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Abstract Background An outbreak of Legionnaires’ Disease took place in the Swedish town Lidköping on Lake Vänern in August 2004 and the number of pneumonia cases at the local hospital increased markedly. As soon as the first patients were diagnosed, health care providers were informed and an outbreak investigation was launched. Methods Classical epidemiological investigation, diagnostic tests, environmental analyses, epidemiological typing and meteorological methods. Results Thirty-two cases were found. The median age was 62 years (range 36 – 88) and 22 (69%) were males. No common indoor exposure was found. Legionella pneumophila serogroup 1 was found at two industries, each with two cooling towers. In one cooling tower exceptionally high concentrations, 1.2 × 109 cfu/L, were found. Smaller amounts were also found in the other tower of the first industry and in one tower of the second plant. Sero- and genotyping of isolated L. pneumophila serogroup 1 from three patients and epidemiologically suspected environmental strains supported the cooling tower with the high concentration as the source. In all, two L. pneumophila strains were isolated from three culture confirmed cases and both these strains were detected in the cooling tower, but one strain in another cooling tower as well. Meteorological modelling demonstrated probable spread from the most suspected cooling tower towards the town centre and the precise location of four cases that were stray visitors to Lidköping. Conclusions Classical epidemiological, environmental and microbiological investigation of an LD outbreak can be supported by meteorological modelling methods. The broad competence and cooperation capabilities in the investigation team from different authorities were of paramount importance in stopping this outbreak.

Background: Some aggressive acts committed by individuals with psychotic spectrum disorders (PSD) are understandable in the context of interpersonal conflict or goal attainment, yet others are unpredictable, arising from delusions or hallucinations (psychotically driven aggressive acts, PDA). It is unknown if there are underlying differences in cognitive or perceptive social cognition in relation to aggression motivation in PSD., Method: We compared differences in social cognition performance between 49 individuals with PSD who had committed PDA with those exhibiting other types of aggression (n = 31) (non-PDA) and to community controls (n = 81) on the Swedish version of Double Movie for the Assessment of Social Cognition - Multiple Choice (DMASC-MC). Participants with PSD had more than 3 months of clinical stability and substance use abstention and stable antipsychotic medication doses. General intellectual ability was assessed with the information and matrix reasoning subtests of the Wechsler Intelligence Scales., Results: The PSD group with a history of PDA exhibited lower total and perceptive social cognition scores on the DMASC-MC than the non-PDA group and controls. In addition, they also showed lower cognitive scores compared to typical controls. Lower total scores were associated with lower scores on Wechsler intelligence subtests information and matrix reasoning. Taking this into account, the PDA group still had lower social cognition scores. There were no associations of antipsychotic medication dosages, positive or negative symptoms with social cognition scores. Higher antipsychotic dosage at the time of DMASC-MC testing and social cognition scores predicted a past history of PDA., Conclusions: We conclude that impaired social cognition, particularly perceptive social cognition, is associated with PDA in individuals with PSD.

Social interactions require decoding of subtle rapidly changing emotional cues in others to facilitate socially appropriate behaviour. It is possible that impairments in the ability to detect and decode these signals may increase the risk for aggression. Therefore, we examined violent offenders with schizophrenia spectrum disorders (SSD) and compared these with healthy controls on a computerized paradigm of briefly presented double masked faces exhibiting 7 basic emotions. Our hypotheses were that impaired semantic understanding of emotion words and low cognitive ability would yield lowest emotion recognition. SSD exhibited lower accuracy of emotion perception than controls (46.1% compared with 64.5%, p  = 0.026), even when considering the unbiased hit rate (22.4% compared with 43%, Z = 2.62, p  < 0.01). Raw data showed uncommon but significant misclassifications of fear as sad, disgust as sad, sad as happy and angry as surprise. Once guessing and presentation frequencies were considered, only overall accuracy differed between SSD and healthy controls. There were significant correlations between cognitive ability, antipsychotic dose, speed and emotion accuracy in the SSD group. In conclusion, that there were no specific emotion biases in the SSD group compared to healthy controls, but particular individuals may have greater impairments in facial emotion perception, being influenced by intellectual ability, psychomotor speed and medication dosages, rather than specifically emotion word understanding. This implies that both state and trait factors influence emotion perception in the aggressive SSD group and may reveal one source of potential misunderstanding of social situations which may lead to boundary violations and aggression., Competing Interests: None of the authors have conflict of interests., (© 2019 The Authors.)

Background: Therapeutic drug monitoring (TDM) could improve current TB treatment, but few studies have reported pharmacokinetic data together with MICs., Objectives: To investigate plasma concentrations of rifampicin, isoniazid, pyrazinamide and ethambutol along with MICs., Methods: Drug concentrations of rifampicin, isoniazid, pyrazinamide and ethambutol were analysed pre-dose and 2, 4 and 6 h after drug intake at week 2 in 31 TB patients and MICs in BACTEC 960 MGIT were determined at baseline. The highest plasma concentrations at 2, 4 and 6 h post-dose (Chigh) were determined, as well as estimates of Chigh/MIC and area under the concentration-time curve (AUC0-6)/MIC including the corresponding ratios based on calculated free-drug concentrations. This trial was registered at www.clinicaltrials.gov (NCT02042261)., Results: After 2 weeks of treatment, the median Chigh values for rifampicin, isoniazid, pyrazinamide and ethambutol were 10.0, 5.3, 41.1 and 3.3 mg/L respectively. Lower than recommended drug concentrations were detected in 42% of the patients for rifampicin (<8 mg/L), 19% for isoniazid (<3 mg/L), 27% for pyrazinamide (<35 mg/L) and 16% for ethambutol (<2 mg/L). The median Chigh/MIC values for rifampicin, isoniazid, pyrazinamide and ethambutol were 164, 128, 1.3 and 2.5, respectively, whereas the AUC0-6/MIC was 636 (range 156-2759) for rifampicin and 351 (range 72-895) for isoniazid., Conclusions: We report low levels of first-line TB drugs in 16%-42% of patients, in particular for rifampicin. There was a wide distribution of the ratios between drug exposures and MICs. The future use of MIC determinations in TDM is dependent on the development of a reference method and clinically validated pharmacokinetic/pharmacodynamic targets.

A previous study of 76 plant species on Spitsbergen in the High Arctic concluded that structures resembling arbuscular mycorrhizas were absent from roots. Here, we report a survey examining the roots of 13 grass and forb species collected from 12 sites on the island for arbuscular mycorrhizal (AM) colonisation. Of the 102 individuals collected, we recorded AM endophytes in the roots of 41 plants of 11 species (Alopecurus ovatus, Deschampsia alpina, Festuca rubra ssp. richardsonii, putative viviparous hybrids of Poa arctica and Poa pratensis, Poa arctica ssp. arctica, Trisetum spicatum, Coptidium spitsbergense, Ranunculus nivalis, Ranunculus pygmaeus, Ranunculus sulphureus and Taraxacum arcticum) sampled from 10 sites. Both coarse AM endophyte, with hyphae of 5-10 μm width, vesicles and occasional arbuscules, and fine endophyte, consisting of hyphae of 1-3 μm width and sparse arbuscules, were recorded in roots. Coarse AM hyphae, vesicles, arbuscules and fine endophyte hyphae occupied 1.0-30.7, 0.8-18.3, 0.7-11.9 and 0.7-12.8% of the root lengths of colonised plants, respectively. Principal component analysis indicated no associations between the abundances of AM structures in roots and edaphic factors. We conclude that the AM symbiosis is present in grass and forb roots on Spitsbergen.

Psychotic symptoms are prevalent in schizophrenia, bipolar disorder, and other psychiatric and neurological disorders, yet the neurobiological underpinnings of psychosis remain obscure. In the last decade, a large number of magnetic resonance imaging studies have shown differences in local gray matter volume between patients with different psychiatric syndromes and healthy controls. Few studies have focused on the symptoms, which these syndromes are constituted of. Here, we test the association between psychosis and gray matter volume by using a sample of 167 subjects with bipolar disorder, with and without a history of psychosis, and 102 healthy controls. Magnetic resonance images were analyzed on group level using a voxel-wise mass univariate analysis (Voxel-Based Morphometry). We found that patients with a history of psychosis had smaller gray matter volume in left fusiform gyrus, the right rostral dorsolateral prefrontal cortex, and the left inferior frontal gyrus compared with patients without psychosis and with healthy controls. There was no volume difference in these areas between the no-psychosis group and healthy controls. These areas have previously been structurally and functionally coupled to delusions and hallucinations. Our finding adds further evidence to the probability of these regions as key areas in the development of psychotic symptoms., (© The Author 2016. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The traditional concept of 'categorical' psychiatric disorders has been challenged as many of the symptoms display a continuous distribution in the general population. We suggest that this is the case for emotional dysregulation, a key component in several categorical psychiatric disorder constructs. We used voxel-based magnetic resonance imaging morphometry in healthy human subjects (n = 87) to study how self-reported subclinical symptoms associated with emotional dysregulation relate to brain regions assumed to be critical for emotion regulation. To measure a pure emotional dysregulation, we also corrected for subclinical symptoms of non-emotional attentional dysregulation. We show that such subclinical emotional symptoms correlate negatively with the grey matter volume of lateral orbitofrontal cortex bilaterally-a region assumed to be critical for emotion regulation and dysfunctional in psychiatric disorders involving emotional dysregulation. Importantly, this effect is mediated both by a decrease in volume associated with emotional dysregulation and an increase in volume due to non-emotional attentional dysregulation. Exploratory analysis suggests that other regions involved in emotional processing such as insula and ventral striatum also show a similar reduction in grey matter volume mirroring clinical disorders associated with emotional dysregulation. Our findings support the concept of continuous properties in psychiatric symptomatology., (© The Author (2015). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.)

Background: Neuroinflammation is increasingly recognized as contributing to the pathogenesis of depression. Key inflammatory markers as well as kynurenic acid (KYNA) and quinolinic acid (QUIN), both tryptophan metabolites, have been associated with depressive symptoms and suicidality. The aim of the present study is to investigate the peripheral concentration of cytokines and tryptophan and kynurenine metabolites in patients with unipolar treatment-resistant depression before and after electroconvulsive therapy (ECT), the most effective treatment for depression., Methods: Cytokines in plasma from patients with major depressive disorder (MDD; n = 19) and healthy volunteers (n = 14) were analyzed with electrochemiluminescence detection. Tryptophan and kynurenine metabolites were detected with high-performance liquid chromatography (HPLC) and LC/MS. KYNA was analyzed in a second healthy control cohort (n = 22)., Results: Patients with MDD had increased plasma levels of interleukin (IL)-6 compared to healthy volunteers (P < 0.05). We also found an altered kynurenine metabolism in these patients displayed by decreased plasma levels of KYNA (P < 0.0001) as well as a significantly increased QUIN/KYNA ratio (P < 0.001). Plasma levels of tryptophan, kynurenine, and QUIN did not differ between patients and controls. Treatment with ECT was associated with a significant decrease in the plasma levels of tryptophan (P < 0.05), kynurenine (P < 0.01), and QUIN (P < 0.001), whereas plasma levels of KYNA did not change. The QUIN/KYNA ratio was found to significantly decrease in ECT-treated patients (P < 0.05). There was a significant inverse correlation between symptom severity and kynurenine levels at baseline (r = -0.67, P = 0.002)., Conclusions: This study confirms an imbalanced kynurenine pathway in MDD supporting the hypothesis of a netstimulation of N-methyl-D-aspartic acid (NMDA) receptors in the disorder. Treatment with ECT profoundly decreased QUIN, an NMDA-receptor agonist previously suggested to be implicated in the pathogenesis of depression, an effect that might have bearing for the good clinical outcome of ECT.

Psychomotor disturbances are prominent in bipolar disorder patients with a history of psychosis, but their neural correlates remain largely unexplored. We hypothesized that these psychomotor disturbances are associated with morphometric changes in functionally specific regions of the basal ganglia and thalamus. To test if psychomotor performance is associated with changes in volume and shape in these brain regions, we investigated 20 euthymic bipolar disorder patients with a history of psychosis and 20 healthy controls with structural magnetic resonance imaging and vertex-based morphometry. Within the patient group, the local shape of the basal ganglia was significantly associated with longer duration of illness, increased number of manic episodes, and treatment with antipsychotics. There were neither any statistically significant associations between psychomotor performance and morphometric measures in the patient group, nor any significant morphometric differences between patients and controls. We conclude that euthymic subjects with bipolar disorder and a previous history of psychosis show shape changes in regions of the basal ganglia associated to clinical variables that may predict psychomotor disturbances in bipolar disorder.

Inflammation has been linked to the pathophysiology of bipolar disorder based on studies of inflammation markers, such as cytokine concentrations, in plasma and serum samples from cases and controls. However, peripheral measurements of cytokines do not readily translate to immunological activity in the brain. The aim of the present study was to study brain immune and inflammatory activity. To this end, we analyzed cytokines in cerebrospinal fluid from 121 euthymic bipolar disorder patients and 71 age and sex matched control subjects. Concentrations of 11 different cytokines were determined using immunoassays. Cerebrospinal fluid IL-8 concentrations were significantly higher in patients as compared to controls. The other cytokines measured were only detectable in part of the sample. IL-8 concentrations were positively associated to lithium- and antipsychotic treatment. The findings might reflect immune aberrations in bipolar disorder, or be due to the effects of medication., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Bipolar disorder (BD) is characterized by mood swings between manic and depressive states. The etiology and pathogenesis of BD is unclear, but many of the affected cognitive domains, as well as neuroanatomical abnormalities, resemble symptoms and signs of small vessel disease. In small vessel disease, cerebrospinal fluid (CSF) markers reflecting damages in different cell types and subcellular structures of the brain have been established. Hence, we hypothesized that CSF markers related to small vessel disease may also be applicable as biomarkers for BD. To investigate this hypothesis, we sampled CSF from 133 patients with BD and 86 healthy controls. The concentrations of neurofilament light chain (NF-L), myelin basic protein (MBP), S100B, and heart-type fatty acid binding protein (H-FABP) were measured in CSF and analyzed in relation to diagnosis, clinical characteristics, and ongoing medications. Hereby we found an elevation of the marker of subcortical axonal damage, NF-L, in bipolar subjects. We also identified positive associations between NF-L and treatment with atypical antipsychotics, MBP and lamotrigine, and H-FABP and lithium. These findings indicate axonal damage as an underlying neuropathological component of bipolar disorder, although the clinical value of elevated NF-L remains to be validated in follow-up studies. The associations between current medications and CSF brain injury markers might aid in the understanding of both therapeutic and adverse effects of these drugs.

Blood-cerebrospinal barrier (BCB) dysfunction has previously been shown in subjects with schizophrenia and depressed patients with attempted suicide. Bipolar disorder (BPD) shares clinical features with both these disorders, but it is unknown if the integrity of the BCB is altered also in BPD. To assess if BCB function in BPD we surveyed 134 mood-stabilized BPD patients and 86 healthy controls. Serum and cerebrospinal fluid (CSF) samples were collected and analyzed for albumin concentration by immunonephelometry. CSF/serum albumin ratio, an established measure of BCB function, was significantly elevated in BPD patients as compared to controls. After stratifying patients according to diagnostic subtype, BPD I patients had the highest CSF/serum albumin ratios. Moreover, BPD patients on antipsychotic treatment had higher CSF/serum albumin ratio than BPD patients on other treatments. When excluding BPD patients on antipsychotic treatment the difference in CSF/serum albumin ratio between the BPD and control groups disappeared. In conclusion, antipsychotic treatment in BPD is associated with elevated CSF/serum albumin ratio, tentatively as a sign of impaired BCB function. Whether this elevation is caused by antipsychotic treatment or is associated with a certain subtype of BPD, requiring antipsychotic treatment, remains to be determined., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

The performance of a commercially available Seegene Seeplex STI Master Panel 3 multiplex PCR for Candida species identification was compared with an internal transcribed spacer 2 (ITS2) PCR assay. We found that the Seeplex assay was specific for identification of C. albicans, C. krusei, C. parapsilosis, C. glabrata, C. tropicalis and C. dubliniensis., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: Bipolar disorder is a common psychiatric mood disorder that is defined by recurrent episodes of abnormally elevated mood and depression. Progressive structural brain changes in individuals with bipolar disorder have been suggested to be associated with defects in the secretion of neurotrophic factors. We sought to assess how the regulated secretory pathway in the brain is affected in patients with bipolar disorder by measuring chromogranin B and secretogranin II, which are 2 cerebrospinal fluid (CSF) biological markers for this process., Methods: We measured the concentrations of chromogranin B (peptide 439-451) and secretogranin II (peptide 154-165) in the CSF of patients with well-defined bipolar disorder and healthy controls. The lifetime severity of bipolar disorder was rated using the Clinical Global Impression (CGI) scale., Results: We included 126 patients with bipolar disorder and 71 healthy controls in our analysis. Concentrations of secretogranin II were significantly lower in patients with bipolar disorder type I than in healthy controls. The reduction was most pronounced in patients with high CGI scores (i.e., severe disease)., Limitations: The cross-sectional design of the current study limits the ability to pinpoint the causalities behind the observed associations., Conclusion: This study shows that the CSF marker secretogranin II has the potential to act as a biological marker for severe forms of bipolar disorder. Our findings indicate that patients with bipolar disorder possess defects in the regulatory secretory pathway, which may be of relevance to the progressive structural brain changes seen in those with severe forms of the disease.

Background: Cognitive deficits have been documented in patients with bipolar disorder. Further, it has been suggested that the degree and type of cognitive impairment differ between bipolar I and bipolar II disorder, but data is conflicting and remains inconclusive. This study aimed to clarify the suggested differences in cognitive impairment between patients with bipolar I and II disorder in a relatively large, clinically stable sample while controlling for potential confounders., Methods: 67 patients with bipolar I disorder, 43 with bipolar II disorder, and 86 randomly selected population-based healthy controls were compared. A number of neuropsychological tests were administered, assessing verbal and visual memory and executive functions. Patients were in a stable phase during testing., Results: Patients with bipolar type I and type II were cognitively impaired compared to healthy controls, but there were no statistically significant differences between the two subtypes. The strongest predictor of cognitive impairment within the patient group was current antipsychotic treatment., Conclusions: The present study suggests that the type and degree of cognitive dysfunction is similar in bipolar I and II patients. Notably, treatment with antipsychotics - but not a history of psychosis - was associated with more severe cognitive impairment. Given that patients with bipolar I disorder are more likely to be on antipsychotic drugs, this might explain why some previous studies have found that patients with type I bipolar disorder are more cognitively impaired than those with type II.

A prospective observational nationwide investigation was performed from September 2005 to August 2006 to study the epidemiology of candidaemia in Sweden. From 385 patients, 403 isolates were recovered, yielding an incidence of 4.2 cases per 100 000 inhabitants. Candida albicans was the most common species (61%), followed by Candida glabrata (20%) and Candida parapsilosis (9%). The rates of resistance to fluconazole were ≤ 1% in C. albicans and 6-29% in non-albicans species other than C. glabrata and Candida krusei. Resistance to voriconazole was rare, except for C. glabrata and C. krusei. Only three isolates had reduced susceptibility to amphotericin B, and one had reduced susceptibility to caspofungin., (© 2012 The Authors Clinical Microbiology and Infection © 2012 European Society of Clinical Microbiology and Infectious Diseases.)

Bipolar disorder is a psychiatric disorder characterized by recurrent episodes of mania/hypomania and depression. Progressive cognitive dysfunction such as impairments in executive function and verbal memory is common in euthymic bipolar patients. The cerebrospinal fluid has previously been used to study neurodegenerative processes in Alzheimer's disease, from which changes in three core biomarkers have emerged as indicative of degeneration: amyloid β, total tau, and hyperphosphorylated tau. Here, neurodegeneration in bipolar disorder was investigated by assessing the association between bipolar disorder and cerebrospinal fluid biomarkers for neurodegenerative processes. Cerebrospinal fluid was obtained from 139 bipolar disorder patients and 71 healthy controls. Concentrations of total and phosphorylated tau, amyloid β1-42, amyloid β38/β40/β42, and the soluble forms of amyloid precursor protein were measured in patients vs controls. The concentrations of the soluble forms of amyloid precursor protein were significantly lower in bipolar patients compared with controls. The amyloid β42/amyloid β38 and the amyloid β42/amyloid β40 ratios were higher in bipolar patients than controls. There were no discernible differences in the concentrations of total/phosphorylated tau, amyloid β1-42, or amyloid β38/β40/β42. The concentrations of the biomarkers within the bipolar patient group were further associated with different ongoing medical treatments and diagnostic subgroups. The findings suggest that the amyloid precursor protein metabolism is altered in bipolar disorder. The results may have implications for the understanding of the pathophysiology of bipolar disorder and for the development of treatment strategies. Importantly, there were no signs of an Alzheimer-like neurodegenerative process among bipolar patients.

Paranoia is commonly a mood-incongruent psychotic symptom of mania which may be related to dopamine dysregulation. Progesterone and its metabolite allopregnanolone (ALLO) have been found in animals to antagonize the effects of dopamine. We therefore examined serum progesterone, its endogenous antagonist DHEAS and polymorphisms of the genes coding for certain steroidogenetic enzymes (AKR1C4, HSD3B2, and SRD5A1) in 64 males and 96 females with bipolar 1 or 2 disorder with or without paranoid ideation during mood elevation. Euthymic morning serum progesterone, DHEAS and cortisol concentrations were measured in males and in premenopausal women who were in follicular phase and not taking oral contraceptives. In women only, SNPs in AKR1C4 reduced the likelihood of having exhibited paranoid ideation by circa 60%. The haplotype of all 4 SNPs in the AKR1C4 gene reduced the risk of exhibiting paranoia by 80% (OR 0.19, 95% CI 0.06-0.61, p=0.05). A history of paranoid ideation was not, however, related to progesterone or DHEAS concentration. Serum DHEAS and progesterone concentrations were lower in men who had shown paranoid ideation during mania/hypomania compared with those who had not (F=7.30, p=0.006) however this was not coupled to polymorphisms in the selected genes. The ancestral G in rs4659174 in HSD3B2 was in men associated with a lower risk of paranoid ideation (likelihood ratio χ(2) 3.97, p=0.046, OR 0.31 (95% CI 0.10-0.96)) but did not correlate with hormone concentrations. Hence, gene variants in the steroidogenetic pathway and steroids concentration differences may be involved in the susceptibility to paranoia during mood elevation., (Copyright © 2012 Elsevier B.V. and ECNP. All rights reserved.)

Background: Using scanning electron microscopy, microscopic structures have been identified in fresh cerebrospinal fluid (CSF) in patients with schizophrenia and bipolar disorder, but only rarely in control subjects. However, it has not been determined whether these microscopic particles represent state or trait markers, i.e. if their presence is related to clinical manifestations of the disease or if they also can be found in as yet asymptomatic individuals with a genetic liability. This question can be addressed by studying twins discordant or concordant for schizophrenia or bipolar disorder., Methodology/principal Findings: We investigated microscopic structures in CSF in 102 individuals: 21 monozygotic and 16 dizygotic twins affected or not affected with schizophrenia, schizoaffective disorder or bipolar disorder and in 65 healthy singleton controls. A first and a second fraction of CSF was freshly applied on filters and examined by scanning electron microscopy technique. Spherical particles with lipid appearance averaging between 0.1 to 8.0 µm in diameter were detected in the center of the filter as well as located in the margins of larger aggregates binding in a viscous state. Structures were found in 12 of 17 probands, 5 of 12 healthy co-twins and 3 of 73 healthy controls. Thus, a positive microscopic finding significantly increased the likelihood of belonging to the proband group (OR=48, 95% CL: 8.2-550, p<0.0001) and the co-twin-group (OR=16, 95% CL: 2.0-218, p=0.006). Age, sex, history of alcohol abuse or anxiety syndrome, somatic disorder and markers of acute inflammatory activity did not account for group differences; nor did exposure to psychotropic medication., Conclusion: Presence of microscopic particles in CSF may possibly reflect trait dependent genetic or environmental vulnerability in patients with schizophrenia, schizoaffective disorder or bipolar disorder.

Background: Irritable mood during mood elevation is common in bipolar disorder. The progesterone metabolite allopregnanolone (ALLO) has been implicated in other disorders presenting with irritability. This study aimed to test whether a history of manic/hypomanic irritability is associated with low serum progesterone levels; and whether single nucleotide polymorphisms (SNPs) in gene coding for steroidogenetic enzymes (HSD3B2, SRD5A1 and AKR1C4 were coupled to previous manic irritability and/or with serum progesterone concentrations., Methods: Morning serum progesterone concentrations during euthymic phase of bipolar illness types 1 and 2 were assessed in 71 males and 107 females. Previous manic/hypomanic irritability was assessed using the Affective Disorders Evaluation. Selected SNPs were analyzed: i) aldoketoreductase-type-4 (AKR1C4 - rs17306779, rs3829125, rs10904440, rs12762017, and rs11253048), ii) 3-β-hydroxysteroid-dehydrogenase (HSD3B2 - rs4659174, rs2854964, and rs3765948), iii) steroid-5-α-reductase (SRD5A1 - rs8192139, rs181807, rs3822430, and rs3736316)., Results: In males, progesterone concentrations were lower in those who had shown manic/hypomanic irritability compared with nonirritable (F=7.05, p=0.0099). SNPs rs17306779, rs3829125, and rs10904440 were associated with manic/hypomanic irritability. A cystine to serine change at position 145 in AKR1C4 (rs3829125) was associated with lower serum progesterone (F=6.34, p=0.014). There were no associations in females., Limitations: Relatively small sample sizes., Conclusion: Low progesterone levels and a cystine to serine change at position 145 in AKR1C4 gene are associated with manic/hypomanic irritability in males. Given that the enzyme AKR1C4 has both dehydrogenating and reductive activities in the steroidogenetic pathway, a missense variation in the gene may predispose to manic/hypomanic irritability by altering the relationship between progesterone and ALLO concentrations in the brain., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Objectives: To describe wild-type distributions of the MIC of fluoroquinolones for Mycobacterium tuberculosis in relation to current critical concentrations used for drug susceptibility testing and pharmacokinetic/pharmacodynamic (PK/PD) data., Methods: A 96-stick replicator on Middlebrook 7H10 medium was used to define the MICs of ciprofloxacin, ofloxacin, moxifloxacin and levofloxacin for 90 consecutive clinical strains and 24 drug-resistant strains. The MICs were compared with routine BACTEC 460 susceptibility results and with MIC determinations in the BACTEC MGIT 960 system in a subset of strains using ofloxacin as a class representative. PK/PD data for each drug were reviewed in relation to the wild-type MIC distribution., Results: The wild-type MICs of ciprofloxacin, ofloxacin, moxifloxacin and levofloxacin were distributed from 0.125 to 1, 0.25 to 1, 0.032 to 0.5 and 0.125 to 0.5 mg/L, respectively. The MIC data correlated well with the BACTEC 960 MGIT and BACTEC 460 results. PD indices were the most favourable for levofloxacin, followed by moxifloxacin, ofloxacin and ciprofloxacin., Conclusions: We propose S (susceptible)

Previous studies have suggested that insulin-like growth factor-I (IGF-I) and its binding proteins (IGFBPs) have a pathogenetic role in idiopathic osteoporosis. To investigate this question further we compared 20 men with idiopathic osteoporosis with 12 healthy, age-matched men regarding growth hormone (GH) secretion and sensitivity. GH samples were drawn every 30 minutes for 24 hours from 12 of the patients and all controls, and cumulated GH secretion (24 hGH) was derived. Peak GH secretion (peakGH) was provoked by an insulin tolerance test. There were no differences between the groups in serum IGF-I (162 +/- 30 vs 163 +/- 47 micrograms/liter, mean +/- SD), IGFBP-3 (2474 +/- 263 vs 2568 +/- 197 micrograms/liter), 24 hGH (1.34 +/- 1.26 vs 0.79 +/- 0.43 U), or peakGH (53.0 +/- 21.5 vs 44.1 +/- 19.8 mU/liter). Patients and controls were given GH (2.4 U/day) for 1 week. Serum levels of markers for bone turnover increased significantly in both groups, with no difference in response to GH between the groups. The increase in urinary bone resorption markers was only significant in the controls. In the patients, but not in the controls, there were significant positive correlations between indices for GH secretion and markers for bone turnover at baseline and significant negative correlations with relative changes in bone markers during GH treatment. In this study no difference in GH secretion was found between men with idiopathic osteoporosis and controls, but the findings suggest that the GH/IGF-I axis could play a regulatory role in bone metabolism in men with this condition.

The aim of the present study was to develop a PCR-based method to detect and identify fungi directly from human venous blood. We used broad-range PCR primers that targeted a part of the large subunit 28S rRNA genes. To obtain species-specific hybridisation probes, type strains of Candida albicans, C. glabrata, C. krusei, C. parapsilosis, C. tropicalis and Cryptococcus neoformans were PCR amplified, and the amplicons were analysed by gene sequencing. Based on the sequence analysis, species-specific probes that targeted variable regions were designed and used in hybridisation analyses. Between 2 to 10 fungal cells/ml of spiked blood samples could be detected and correctly identified to species. We applied the technique to blood samples obtained from two patients with or two patients without verified candidaemia. The three samples of candidaemia patients were correctly identified to species level, and those of the negative patients remained negative. This method is a potential tool for diagnosis of systemic invasive candidiasis.

Objective: Effects of short-term administration of growth hormone (GH) with respect to gender and oral contraceptives (OCs) were investigated in healthy young adults., Design: Open, prospective 2-week study., Setting: Clinical research centre, university hospital., Subjects: Three groups of healthy young adults were included: six men, six women with normal menstrual cycles, and six women taking OCs., Interventions: The subjects were given recombinant human GH subcutaneously for 2 weeks: 1 U m-2 body surface daily during the first week, and 3 U m-2 daily during the second week., Main Outcome Measures: Serum samples were drawn in the morning after overnight fasting on days 0, 3, 7, 10 and 14, and were analysed for GH, insulin-like growth factor 1 (IGF-1), insulin, testosterone, sex hormone-binding globulin (SHBG), lipids and markers of bone metabolism. Second-void morning urine was analysed for deoxypyridinoline (Dpyr)., Results: During administration of GH, serum IGF-1 increased in the men and in the women without OCs (86 and 52%, respectively). In the OC women, IGF-1 did not change significantly. Serum insulin increased in all three groups, with the largest change (122%) in the men and the smallest (47%) in the OC women. Blood glucose was unchanged. Total cholesterol, low-density lipoprotein (LDL) cholesterol and the LDL/high-density lipoprotein cholesterol ratio were reduced in the men only. Biochemical markers of bone resorption (serum procollagen type I, urinary Dpyr) increased in the men, and markers of bone formation (serum osteocalcin and telopeptide of collagen type I) increased in the men as well as in the women not taking OCs. The testosterone/SHBG ratio increased in the men on account of a reduction in SHBG., Conclusion: The response to short-term administration of GH differed in the three groups, with the largest effect in the men and the smallest in the OC women. The inhibitory influence of contraceptives underlines the role of sex steroids in modulating the susceptibility to GH.

Background/aims: The aim was to study IgG immune complex (IC) binding to isolated hepatocytes, Kupffer cells (KCs) and sinusoidal endothelial cells (SECs). Further, we wished to analyze the capacity of IgG ICs to induce release of reactive oxygen metabolites by the IC-binding liver cells., Methods: ICs were formed between (125)I-tyramine-cellobiose-labelled dinitrophenyl-conjugated human serum albumin ((125)I-TC-DNP(10)HSA) and polyclonal rabbit IgG antibodies. Binding of ICs to different rat liver cells in suspension was studied at 4 degrees C. Production of reactive oxygen metabolites was measured by luminol-enhanced chemiluminescence at 37 degrees C., Results: IgG mediated binding of (125)I-TC-DNP(10)HSA to both KCs and SECs, but not to hepatocytes. The binding showed saturation kinetics and was blocked by an excess of unlabelled IgG-ICs. IgG-ICs activated KCs, but not SECs, to a chemiluminescence response., Conclusions: Both KCs and SECs bind IgG-ICs in vitro, probably via Fc receptor interaction. IgG-ICs activate KCs to produce reactive oxygen metabolites. The binding of IgG-ICs to isolated hepatocytes is small., (Copyright 2000 S. Karger AG, Basel)

We recently observed that among patients with GH deficiency due to adult-onset hypopituitarism, men responded with a greater increase in serum levels of insulin-like growth factor I (IGF-I) and biochemical markers of bone metabolism than women when the same dose of recombinant human GH (rhGH) per body surface area was administered for 9 months. In the present study, 33 of the 36 patients in the previous trial (20 men and 13 women) continued therapy for up to 45 months. The dose of rhGH was adjusted according to side-effects and to maintain serum IGF-I within the physiological range. This resulted in a significant dose reduction in the men; consequently, the women received twice as much rhGH as the men (mean +/- SD, 1.9 +/- 1.1 vs. 1.0 +/- 0.6 U/day; P < 0.01). The increases in serum IGF-I levels and serum biochemical markers of bone metabolism were similar in men and women with these doses. The total bone mineral content (BMC) was increased after 33 and 45 months of treatment up to 5.1% (P = 0.004 and 0.0001). Bone mineral density (BMD), BMC, and the area of the femoral neck and the lumbar spine were also significantly increased after 33 and 45 months of treatment. When analyzed by gender, total body BMC, femoral neck BMD and BMC, and spinal BMC were significantly increased in males, but not in females (P < 0.05-0.01). In conclusion, rhGH treatment continued to have an effect on bone metabolism and bone mass for up to 45 months of therapy. The changes in bone mass were greater in the men, although they received lower doses of rhGH than the women. The results indicate that the sensitivity to GH in adult patients with GH deficiency is gender dependent.

Estrogen deficiency is an important pathogenetic factor in female osteoporosis, and androgens are known to have anabolic effects on bone. In this study we have compared 12 men with idiopathic osteoporosis, age 27-55 years, with 12 age-matched men, with respect to serum levels of sex steroids, biochemical markers of bone turnover, bone density, and body composition. All subjects showed values within the normal range for all hormonal parameters. The patient group compared with the controls had significantly lower serum levels of estradiol (71 +/- 13 versus 85 +/- 14 pmol/liter, P < 0.03); estradiol/sex hormone-binding globulin (SHBG) ratio (22.4 +/- 12.1 versus 39.5 +/- 18.6 pmol/mg, P < 0.02); free androgen index (51.0 +/- 19.4 versus 74.1 +/- 33.1%, P < 0.05); and higher SHBG (3.7 +/- 1.6 versus 2.5 +/- 1.0 mg/liter; P < 0.04). The men with idiopathic osteoporosis had significantly lower body mass index (23.2 +/- 2.8 versus 25.9 +/- 3.3 kg/m2, P < 0.05); and a tendency to lower percentage of total body fat (14.2 +/- 5.5 versus 18.6 +/- 6.0%; P < 0.10) than the controls. Regression analyses revealed that bone mineral density in femoral neck correlated significantly and positively with the ratio estradiol/SHBG (r = 0.67; P < 0.04) and negatively with SHBG concentrations (r = -0.63; P < 0.04) in the group of patients. These findings could represent a pathogenetic mechanism in male idiopathic osteoporosis.

Several trials with growth hormone (GH) replacement therapy in adults with GH deficiency have been conducted during the last 10 years. Beneficial effects of treatment on bone density, physical capacity, body composition, lipid profile and quality of life have been reported. It has long been known that GH secretion is greater in women than in men, despite similar reference ranges of serum insulin-like growth factor (IGF)-I in adult men and women. It has also been reported that sex steroids influence not only GH secretion but also the local synthesis of IGF-I in target tissues and the expression of the GH receptor in various other tissues. However, it has been acknowledged only recently that there is a clinically significant gender difference in the response to GH treatment in adults with GH deficiency and, consequently, a need to adjust the dose of recombinant human GH (rhGH). We report the results of a placebo-controlled study in 36 men and women with GH deficiency who received the same dose of rhGH per body surface area (1.25 U/m2 per day) for 9 months. We observed significantly greater responses in male patients than in female patients with regard to the changes in serum levels of IGF-I, body composition and biochemical markers of bone metabolism. When these patients continued to receive GH replacement therapy for an additional 24 months, the dose of rhGH was adjusted to the serum levels of IGF-I. As a result, the dose administered to the male patients was reduced to nearly half that given to the female patients (1.0 vs 1.9 U/day) and the serum levels of IGF-I and of biomarkers of bone turnover increased to the same extent in patients of both sexes. However, an increase in bone density of the hip and the lumbar spine after a total of 33 months of rhGH treatment was observed only in the male patients; no significant changes in bone density were found in the female patients. The reason for the observed difference in GH response between men and women with GH deficiency is not known, although the different sex steroid pattern cannot be excluded as a contributing factor.

Idiopathic osteoporosis in younger individuals could be related to reduced bone formation rather than increased bone resorption, and disturbances in GH or insulin-like growth factor (IGF)-I production could be involved in its pathogenesis. In the present study, men with idiopathic osteoporosis were compared with healthy men, with respect to bone histomorphometry and to serum levels of IGF-I, IGF-II, IGF binding protein (IGFBP)-2 and IGFBP-3, and 24-h urinary excretion of GH. Mean wall thickness was reduced in the patients (48.3 +/- 7.2 vs. 61.7 +/- 5.4 microns, P < 0.001). Also, resorption depth was decreased, albeit to a lesser degree (54.4 +/- 3.8 vs. 60.7 +/- 5.3 microns, P < 0.01), thus creating a pronounced negative balance (-6.04 +/- 9.8 vs. 0.96 +/- 3.2 microns, P < 0.05). In the patients, serum concentrations of IGFBP-3 were reduced, compared with controls, with a 46% lower mean value; whereas levels of IGF-I, IGF-II, IGFBP-2, and GH were similar in the two groups. Thus, there was a significant negative balance caused by a pronounced decrease in wall thickness in men with idiopathic osteoporosis. The finding of low IGFBP-3 levels in these patients is interesting, in view of previous clinical and experimental findings, but its pathophysiological significance remains to be determined.

Thirty-six patients with adult-onset GH deficiency (GHD) were examined before and after 9 months of treatment with recombinant GH. The study was conducted as a double blind, placebo-controlled, 21-month trial with a cross-over design, with each treatment period lasting for 9 months. The same dose, adjusted for body surface area, was given to men (n = 21) and women (n = 15), and the effects on body composition and biochemical parameters were evaluated with respect to gender. The extent of GHD, assessed before therapy from basal GH secretion and GH release in response to provocative tests, did not differ between the two groups. The men, however, had higher serum insulin-like growth factor I concentrations than the women (mean +/- SD, 126 +/- 71 vs. 61 +/- 32 micrograms/L; P = 0.0003), less body fat, and greater lean body mass. Upon treatment, insulin-like growth factor I concentrations increased more in men than in women (by 305 +/- 136 and 198 +/- 96 micrograms/L, respectively; P = 0.02). The men lost more body fat than the women (7.4 +/- 4.1% vs. 3.3 +/- 3.8%; P = 0.002), whereas the difference in gain in lean body mass failed to reach statistical significance. Serum levels of total cholesterol, low density lipoprotein cholesterol, apolipoprotein B, and plasminogen activator inhibitor-1 decreased in the male group (P = 0.003, P = 0.03, P = 0.0009, and P = 0.01, respectively), but not in the females. Serum markers of bone formation, namely osteocalcin, procollagen type I, bone-specific alkaline phosphatase, and a marker of bone resorption, telopeptide of collagen type I, increased more markedly in men than in women. Lipoprotein(a) increased to a similar extent in the male and female groups. The data demonstrate that men and women with GHD display marked differences in their responsiveness to GH replacement therapy. These differences should be taken into consideration when optimizing the treatment of GHD patients.

Interleukin-6 (IL-6) is known to enhance osteoclast recruitment, and thereby bone resorption. Thus, IL-6 has been proposed to mediate hypercalcemia in multiple myeloma and the enhanced osteoclastic activity seen in postmenopausal osteoporosis. We recently reported that the calcium concentration in plasma affects IL-6 secretion from mononuclear blood cells. To investigate the underlying mechanism, we have studied the effect of calcium on IL-6 formation in mononuclear blood cells ex vivo and in vitro. Thirteen healthy volunteers were given 1 g of calcium orally after overnight fasting. Plasma levels of ionized calcium (pCa2+) and serum levels of parathyroid hormone (sPTH) were measured after 2 and 4 h, with all subjects still fasting. After 2 h, pCa2+ was increased and sPTH decreased in all 13 persons. IL-6 secretion ex vivo from mononuclear blood cells drawn 4 h after calcium intake was increased 185% as compared with IL-6 secretion from cells drawn just before calcium intake. In control experiments without calcium intake, there was no alteration in pCa2+ and no effect on IL-6 secretion from mononuclear blood cells. In vitro studies revealed that stimulation of isolated mononuclear blood cells with physiological concentrations of calcium dose-dependently increased IL-6 secretion with an estimated EC50 at 1.2 mM Ca2+. No effect on the IL-6 secretion was seen following treatment of the isolated mononuclear blood cells with PTH or calcitonin. These observations demonstrate that the plasma calcium concentration affects IL-6 secretion from mononuclear blood cells. The in vitro data indicate the involvement of a direct calcium sensing mechanism. These findings might have implications in hypercalcemia and should also be borne in mind when considering the role of cytokines in osteoporosis.

The handling of free and IgG-complexed dinitrophenylated human serum albumin (DNP-HSA) by human dendritic cells (DC) cultured with granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4) was studied. It has been shown that the amount of uncomplexed or IgG-complexed antigen required by DC to start an immune response is low compared with other antigen-presenting cells. We therefore examined whether such efficient presentation of immune complexes is due to an enhanced Fc gamma RII-mediated endocytosis or to a specialized and efficient antigen handling, i.e., macropinocytosis. The Fc gamma RII expression was found to be heterogeneous on the GM-CSF- and IL-4-cultured DC, i.e. it ranges from low to high expression. The handling of antigen and immune complexes revealed, that the level of binding and uptake of IgG-DNP-HSA complexes by in vitro expanded DC is low compared with free antigen. Uncomplexed DNP-HSA is probably handled either by endocytosis via receptors being more abundant and/or efficient than the Fc gamma RII or via non-receptor-mediated endocytosis. The binding and uptake of IgG-complexed DNP-HSA was blocked by anti-Fc gamma RII antibody, indicating the specificity of the interaction.

Injections with growth hormone (GH) or insulin-like growth factor I (IGF-I) have been proposed for anabolic therapy in osteoporosis. In a cross-over study, 12 men with idiopathic osteoporosis received daily subcutaneous injections of GH (2 IU/m2) or IGF-I (80 micrograms/kg) for 7 days with 12 weeks of wash-out. Serum levels of procollagen type I increased by 29% following treatment with GH (P < 0.001) and by 43% with IGF-I (P < 0.001 compared with pretreatment levels; P < 0.05 compared with GH injections), whereas both treatments rendered a 20% increase in osteocalcin concentrations (P < 0.001), indicating enhanced bone formation. There was also evidence of stimulated bone resorption, as the urinary levels of deoxypyridinoline increased by 44% following GH injections (P < 0.001) and by 29% following IGF-I (P < 0.001), and there were 28% higher serum concentrations of IGF-I after GH than after IGF-I injections. Although markers of bone metabolism increased under both treatments, comparison of the treatments suggests that IGF-I enhanced formation of collagen type I more than did GH. Furthermore, the stimulation of bone resorption was detected as soon as 4 days after the initiation of GH injections. Some of the differences might be dose-dependent, but could also indicate separate mechanisms at the cellular level.