Secondary haemophagocytic lymphohistiocytosis: Experience from the Uppsala University Hospital

Background. Haemophagocytic lymphohistiocytosis (HLH) is a rare clinical syndrome characterized by fever, hepatosplenomegaly, cytopenia, and progressive multiple-organ failure. HLH in adults is often secondary to autoimmune diseases, cancer, or infections in contrast to familial HLH. Treatment of secondary HLH is directed against the triggering disease in addition to immunosuppressive therapy, the latter commonly according to the HLH-2004 protocol.Methods. We conducted a retrospective study to identify triggering diseases, disease-specific and immunosuppressive therapy administered, and prognosis in adult patients with secondary HLH. Patient data were collected from October 2010 to January 2015.Results. Ten adult patients with secondary HLH were identified. Seven were men, and the median age at diagnosis was 62 years. Five cases were triggered by malignant disease and five by infection. The median patient fulfilled five of the eight HLH-2004 diagnostic criteria. All patients fulfilled the criteria fever, cytopenia, and ferritin >500 µg/L. Median time from hospital admission to HLH diagnosis was 20 days. Four patients received immunosuppressive therapy according to the HLH-2004 protocol. The prognosis was dismal, especially for the patients with malignancy-associated HLH, of whom all died.Conclusion. HLH should be suspected in patients who present with fever, cytopenia, and ferritin >500 µg/L. Secondary HLH has a dismal prognosis. None of the patients with HLH triggered by malignancy survived. Achieving remission of the triggering disease seems to be important for a favourable outcome as, in all surviving patients, the haemophagocytic syndrome resolved after remission of the underlying infection.     

Validation of the Karolinska sleepiness scale against performance and EEG variables.

OBJECTIVE: The Karolinska sleepiness scale (KSS) is frequently used for evaluating subjective sleepiness. The main aim of the present study was to investigate the validity and reliability of the KSS with electroencephalographic, behavioral and other subjective indicators of sleepiness. METHODS: Participants were 16 healthy females aged 33-43 (38.1+/-2.68) years. The experiment involved 8 measurement sessions per day for 3 consecutive days. Each session contained the psychomotor vigilance task (PVT), the Karolinska drowsiness test (KDT-EEG alpha & theta power), the alpha attenuation test (AAT-alpha power ratio open/closed eyes) and the KSS. RESULTS: Median reaction time, number of lapses, alpha and theta power density and the alpha attenuation coefficients (AAC) showed highly significant increase with increasing KSS. The same variables were also significantly correlated with KSS, with a mean value for lapses (r=0.56). CONCLUSIONS: The KSS was closely related to EEG and behavioral variables, indicating a high validity in measuring sleepiness. SIGNIFICANCE: KSS ratings may be a useful proxy for EEG or behavioral indicators of sleepiness.     

Left main coronary artery stenosis no longer a risk factor for early and late death after coronary artery bypass surgery--an experience covering three decades.

OBJECTIVE: To analyse early and late mortality after coronary artery bypass grafting (CABG) in patients with and without left main coronary artery (LMCA) stenosis during the 30-year period 1970-1999. METHODS: A total of 1888 of 10,647 patients (18%) who underwent a first isolated CABG at the Karolinska Hospital in Stockholm, Sweden, during 1970-1999 had significant left main coronary artery stenosis. The Swedish National Cause of Death Register was used to determine mortality up to five years after the operation. RESULTS: The proportion of patients with LMCA stenosis of all CABG patients increased from 7% during the 1970s to 26% in 1999. During 1970-1984 early mortality was 5.8% in patients with LMCA stenosis compared with 1.5% in patients without LMCA stenosis (odds ratio (OR) 3.7 (95% confidence interval (CI) 1.8-7.6)). The corresponding rates during 1995-1999 were 2.0% versus 2.2% (OR 0.8 (95% CI 0.5-1.5)), respectively. The increased risk of early death in patients with LMCA stenosis was neutralised in males during 1985-1994 and in females during 1995-1999. Five-year survival in males was 88% after operations performed during 1994-1999 compared with 82% after CABG performed during 1970-1984. Five-year mortality, exclusive of early deaths, during 1970-1984 was higher in patients with LMCA stenosis (12.8%) than in those without (8.4%) (relative risk 1.7 (95% CI 1.1-2.5)). An increased risk of late mortality in patients with LMCA stenosis was neutralised in males during 1985-1994 and in females during 1995-1999. CONCLUSIONS: During 1970-1999 there was a decrease of early and five-year mortality in patients with LMCA stenosis after CABG despite increase of patient age and risk factors. There were gender differences so that the risk of death in patients with compared with in those without LMCA stenosis was neutralised in males during 1985-1994 and in females during 1994-1999. The continuous decline of mortality during three decades most likely reflects improvement of the peri- and postoperative management of patients undergoing CABG during this period.     

Acute tolerance to ethanol using drug discrimination and open-field procedures in rats

This study examined the phenomenon of acute tolerance to ethanol (ETOH) using drug discrimination learning (DDL), and open-field (OF) procedures. In DDL, rats were trained to discriminate between ETOH (1.2 g/kg) and saline. Doses of ETOH lower (0.6 and 0.9 g/kg), or higher (1.8 and 2.4 g/kg) than the training dose were tested to examine possible influence of ETOH pretreatment doses on the expression of acute tolerance. To assess concentrations of ETOH in the organism, a rebreathed air procedure was used. Equal concentrations after different ETOH doses were achieved by postponing the tests until sufficient time had elapsed. Only doses of ETOH higher than the training dose produced acute tolerance in the DDL procedure. For the response-time data no acute tolerance was observed. In the OF experiment, the occurrence of acute tolerance was examined for different spontaneous behaviours in drug-naive animals. At equal ETOH concentrations, the group examined during the descending phase of intoxication (1.8 g/kg, 60 min post-injection), reared significantly more than the group tested during the ascending phase (1.5 g/kg, 10 min post-injection). Other OF behaviours did not differ significantly between the two time intervals. Thus, it is suggested that acute tolerance is seen both in ETOH naive and in ETOH pre-exposed rats. However, in DDL acute tolerance was observed only when doses higher than the training dose of ETOH were evaluated.     

Chemoattractant-induced NADPH oxidase activity in human monocytes is terminated without any association of receptor-ligand complex to cytoskeleton

When the chemotactic peptide formylmethionyl-leucyl-phenylalanine binds to its cell surface receptor, a transmembrane signal is generated that activates the superoxide-producing NADPH oxidase of human phagocytes. Comparing monocytes and neutrophils with regard to the production of superoxide anion induced by the peptide, we found a similar time-course for both types of cells. In neutrophils, ligand binding induced a conversion of the receptor to a high-affinity form, a change suggested to be due to an association of the receptor-ligand complex to the Triton X-100-insoluble cytoskeleton. This event has been hypothesized to terminate the signal that activates the NADPH oxidase and thereby results in cessation of the cellular production of superoxide anion. Neutrophils preincubated with the cytoskeleton-disrupting drug cytochalasin B showed an increased and prolonged superoxide anion production after activation with the peptide, thus indicating that the cytoskeleton is involved in terminating this response. Formylmethionyl-leucyl-phenylalanine was also found to induce polymerization of actin in monocytes; however, cytochalasin B had no effect on the peptide-induced generation of superoxide anion in these cells. Furthermore, also in monocytes, ligand binding induced a conversion of the receptor to a high-affinity form; however, the receptor-ligand complex did not coisolate with the Triton X-100-insoluble cytoskeleton. These results indicate that, in monocytes, the NADPH oxidase activating pathway is terminated without any association of the receptor-ligand complex to the Triton X-100-insoluble cytoskeleton.     

The regulatory role of FSH in steroid formation by luteinized human granulosa cells in culture

Granulosa cells were aspirated from human pre-ovulatory folliclesfollowing a combined clomiphene-gonadotrophin stimulation inan in-vitro fertilization (IVF) programme. The cells were culturedfor 8 days in medium M199 containing 10% bovine fetal calf serumunder 5% CO₂ in air. Pure human FSH and human LH were addedalone or in combination to the culture in various concentrationsand the progesterone (P) and oestradiol-17 (E₂) levels in themedium were measured every second day by a conventional RIAtechnique. In the presence of FSH or LH the formation of P increased2- to 3-fold with the pronounced effect after 4 to 6 days inculture. Addition of testosterone (T) (3 ? 10^–7 M) tothe culture medium affected neither basal nor gonadotrophinstimulated P formation. In this system, only minute amountsof E₂ were formed and neither FSH nor LH stimulated its formation.When the medium was fortified with T, basal E₂ formation increased50- to 100-fold. FSH further stimulated this conversion significantlyafter 6 and 8 days of culture, while LH had no significant influence.     

Receiver operating characteristic study of image preprocessing for teleradiology and digital workstations

The purpose of this study was to evaluate whether digitized analog images displayed on a digital workstation can be improved by using a preprocessing algorithm, and if so, whether the quality of the resulting images can reach that of the original films. The material contained 120 difficult cases (about 50% with selected pathology). Four radiologists each evaluated half of the randomly ordered cases with the digital workstation and half of the cases with the original radiographs. The data were compared with a previous similar study, where the workstation had no option for preprocessed images. Preprocessed digital images were clearly superior to digital images without preprocessing, although for those of the highest diagnostic difficulty they were inferior to the original films. The preprocessing algorithm has improved the diagnostic quality of the digital workstation. There is room yet for improvement compared to plain films, although the current setup may be sufficient in some settings.     

Ovarian hormone effects on 5-hydroxytryptamine(2A) and 5-hydroxytryptamine(2C) receptor mRNA expression in the ventral hippocampus and frontal cortex of female rats

Alterations in female gonadal hormones are associated with anxiety and mood changes. The aim of the present study was to determine influences of chronic gonadal hormone supplementation on 5-HT(2A) and 5-HT(2C) receptor mRNA levels in the ventral hippocampus and the frontal cerebral cortex. Ovariectomized adult female Sprague-Dawley rats (n=37) received implantation of subcutaneous pellets containing different dosages of 17beta-estradiol alone or in combination with progesterone, or placebo pellets, for 2 weeks. Serotonin receptor mRNA levels were analyzed by in situ hybridization in the ventral hippocampus and 5-HT(2A) receptor mRNA also in the frontal cortex. Estradiol treatment in combination with low-dose progesterone increased 5-HT(2A) receptor mRNA by 43% in the CA2 region of the ventral hippocampus, while estradiol combined with high-dose progesterone increased the expression of this gene by 84% in ventral CA1. 5-HT(2A) mRNA expression in the frontal cortex was not influenced by hormone manipulation. 5-HT(2C) receptor gene expression was in the ventral hippocampus decreased in the CA2, ventral CA1 and the subiculum subregions by high-dose estradiol treatment (8-20% decreases). Effects on mood by gonadal hormones can be mediated, at least partly, through influences on 5-HT(2A) and 5-HT(2C) receptor expression.     

Drug discrimination procedures: Differential characteristics of the drug A vs drug B and the drug A vs drug B vs no drug cases

Two groups of pigeons with a history of two choice operant drug discrimination tasks (3.0 mg/kg morphine versus 5.6 mg/kg cocaine, and 3.0 mg/kg morphine versus 3.0 mg/kg cocaine, respectively; Swedberg and Järbe 1985) were subjected to three choice tasks in which responses on a third manipulandum were reinforced in the no drug condition. Training drugs generalization gradients in both groups were similar to those normally obtained in two choice drug versus no drug tasks. The salience differences between the training stimuli within the groups observed in the previous two choice task did not differentially affect the three choice discrimination gradients. Tests with novel drugs after the introduction of the no drug condition yielded increased responding to the no drug condition with the exception of the dopamine agonist apomorphine. Results are discussed in terms of a discrimination learning model specifying principles of relative discriminative stimulus control in various discrimination cases.Portions of these data were presented at the International Union of Pharmacology, IUPHAR, 9th International Congress of Pharmacology Satellite Meeting: European Study Group for Internal Stimulus Control by Electrical Stimulation, Drugs and Other Means, ESISC, London, July 29–August 3, 1984 (Swedberg and Järbe 1984). An earlier version of this work appears in the doctoral thesis by the first author (Swedberg 1985).