Intra-Abdominal Nocardiosis-Case Report and Review of the Literature.

Nocardiosis is primarily an opportunistic infection affecting immunosuppressed individuals, in whom it most commonly presents as pulmonary infection and sometimes cerebral abscesses. Isolated abdominal or retroperitoneal nocardiosis is rare. Here, we report the second case, to our knowledge, of isolated abdominal nocardiosis due to Nocardia paucivorans and provide a comprehensive review of intra-abdominal nocardiosis. The acquisition of abdominal nocardiosis is believed to occur via hematogenous spreading after pulmonary or percutaneous inoculation or possibly via direct abdominal inoculation. Cases of Nocardia peritonitis have been reported in patients on peritoneal dialysis. Accurate diagnosis of abdominal nocardiosis requires histological and/or microbiological examination of appropriate, radiologically or surgically obtained biopsy specimens. Malignancy may initially be suspected when the patient presents with an abdominal mass. Successful therapy usually includes either percutaneous or surgical abscess drainage plus prolonged combination antimicrobial therapy.

Systematic De-escalation of Successful Triple Antiretroviral Therapy to Dual Therapy with Dolutegravir plus Emtricitabine or Lamivudine in Swiss HIV-positive Persons.

BACKGROUND: Studies increasingly suggest that the efficacy of certain dual antiretroviral therapy (ART) combinations is equal to triple ART. Increasing concerns among HIV-positive patients and physicians in Switzerland include ART cost and long-term ART safety and toxicity, i.e. taking only as many ART agents as necessary. The aims of this retrospective analysis are to report on the de-escalation of our entire clinic population of eligible patients with well-controlled HIV-infection to dolutegravir-containing dual ART. METHODS: Starting in March 2015, we systematically considered the de-escalation of eligible patients to either dolutegravir/emtricitabine or dolutegravir/lamivudine, by discontinuing tenofovir disoproxil fumarate or abacavir. We report on the virological efficacy, tolerability and patient satisfaction ≥ 48 weeks after de-escalation. FINDINGS: Of 106 HIV-positive patients followed in our clinic, 70 patients were de-escalated. Three returned to triple ART (insomnia after dolutegravir start, n = 2; new wish for single tablet regimen, n = 1). All de-escalated patients and all who continued triple ART had suppressed HIV viremia at last follow-up and were satisfied with their ART regimen, except for one patient who had virological failure after ART discontinuation in the setting of major depression. The most common reasons to not de-escalate included hepatitis B co-infection (n = 6), physician's concern about ART adherence (n = 6), patient reluctance to switch from a single tablet to a 2-tablet regimen (n = 7), patient satisfied with current ART (n = 5) and others (n = 12). INTERPRETATION: ART de-escalation to dolutegravir/FTC or dolutegravir/3TC is possible in the majority of patients virologically suppressed on triple ART, and may effectively address patient and physician concerns about long-term safety and cost of ART.

Pathogen- and antibiotic-specific effects of prednisone in community-acquired pneumonia.

In a double-blind, randomised, placebo-controlled trial of hospitalised patients with community-acquired pneumonia (CAP), we demonstrated shorter time to clinical stability (TTCS) with adjunct corticosteroid therapy compared with placebo.We did a pre-planned, exploratory analysis of any association between microbiological diagnosis, antibiotic treatment and procalcitonin level and effect of prednisone on TTCS, mortality, and CAP complications (n=726 participants, enrolled between December 2009 and May 2014). Multiplex viral real time PCR was systematically performed in nasopharyngeal swabs beginning November 2011 (n=489). Other investigations and treatments were at the discretion of the physician. Effect modification was tested with inclusion of interaction terms in the statistical models.Reduced TTCS with prednisone was seen in all microbiological, antibiotic, procalcitonin and afebrile patient subgroups. We found evidence for a different prednisone response in patients with pneumococcal pneumonia in whom intravenous antibiotic duration was not shorter (interaction p=0.01) with prednisone, as was observed in the remaining study population. In patients without macrolide treatment, rehospitalisations were not lower with prednisone (interaction p=0.04). After adjustment for multiple testing, these subgroup effects were no longer significant.Prednisone was associated with shorter TTCS independent of CAP aetiology. In pneumococcal pneumonia, prednisone effects on secondary endpoints may be less favourable.

Adjunct prednisone therapy for patients with community-acquired pneumonia: a multicentre, double-blind, randomised, placebo-controlled trial.

BACKGROUND: Clinical trials yielded conflicting data about the benefit of adding systemic corticosteroids for treatment of community-acquired pneumonia. We assessed whether short-term corticosteroid treatment reduces time to clinical stability in patients admitted to hospital for community-acquired pneumonia. METHODS: In this double-blind, multicentre, randomised, placebo-controlled trial, we recruited patients aged 18 years or older with community-acquired pneumonia from seven tertiary care hospitals in Switzerland within 24 h of presentation. Patients were randomly assigned (1:1 ratio) to receive either prednisone 50 mg daily for 7 days or placebo. The computer-generated randomisation was done with variable block sizes of four to six and stratified by study centre. The primary endpoint was time to clinical stability defined as time (days) until stable vital signs for at least 24 h, and analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00973154. FINDINGS: From Dec 1, 2009, to May 21, 2014, of 2911 patients assessed for eligibility, 785 patients were randomly assigned to either the prednisone group (n=392) or the placebo group (n=393). Median time to clinical stability was shorter in the prednisone group (3·0 days, IQR 2·5-3·4) than in the placebo group (4·4 days, 4·0-5·0; hazard ratio [HR] 1·33, 95% CI 1·15-1·50, p<0·0001). Pneumonia-associated complications until day 30 did not differ between groups (11 [3%] in the prednisone group and 22 [6%] in the placebo group; odds ratio [OR] 0·49 [95% CI 0·23-1·02]; p=0·056). The prednisone group had a higher incidence of in-hospital hyperglycaemia needing insulin treatment (76 [19%] vs 43 [11%]; OR 1·96, 95% CI 1·31-2·93, p=0·0010). Other adverse events compatible with corticosteroid use were rare and similar in both groups. INTERPRETATION: Prednisone treatment for 7 days in patients with community-acquired pneumonia admitted to hospital shortens time to clinical stability without an increase in complications. This finding is relevant from a patient perspective and an important determinant of hospital costs and efficiency. FUNDING: Swiss National Science Foundation, Viollier AG, Nora van Meeuwen Haefliger Stiftung, Julia und Gottfried Bangerter-Rhyner Stiftung.

Corticosteroid treatment for community-acquired pneumonia--the STEP trial: study protocol for a randomized controlled trial.

BACKGROUND: Community-acquired pneumonia (CAP) is the third-leading infectious cause of death worldwide. The standard treatment of CAP has not changed for the past fifty years and its mortality and morbidity remain high despite adequate antimicrobial treatment. Systemic corticosteroids have anti-inflammatory effects and are therefore discussed as adjunct treatment for CAP. Available studies show controversial results, and the question about benefits and harms of adjunct corticosteroid therapy has not been conclusively resolved, particularly in the non-critical care setting. METHODS/DESIGN: This randomized multicenter study compares a treatment with 7 days of prednisone 50 mg with placebo in adult patients hospitalized with CAP independent of severity. Patients are screened and enrolled within the first 36 hours of presentation after written informed consent is obtained. The primary endpoint will be time to clinical stability, which is assessed every 12 hours during hospitalization. Secondary endpoints will be, among others, all-cause mortality within 30 and 180 days, ICU stay, duration of antibiotic treatment, disease activity scores, side effects and complications, value of adrenal function testing and prognostic hormonal and inflammatory biomarkers to predict outcome and treatment response to corticosteroids. Eight hundred included patients will provide an 85% power for the intention-to-treat analysis of the primary endpoint. DISCUSSION: This largest to date double-blind placebo-controlled multicenter trial investigates the effect of adjunct glucocorticoids in 800 patients with CAP requiring hospitalization. It aims to give conclusive answers about benefits and risks of corticosteroid treatment in CAP. The inclusion of less severe CAP patients will be expected to lead to a relatively low mortality rate and survival benefit might not be shown. However, our study has adequate power for the clinically relevant endpoint of clinical stability. Due to discontinuing glucocorticoids without tapering after seven days, we limit duration of glucocorticoid exposition, which may reduce possible side effects. TRIAL REGISTRATION: 7 September 2009 on ClinicalTrials.gov: NCT00973154.

TLR2 is required for the altered transcription of p75NGF receptors in gram positive infection.

Neuroimmune interactions play a decisive role in neuronal cell survival and cell death during neuronal injury, oxidative and free radical stress. In neurons, NGF occupancy of p75 neurotrophin receptor (p75(NTR)) has been shown to promote neuronal apoptosis, while occupancy of tropomyosin receptor kinase A (TrkA) promotes survival of injured neurons. In macrophages, recent results suggest that NGF via TrkA mediates resistance to cell death through the interaction with TLR2. We have investigated the transcriptional regulation of TrkA, p75(NTR) and their ligand nerve growth factor beta (NGFbeta) upon stimulation with the TLR2 ligand Staphylococcus aureus in the spleen of C57BL/6 mice, TLR2 (-/-) and p75(NTR) (-/-) mice. S. aureus challenge (i.p.) resulted in a significant increase in NGFbeta mRNA levels in C57BL/6 (100%), TLR2 (-/-) (300%) and p75(NTR) (-/-) mice (355%). TrkA mRNA levels were upregulated only in p75(NTR) (-/-) mice (87%) whereas in TLR2 (-/-) mice they remained unchanged and even decreased in C57BL/6 mice (46%). p75(NTR) mRNA was increased in spleen of C57BL/6 mice (60%) whereas the levels in TLR2 (-/-) mice remained almost unchanged. Finally, TLR2 mRNA was upregulated by 350% in C57BL/6 mice and by 283% in p75(NTR) (-/-) mice. These data suggest that in splenocytes signaling via TLR2 is required for Gram positive infection mediated alteration of neurotrophin receptor expression as observed in an in vivo infection model with transgenic mice. This observation provides a link between Gram-positive infection and neurotrophic responses, which may be important in preserving neurons at sites of the infection.

Sensory neuronal phenotype in galanin receptor 2 knockout mice: focus on dorsal root ganglion neurone development and pain behaviour.

Galanin is a 29-amino-acid peptide expressed in dorsal root ganglion (DRG) neurones and spinal dorsal horn neurones. It affects pain threshold and has developmental and trophic effects. Galanin acts at three G-protein-coupled receptors, galanin receptors (GalR1-3), each expressed in the DRGs as suggested by in situ hybridization and/or reverse transcriptase-polymerase chain reaction. The GalR2 knockout (-/-) mice permit studies on the contributions of this receptor subtype to the role of galanin at the spinal level. At 1 week after sciatic nerve transection (axotomy), there were 16-20% fewer neurones in intact and contralateral DRGs of -/- mice as compared with wild-type (WT) mice. In addition, a significant neurone loss (26% reduction) was found in the ipsilateral DRGs of WT mice, whereas no further neurone loss was seen in -/- mice. Expression of several peptides has been examined after axotomy, including galanin, neuropeptide Y and two of its receptors as well as substance P, and no significant differences were found between -/- and WT mice in either ipsi- or contralateral DRGs, respectively. After thermal injury and spinal nerve ligation, onset and duration of hyperalgesia in the injured paw were similar in GalR2-/- and WT animals. Recovery from spinal nerve ligation-caused allodynia had the same kinetics in -/- and WT animals. These data are in line with earlier observations from the peripheral and central nervous system, suggesting that galanin actions mediated by GalR2 subtype are of importance in neurodevelopment and neuroprotection.

Homodimerization and internalization of galanin type 1 receptor in living CHO cells.

Galanin is a 29- to 30-aa-long neuropeptide affecting feeding, cognitive, and sexual behavior. It exerts its effects through galanin receptors 1, 2 and 3, which are all seven transmembrane domain G-protein coupled receptors (GPCRs). The GPCRs have been shown to function as monomers, homodimers, heterodimers and oligomers. In this study, we examined the extent of galanin receptor 1 (GalR1) dimerization and internalization in living CHO cells using fluorescence resonance energy transfer (FRET) and time lapse confocal imaging. Ratio imaging analysis and emission spectral analysis revealed substantial homodimerization of GalR1. In addition, internalization of GalR1 after 1h of agonist stimulation with the GalR1 agonist galanin (1-29) was observed with time lapse fluorescence imaging, whereas stimulation with the GalR2 specific agonist galanin (2-11) did not lead to internalization. Treatment of GalR1 transfected cells with the non-selective adenylyl cyclase activator forskolin influenced the rate of internalization when administered together with galanin (1-29). These results indicate that GalR1 can act as a dimer on the cell surface and that receptor desensitization and internalization was observed after stimulation with the agonist galanin (1-29). Western blots further confirm the FRET data that GalR1-XFP dimerizes and can be detected in the cell as a monomer or dimer using antibodies to XFP. Internalization and dimerization of GalR1 is shown, contributing to the regulation of galanergic signaling.

Uncoupling protein 2 protects dopaminergic neurons from acute 1,2,3,6-methyl-phenyl-tetrahydropyridine toxicity.

Oxidative stress is implicated in the death of dopaminergic neurons in sporadic forms of Parkinson's disease. Because oxidative stress can be modulated endogenously by uncoupling proteins (UCPs), we hypothesized that specific neuronal expression of UCP2, one member of the UCP family that is rapidly induced in the CNS following insults, could confer neuroprotection in a mouse model of Parkinson's disease. We generated transgenic mice overexpressing UCP2 in catecholaminergic neurons under the control of the tyrosine hydroxylase promoter (TH-UCP2). In these mice, dopaminergic neurons of the substantia nigra showed a twofold elevation in UCP2 expression, elevated uncoupling of their mitochondria, and a marked reduction in indicators of oxidative stress, an effect also observed in the striatum. Upon acute exposure to 1,2,3,6-methyl-phenyl-tetrahydropyridine, TH-UCP2 mice showed neuroprotection and retention of locomotor functions. Our data suggest that UCP2 may represent a drug target for slowing the progression of Parkinson's disease.

High frequency of TNF alleles -238A and -376A in individuals from northern Sardinia.

The G to A single nucleotide polymorphisms (SNPs), at position -376, -308 and -238 in the promoter of the tumor necrosis factor alpha (TNF) gene, have been independently correlated with numerous diseases. Alleles TNF(-376A) and TNF(-238A) are normally found throughout the world with very low frequencies. We investigated the frequency of these SNPs in Sicilian subjects hospitalized after traumatic brain injury and in three groups of subjects from northern Sardinia: healthy subjects and individuals with multiple sclerosis or ischemic stroke. While no significant difference was found between healthy and disease subjects, the frequency of TNF(-376A) and TNF(-238A) was elevated up to 10 times in Sardinia compared to Sicily and other populations throughout the world. These elevated frequencies may be the result of genetic drift or of selective pressure on TNF itself or on neighboring genes, including the HLA. Malaria, endemic to Sardinia until the end of the 1940s, and the bubonic plague, are among the possible causes of selection. These findings indicate that Sardinia is an ideal location to further elucidate the correlation between TNF or HLA polymorphisms and diseases, including multiple sclerosis and type-I diabetes, present with an unusually high frequency and co-morbidity in Sardinia.

Cross-linking cellular prion protein triggers neuronal apoptosis in vivo.

Neuronal death is a prominent, but poorly understood, pathological hallmark of prion disease. Notably, in the absence of the cellular prion protein (PrPC), the disease-associated isoform, PrPSc, appears not to be intrinsically neurotoxic, suggesting that PrPC itself may participate directly in the prion neurodegenerative cascade. Here, cross-linking PrPC in vivo with specific monoclonal antibodies was found to trigger rapid and extensive apoptosis in hippocampal and cerebellar neurons. These findings suggest that PrPC functions in the control of neuronal survival and provides a model to explore whether cross-linking of PrPC by oligomeric PrPSc can promote neuronal loss during prion infection.