The use of muscle biopsy in the diagnosis of systemic vasculitis affecting small to medium-sized vessels: a prospective evaluation in Japan.

OBJECTIVES: The aim of this study was to assess the use of muscle biopsy for histopathological confirmation of small vessel vasculitis (SVV) or medium vessel vasculitis (MVV). METHOD: Muscle biopsies were performed for all consecutive cases of suspected SVV or MVV seen at Tokyo Metropolitan Tama Medical Centre between February 2012 and May 2014 except those for which a skin or renal biopsy was indicated. RESULTS: Forty-nine patients underwent muscle biopsies. All patients were followed for a minimum of 6 months. Diagnosis of SVV or MVV was made in 35 patients. An unrelated condition was diagnosed in 11 patients and no diagnoses were made in three patients. Of the 35 patients in whom SVV or MVV was diagnosed, positive muscle biopsies were obtained in 20 patients [15 microscopic polyangiitis (MPA), three polyarteritis nodosa (PAN), and two eosinophilic granulomatosis with polyangiitis (EGPA)], while other findings led to the same diagnosis in 15 (seven MPA, four GPA, three PAN, and one rheumatoid vasculitis). The sensitivity of the muscle biopsy was 57% [20/35; 95% confidence interval (CI) 50-57]. Of 13 patients presenting with peripheral neuropathy, the muscle biopsy demonstrated vasculitis in nine patients, with 75% sensitivity (9/12; 95% CI 69-75). There were no complications in the procedure apart from delayed wound healing in one patient. CONCLUSIONS: Muscle biopsy is a safe method that offers a high diagnostic yield for SVV or MVV, especially in patients with vasculitic neuropathy.

Altered Mayer wave and baroreflex profiles in high spinal cord injury.

Spinal sympathetic neurons are distributed in cord segments from Th1 to L3. High spinal cord injury demonstrates severe orthostatic hypotension, but not lower cord injury. It remains to be clarified as to where is the critical spinal level disturbing neural cardiovascular regulations in response to orthostatic stress. To address this issue, beat-to-beat blood pressure (BP) (measured using a Finapres device) and RR interval (measured electrocardiographically) were recorded at rest and in a 60 degree head-up position in 26 patients with varying levels of spinal cord injury (C4 to Th12) and in 15 healthy (control) subjects. Sympathetic vascular tone was examined by the Mayer wave power spectrum of systolic blood pressure (SBP) variability. Baroreflex sensitivity was examined by transfer function analysis of SBP and RR interval variabilities. The Mayer wave power spectrum increased in response to postural shift in most patients injured at Th4 or below, whereas this parameter either remained unchanged or decreased in patients with higher-level injury. Baroreflex sensitivity tended to decrease with postural shift in patients injured at Th3 or below, whereas this parameter increased in all patients with higher-level injury. We divided spinal patients into high-level injury (Th3 or above, n = 14) and low-level injury (Th4 or below, n = 12) groups. Systolic blood pressure significantly fell (-10 +/- 4 mm Hg, P < .05) with postural shift in high-level injury group but did not change in low-level injury group or in control subjects. The low-level injury group and the control group demonstrated essentially similar autonomic nervous responses to postural shift, ie, a significant increase in Mayer wave power and an insignificant decrease in baroreflex sensitivity. On the contrary, the high-level injury group showed opposite responses, ie, an insignificant decrease in Mayer wave power and a significant increase in baroreflex sensitivity in response to postural shift. We conclude that spinal cord injury at Th3 or above eliminates normal neural cardiovascular responses to mild orthostatic stress in humans.

Influence of night shift work on psychologic state and cardiovascular and neuroendocrine responses in healthy nurses.

Night shift work has often been associated with increasing degree and frequency of various psychologic complaints. The study examined whether psychologic states after night work are related to adaptive alterations of the cardiovascular and neuroendocrine systems. We studied 18 healthy nurses (age 29+/-2 years) engaged in a modified rapid shift rotation system (day work, 8:15-17:15; evening work, 16:00-22:00; night work, 21:30-8:30). Blood pressure, heart rate, RR interval variability (L/H and HF power spectrum for sympathetic and vagal activities), and physical activity were measured using a multibiomedical recorder for 24 h from the start of work during the night and day shifts. Plasma ACTH and cortisol concentrations were measured at the end of each shift and at 8:30 AM on a day of rest. Each subject's psychologic state was assessed using a validated questionnaire. Among the parameters measured, scores for confusion, depression, anger-hostility, fatigue and tension-anxiety were highest, and scores for vigor lowest, after a night shift. Systolic blood pressure and heart rate during work were lower during night shift than during day shift (119+/-2 vs. 123+/-1 mmHg, p<0.05 and 75+/-1 vs. 84+/-2 bpm, p<0.001, respectively). Both parameters were lower still (p<0.005 and p<0.05) when measured outside of the hospital under waking conditions following a night shift than following a day shift, even though the levels of physical activity were similar. The HF power spectrum of RR interval variability was greater not only during work (24.2+/-2.1 vs. 18.5+/-1.8 ms, p<0.005) but also during the awake period (29.1+/-2.5 vs. 24.4+/-2.6 ms, p<0.005) after the night shift compared with the day shift. Plasma ACTH and cortisol concentrations were lower after night work than in the day of rest (7.3+/-1.2 vs. 11.5+/-2.3 pg/ml, p<0.1 and 11.1+/-1.1 vs. 14.4+/-1.1 mg/dl, p< 0.05). Systolic and diastolic blood pressures during night shift work and the subsequent awake period correlated positively with scores for vigor and negatively with scores for confusion (p<0.05). Plasma ACTH and cortisol concentrations did not correlate with any psychologic scores. We conclude that psychologic disturbances after night work were associated with altered cardiovascular and endocrine responses in healthy nurses. Some of the psychologic complaints may be attributable to lower waking blood pressure.

Type A behavior is associated with an increased risk of left ventricular hypertrophy in male patients with essential hypertension.

OBJECTIVE: To determine whether type A behavior, which is associated with a risk of coronary heart disease, affects left ventricular hypertrophy in patients with essential hypertension. DESIGN: Cross-sectional study of 88 untreated patients with mild to moderate essential hypertension (33 men, mean +/- SEM age 54 +/- 1 years). METHODS: We measured the type A behavior score using a standardized questionnaire, left ventricular mass index using M-mode echocardiography and 24 h mean ambulatory blood pressure (recorded every 30 min). Beat-to-beat blood pressure was also measured using a Finapres device in patients at rest and during mental stress (counting backward) to determine the blood pressure response to stress. RESULTS: The left ventricular mass index was correlated with the type A behavior score (r = 0.214, P < 0.05), age (r = 0.266, P < 0.05), 24 h mean systolic and diastolic blood pressures (r = 0.391, P < 0.001, and r = 0.382, P < 0.001, respectively), systolic blood pressure both at rest and during stress (r = 0.255, P < 0.05, and r = 0.215, P < 0.05, respectively), and the variability of both systolic and diastolic blood pressures at rest (r = 0.253, P < 0.05, and r = 0.321, P < 0.01, respectively). Stepwise multiple linear regression analysis demonstrated that age was associated with an increase in the left ventricular mass index for both sexes (P = 0.004 for males, P = 0.003 for females). The type A behavior score predicted a greater increase in left ventricular mass index in men (P = 0.018) but not in women. The 24 h mean systolic blood pressure was associated with a greater increase in left ventricular mass index in women (P < 0.001) but not in men. CONCLUSION: Type A behavior is an independent risk factor for left ventricular hypertrophy in male patients with essential hypertension.

Psychobehavioral factors involved in the isolated office hypertension: comparison with stress-induced hypertension.

OBJECTIVE: To investigate the psychobehavioral factors involved in the isolated clinic blood pressure elevation and hypertension induced by mental stress. DESIGN AND METHODS: We studied 73 untreated patients with essential hypertension defined as World Health Organization stage I or II (28 men and 45 women, mean age 55 +/- 11 years). The amount of isolated clinic blood pressure elevation was examined in terms of the difference between clinic and daytime ambulatory blood pressures. Blood pressure (measured using a Finapres device) and R-R interval (measured electrocardiographically) were continuously monitored with subjects at rest and under mental stress (counting backward) to examine the cardiovascular response to the stress. Psychobehavioral characteristics such as anger, anxiety, tension, type A behavior pattern, and nervousness were evaluated and scored using structured interviews and self-reporting questionnaires. RESULTS: The anger score was inversely correlated to the clinic-ambulatory blood pressure difference for the systolic (r = -0.308, P < 0.01) and diastolic (r = -0.233, P < 0.05) blood pressures. The score for type A behavior pattern tended to be inversely correlated to the clinic-ambulatory blood pressure difference for diastolic blood pressure (r = -0.209, P < 0.1). The nervousness score was positively correlated to stress-induced increase in the systolic (r = 0.249, P < 0.05) and diastolic (r = 0.232, P < 0.05) blood pressures. The clinic-ambulatory blood pressure difference was not related to the blood pressure rise induced by mental stress (r = 0.170 for systolic blood pressure; r = 0.112 for diastolic blood pressure). CONCLUSION: The isolated clinic blood pressure elevation and hypertension due to mental stress were related to different psychobehavioral factors.

Circadian blood pressure rhythm in patients with higher and lower spinal cord injury: simultaneous evaluation of autonomic nervous activity and physical activity.

OBJECTIVE: To examine the relationships among the circadian rhythms of blood pressure, autonomic nervous function, and physical activity of patients with varying levels of spinal cord injury. DESIGN AND METHODS: We studied 19 patients with spinal cord injury [10 tetraplegic patients with cervical cord injury (C4-C7), and nine paraplegic patients with thoracic cord injury (Th6-Th12)] compared with 16 control subjects. A new multibiomedical recorder was used to measure blood pressure (every 30 min), cardiac vagal activity (hourly frequency of R-R50), and physical activity (integrated acceleration/min) for 24 h under hospital conditions. Systemic sympathetic nervous activity and sympathoadrenal functioning were assessed by examination of hormone levels in the blood. RESULTS: Daytime and night-time values were compared; the variations in systolic and diastolic blood pressures and heart rate were slight in members of the tetraplegia group, but almost normal differences were observed in members of the paraplegia group. The circadian profile of cardiac vagal activity was normal for both patient groups, suggesting that an alteration in the sympathetic nervous rhythm had occurred in the tetraplegic patients. The plasma norepinephrine level was lower in members of the tetraplegia group than it was in members of the control group (P< 0.001), but was normal in members of the paraplegia group. The plasma level of epinephrine was lower in members of the tetraplegia (P< 0.05) and the paraplegia (P < 0.1) groups than it was in members of the control group. Daytime physical activity of members of both groups of patients was lower than that of subjects in the control group (P< 0.001 for both). CONCLUSION: The central sympathoexcitatory pathway to the upper thoracic cord plays a critical role in the maintenance of normal circadian blood pressure rhythm in humans. Motor nerve functioning and sympathoadrenal secretion are not essential to this regulation.

Dopamine tonically modulates natriuresis in the saline-expanded dogs.

Dopamine (DA) has been shown to be an endogenous catecholamine that promotes natriuresis by activating tubular DA receptors, but its role on natriuresis appears to be equivocal, and the precise mechanisms and signaling pathway of multiple DA's receptor subtypes are not yet clarified. We used low dose of DA intravenously in saline (S) volume-expanded dogs to see the alterations in natriuresis. The results showed that there is a critical dose that induces no enhancement of natriuresis of volume expansion, and that the lower and higher doses of DA produced relatively larger natriuresis. Pretreatment of metoclopramide (MCP) in this settings caused even higher and significant increases of natriuresis. In conclusion, DA seems to determine tonically the level of natriuresis in saline-expanded dogs. DA may exert a dual effect on signal transduction pathways such that one leading to antinatriuresis with high affinity and the other to natriuresis with low affinity signaling cascades for DA. MCP may block the antinatriuretic limb of the signaling pathway.

Electrophysiological study of L-lysine transport across Triturus proximal tubule: evidence for Na(+)-independent entry and Na(+)-dependent exit.

Cell membrane depolarization induced by intraluminal injection of lysine was entirely independent of the presence of Na+ in Triturus proximal tubule, confirming our previous observation. The amplitude of the depolarization conformed to Michaelis-Menten kinetics regardless of the presence or absence of Na+ in the perfusion solutions. pH of the intraluminal solution had no effect on the electrical response in its range from 5.5 to 8.5. In a Na(+)-free medium, particularly in a Tris-substituted medium, the depolarization induced by a constant concentration of lysine gradually decreased in its size when injection followed by washout of lysine was repetitively tested. The addition of Na+ to the peritubular side after extinction of the responsiveness resulted in a significant restoration of the voltage response to intraluminal lysine. In addition, influx of Na+ from the peritubular fluid into the cells was significantly greater in lysine-loaded tubules than in nonloaded tubules as indicated by a greater rate of increase in intracellular Na+ activity in the presence of ouabain. The data strongly suggest that lysine enters the cells via an electrogenic uniport mechanism and leaves the cells via Na+:amino acid exchange transport mechanism.

Medroxyprogesterone acetate for lung cancer.

A 70-year-old man having severe ischemic heart diseases developed bilateral, duplicate lung cancer of large cell and squamous cell types. Chemoimmunotherapy consisting of carmofur, picibanil inhalation, i.m. sizofilan, and peroral bestatin was started, and 3 months later, peroral medroxyprogesterone acetate was added. The tumor regressed, and the patient survived more than 34 months. This type of nonaggressive regimen may thus be useful for tumors other than adenocarcinomas, too.

ST segment changes under occlusion of the proximal portion of major coronary arteries in the isolated canine heart.

We studied the mechanisms of ST segment displacement in the ECG recorded from the epi- and subendocardium of ischemic ventricles in the isolated and perfused canine heart. ST segment changes were observed in association with a relatively large area of ischemia produced by occlusion of the left anterior descending and septal arteries (LAD + Sept.) or of the left circumflex artery (LCx). Contrary to previous reports, we found that the amount of subendocardial ST elevation was not always greater than that in the epicardial ECG recorded at the center of ischemia. Also, in the non-ischemic area, the degree of the ST depression in the subendocardial record was nearly the same as the epicardial record. On the other hand, the degree of the epicardial ST elevation on the border zone was always smaller than that at the ischemic center, which seemed to be due to the broadness of the border zone. The amplitude of the ST depression in the non-ischemic area was greater when the recording electrode was near the ischemic border, which supports the solid angle theory. The degrees of both ischemic ST elevation and reciprocal ST depression in the LCx perfused area were always greater than in the LAD + Sept. perfused area. These results strongly suggest that ST segment displacement depends on the relative position of the recording electrode to the electric double layer which exists at the border between the ischemic and non-ischemic area.

Mechanical interaction between the ventricles.

We investigated ventricular interaction by the use of six excised, perfused, canine hearts. In this preparation, we could change the filling pressure of the right and left ventricles independently, thereby breaking the normal series-pump arrangement. We found that mechanical ventricular interaction exists in diastole and in systole. Namely, not only decreased diastolic ventricular compliance, but also the reduced performance in either ventricle was found, when the opposite ventricular pressure was increased. Thus, when the opposite ventricular filling pressure increases, we suspect that systolic ventricular function of either ventricle will be depressed significantly by these two factors; i.e., the Frank-Starling effect due to decreased ventricular diastolic volume following decreased diastolic ventricular compliance, and the depressed systolic ventricular function. Clinically, these findings may be important in considering the mechanism of the occurrence of simultaneous reduced performance of both ventricles in cases when only one side of the ventricle is affected hemodynamically and its filling pressure is greatly increased in various pathological states such as heart failure.

A comparison of left ventricular volume-pressure relations of excised perfused canine hearts in isovolumic contraction, arrest and fibrillation.

The purpose of the present investigation was to study the effects of various conditions such as beating, arrest and fibrillation on left ventricular (LV) diastolic compliance. In coronary-arterially perfused canine isolated hearts, LV volume-pressure (v-p) relations for both inflation and deflation were obtained by infusing and withdrawing a saline. The v-p curves of inflation and deflation were both sigmoidal, but the resultant v-p relations for deflation produced a shift to the left inflation curves, showing hysteresis between inflation and deflation in three ventricular states. The effect of arrest or fibrillation, especially of fibrillation, on LV distensibility was discernible, and the resultant v-p relations produced a marked shift to the right, showing an apparent decrease in LV volume (LVv) at a given filling pressure. It was concluded that it is very questionable to identify the stiffness of the beating heart with the non-beating heart.

The effect of graded coronary flow reduction in the left anterior descending and septal arteries on left ventricular function in the canine heart.

WE quantitatively analyzed the effect of graded left anterior descending and septal coronary flow (LAD + septal flow) reduction on left ventricular function with a left ventricular end-diastolic pressure (LVEDP) of 6 mm Hg and 12 mm Hg. We used an isolated, ejecting, canine heart preparation ( n = 8), the coronary flow of which could be controlled independently of the aortic pressure. We kept the other hemodynamic variables - heart rate, left circumflex coronary flow, right coronary flow and aortic input impendance - constant within their normal physiologic range. We considered this reduction in LAD + septal flow to be analogous to that of the most frequent lesion in ischemic heart disease. There was no plateau in the left ventricular work caused by this reduction of the regional coronary flow. Therefore, the plateau commonly reported in previous studies may be partially a result of the compensatory elevation of LVEDP, which is necessary to maintain the left ventricular work.

Effects of changes in the aortic input impedance on systolic pressure-ejected volume relationships in the isolated supported canine left ventricle.

We examined the effects of aortic input impedance alteration on left ventricular pressure, aortic flow and ejected volume (integral value of aortic flow), in an isolated blood perfused ejecting canine heart, with special reference to end-systolic values. A hydraulic model which stimulates an aortic input impedance was attached to the aortic root of an excised heart. Left ventricular end-diastolic pressure was kept constant by electrical pacing. Three coronary arteries were perfused with arterial blood from support dogs. When the peripheral resistance in the hydraulic model was changed, there were inverse linear relationships between stroke volume and mean left ventricular systolic pressure and between ejected volume and pressure at end-systole. Time interval from the onset of contraction to end-systole did not change. Thus the relation between stroke volume and mean left ventricular pressure obtained by changes in peripheral resistance is governed by a source resistance, which can be considered as the contractile state of the ventricle. When the capacitance (arterial compliance) was changed, there was no inverse linear relation between stroke volume and mean systolic pressure. In many cases, there was an inverse linear relationship between ejected volume and pressure at end-systole. However, an increase in capacitance prolonged the time interval from the onset of contraction to end-systole. We conclude that the end-systolic pressure-ejected volume relationship in the ejecting heart is governed not only by contractility but also by arterial capacitance.

Energy transduction and adenine nucleotides in mitochondria from rat liver after hypoxic perfusion.

The characteristics of mitochondria isolated from perfused livers of rats under hypoxic or oxic conditions were studied. The electron transfer activity was about 60% of normal after hypoxic perfusion for 3 h, but respiratory control was abolished almost completely. These parameters recovered considerably on subsequent oxic perfusion. The adenine nucleotide contents and their net uptake decreased in hypoxia, closely correlated with the energy transduction. Energy-dependent nicotinamide nucleotide transhydrogenase activity and NAD reduction by succinate in submitochondrial particles were most severely inhibited after hypoxic perfusion and were also correlated with adenine nucleotide contents in the particles. These results are discussed in terms of the involvement of adenine nucleotides in energy-transducing systems in mitochondrial membranes.