Clinical response to antibiotic therapy for community-acquired pneumonia

Childhood community-acquired pneumonia is a common and potentially serious problem worldwide. Unless the patient has bacteraemia or pleural empyema, aetiological diagnostics are limited and antibiotic treatment is empirical. Published data on expected response to therapy are scarce. To determine the clinical response to antibiotic treatment in a developed country in otherwise healthy children with community-acquired pneumonia, we conducted a prospective study of 153 hospitalised children with pneumonia. The role of 17 microbes as potential causative agents was evaluated. The duration of fever (>37.5°C) and hospitalisation were studied as objective measures of recovery. A potential aetiology was found in 83% of 153 patients: 29% of the patients had sole viral and 26% sole bacterial and 29% mixed viral-bacterial infections. The median duration of fever after the onset of antibiotic treatment (mainly penicillin G) was 14 h and the median duration of hospitalisation was 48 h. Patients with mixed viral-bacterial infection became afebrile more slowly than those with either sole viral or sole bacterial infections. Conclusion: the findings indicate that in a developed country, children with pneumonia make a rapid, uneventful recovery needing only a short hospital stay. Expensive and time-consuming microbiological investigations are not required once bacterial sepsis has been excluded.Abbreviations CAP community-acquired pneumonia - RSV respiratory syncytial virus     

Circulating glucocorticoid bioactivity in the preterm newborn after antenatal betamethasone treatment

Antenatal glucocorticoid treatment of mothers at risk of premature delivery is highly cost-effective in reducing neonatal mortality and morbidity. However, there is only limited information on the actual glucocorticoid bioactivity (GBA) reaching the fetus. By employing a recently developed recombinant cell bioassay, we studied circulating GBA in preterm newborns exposed to the standard antenatal betamethasone regimen (12 mg betamethasone twice, 24-h interval, for the mother; repeated in 7-10 d if required). Plasma GBA and cortisol concentrations were measured in cord blood of 71 infants (mean gestational age, 28.9 wk; range, 24.6-32 wk; mean birth weight, 1208 g; range, 480-2010 g). The median time between the last administered betamethasone dose and birth was 2.0 d. Cord GBA ranged from less than 15.6 to 170 nmol/liter cortisol equivalents. The level was highly dependent on the time between the last betamethasone dose and birth, i.e. infants born shortly (<12 h) after the last steroid dose displayed on average 4-fold higher GBA than that in the reference group (infants with >7 d since the last betamethasone dose before birth or without treatment; 74 vs. 21 nmol/liter cortisol equivalents; P < 0.0001). By contrast, if more than 72 h had elapsed between the last steroid dose and birth, circulating GBA was strongly dependent on cord cortisol (r = 0.85; P < 0.0001; n = 30). In multiple regression analysis adjusted for cord cortisol concentration and the time since the last steroid dose, increased umbilical artery resistance, a sign of severe fetal distress, was associated with lower cord GBA (P = 0.01). In conclusion, antenatal exposure of preterm fetuses to betamethasone causes a sizeable, but brief, peak of supraphysiological GBA, and approximately 3 d after the last betamethasone dose, circulating GBA derives from cord cortisol concentration.     

Reduced circulating androgen bioactivity in patients with prostate cancer

BACKGROUND: Previous studies on immunoreactive androgen levels in serum have revealed equivocal associations with the risk of prostate cancer (CaP). The aim of this study was to compare serum biological androgen activity between men with newly diagnosed CaP and age-matched men with benign prostatic hyperplasia (BPH). METHODS: Caucasian men with newly diagnosed, untreated CaP (n = 101) and age-matched patients with BPH (n = 103) were investigated. Serum androgen bioactivity (ABA) levels were measured using a recently developed recombinant cell bioassay. RESULTS: In comparison to men with BPH, CaP patients with Gleason score >or=8 (n = 16) had lower serum ABA (P < 0.05), and patients with Gleason score or=8 (P = 0.07) displayed suppressed ABA levels in relation to serum testosterone. As the entire group, men with CaP (n = 101) had significantly lower serum ABA than age-matched men with BPH (n = 103): median 3.0 nM (range, 0.8-6.4 nM) versus 3.2 nM (range, 0.8-7.9 nM) testosterone equivalents, respectively (P < 0.005). By contrast, serum immunoreactive testosterone and SHBG concentrations and free androgen indices did not differ significantly between the two groups. CONCLUSIONS: Patients with CaP have lower serum ABA than controls with BPH, and men with low or high Gleason score display suppressed circulating ABA-to-testosterone ratio. These features may reflect interaction between variables such as the degree of tumor differentiation and tumor volume with androgen metabolism.     

Catechol-O-methyltransferase and monoamine oxidase A genotypes and drug response to conventional neuroleptics in schizophrenia

Biogenic amine synthesis and degradation are involved in the pathogenesis of schizophrenia. Catechol-O-methyltransferase and monoamine oxidase enzymes are important agents in the metabolic inactivation of these neurotransmitters (ie, dopamine, serotonin, and norepinephrine). Functional polymorphism in the catechol-O-methyltransferase and monoamine oxidase A genes causes variation in enzyme activities. We investigated the relationship of catechol-O-methyltransferase Val158Met and monoamine oxidase A promoter repeat polymorphism with response to conventional neuroleptic treatment in schizophrenia.Ninety-four schizophrenic patients formed 2 different study populations. The responders had experienced a fair and steady response to conventional neuroleptics. The nonresponders had failed to achieve an acceptable response to conventional neuroleptics. We also used a control population of 94 age-matched and gender-matched blood donors. Genotyping of the catechol-O-methyltransferase and monoamine oxidase A genes was performed by polymerase chain reaction.Forty-three percent of the nonresponders had a low activity catechol-O-methyltransferase genotype compared with 16% of the responders (P = 0.009). Monoamine oxidase A genotype alone did not differ significantly between the groups. Moreover, the risk of having both low-activity catechol-O-methyltransferase and monoamine oxidase A genotypes was over 6 times more common (odds ratio = 6.16, P = 0.03) in the nonresponders compared with responders. The whole population of patients with schizophrenia did not differ from the controls.The low-activity catechol-O-methyltransferase genotype may be associated with unsatisfactory drug response to conventional neuroleptics or alternatively be involved in a subset of schizophrenics. The role of monoamine oxidase A genotype seems to be additive in this respect.     

Important amino acids for the function of the human MT1 melatonin receptor

Models of G protein-coupled melatonin receptor structure suggest that ligand recognition occurs in a binding pocket formed by transmembrane helices III, V and VII. Constitutively active mutations in G protein-coupled receptors have revealed that transmembrane helix III/intracellular loop 2 interface and transmembrane domain VI are critical regions in receptor activation. In this study, nine site-directed mutants of the human MT1 melatonin receptor were created to test the importance of specific amino acids in these regions in ligand recognition and receptor activation events. We analyzed ligand binding, G protein activation and subcellular localization of MT1 receptors transiently expressed in COS-7 cells. Receptor ELISA was employed to study expression levels of N-terminally HA epitope tagged wild-type and mutant MT1 receptors. Mutations in histidine H195 (His(5.46)) in transmembrane domain V reduced receptor affinity for 2-[125I]iodomelatonin. Several other mutants had diminished expression on the plasma membrane. Amino acids M107 (Met(3.32)) in transmembrane domain III and S280 (Ser(7.46)) in transmembrane domain VII were found not to participate in ligand recognition in human MT1 receptor. Constitutive activity was not obtained with mutations in N124 (Asn(3.49)) or P253 (Pro(6.50)). These mutants failed to bind 2-[125I]iodomelatonin and had reduced expression levels. The need to upgrade current melatonin receptor models has become evident. Several important amino acids for the human MT1 melatonin receptor function were revealed in the current study, with effects of mutations ranging from slightly reduced affinity or efficacy to complete loss of function.     

Diagnostic rapid tests for acute hantavirus infections: specific tests for Hantaan,Dobrava and Puumala viruses versus a hantavirus combination test

Hantaviruses infecting humans in Eurasia include Hantaan, Seoul, Puumala and the closely related Dobrava and Saaremaa viruses. These viruses are causative agents of hemorrhagic fever with renal syndrome (HFRS), which is recognized as a severe health care problem in several countries. Diagnostics of hantavirus infections relies on serology, performed principally with enzyme immunoassay (EIA) or immunofluorescence assay (IFA). We developed four 5-min immunochromatographic IgM-antibody tests for diagnostics of acute Puumala, Dobrava and Hantaan virus infections and a similar combination test to detect all Eurasian pathogenic hantavirus infections. We evaluated the assays using 100 fingertip blood samples collected randomly from Finnish volunteers, 28 confirmed hantavirus IgM-negative sera, and 77 sera from patients with acute infections of various hantaviruses. The specificities and sensitivities of the Puumala-, Dobrava- and Hantaan virus -specific tests varied from 96 to 100%, whereas, the combination test showed 96% specificity and 80 to 93% sensitivity. Cross-reactions were observed commonly between the Dobrava and the Hantaan virus tests, but only rarely between the Puumala and the Hantaan virus, or the Puumala and the Dobrava virus, tests. Altogether, the rapid tests showed less cross-reactivity than the respective EIA tests. According to the results, the performance of these tests meets well the requirements for diagnostic use. Nevertheless, the specific one-antigen tests were markedly more sensitive than the combination test. However, if optimized, a combination test would be suitable for regions where several hantaviruses circulate.     

Dopamine receptor D2 -141C Insertion/Deletion polymorphism in a Finnish population with schizophrenia

We examined the occurrence of the -141C Ins/Del polymorphism in 93 Finnish patients with schizophrenia. In comparison with previous studies with Japanese and Caucasian populations, the incidence of this polymorphism was unexpectedly low. The findings suggest that the frequency of the -141C Ins/Del polymorphism is lower in Northern Europe compared to other Caucasian and Japanese populations.     

S-[18F]fluoromethyl-(+)-McN5652, a PET tracer for the serotonin transporter: evaluation in rats

The [(18)F]fluoromethyl analog of (+)-McN5652 ([(18)F]FMe-McN) for imaging serotonin transporter (SERT) with positron emission tomography (PET) has recently been synthesized. We describe here the biological evaluation of [(18)F]FMe-McN in rats. Biodistribution studies of [(18)F]FMe-McN in rat brain ex vivo after an intravenous injection showed a high accumulation of radioactivity in the regions rich in SERT, such as raphe nuclei, hypothalamus, thalamus, substantia nigra, locus coeruleus, and amygdala. Region-to-cerebellum ratios reached a maximum value of 9 in raphe nuclei within 3.5 h after administration. The specificity and selectivity of [(18)F]FMe-McN binding to SERT was studied by preinjecting blocking doses of serotonin, norepinephrine, and dopamine transporter inhibitors. Fluoxetine, a specific inhibitor for SERT, decreased the specific binding of [(18)F]FMe-McN in raphe nuclei by 91 +/- 4%; in other regions rich in SERT, similar results were obtained. GBR12909 and nisoxetine, selective inhibitors for dopamine transporter (DAT) and norepinephrine transporter (NET), respectively, showed no significant effects on the uptake of [(18)F]FMe-McN. Our studies show that [(18)F]FMe-McN has a clear potential as a tracer for studies with PET of SERT function in humans.     

Personality traits and striatal dopamine synthesis capacity in healthy subjects

OBJECTIVE: Neuroimaging and genetic studies suggest that individual differences in the brain dopaminergic system contribute to the normal variability of human personality (e.g., social detachment and novelty seeking). The authors studied whether presynaptic dopamine function is also associated with personality traits. METHOD: Presynaptic dopamine synthesis capacity in the brain was measured with positron emission tomography and [(18)F]fluorodopa in 33 healthy adults, and personality traits were assessed with the Karolinska Scales of Personality. Associations were studied by using a linear regression model controlling for the effects of age and gender on both variables. RESULTS: High scores on two of the anxiety-related personality scales, somatic anxiety and muscular tension, and on one aggressivity-related scale, irritability, were significantly associated with low [(18)F]fluorodopa uptake in the caudate. No statistically significant associations were observed between [(18)F]fluorodopa uptake and the detachment scale or scales related to novelty-seeking behavior (impulsiveness and monotony avoidance). CONCLUSIONS: The results suggest a role for the dopaminergic system in the regulation of anxiety in healthy subjects. Together with previous studies, they also indicate differential involvement of various components of the dopaminergic system in normal and pathological personality traits.     

Overexpression of spermidine/spermine N1-acetyltransferase elevates the threshold to pentylenetetrazol-induced seizure activity in transgenic mice

Activation of polyamine catabolism in transgenic mice through an overexpression of spermidine/spermine N(1)-acetyltransferase (SSAT) results in a massive overaccumulation of the diamine putrescine in most tissues including brain. Putrescine pool in transgenic animals was strikingly expanded in every six brain regions analyzed at present. Pons (23-fold), cerebellum (37-fold), cerebrum (34-fold), and hippocampus (16-fold) showed the greatest increases in putrescine levels. Moreover, the molar ratio of putrescine to spermidine was increased in the different brain regions of the transgenic animals on an average of nearly 40-fold. Upon an exposure of the animals to pentylenetetrazol (PTZ) infusions, a compound known to induce epilepsy-like seizure activity, the SSAT transgenic mice showed significantly elevated seizure threshold to both clonic and tonic convulsions in comparison with their syngenic littermates. This difference, however, disappeared when the animals were treated with ifenprodil prior to PTZ infusions. The latter compound acts as an antagonist of N-methyl-D-aspartate receptor by binding to the polyamine site of the receptor. Overexpression of SSAT likewise appeared to protect the transgenic animals from PTZ-induced neuron loss in the hippocampus. As putrescine is known to serve as a precursor to gamma-aminobutyric acid (GABA), we carried out (1)H NMR analyses the results of which revealed that the levels of the inhibitory amino acid GABA and its excitatory counterpart glutamate were indistinguishable in syngenic and transgenic animals in all brain regions analyzed. The present results suggest that the frequently observed enhanced accumulation of putrescine in response to brain insults belongs to neuroprotective measures rather than being a cause of the subsequent injury.