Platelet transfusion: a dose-response study

Early recommendations on prophylactic transfusion of thrombocytopenic patients involved a standard platelet dose of about 0.5 x 10(11)/10 kg body weight. Given the lack of data supporting this dose, we prospectively studied the dose response to platelet transfusions in adults and children with hematologic malignancies. Each patient received, in similar clinical conditions, a medium, high, and very high dose of fresh (< 24 hours old) ABO-compatible platelets, in the form of apheresis platelet concentrates (APC). For the adults, the medium dose was defined as APC containing between 4 and 6 x 10(11) platelets, the high dose between 6 and 8 x 10(11), and the very high dose > 8 x 10(11); for the children, the three doses corresponded to 2 to 4, 4 to 6, and > 6 x 10(11) platelets. The end points were the platelet increment, platelet recovery, and the transfusion interval, and the results were compared with a paired t-test. Sixty-nine adults and 13 children could be assessed. Recoveries in the adults were similar with the three doses (from 28% to 30%), but the high and very high doses led to a significantly better platelet increment (52 and 61 x 10(9)/L, respectively) than the medium dose (33 x 10(9)/L, P < .01). The main difference was in the transfusion interval, which increased with the dose of platelets transfused, from 2.6 days with the medium dose to 3.3 and 4.1 days with the high and very high doses, respectively (P < .01). The positive effect of the high dose was observed regardless of pretransfusional clinical status, but was more marked in patients with no clinical factors known to impair platelet recovery. In these patients, a platelet dose of 0.07 x 10(11) per kg of body weight led to a transfusion interval of more than 2 days in 95% of cases. In patients with clinical factors favoring platelet consumption, the proportion of transfusions yielding an optimal platelet increment and transfusion interval increased with the dose of platelets. The platelet dose-effect was also significant in the children, in whom the high and very high doses led to 1.5-fold to twofold higher posttransfusion platelet counts and transfusion intervals. We conclude that transfusion of high platelet doses can reduce the number of platelet concentrates required by thrombocytopenic patients and significantly reduce donor exposure.     

Low-dose growth hormone-releasing hormone tests: a dose-response study

We have evaluated parameters of the serum growth hormone (GH) concentration response to saline and 1-, 10- and 100-micrograms intravenous bolus doses of amide analogue of GH-releasing hormone (GHRH (1-29)NH2) given in random order to 10 adult male volunteers of median body weight 68 (60-90)kg. Compared with saline, both 10- and 100-micrograms GHRH(1-29)NH2 doses (but not 1 microgram) resulted in significant peak GH responses (means and 95% confidence intervals: 24.03 (11.22-51.29) vs 26.09 (16.40-41.50) mU/l, respectively). Although the average rate of serum GH rise was similar after both 10 micrograms (2.05 (1.13-2.97) mU.l-1.min-1) and 100 micrograms of GHRH(1-29)NH2 (1.52 (0.69-2.35) mU.l-1.min-1; ANOVA F = 0.93, p = 0.35), the average rate of serum GH decline after peak GH was slower after the higher dose (10 micrograms vs 100 micrograms: 0.65 (0.40-0.90) vs 0.37 (0.23-0.50) mU.l-1.min-1; ANOVA F = 5.14, p = 0.04), suggesting continued GH secretion. Increasing GHRH(1-29)NH2 doses delayed the time to peak GH (1 microgram: 7.00 (3.50-10.52) min; 10 micrograms: 15.80 (13.62-17.98) min; 100 micrograms: 24.80 (18.40-31.12) min) and serum GH levels were still elevated significantly 2 h after injection of 100 micrograms GHRH(1-29)NH2 compared with other doses (saline: 0.98 (0.48-2.04) mU/l; 1 microgram: 0.68 (0.48-0.93) mU/l; 10 micrograms: 1.07 (0.56-2.04) mU/l; 100 micrograms: 5.01 (2.34-10.86) mU/l; ANOVA F = 11.10, p < 0.001). In a second study we tested five adult male volunteers with lower doses (0.5-10 micrograms) of GHRH(1-29)NH2.(ABSTRACT TRUNCATED AT 250 WORDS)     

Circulating angiotensin II and renal sodium handling in man: a dose-response study

1. Animal studies have shown that angiotensin II has a biphasic effect on urinary sodium excretion. To examine whether this is also true in man, we studied seven salt-replete male subjects in a single-blind placebo-controlled manner. 2. While undergoing maximum diuresis, subjects were infused with 0, 1, 2, 5 or 10 ng of angiotensin II min-1 kg-1 over 80 min. Subjects were studied while seated, and stood every 20 min for urine collection. 3. Angiotensin II produced a dose-dependent antidiuretic effect. The urine flow rate, in ml/min expressed as the change from baseline with increasing dose of angiotensin, was: +3.4 +/- 1.77, -1.26 +/- 0.49 (P < 0.05), -2.75 +/- 1.23 (P < 0.05), -4.21 +/- 0.82 (P < 0.05) and -6.51 +/- 1.07 (P < 0.01). 4. In contrast, the effect of angiotensin II on sodium excretion showed a flat dose-response curve beyond 5 ng min-1 kg-1. The urinary sodium excretion, in mumol/min expressed as the change from baseline with increasing dose of angiotensin, was: 9.5 +/- 21.2, -18.9 +/- 29.6, -37.0 +/- 11.6 (P < 0.05), -67.7 +/- 19.6 (P < 0.01) and -63.8 +/- 14.3 (P < 0.01). 5. The fractional distal reabsorption of sodium, determined by using the lithium clearance technique, showed a rise with all doses of angiotensin II used and reached statistical significance with the top two doses. 6. Unlike antidiuresis, antinatriuresis after graded doses of angiotensin II in human subjects showed a flat dose-response curve beyond 5 ng min-1 kg-1. Pressor doses of angiotensin II also have a significant effect on the distal tubule in promoting sodium reabsorption.     

Propranolol plus isosorbide-5-mononitrate for portal hypertension in cirrhosis: long-term hemodynamic and renal effects

The effect on kidney function, vasoactive systems and ascites outcome of long-term treatment with propranolol plus isosorbide-5-mononitrate, a combined therapy proven more effective than propranolol alone in decreasing portal pressure in the cirrhotic patient, is unknown. Thirty cirrhotic patients who survived acute variceal bleeding and were treated with propranolol plus isosorbide-5-mononitrate were studied. Portal and systemic hemodynamics (n = 15), inulin clearance, free water clearance, plasma renin activity, aldosterone concentration and prostaglandin E2 excretion (n = 20) were measured before and after 3 mo of treatment. In addition, data on ascites outcome in the entire series after a mean follow-up of 9.6 mo were compared with those of 30 patients undergoing elective sclerotherapy and with those of 30 patients treated with propranolol alone matched for age, sex, presence of ascites, Child-Pugh class and mean follow-up length included in other randomized controlled trials. Combined therapy significantly decreased the hepatic venous pressure gradient and azygos blood flow. In addition, no changes in inulin clearance, free water clearance, plasma renin activity, aldosterone concentration and prostaglandin E2 excretion occurred, despite a mild decrease in mean arterial pressure. Moreover, no differences among the three groups of patients studied in ascites outcome were found. These results suggest that long-term treatment with propranolol plus isosorbide-5-mononitrate does not impair kidney function, vasoactive systems or ascites outcome in cirrhotic patients.     

Smoking and Parkinson''s disease: a dose-response relationship

BACKGROUND: Previous studies questioned the link between early childhood anemia and detrimental child development. OBJECTIVE: A population-based study was conducted to examine the association between early childhood anemia and mild or moderate metal retardation at 10 y of age. DESIGN: The present study linked early childhood nutrition data collected by the Special Supplemental Program for Women, Infants, and Children (WIC) and school records. Hemoglobin values were used to determine the relation between anemia in early life and children's placement in special education classes for mild or moderate mental retardation. Subjects were all participants in the WIC program. A computer program was used to link data from birth, WIC, and school records. RESULTS: Logistic regression showed an increased likelihood of mild or moderate mental retardation associated with anemia, independent of birth weight, maternal education, sex, race-ethnicity, the mother's age, or the child's age at entry into the WIC program. CONCLUSION: These findings support the proposition that efforts to prevent mild and moderate mental retardation should include providing children with adequate nutrition during early childhood.     

A dose-response study of the effect of flutamide on benign prostatic hyperplasia: results of a multicenter study

OBJECTIVE: To compare morbidity and mortality rates of low birth weight (LBW) and appropriate birth weight infants born at term, focusing on diarrheal and respiratory infections. STUDY DESIGN: A cohort of 133 LBW infants (1500 to 2499 gm) and 260 appropriate birth weight infants (3000 to 3499 gm), individually matched by sex and season of birth, were followed for the first 6 months of life. None had congenital anomalies and all were from poor families living in the interior of Pernambuco, northeast Brazil. Data on infant deaths, hospitalizations, and morbidity were collected prospectively through daily home visits (except Sundays) from birth through week 8, then twice weekly for weeks 9 to 26. The effects of birth weight were assessed with a variety of multivariable techniques, controlling for confounders. RESULTS: Of the LBW infants, 56% were wasted (thin), 23% were stunted, and 17% were both wasted and stunted. The LBW infants (median 2380 gm) experienced a sevenfold higher mortality rate and fourfold higher rate of hospitalization than appropriate birth weight infants. Almost all deaths and hospitalizations were in the postneonatal period. The LBW infants also experienced 33% more days with diarrhea and 32% more days with vomiting (p = 0.003 in each case). The prevalences of cough and fever were not significantly different. CONCLUSIONS: Infant deaths, hospitalizations, and diarrheal morbidity are increased in term LBW infants who have only a modest weight deficit.     

Stress-management training for essential hypertension: a controlled study

Forty three patients with essential hypertension participated in a study on the effectiveness of stress-management training for essential hypertension. After 6-9 clinic and 48 self-measured readings of systolic and diastolic blood pressures (SBP and DBP), 22 patients were treated with a program based on education, relaxation, and problem-solving training; and another 21 patients were assigned to a waiting list control group. At post-treatment, mean reductions of clinic BP (17/13 mm Hg vs. 6.9/4.7 mm Hg for SBP/DBP), percentages of subjects who achieved at least a 5 mm Hg reduction (86/86% vs. 48/48% for SBP/DBP) and percentages of subjects who in addition achieved a normotensive level (59/68% vs. 29/14% for SBP/DBP) were significantly higher in the treated group than in the control group. Concerning self-measured BP, the effectiveness of the stress-management training was not so considerable (mean reductions of 3.6/2.4 mm Hg and percentages of subjects who achieved a 5 mm Hg reduction of 52/38% for SBP/DBP), but it was significant and maintained in a 4-month follow-up assessment (mean reductions of 4/2 mm Hg and percentages of subjects who achieved a 5 mm Hg reduction of 48/33% for SBP/DBP). It is suggested that stress-management training can be beneficial for treatment of essential hypertension.     

Individual differences in the stress-response-dampening effect of alcohol: A dose-response study.

Recent evidence suggests that alcohol consumption can lead to attenuated stress response, but parameters such as dose and personality traits appear to influence the magnitude of alcohol's effects. To better characterize these relations, 96 21–30 yr old male social drinkers were assigned to either a placebo, a moderate, or a high dose of alcohol and then had heart rate and a self-report measure of anxiety taken during a stressful social interaction. Consistent with previous research, alcohol dampened both heart rate and, to a lesser extent, anxiety responses to the stressor. Because the reduced heart rate responsivity was obtained in the absence of increased basal heart rate, it is suggested that cardiovascular stress response dampening (SRD) does not appear to be an artifact of an initial values effect. Although there was some evidence that Ss with prealcoholic personality traits were especially sensitive to the SRD effect of alcohol, this effect did not appear to be strong or robust across alternative measures of prealcoholic traits. There was no evidence that self-consciousness or expectancies for tension-reducing alcohol effects were associated with stress responsivity in Ss consuming alcohol. (43 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Idiopathic intracranial hypertension without papilledema: a case-control study in a headache center

OBJECTIVE: To compare the clinical features of patients with chronic daily headache (CDH) with idiopathic intracranial hypertension without papilledema (IIHWOP) to those with normal CSF pressure. METHODS: A case-control study was conducted at a tertiary headache center. Cases consisted of 25 consecutive patients (24 women, 1 man, 38 +/- 6 years) with IIHWOP diagnosed between June 1989 and June 1996. IIHWOP was diagnosed if pressure was 200 mm CSF on two occasions and there was no papilledema. Control subjects consisted of patients with refractory CDH who had normal CSF pressure on lumbar puncture performed between June 1992 and June 1996 (n = 60, 50 women, 10 men, 36 +/- 11 years). A structured telephone follow-up was done from July 1996 to March 1997. Comparisons made between the two groups included demographics and headache profiles, both at the initial evaluation and at follow-up. RESULTS: The initial headache characteristics did not differ between the two groups: most had transformed migraine with analgesic overuse. Significant predictors of IIHWOP included pulsatile tinnitus (odds ratio [OR] = 13.0) and obesity (OR = 4.4). Visual symptoms did not differ significantly. The prognosis of the two groups of patients was similar. CONCLUSIONS: Pulsatile tinnitus and obesity suggest possible IIHWOP in patients with CDH. Treatment of patients with increased intracranial pressure was not satisfactory.     

Formoterol inhaled as dry powder or via pressurized metered-dose inhaler in a cumulative dose-response study

Formoterol administered by a dry-powder (DP) capsule inhaler was compared with a pressurized metered-dose inhaler (pMDI) with regard to bronchodilating and systemic effects. The study used a double-blind, crossover, double-dummy technique. Twelve patients with moderate reversible asthma in a stable phase were examined on two separate study days, and the inhalers were given in randomized order. After baseline measurements, increasing doses of formoterol were given at intervals of 75 min. FEV1 and heart rate and tremor measurements were repeated after each dose, and the doses were 12 + 12 + 24 + 48 micrograms, giving a total dose of 96 micrograms. The peak expiratory flow rate (PEFR) was recorded in the morning before the first dose, after the last dose, and then repeatedly at home until 19 h after the last dose. There was an equal increase in ventilatory capacity at each dose level, independent of inhaler device. Repeated PEFR measurements after the last dose did not reveal any differences in duration of effect. There was a slight but statistically significant increase in heart rate and tremor after the highest doses of the DP formulation compared to the pMDI. These systemic effects can probably be explained by the reduced oral deposition of the aerosol caused by using a spacer. This study indicates that the DP and pMDI formulations of formoterol are equipotent in bronchodilation.     

Peptides and anxiety: a dose-response evaluation of pentagastrin in healthy volunteers

A large body of data suggest that brain cholecystokinin (CCK) systems are involved in the regulation of anxiety, and numerous studies have demonstrated that CCK-4, a CCKB agonist, reliably induces panic attacks in patients with panic disorder. Recently, pentagastrin, a commercially available CCKB agonist, has been reported to have similar anxiogenic properties. To further explore the utility of pentagastrin as a challenge agent and to determine whether its effects are dose-related, a dose-response study was conducted in ten healthy volunteers. Pentagastrin (0.2 microgram/kg, 0.6 microgram/kg and 1.0 microgram/kg) and inactive placebo were infused over one minute on four separate challenge days in a double-blind fashion. Subjects received pentagastrin while participating in a structured social interaction task. Repeated measures of anxiety, blood pressure, pulse, ACTH, and cortisol were taken at baseline and postinfusion. Pentagastrin administration led to increases in anxiety, pulse, ACTH, cortisol and physical symptoms of panic, in a dose-related manner. Participation in the social interaction task led to increases in measures of anxiety as well as increases in pulse and blood pressure. Few differences were found between the 0.2 microgram/kg dose of pentagastrin and placebo, or between the 0.6 microgram/kg and the 1.0 microgram/kg doses of pentagastrin. These findings support the notion that CCK systems are involved in the regulation of anxiety, and suggest that the 0.6 microgram/kg dose may be optimal for increasing symptoms of anxiety while minimizing unpleasant side effects. The powerful anxiogenic effects of the social interaction task underscore the importance of contextual variables in challenge studies.     

Evaluation of the angiotensinogen locus in human essential hypertension: a European study

Adult male Wistar rats were implanted bilateraly with bipolar electrodes in substantia nigra-ventral tegmental area (SN-VTA) to experience intracranial self-stimulation (ICSS) for 15 min per day over a period of 10 days. These rats were then assessed for the acquisition and performance of the operant and the spatial learning tasks. ICSS experienced rats showed rapid acquisition of both the operant and the spatial learning tasks. Both the lever press performance for 7 sessions in the operant learning task and mean number of alternations per session in the spatial learning task were significantly higher (p < .001) in ICSS experienced rats compared with controls. The results suggest that prior ICSS experience facilitates the acquisition and performance in both the operant and the spatial learning tasks, which may be due to the structural and neurochemical alterations in the hippocampus induced by ICSS experience.     

Epidemiology of idiopathic intracranial hypertension: a prospective and case-control study

Congenital deformities frequently produce problems not always discernible at birth. Often, a period of time is required for the development of signs and symptoms. The present discussion presents the intrauterine anatomy of a midterm fetus relative to conditions of the hip and thigh. Cryomicrotomy is used in this study to present the best anatomical evidence of the morphology involved.     

Buprenorphine-induced alterations of cocaine's reinforcing effects in rhesus monkey: a dose-response analysis

Buprenorphine reduces cocaine self-administration by rhesus monkeys, opiate- and cocaine-dependent men and polydrug abusers, but the mechanisms underlying these cocaine-opiate interactions are not well understood. In the present study, the effects of daily placebo or buprenorphine (0.1, 0.3 and 1.0 mg/kg) treatment on cocaine self-administration (0.001-0.3 mg/kg/inject) were examined in five cocaine-experienced rhesus monkeys. Saline and each of six cocaine doses were available in an irregular order. Responding for cocaine (or saline) and food was maintained on a second order FR4 (VR 16:5) schedule of reinforcement. During placebo treatment, the daily number of cocaine injections increased as the unit dose was increased and then decreased at higher doses. Cocaine doses that maintained the highest rates of responding during placebo treatment were more resistant to buprenorphine's effects. The typical increase in response rate during the first five cocaine injections of a session also was attenuated by buprenorphine. The ascending limb of the cocaine dose-response curve was shifted downward and approximately one log unit to the right during low-dose buprenorphine treatment (0.1 mg/kg/day). In contrast, individual response rates for food pellets were unaffected. We conclude that buprenorphine selectively decreases self-administration of some unit doses of cocaine at doses that have minimal effects on food-maintained responding.     

Ribosomal protein insufficiency and the minute syndrome in Drosophila: a dose-response relationship

Minutes comprise > 50 phenotypically similar mutations scattered throughout the genome of Drosophila, many of which are identified as mutations in ribosomal protein (rp) genes. Common traits of the Minute phenotype are short and thin bristles, slow development, and recessive lethality. By mobilizing a P element inserted in the 5' UTR of M(3)95A, the gene encoding ribosomal protein S3 (RPS3), we have generated two homozygous viable heteroalleles that are partial revertants with respect to the Minute phenotype. Molecular characterization revealed both alleles to be imprecise excisions, leaving 40 and 110 bp, respectively, at the P-element insertion site. The weaker allele (40 bp insert) is associated with a approximately 15% decrease in RPS3 mRNA abundance and displays a moderate Minute phenotype. In the stronger allele (110 bp insert) RPS3 mRNA levels are reduced by approximately 60%, resulting in an extreme Minute phenotype that includes many morphological abnormalities as well as sterility in both males and females due to disruption of early gametogenesis. The results show that there is a correlation between reduced RPS3 mRNA levels and the severity of the Minute phenotype, in which faulty differentiation of somatic tissues and arrest of gametogenesis represent the extreme case. That heteroalleles in M(3)95A can mimic the phenotypic variations that exist between different Minute/rp-gene mutations strongly suggests that all phenotypes primarily are caused by reductions in maximum protein synthesis rates, but that the sensitivity for reduced levels of the individual rp-gene products is different.