Effects of ex vivo platelet supplementation on platelet aggregability in blood samples from patients treated with acetylsalicylic acid, clopidogrel, or ticagrelor.

BACKGROUND: Transfusion of platelet concentrate is often used to treat bleeding in patients on platelet inhibitors, but little is known about its efficacy between different inhibitors. We assessed the effect of ex vivo platelet supplementation on platelet aggregability in blood samples from patients treated with acetylsalicylic acid (ASA), clopidogrel, or ticagrelor. METHODS: Platelet aggregability was investigated with multiple electrode aggregometry with adenosine diphosphate (ADP), arachidonic acid (to assess ASA-dependent aggregability), and thrombin receptor activating peptide-6 (TRAP) as activators in whole-blood samples from patients treated with ASA (n=10), ASA+clopidogrel (n=15), or ASA+ticagrelor (n=15), and from healthy controls (n=10). Aggregability was measured before and after supplementation of AB0-compatible fresh apheresis platelets (+46, +92, and +138×10(9) litre(-1)). RESULTS: Both ASA-dependent and ADP-dependent aggregability improved in a dose-dependent fashion after platelet supplementation. ASA-dependent aggregability was completely restored in all patient groups, but there was only a small improvement in ADP-dependent aggregability in patients on dual antiplatelet therapy. There was less effect of platelet supplementation on ADP- and ASA-dependent aggregability in ticagrelor-treated patients than in clopidogrel-treated patients [3.9 (95% confidence interval 1.6-6.3) vs 9.0 (5.2-12.8) AU×min (P=0.021) and 48 (36-59) vs 69 (60-78) AU×min (P=0.004), respectively, at the highest platelet dose]. CONCLUSIONS: Platelet supplementation improved platelet aggregability independently of antiplatelet therapy. The effect on ADP-dependent platelet inhibition was limited however. Reduced effect of platelet transfusion is more likely within 2 h of drug intake in patients treated with ASA+ticagrelor compared with ASA+clopidogrel.

The effect of withdrawal of food iron fortification in Sweden as studied with phlebotomy in subjects with genetic hemochromatosis.

OBJECTIVES: The iron fortification of food in Sweden, the highest in the world, was withdrawn 1st January 1995, because the effect upon target groups was considered to be uncertain. We wanted to study the effect of such a dietary experiment. DESIGN: Comparative cross over study. SETTING: Out patient service and Blood Bank. SUBJECTS: Sixteen men aged 24-73 y on maintenance phlebotomy after treatment for iron overload. One was excluded because of inflammatory disease. INTERVENTIONS: Quantitative phlebotomy with serial measurements of Hb conc., % transferrin saturation and serum ferritin concentration. MAIN OUTCOME MEASURES: Iron absorption was measured by phlebotomy during two periods, with and without iron fortification. 1 g Hb = 3.4 mg Fe. RESULTS: Iron absorption was significantly reduced (P < 0.001) when iron fortification was withdrawn from a mean of 4.27 +/- 1.2 to 3.63 +/- 1.1 mg/d. The difference of 0.65 mg/d (95% c.i. 0.32-0.97) corresponds to the fraction of iron derived from fortification. Intervals between donations had to be extended from 59 +/- 15 to 69 +/- 17 d (P < 0.01) to avoid induction of iron deficiency anemia. The iron content of the fortified diet averaged 15.4 mg/d, of which the fortified fraction constituted 4.1 mg/d (27%). The relative bioavailability of carbonyl iron used as fortificant was 38%. CONCLUSIONS: The relative bioavailability of carbonyl iron used as fortificant was higher than previously reported. Target groups such as menstruating females will probably be affected by a higher prevalence of iron deficiency when food is no longer fortified. People with genetic hemochromatosis will accelerate into clinical disease at a slower rate.

Integration in trigeminal premotor interneurones in the cat. 1. Functional characteristics of neurones in the subnucleus-gamma of the oral nucleus of the spinal trigeminal tract.

The profile of integration in a sample of 183 interneurones localized in the subnucleus-gamma of the oral nucleus of the spinal trigeminal tract (NVspo-gamma) has been analyzed. 134 neurones were tested for inputs from primary afferents of the trigeminal, facial and cervical nerves as well as for inputs from the midbrain and from the cervical spinal cord. The remaining 49 neurones were tested for inputs from the primary afferents and for descending convergence from defined sites within the oro-facial primary projections of the cerebral cortex. It was found that the interneurones, mainly recorded in the dorsal and dorsomedial aspect of the NVspo-gamma, receive short latency inputs from the low threshold oral and perioral afferents and longer latency inputs from the high threshold jaw and neck muscle afferents. There was evidence for convergence from the cervical segmental level (29%) and some of the neurones had axon terminals in the superior colliculus. However, the interneurones did not receive a descending tectal input. About 80% of the NVspo-gamma interneurones were activated from the orofacial primary projection fields within cytoarchitectonic areas 3a and 3b of the coronal gyrus. This input was topographically organized and the neurones were activated from the same oral and perioral region of the periphery as the cortical region from which the descending projections themselves originated. Minimum latencies indicated a monosynaptic connection. The convergence profile onto the NVspo-gamma interneurones appeared unique as compared with interneurones located in the intertrigeminal area. Aspects of the possible functional roles of the NVspo-gamma neurones are discussed in relation to ongoing oro-facial ("masticatory") movements. The properties of a selected sample of NVspo-gamma interneurones, which were antidromically activated from the digastric subnucleus of the trigeminal motor nucleus, are reported in a companion paper (Olsson and Westberg 1991).

The effect of iron fortification of the diet on clinical iron overload in the general population.

The gene coding for idiopathic hemochromatosis is prevalent in Sweden, the country with the highest iron fortification of food (42%) in the world. We wanted to study if this highly iron-fortified diet had negative effects on the iron situation in carriers of the iron-loading genes. Iron stores averaged 6.7 grams in male homozygotes who were mainly identified through laboratory screening. It was 3.4 grams in female homozygotes. By HLA typing of family members of these homozygous probands, 39 additional homozygotes and 172 heterozygotes were detected. Serum ferritin averaged 620 micrograms/l in 20 male and 168 micrograms/l in 19 female homozygotes in the family screening. Storage iron as measured by serum ferritin concentration was slightly but significantly higher in male heterozygotes than controls (117 micrograms/l versus 87 micrograms/l, p less than 0.02). There was no further increase in serum ferritin concentration with age after 40 years. Heterozygotes showed no clinical signs of iron damage. These findings do not indicate that carriers of the iron-loading genes in Sweden have been adversely affected by the highly iron-fortified diet of the country.

Renal and hormonal responses to atrial natriuretic peptide infusions in goats on high and low sodium intake.

Synthetic atrial natriuretic peptide (ANP) was infused intravenously (1 microgram min-1; 60 min) in five goats during two series of experiments. For at least 4 weeks before the ANP infusions the goats received either no salt supplementation (= low sodium diet), or were given 16 g NaCl mixed with the food each day (Na = 274 mmol day-1; high sodium intake). The goats were changed between the treatments at random. ANP infusions caused diuresis, natriuresis and haemoconcentration during both diets. The urinary Na excretion increased about four-fold during the high sodium intake, and about 10 times during the low sodium intake. The urinary K excretion increased significantly during the low sodium diet, but decreased slightly during the high sodium intake. During both diets the K excretion became significantly lowered after the infusions. The mean glomerular filtration rate (GFR) was generally lower during the low sodium diet, but increased significantly during ANP infusions on both diets. The GFR returned to baseline immediately after the infusions, in contrast to urine flow and urinary Na excretion. Renal free water clearance increased slightly at the end of the infusion during the low sodium diet, but did not change during the high salt diet. Plasma renin activity (PRA) and plasma aldosterone concentration fell during ANP infusions in goats on the low sodium intake, but did not change significantly during the high sodium diet. These results indicate that the diuresis and natriuresis observed during intravenous ANP infusions in goats are mainly due to increased GFR.(ABSTRACT TRUNCATED AT 250 WORDS)

Central control of vasopressin release and thirst.

The effects of changes in the composition and/or the volume of the extracellular fluid on central receptors involved in the regulation of water balance are discussed. A review of results obtained in adults is given, followed by a discussion of possible roles for vasopressin during the neonatal period.

Low threshold afferent projections from the oral cavity and the face to the cerebral cortex of the cat.

The projections of low threshold afferents from the oral cavity and the face to the cerebral cortex of cats anaesthetized with chloralose were investigated. The projection fields of the ipsi- and contralateral lingual, inferior alveolar, mental, superior alveolar, infraorbital, (separate branches from whiskers and nose), ophthalmic, great auricular and the contralateral superficial radial nerves were localized. Surface potentials of short latency and maximal amplitude were recorded and their location traced on photographs of the rostral part of the right cerebral hemisphere. Reference points were indicated with india ink punctures. The extent of the cytoarchitectonic areas was determined on histological serial sections and the borders transferred to the photographs of the hemisphere. The features of the projections were related to the cytoarchitecture and to the pattern of the gyri and sulci. It was observed that the low threshold afferents from the oral cavity and the face projected via fast conducting, presumably three synaptic paths, to separate locations in areas 3a, 3b, 5a and 6a beta. The projections to area 3b were somatotopically organized starting with the auricular and the ophthalmic nerve projections lateral to the 3b projection of the forelimb in the posterior sigmoid gyrus and continuing with the maxillary nose, maxillary whiskers, mental nerve, superior alveolar, inferior alveolar and lingual nerve fields along the coronal gyrus towards the presylvian sulcus. The somatotopy was, however, not isomorphic with the body surface but displayed consecutive, overlapping bands across area 3b. The projections to area 3a were similarly organized. The somatotopy was less obvious in area 5a and 6a beta. Convergent projections with responses of slightly longer latency were observed in area 43 (gyrus orbitalis).

The effect of electrical stimulation in the hypothalamus on the monosynaptic jaw closing and the disynaptic jaw opening reflexes in the cat.

The effects of electrical stimulation in the hypothalamus on the monosynaptic jaw closing and the disynaptic jaw opening reflexes were investigated in cats anaesthetized with chloralose. The hypothalamic electrodes were located by observation of behavioural attack responses in the unanaesthetized animal and by means of Horsley-Clarke coordinates. The locations were verified in histological serial sections. Hypothalamic conditioning with trains of 3--10 pulses, 0.5 ms duration, 0.5 mA, 500 Hz, evoked a strong facilitation of the jaw closing reflex and a facilitation followed by an inhibition of the jaw opening reflex. These effects differed from those elicited from the cerebral cortex. The hypothalamic effects had a longer latency (11--13 ms) and required a longer train of conditioning stimuli than was the case with those evoked from the cortex. Bilateral ablation of the sensorimotor cerebral cortex or lesion of the pyramids at the lower pontine level diminished but did not abolish the hypothalamic effects. They did, however, disappear after lesions including the ventral midbrain tegmentum. The stimulus positions eliciting the largest hypothalamic effects on the jaw reflexes were located in a region extending medio-laterally from the perifornical area to the entrance of the ansa lenticularis in the lateral hypothalamus. Rostro-caudally the location was found at the level of the ventromedial hypothalamic nucleus and the anterior hypothalamus just rostral to this nucleus. The region corresponds to those parts of the hypothalamus from which agonistic and feeding responses have been evoked. It is suggested that the observed hypothalamotrigeminal mechanism may exercise a tonic influence on the trigeminal motoneurones, thereby controlling the set point of the biting force. The implications of this hypothesis on the etiology of bruxism and the myofascial pain dysfunction are discussed.

Preclinical hemochromatosis in a population on a high-iron-fortified diet.

Three hundred forty-seven (96.4%) of all persons aged 30 to 39 years were screened with serum iron and iron binding capacity measurements to determine the incidence of hemochromatosis in a population. No women had signs of iron overload; however, nine men (5%) had persistenly elevated serum iron levels. In four men (2%), increased iron stores was found with a distribution like that in the early stages of hemochromatosis. In combination with recent findings of clinical hemochromatosis at our hospital, this study suggests that this condition is not as rare as has been reported earlier.