Minutes In Normal Subjects Research Articles

Reaction Test for Competence in Visual Pathway Lesions

Performance in the visual environment was evaluated with a central fixation or a search target in 11 positions within 34° on a CRT, superimposed on a landscape. Reaction times were recorded. We examined 24 patients aged 26–83, with lesions of the visual pathways and homonymous visual field defects, and 18 normal subjects aged 23–79. This simple test takes about 1 minute in normal subjects and four or more minutes in neurological patients. The test may be used to quantify saccadic adaptation to disability from homonymous field defects and to monitor the training effects of visual rehabilitation.

Somatostatin and analogues in portal hypertension

Somatostatin (SST) is a 14–amino acid peptide first isolated 30 years ago from the hypothalamus as a growth hormone–inhibitory substance.1 Since then, SST has been extensively studied and has been found to exert a variety of biologic effects. SST inhibits the secretion of a number of hormones in the gastrointestinal tract and endocrine pancreas. Some of these hormones, particularly glucagon, have been shown to contribute to the maintenance of portal hypertension.2 This property provided the rationale for the introduction of SST in hepatology for the treatment of variceal bleeding.3 Five SST receptors (SSTR 1-5) have been cloned to date,4 but information about their tissue distribution is scarce. It has been suggested that human blood vessels and pancreatic islets express predominantly SSTR-2,5 but receptor pattern may vary between different vascular territories. This has not been thoroughly evaluated. Also, the recent finding that hepatic stellate cells express SSTR-1, -2, and -3 in cirrhotic rat liver, but not in normal liver,6 requires confirmation in humans because there are species differences in receptor distribution. SST has a very short half-life, 1 to 3 minutes in normal subjects,7 and must be administered as a continuous infusion. This prompted the search for analogues with longer half-lives. Several hundred were synthesized, but only the cyclic octapeptides octreotide (OCT), lanreotide, and vapreotide have become available.8 OCT, with a half-life of 2 hours, was the first SST analogue introduced in clinical practice. It can be administered subcutaneously and it is much more potent than native SST inhibiting growth hormone, glucagon, and insulin.9 Half-lives of SST and OCT are prolonged in elderly patients and patients with renal and liver failure.7,10-12 SST analogues have different receptor affinities as compared with the natural compound (Fig. 1). Although SST binds equally to all 5 receptors, OCT binds with high affinity to SSTR-2 and -5, with moderate affinity to SSTR-3, and does not bind to SSTR-1 or -4. Vapreotide and lanreotide have a similar profile, but they bind to SSTR-4 with intermediate affinity.9 These distinct binding affinities may translate in some differences in their effects in cirrhotic patients.

Inhibition of tissue factor pathway during intermittent pneumatic compression: A possible mechanism for antithrombotic effect.

Intermittent pneumatic compression (IPC) devices are an effective prophylaxis against lower extremity deep vein thrombosis. Their antithrombotic effect has been attributed to a reduction in venous stasis and enhanced fibrinolysis. The initiating mechanism for blood coagulation is the tissue factor (TF) dependent pathway, which is inhibited by tissue factor pathway inhibitor (TFPI). We have investigated the effect of IPC on the TF pathway in 6 normal subjects and 6 patients with postthrombotic venous disease undergoing IPC for 120 minutes; all subjects were studied with each of 5 IPC devices. In normal subjects and patients, plasma factor VIIa (FVIIa) activity (the activated form of factor VII [FVII]) declined from mean values ranging 51 to 65 and 50 to 53 mU/mL before IPC with different devices to 10 to 13 and 20 to 22 mU/mL at 180 minutes, respectively (P<0.001 for all groups). FVII antigen levels were unchanged. Plasma TFPI (P<0.001) rose from mean baseline values ranging 69 to 79 and 57 to 61 ng/mL to 76 to 123 and 71 to 79 ng/mL at 180 minutes in normal subjects and patients, respectively (P<0. 001 for all groups). Plasma prothrombin fragment F1.2 levels showed minimal changes. There was an inverse relationship between TFPI and FVIIa in normal subjects (r=-0.31, P=0.001) and patients (r=-0.37, P<0.001). IPC results in an increase in plasma TFPI and decline in FVIIa. Inhibition of TF pathway, the initiating mechanism of blood coagulation, is a possible mechanism for the antithrombotic effect of IPC.

The frequency and amplitude of growth hormone secretory episodes as determined by deconvolution analysis are increased in adolescents with insulin dependent diabetes mellitus and are unaffected by short-term euglycaemia.

High overnight plasma growth hormone (GH) levels in insulin-dependent diabetes mellitus (IDDM) are reflected in both an increase in the GH pulse amplitude and elevated baseline GH concentrations. To determine whether these are a result of an increase in GH secretory episodes, we undertook deconvolution analysis of overnight GH profiles using previously determined half-life data. Deconvolution of overnight GH profiles (2000-0800 h) was undertaken from normal and diabetic adolescents (either on their usual insulin regime (n = 15), during overnight euglycaemic clamp using a variable rate insulin infusion (n = 29), or during clamp plus 100 mg pirenzepine to suppress endogenous GH (n = 7)). Thirty-five normal and 29 diabetic adolescents of both sexes at all stages of puberty. GH secretory rates were calculated from deconvolution analysis, and Fourier transformation was increased mean overnight GH secretion when analysed by sex and by puberty stage compared to normal subjects; overnight GH secretion median (range) of diabetic group 1.88 (0.56-3.81) mU/min; control group 0.62 (0.32-1.92) mU/min (P < 0.001). Fourier transform analysis of these secretory episodes showed greater pulse frequency in the diabetics with dominant pulse periodicity of 90 minutes compared with 135 minutes in normal subjects. During overnight euglycaemia, mean +/- SEM overnight GH secretory rates were comparable to subjects' usual regime night (1.82 +/- 0.33 vs 1.91 +/- 0.37 mU/min) and there was no change in the dominant pulse periodicity of 90 minutes. Pirenzepine administration in diabetic subjects significantly reduced overnight GH secretion from 1.57 +/- 0.19 to 0.71 +/- 0.80 mU/min (P < 0.001) showing a median (range) reduction of 63 (9.3-82.8)% when compared to the subjects' clamp night. However, dominant pulse periodicity was not altered by pirenzepine administration, and remained at 90 minutes. In patients with insulin-dependent diabetes mellitus there is an increase in both the amplitude and frequency of pulsatile GH secretion compared to normal subjects, which is not affected by maintenance of overnight normoglycaemia. The anticholinergic drug pirenzepine appears to suppress the amplitude of GH pulse secretion but has no effect on frequency.

Improvement of Capillary Permeability in Patients with Venous Hypertension After Treatment with TTFCA

The VSC (vacuum suction chamber) device, a new system to evaluate local capillary permeability, was used with laser Doppler flowmetry to study variations of permeability and of the microcirculation in 10 normal subjects; in 22 patients with moderate, superficial venous hypertension; and in 12 patients with postphlebitic limbs and severe venous hypertension. All these patients had distal (ankle and foot edema) in the evening. After a first assessment these subjects were studied again after two weeks without treatment and after two weeks' treatment with total triterpenic fraction of centella asiatica (TTFCA), tablets, 60 mg, tid. The VSC produces a wheal on the skin of the perimalleolar region that disappears (in average) in less than sixty minutes in normal subjects. The disappearance time (DT) is greater in conditions of increased capillary filtration and permeability. The three groups of subjects (normal and those with superficial and severe venous hypertension) had significantly different, increasing disappearance time of the wheals at the first observation. There were no significant changes after two weeks' observation, but after 2 weeks' treatment with TTFCA, there was a significant decrease of DT both in limbs with superficial and with deep venous incompetence. The improvement (decrease) of the abnormally increased capillary permeability was associated with a significant improvement of the microcirculation and symptoms (studied by an analogue scale line). In conclusion this study showed a combined improvement of the microcirculation and capillary permeability after treatment with TTFCA and the possibility of using the VSC to evaluate the effects of drugs (or other treatment) on local capillary permeability in patients with venous hypertension.

D-xylose absorption and disposition in patients with moderately impaired renal function.

D-Xylose kinetics were studied after oral and intravenous administration to 10 patients with impaired renal function, three of whom were being evaluated for intestinal malabsorption. The 0.32 +/- 0.06 L/kg (mean +/- SD) distribution volume of D-xylose in patients with uncomplicated renal impairment was larger than the value of 0.23 +/- 0.04 L/kg that we reported previously for normal subjects (P less than 0.01). Renal clearance was also reduced, averaging 87% of glomerular filtration rate estimated from creatinine clearance, so that the elimination-phase half-life was prolonged to 138 +/- 39 minutes from 75 +/- 11 minutes in normal individuals (P less than 0.01). The 25 gm oral D-xylose dose was 77.4% +/- 14.8% absorbed in the patients with uncomplicated renal impairment, similar to the 69.4% +/- 13.6% absorption reported in normal individuals. However, the absorption half-life was prolonged from 31 +/- 12 minutes in normal subjects to a value of 62 +/- 23 minutes (P less than 0.02). Of the usual clinical indexes of D-xylose absorption, the serum concentration measured 1 hour after the oral dose was best correlated with the extent of D-xylose absorption (r = 0.76; P less than 0.01), and the standard lower normal limit of 0.2 mg/ml was satisfactory.

Cholecystokinin metabolism in man and dogs.

We have developed a sensitive, specific and reproducible radioimmunoassay for cholecystokinin (CCK) with which basal levels of CCK of between 400-800 pg/ml have been measured in normal man, in patients with diabetes and with duodenal ulcer disease, and in normal dogs. After a meal, circulating levels of CCK rose to 1000-1200 pg/ml in human subjects. Release of CCK was more rapid in diabetic and duodenal ulcer patients than in normal subjects, but elevated postprandial levels persisted much longer in normal subjects. Patients with the Zollinger-Ellison syndrome had elevated values of cholecystokinin which rose after a meal. Lack of correlation between elevated basal levels of gastrin and CCK in patients with the Zollinger-Ellison syndrome suggest that the hypercholecystokininemia may be absolute. The disappearance half-time of exogenous CCK was about 21/2 minutes in normal subjects as well as in diabetic and duodenal ulcer patients. Studies in dogs demonstrated no uptake of basal levels of cholecystokinin by the kidney; on infusion of exogenous CCK-33, the kidney extracted 43% of the total CCK presented and 56% of the integrated CCK. We conclude that: 1) circulating basal and postprandial levels of CCK may be measured in a reproducible fashion; 2) postprandial release of CCK is more rapid in diabetic and duodenal ulcer patients than in normal man; 3) the disappearance half-time of exogenous CCK in man and dogs is about 21/2 minutes; 4) the kidney is a major site for uptake of CCK.

Insulin metabolism in hypothyroidism.

Insulin resistance has been invoked to explain the glucose intolerance observed in hypothyroid patients. This possibility was studied by determining fractional and metabolic clearances of intravenously administered porcine crystalline insulin (0.1 U./kg.) and its effect on plasma glucose concentration in ten hypothyroid patients, ten normal subjects, and six treated euthyroid patients. Following administration of porcine insulin, serum immunoreactive insulin concentrations during the period of observation were similar in hypothyroid patients, in normal control subjects, and in treated euthyroid patients. Similarly, no significant differences in the mean half-life, distribution space, or fractional and metabolic clearances of insulin were observed among any of the three groups. In response to insulin administration, plasma glucose concentrations declined to the nadir of 36 +/- 4, 43 +/- 3, and 38 +/- 4 mg. per 100 ml. in hypothyroid patients, normal control subjects, and treated euthyroid patients, respectively. Thereafter, plasma glucose steadily increased and approached the baseline value at ninety minutes in normal subjects and treated euthyroid patients. In contrast, the plasma glucose values remained significantly lower than the baseline for the rest of the procedure in hypothyroid patients. The present study demonstrates that there is no evidence of resistance to the action of insulin in hypothyroid patients. The observation of prolonged hypoglycemic action of exogenously administered insulin in hypothyroid patients might in fact suggest increased sensitivity to insulin action. These findings indicate that glucose intolerance of the hypothyroid state is not characterized by insulin resistance.

Clinical studies on regulatory system of thyroid hormone secretion and serum triiodothyronine. Part. I. Solid-state radioimmunoassy for human serum TSH and its clinical application (author's transl)

A solid-state RIA method using a plastic microtiter plate for human TSH was developed: 1) The choice of carrier protein for standard TSH was critical in this method and pooled sera from untreated Graves patients was found to be suitable for this purpose. The mean lowest detectable TSH level was 0.2 muU/assay, which was almost equal to those reported by other methods. This method is superior in simple assay procedure, especially in the separation of bound and free TSH and in the shorter incubation time required in the double antibody method. 2) Serum TSH concentration in 22 normal subjects, 17 patients with Graves' disease, 35 Hashimoto's thyroiditis, 18 primary hypothyrodism, 16 simple goiter, 4 nodular goiter and 7 secondary hypothyroidism was estimated as 4.7 +/- 2.0 muU/ml (mean +/- s.d.), 2.1 +/- 0.2 mu/U/ml, 14.1 +/- 26.5 muU/ml, 211 +/- 177 muU/ml, 3.6 +/- 2.4 muU/ml, 3.2 +/- 2.4 muU/ml and 2.6 +/- 1.0 muU/ml, respectively. 3) A statistically significant and hyperbolic inverse correlation (r= --0.37, N=90) was found between TSH and T4 levels. Some cases with normal T4 level were found to be high in TSH levels. It was also noted that 36 of 65 euthyroid cases (55.4%) who had been treated with 131I for Graves' disease showed elevated TSH levels. 4) After intravenous injection of 500 mug TRH, TSH level reached its peak value of 8 to 32 muU/ml at 15 to 45 minutes in normal subjects. Low to no response was found in patients with Graves' disease. An exaggerated response in patients with primary hypothyroidism to TRH was observed and an inhibitory process in TSH production at the pituitary level was suggested in patients with Cushing syndrome. Hypothyroid patients with pituitary lesion showed low or no response, on the other hand some hypothyroid patients with lesions around the pituitary and hypothalamus showed high basal TSH and exaggerated response to TRH.

Pharmacokinetics of metolazone in normal subjects and in patients with cardiac or renal failure.

The pharmacokinetics of metolazane (Zaroxolyn) have been studied in normal adult volunteers after oral or intravenous administration and after oral administration in patients requiring diuretic therapy fOT severe renal failure, fOT moderate renal failure, and for heart disease. Following intravenous administration in normal subjects, plasma concentration fell in a bi‐exponential fashion. The data were fitted to the two‐compartment open model and the appropriate kinetic parameters were calculated. The drug was faund to be extensively distributed in the tissue compartment, anly one third of the body cantent after equilibrium being in the plasma compartment. The elimination rate constant was 0.13 hr‐1. Clearance of metolazone from the central compartment was approximately equal to creatinine clearance and ranged from 110 ml per minute in normal subjects to 20 ml per minute in severe renal failure. Absorption was 64% in normal controls, hut as little as 40% of the oral dose was ahsorbed in some patients. Abaut 95% of plasma metolazone was bound to plasma pro teins in normal controls. This figure fell to 90% in severe renal failure. About 10% of the dose was excreted in bile by normal subjects.

Effects of repeated tonometry: genuine and sham measurements.

Repeated applanation tonometry every minute in normal subjects gave a direct pressure reduction of about 3 mmHg in five minutes and a lower consensual pressure reduction. Sham measurements had no corresponding effect, nor was the initial IOP reduced after sitting at the tonometer for five minutes before tonometry. The spacing of the measurements and the length of time the applanation body was left on the cornea influenced the decrease curve.—

Clinical studies on ACTH in the blood. 3. Fate of exogenous ACTH in the blood measured by immuoassay and bioassay

After 2 I.U. of ACTH preparations (Organon) being quickly administered intravenously into 3 patients without renal, hepatic and metabolic dysfunctions (normal subjects), 3 patients with hyperthyroidism, 3 patients with hypothyroidism, 2 patients with hepatic diseases and 2 patients with uremia, blood samples were withdrawn 2, 5, 10, 20 and 30 minutes after the end of ACTH administration. Plasma ACTH was measured by a ra-dioimmunoassay using salt-precipitation technique, after having been extracted with the acid-alcohol method. In some of the cases, plasma ACTH was estimated by a modification of the method of Lipscomb and Nelson at a couple of time-points after the ACTH injection. The mean immunological half-life of exogenous ACTH in blood was about 14 minutes in normal subjects, about 33 min. in uremic patients, about 31 min. in patients with hypothyroidism, about 16 min. and 14 min. in patients with hyperthyroidism and hepatic disease, respectively. Therefore, there seemed to be a tendency that immunological half-lives of ACTH were longer in patients with hypothyroidism and uremia than in other cases. In most of the cases, the immunological half-life was longer than the biological one, especially in patients with thyroid disorders. When the biological ACTH level was compared with the immunological one, the former was noticed to be several to 20 times higher than the latter in value. The difference became more remarkable, as time elapsed after the end of ACTH administration.These data suggest that there remained in the blood stream fragments of ACTH which had lost biological activities but still retained immunological activities.

MEASUREMENT OF BLOOD-FLOW THROUGH SKELETAL MUSCLE BY INTRAMUSCULAR INJECTION OF XENON-133

Clearance of the radioactive inert gas 133Xenon injected muscularly was studied in 46 healthy subjects and 13 patients with radiologically verified occlusive disease of the main arteries of the legs and intermittent claudication. In contrast with 24Na or 131 I ions 133Xenon diffused freely across cell membranes and local muscle blood-flow can therefore readily be calculated in ml per 100 g per minute from the 133Xenon clearance-rate. Muscle blood flow (MBF) averaged 1.5 ml per 100 g per minute at rest in patients with vascular disease. This was not significantly lower than the average of 2.0 ml per 100 g per minute in healthy persons over age 50. Healthy subjects younger than 50 years had an average resting MBF of 2.2 ml per 100 g per minute. After work induced ischemia maximal MBF inpatients with vascular disease averaged 17 ml per 100 g per minute. This value was significantly below the corresponding normal values of 55 and 52 ml per 100 g per minute in the normal subjects. In the same patients the average time until maximal reactive hyperemia was reached was significantly longer--2.3 minutes in contrast to 0.4 minutes in normal subjects. The 133Xenon values accorded well with the results usually found by means of venous occlusion plethysmography but unlike this method 133Xenon can be used to measure MBF directly during muscular work with little interference from non-muscular tissues.

A comparative study of the metabolism of hydrocortisone and prednisolone.

Intravenous infusions of the succinate esters of hydrocortisone and prednisolone were given to normal subjects and to patients with hepatic or renal disease in order to study the basis for the differing glucocorticoid effectiveness of the compounds. The plasma half-time of free 17-hydroxycorticosteroids after intravenous administration of hydrocortisone esters to normal young men was 113 minutes. The plasma half-time of free 17-hydroxycorticosteroids after intravenous administration of prednisolone esters was 204 to 241 minutes in normal subjects and in patients with renal or hepatic disease. The fact that prednisolone has a longer plasma half-time than hydrocortisone gives no clear insight into the reasons for the increased glucocorticoid effects of prednisolone compared to equivalent amounts of hydrocortisone, and their roughly similar effects on salt metabolism. The contrast in the action of the two compounds must depend on their intrinsic structures or on their different pathways of metabolism. Liver disease caused only slight delay in plasma removal of 17-hydrox3rcorticosteroids after prednisolone in contrast to the marked prolongation that occurs after hydrocortisone. Although patients with renal disease excreted only small amounts of free 17-hydroxycorticosteroids in their urine after intravenous prednisolone, the plasma half-time was not decreased. The rate of fall of plasma free 17-hydroxycorticosteroids after intravenous prednisolone is determined in large part by the rate of removal by organs outside the liver or kidney.