Dose-dependent Inhibition of Platelet Function by Acetaminophen in Healthy Volunteers

Background: Acetaminophen (paracetamol) is widely used for postoperative analgesia. Its mechanism of action is inhibition of prostaglandin synthesis in the central nervous system, and acetaminophen is traditionally not considered to influence platelet function. The authors studied the dose-dependent inhibition of platelet function by acetaminophen in healthy volunteers.

Methods: Thirteen healthy male volunteers (aged 19-26 yr) were given placebo or 15, 22.5, or 30 mg/kg acetaminophen intravenously in a double-blind, crossover study. Ten and 90 min after infusion, platelet function was assessed by photometric aggregometry and by measuring release of thromboxane B2, analgesia by cold pressor test, and plasma acetaminophen concentrations by high-performance liquid chromatography.

Results: When triggered with 500 [mu]m arachidonic acid, median platelet aggregation (area under the curve) was 25.7, 22.8, 4.1, or 3.6 x 103 area units (P < 0.001) 10 min after placebo or 15, 22.5, or 30 mg/kg acetaminophen, respectively. An increasing concentration of arachidonic acid attenuated the antiaggregatory effect. After 90 min, platelet function was recovering. Release of thromboxane B2 was also dose-dependently inhibited by acetaminophen. Although plasma concentration of acetaminophen increased linearly with the dose, no analgesic effect was detected in the cold pressor test.     

Anterior stabilization of pathologic dens fractures

By an anterior approach, six pathologic dens fractures were stabilized with screws and methyl methacrylate cement. All the patients had immediate pain relief and could be mobilized without external support. Using the anterior approach, the tumor can be removed and the instability neutralized at the site of the lesion.     

Interleukin 1 receptor antagonist (IL1RA) in acute leukaemia: IL1RA is both secreted spontaneously by myelogenous leukaemia blasts and is a part of the acute phase reaction in patients with chemotherapy- induced leucopenia

Abstract: Blast cells derived from peripheral blood of patients with acute myelogenous leukaemia (AML) were cultured in vitro and interleukin 1 receptor antagonist (IL1RA) concentrations determined in culture supernatants. AML blasts derived from patients classified as AML-M4 and AML-M5 subtype showed an increased release of IL1RA. IL1α and IL1β caused a similar increase in AML blast release of IL1RA, and addition of anti-ILl antibodies decreased IL1RA release. IL1RA release from AML blasts was also increased by stem cell factor, tumour necrosis factor α (TNFα), granulocyte-macrophage colony-stimulating factor and macrophage colony-stimulating factor, whereas interleukin 3, interleukin 6, leukaemia inhibitory factor and granulocyte colony- stimulating factor did not significantly alter IL1RA release. When investigating IL1RA serum levels, serum concentrations were decreased in acute leukaemia patients with chemotherapy-induced cytopenia compared with healthy controls. Serum levels of both IL1RA as well as IL1β and soluble TNFα receptors increased when the leucopenic patients developed complicating bacterial infections.     

Basic fibroblast growth factor enhances bone-graft incorporation: Dose and time dependence in rats

In a previous study, we found that basic fibroblast growth factor could stimulate bone-graft incorporation. In the present study, the effects of different doses and implantation times were further studied, using the bone conduction chamber, in rats. Inside the chamber, the graft is isolated from the surrounding tissues except at one end, where small openings embedded in host bone allow ingrowth of tissue. The distance that new tissues had reached from the openings into the graft was measured on histological slides. Bone grafts were obtained from the proximal tibiae of donor rats, frozen at ?70°C, and lipid-extracted. Before implantation, they were soaked overnight in a hyaluronate gel with or without basic fibroblast growth factor and then were fitted into the chambers, which were implanted in the proximal tibiae of recipient rats. In a doseresponse experiment, grafts containing 0.3, 8, 40, 200, or 1,000 ng of basic fibroblast growth factor were compared with grafts treated with carrier gel only, after an implantation time of 6 weeks. Fibrous tissue always penetrated the grafts further than the ingrown bone; the distance that it reached from the ingrowth openings (total ingrowth distance) was increased by all of the doses except 0.3 ng per implant. The distance of bone ingrowth was increased by 8, 40, and 200 ng. The increased total ingrowth with 1,000 ng was due to an increased amount of fibrous tissue ahead of the bone, whereas with the lower doses the increase was due to more bone. Thus, the dose had an effect on the type of ingrown tissue found in the graft. In a time-effect study, grafts treated with 40 ng of basic fibroblast growth factor had a higher uptake of [^99mTc]MDP at 2 and 4 weeks and an increased bone ingrowth distance at 10 weeks. The radioactivity from [¹²⁵I]basic fibroblast growth factor declined with a half-life of 17 hours. The results suggest that basic fibroblast growth factor may be beneficial for the incorporation of contained bone grafts; studies using more clinically relevant models are required.     

Manganese induced brain lesions inMacaca fascicularis as revealed by positron emission tomography and magnetic resonance imaging

A series of positron emission tomography scans was made on two monkeys during a 16-month period when they received manganese(IV)oxide by subcutaneous injection. The distribution of [¹¹C]-nomifensine uptake, indicating dopamine terminals, was followed in both monkey brains. The brain distributions of [¹¹C]-raclopride, demonstrating D₂ dopamine receptors, and [¹¹C]-l-dopa, as a marker of dopamine turnover, were followed in one monkey each. The monkeys developed signs of poisoning namely unsteady gait and hypoactivity. The [¹¹C]-nomifensine uptake in the striatum was reduced with time and reached a 60% reduction after 16 months exposure. This supports the suggestion that dopaminergic nerve endings degenerate during manganese intoxication. The [¹¹C]-l-dopa decarboxylation was not significantly altered indicating a sparing of [¹¹C]-l-dopa decarboxylation during manganese poisoning. A transient decrease of [¹¹C]-raclopride binding occurred but at the end of the study D₂-receptor binding had returned to starting values. The magnetic resonance imaging (MRI) revealed that the manganese accumulated in the globus pallidus, putamen and caudate nucleus. There were also suggestions of gliosis/edema in the posterior limb of the internal capsule. MRI might be useful to follow manganese intoxication in humans as long as the scan is made within a few months of exposure to manganese, i. e. before a reversal of the manganese accumulation.     

Sialylated oligosaccharides in human milk and feces of preterm, full-term, and weaning infants

The amount of free and glycosidically bound sialic acid was quantitated in the oligosaccharide fraction of breast milk from nine women in the 2nd-3rd week of lactation. These amounts showed a certain individual variation but the amount of bound sialic acid was higher than the free sialic acid in each sample. A similar study on the feces from preterm and full-term breast-fed infants revealed that the amount of free sialic acid increased while the bound sialic acid decreased during maturation, which could possibly be a result of increasing activity of an intestinal sialidase in the newborn child. The fecal oligosaccharide patterns in one blood group A secretor breast-fed infant were studied every 2 months during weaning until the age of 1 year. It was seen that the fecal oligosaccharide pattern disappears, along with the blood group A-active compounds, with a corresponding decrease in the amount of breast milk in the diet.     

Different kinetics of lung clearance of technetium-99m labelled diethylene triamine penta-acetic acid in patients with sarcoidosis and smokers

The rate of clearance from the lungs of inhaled technetium-99m labelled diethylene triamine penta-acetic acid (^99mTc-DTPA) is often increased in interstitial lung disease as well as in smoking. In smokers a bi-exponential clearance course of ⁹⁹mTc-DTPA when measured over 3 h has previously been shown. This study was performed to compare the kinetics of clearance of ^99mTc-DTPA, measured for 3 h, in sarcoid patients and healthy smokers. Forty-one never-smoking patients with sarcoidosis and radiological signs of intrathoracic disease were studied. The results were compared with those of 16 healthy current smokers and of 14 healthy never-smokers reported previously. A mono-exponential clearance equation described the clearance in 22 of the sarcoid patients and all normal never-smokers, but with a shorter average tracer half-life in the patients (P<0.05). In 19 patients and all smokers a bi-exponential equation gave a significantly better curve fit. The rate of clearance of the slow component was higher in patients with sarcoidosis than in smokers (P< 0.05). The fraction of the tracer cleared by the fast clearance component was smaller in patients with sarcoidosis than in smokers (P<0.01). Differences in kinetics of clearance of ^99mTc-DTPA in sarcoidosis and smoking could thus be demonstrated, suggesting that the abnormal clearance is caused by diverging pathophysiological mechanisms.     

Bromine-76 and carbon-11 labelled NNC 13-8199, metabolically stable benzodiazepine receptor agonists as radioligands for positron emission tomography (PET)

NNC 13-8241 has recently been labelled with iodine-123 and developed as a metabolically stable benzodiazepine receptor ligand for single-photon emission computed tomography (SPECT) in monkeys and man. NNC 13-8199 is a bromo-analogue of NNC 13-8241. This partial agonist binds selectively and with subnanomolar affinity to the benzodiazepine receptors. We prepared ⁷⁶Br labelled NNC 13-8199 from the trimethyltin precursor by the chloramine-T method. Carbon-11 labelled NNC 13-8199 was synthesised by N-alkylation of the nitrogen of the amide group with [¹¹C]methyl iodide. Positron emission tomography (PET) examination with the two radioligands in monkeys demonstrated a high uptake of radioactivity in the occipital, temporal and frontal cortex. In the study with [⁷⁶Br]NNC 13-8199, the monkey brain uptake continued to increase until the time of displacement with flumazenil at 215 min after injection. For both radioligands the radioactivity in the cortical brain regions was markedly reduced after displacement with flumazenil. More than 98% of the radioactivity in monkey plasma represented unchanged radioligand 40 min after injection. The low degree of metabolism indicates that NNC 13-8199 is metabolically much more stable than hitherto developed PET radioligands for imaging of benzodiazepine receptors in the primate brain. [⁷⁶Br]NNC 13-8199 has potential as a radioligand in human PET studies using models where a slow metabolism is an advantage. Received 19 April and in revised form 10 June 1997     

Attachment loss and serum antibody levels against autologous and reference strains of Actinobacillus actinomycetemcomitans in untreated localized juvenile periodontitis patients

Abstract Immunological data have been suggested to be a potential tool in the diagnosis, classification and monitoring of periodontal diseases. However, the role of circulating antibodies in periodontal patients is poorly understood. Patients suffering from localized juvenile periodontitis (LJP) are often reported to show high titers of serum IgG antibodies against Aetinobaeillus actinomycetemcomitans (A. actinomycetemcotnitans), but several affected patients do not. Most studies use well-known reference strains of the bacterium for testing against the patients' sera. The aim of the present investigation was to study the relationship between serum IgG antibody levels to autologous A. actinomycetemcomitans strains and clinical attachment loss (CAL). In addition, we wanted to assess the patients’serum titers against 4 well-known reference strains of the bacterium as well as their general potential immunoglobulin response. Intravenous blood samples were taken from 23 LJP patients and 10 healthy individuals, and autologous A. actinomycetemcomitans strains were cultured from 18 of the L.JP patients. CAL was measured at 4 different sites around ail present teeth and assessed as a % of teeth with at least 1 site moderately ≥2<5 mm) or severely (≥5 mm) involved. An enzyme-linked immunosorbent assay (ELISA) was performed to evaluate the serum titers of IgG antibodies to A. actinomycetemcomitans antigens. No significant correlation was found between serum IgG antibody titers to autologous strains and CAL. However, there was a trend that low responders had more moderately affected teeth than had high responders and patients with undetectable A. actinomycetemcomitans levels, which is in agreement with a hypothetically protective role of the antibodies. The total counts of immunoglobulin assessed in all participants showed that the predominant class was IgG and the reference group displayed significantly less (p<0.05) IgG and IgG1 counts than the LJP patients. Both the reaction pattern against reference and autologous strains varied widely. We conclude that the specific antibody response against A. actinomycetemcomitans shows a weak correlation to clinical attachment levels in LJP patients.