partially purified with ammonium surfate (3.2M), DEAE-Cellulose ion exchange chromatography (0-0.5M NaCl gradient), and Sephadex G 200 gel filtration. The enzyme was separated into three forms which had different molecular weights of 700000, 290000 and 40000, respectively. The enzymic biochemical characteristics of these three enzymes, however, were identical with regard to their inhibitory effects (bradykinin potentiator c, arg-pro-pro, o-phenanthroline and EDTA), Cl- dependency, optimal pH (8.3) and temperature (37 degrees C), and Km value (2.3mM). The enzymic activity was determined in five normal subjects in three conditions of dietary sodium intake (51, 153 and 340mEq for 5 days, respectively). The enzymic activity correlated well with the concentration of the excreted sodium (r = 0.87, p less than 0.001). There was no significant relation between the enzymic excretion and the concentration of the excreted potassium, nor between the activity and the creatinine excretion. It is suggested that the origin of urinary angiotensin I-converting enzyme is the kidney, and that the enzyme might regulate sodium excretion in cooperation with renal kallikrein-kinin system.

1) Renin-like enzyme of rat aorta was purified by chromatography with DEAE-cellulose and Sephadex G-200. 2) The molecular weight of renin-like enzyme was 124,000 and 72,000 on Sephadex G-200 gel filtration. The isozymes, however, migrated as a single band with molecular weight of 71,000 on SDS/polyacrylamide gel electrophoresis. These isozymes showed the same optimal pH (6.5) and temperature (37 degrees C). 3) Renin-like enzyme showed high activity in the microsomal fraction of the aorta. 4) In one-clip, two-kidney Goldblatt hypertensive rats, the aortic renin concentration increased significantly, but not parallel with the activity in plasma. 5) Renin, widely distributed in subcellular fractions of the aorta, may play a possible role in the local control of vascular tone. It is likely that renin in vascular wall is of local origin.

In order to estimate the modulatory activity of Prostacyclin (PGI2 ) to the vascular reactivity, pressor responses to angiotensin II (A II) and noradrenaline (NA) and PGI2 generation of aorta were measured using the rats of sodium loading or of sodium depletion. On the sodium loading, the blood pressure increased gradually and plasma renin activity (PRA) and plasma aldosterone concentration (PAC) were decreased. The pressor responses to A II and NA were enhanced by sodium loading. The PGI2 generation of aorta was enhanced at the initial stage of sodium loading and decreased thereafter. The increased generation of PGI2 may represent the adaptive mechanism for the attenuation of the sustained elevation in blood pressure. In sodium depletion, the pressor responses to A II and NA were decreased, and PRA and PAC were elevated. PGI2 generation of aorta was also increased. These findings suggested that PGI2 could participate in blood pressure control mechanism on sodium loading and depletion.

Angiotensin-converting enzyme activity of the aortic subcellular fractions (homogenate, mitochondria, microsomes and supernatant) was determined in normotensive and experimental hypertensive rats (1-clip, 1-kidney Goldblatt hypertensive; 1-clip, 2-kidney Goldblatt hypertensive and 2-clip, 2-kidney hypertensive rats). The systolic blood pressure markedly elevated in each group of experimental hypertensive rats, while it did not in normotensive rats. Angiotensin-converting enzyme activity was consistently high in the microsomal and supernatant fractions of the aorta in experimental hypertensive rats as well as in normotensive rats. However, the enzyme activity from each fraction of the aorta in 1-clip, 2-kidney Goldblatt hypertensive rats was significantly higher than that in normotensive and other experimental hypertensive rats. There was no significant difference in the enzyme activity among normotensive, 1-clip, 1-kidney Goldblatt hypertensive and 2-clip, 2-kidney hypertensive rats. The angiotensin-converting enzyme, widely distributed in subcellular fractions of the aorta, may play a possible role in the local control of vascular tone. It seems likely that increased angiotensin-converting enzyme activity in arterial tissue contributes to the initiation or development of hypertension in 1-clip, 2-kidney Goldblatt hypertension in rats.

Captopril, an orally active angiotensin-converting enzyme (ACE) inhibitor, was administered to three patients in an active stage of sarcoidosis. The serum ACE level, aldosterone concentration in plasma and blood pressure decreased rapidly after administration, while plasma renin activity was not significantly changed. It is suggested that inhibition of ACE by captopril offers a possible therapeutic approach to the treatment of sarcoidosis.