Development of oxacillin resistance in a patient with recurrent Staphylococcus aureus bacteremia.

Whole-genome sequencing was used to compare longitudinal isolates of Staphylococcus aureus that developed resistance to oxacillin (MIC up to 16 µg/ml). The mecA gene was absent. A novel 5-bp TATCC frameshift insertion in a gene encoding an ABC transporter similar to that of the teichoic acid translocation ATP-binding protein TagH and a 3-bp GCT nonframeshift insertion in the pdhA pyruvate dehydrogenase gene were detected in the oxacillin-resistant isolates.

Fusarium falciforme vertebral abscess and osteomyelitis: case report and molecular classification.

Fusarium is a ubiquitous mold that can cause superficial infections such as keratitis and onychomycosis in immunocompetent humans; however, infections in immunocompromised hosts can be fatal. We report an unusual case of epidural abscess and vertebral osteomyelitis in a patient with an autoimmune disorder who was on long-term glucocorticoids. Multilocus DNA sequence-based typing revealed that the infection was caused by a novel three-locus haplotype of Fusarium falciforme designated FSSC 3+4qqq.

Antipsychotic drugs elevate mRNA levels of presynaptic proteins in the frontal cortex of the rat.

BACKGROUND: Molecular adaptations are believed to contribute to the mechanism of action of antipsychotic drugs (APDs). We attempted to establish common gene regulation patterns induced by chronic treatment with APDs. METHODS: Gene expression analysis was performed with the Affymetrix U34A array in the frontal cortex (FC) and the striatum of rats chronically treated with two concentrations of either clozapine or haloperidol. Key data were verified with real-time quantitative polymerase chain reaction. RESULTS: Many genes in the FC affected by APD-treatment contribute to similar functions. mRNAs coding for synaptic vesicle docking- and microtubule-associated proteins were upregulated; mRNAs for serine-threonine protein phosphatases were downregulated, whereas the serine-threonine kinases protein kinase A, protein kinase C, and calcium/calmodulin kinase II alpha and IV were upregulated, indicating increased potential for protein phosphorylation. In the striatum, altered gene expression was less focused on genes of particular function or location, and the high concentration of haloperidol had a different gene expression profile than any of the other APD treatments. CONCLUSION: We found an increase in the transcription of genes coding for proteins involved in synaptic plasticity and synaptic activity in the FC. We furthermore found that the gene expression profile of APDs is different between FC and striatum.

Selected rare, noninfectious syndromes associated with HIV infection.

Infrequent and sometimes treatable noninfectious syndromes associated with HIV disease include tenofovir-associated Fanconi syndrome, a proximal renal tubular disorder; pulmonary hypertension that appears to be due to HIV-driven inflammation resulting in endothelial proliferation; thrombotic thrombocytopenic purpura, characterized by intravascular coagulopathy; diffuse infiltrative lymphocytosis syndrome, which can affect multiple organs; and Castleman's disease, a lymphoproliferative disorder that usually occurs in a multicentric form with poor prognosis in HIV-infected patients. This article summarizes a presentation on the characteristics, diagnosis, treatment, and prognosis of these disorders by Molly E. Eaton, MD, at the International AIDS Society-USA course in Atlanta in March 2005.

Molecular evidence for mitochondrial dysfunction in bipolar disorder.

BACKGROUND: The disease mechanism of bipolar disorder remains unknown. Recent studies have provided evidence for abnormal gene expression in bipolar disorder. OBJECTIVE: To determine the expression of 12558 nuclear genes in the human hippocampus in healthy control subjects and those with bipolar disorder or schizophrenia. DESIGN: We used gene arrays to study messenger RNA expression. Data were verified with a real-time quantitative polymerase chain reaction assay. SUBJECTS: We studied 10 healthy control subjects, 9 subjects with bipolar disorder, and 8 subjects with schizophrenia. RESULTS: The expression of nuclear messenger RNA coding for mitochondrial proteins was significantly decreased in the hippocampus in subjects with bipolar disorder but not in those with schizophrenia. Subjects with bipolar disorder were characterized by a pronounced and extensive decrease in the expression of genes regulating oxidative phosphorylation and the adenosine triphosphate-dependent process of proteasome degradation. CONCLUSIONS: These findings point toward a widespread dysregulation of mitochondrial energy metabolism and downstream deficits of adenosine triphosphate-dependent processes in bipolar disorder.

Normalization of cerebrospinal fluid abnormalities after neurosyphilis therapy: does HIV status matter?

To identify factors that affect normalization of laboratory measures after treatment for neurosyphilis, 59 subjects with neurosyphilis underwent repeated lumbar punctures and venipunctures after completion of therapy. The median duration of follow-up was 6.9 months. Stepwise Cox regression models were used to determine the influence of clinical and laboratory features on normalization of cerebrospinal fluid (CSF), white blood cells (WBCs), CSF protein concentration, CSF Venereal Disease Research Laboratory (VDRL) reactivity, and serum rapid plasma reagin (RPR) titer. Human immunodeficiency virus (HIV)-infected subjects were 2.5 times less likely to normalize CSF-VDRL reactivity than were HIV-uninfected subjects. HIV-infected subjects with peripheral blood CD4+ T cell counts of < or =200 cells/ mu L were 3.7 times less likely to normalize CSF-VDRL reactivity than were those with CD4+ T cell counts of >200 cells/ mu L. CSF WBC count and serum RPR reactivity were more likely to normalize but CSF-VDRL reactivity was less likely to normalize with higher baseline values. Future studies should address whether more intensive therapy for neurosyphilis is warranted in HIV-infected individuals.

Chronic electroconvulsive seizure up-regulates beta-catenin expression in rat hippocampus: role in adult neurogenesis.

BACKGROUND: Beta-catenin was discovered as a cytoskeletal protein, constituting a link between the cadherins to the actin cytoskeleton. Aside from this function, beta-catenin is a key effector molecule in the Wnt signaling pathway, serving as a downstream transcription factor. METHODS: In this study, we examined the influence of electroconvulsive seizures (ECS) on the expression of beta-catenin, as well as expression of Wnt-2, in rat hippocampus. Repeated administration of generalized seizures increased levels of beta-catenin immunoreactivity in the subgranular zone of the hippocampus. To assess the relationship of beta-catenin to cell division in the dentate gyrus of the adult rat hippocampus, colocalization of beta-catenin with a marker of cell division was examined. RESULTS: Beta-catenin immunoreactivity was consistently localized in newborn cells in this region, indicating a possible role in cell division and differentiation in adult hippocampus. We also found that ECS treatment significantly increased levels of Wnt-2, one of the ligands that activates beta-catenin signaling. CONCLUSIONS: These results demonstrate that ECS increases Wnt-beta-catenin signaling and suggest that this pathway could mediate in part the neuronal adaptations underlying the therapeutic action of this treatment paradigm.

L-type Ca2+ channel blockers promote Ca2+ accumulation when dopamine receptors are activated in striatal neurons.

Dopamine (DA) receptor-mediated signal transduction and gene expression play a central role in many brain disorders from schizophrenia to Parkinson's disease to addiction. While trying to evaluate the role of L-type Ca2+ channels in dopamine D1 receptor-mediated phosphorylation of the transcription factor cyclic AMP response element-binding protein (CREB), we found that activation of dopamine D1 receptors alters the properties of L-type Ca2+ channel inhibitors and turns them into facilitators of Ca2+ influx. In D1 receptor-stimulated neurons, L-type Ca2+ channel blockers promote cytosolic Ca2+ accumulation. This leads to the activation of a molecular signal transduction pathway and CREB phosphorylation. In the absence of dopamine receptor stimulation, L-type Ca2+ channel blockers inhibit CREB phosphorylation. The effect of dopamine on L-type Ca2+ channel blockers is dependent on protein kinase A (PKA), suggesting that protein phosphorylation plays a role in this phenomenon. Because of the adverse effect of activated dopamine receptors on L-type Ca2+ channel blocker action, the role of L-type Ca2+ channels in the dopamine D1 receptor signal transduction pathway cannot be assessed with pharmacological tools. However, with antisense technology, we demonstrate that L-type Ca2+ channels contribute to D1 receptor-mediated CREB phosphorylation. We conclude that the D1 receptor signal transduction pathway depends on L-type Ca2+ channels to mediate CREB phosphorylation.

Successful use of Plasma Preparation Tubes™ (PPTs) in the COBAS® AmpliPrep/COBAS® TaqMan® HIV-1 test.

BACKGROUND: Since switching to the COBAS(®) AmpliPrep/COBAS(®) TaqMan(®) HIV-1 Test, v. 1.0 from the Amplicor HIV-1 Monitor Test, v. 1.5, an increase in detectable viral load results was noted. We were concerned that this was due to the use of Plasma Preparation Tubes (PPT) in this test. OBJECTIVE: To assess the impact of different pre-analytical processing conditions on HIV-1 viral load results on the COBAS(®) AmpliPrep/COBAS(®) TaqMan(®) HIV-1 Test. STUDY DESIGN: Sixty-three HIV-infected patients were consented and had 3 PPTs and 1 K2EDTA drawn for HIV-1 viral load testing. Three methods of PPT processing were compared against the referent K2EDTA tube which was spun at 1100 × g for 20 min, poured off and frozen; PPT1 was refrigerated with an additional centrifugation prior to testing, PPT2 was processed similarly to EDTA, and PPT3 was centrifuged, frozen and centrifuged again prior to testing. RESULTS: PPT1 and PPT3 yielded results that were most similar to the referent EDTA processing, with a concordance correlation coefficient (CCC) of 0.80 and 0.85, compared to PPT2 with CCC of 0.37. Both PPT1 and PPT3 involved additional centrifugation prior to testing. In 26 patients with residual samples from the PPT2 processing, 9 (34.6%) were found to have the presence of proviral DNA, which likely contributed to the elevated HIV-1 RNA viral loads in these individuals. CONCLUSION: PPTs can be used in the COBAS(®) AmpliPrep/COBAS(®) TaqMan(®) HIV-1 Test with an additional centrifugation in order to avoid misleading elevated HIV-1 RNA viral loads that may change patient management.

A switch in therapy to a reverse transcriptase inhibitor sparing combination of lopinavir/ritonavir and raltegravir in virologically suppressed HIV-infected patients: a pilot randomized trial to assess efficacy and safety profile: the KITE study.

A nucleoside reverse transcriptase inhibitor (NRTI) backbone is a recommended component of standard highly active antiretroviral therapy (sHAART). However, long-term NRTI exposure can be limited by toxicities. NRTI class-sparing alternatives are warranted in select patient populations. This is a 48-week single-center, open-label pilot study in which 60 HIV-infected adults with plasma HIV-1 RNA (<50 copies/ml) on sHAART were randomized (2:1) to lopinavir/ritonavir (LPV/r) 400/100 mg BID+raltegravir (RAL) 400 mg BID switch (LPV-r/RAL arm) or to continue on sHAART. The primary endpoint was the proportion of subjects with HIV-RNA<50 copies/ml at week 48. Secondary efficacy and immunologic and safety endpoints were evaluated. Demographics and baseline lipid profile were similar across arms. Mean entry CD4 T cell count was 493 cells/mm(3). At week 48, 92% [95% confidence interval (CI): 83-100%] of the LPV-r/RAL arm and 88% (95% CI: 75-100%) of the sHAART arm had HIV-RNA<50 copies/ml (p=0.70). Lipid profile (mean ± SEM, mg/dl, LPV-r/RAL vs. sHAART) at week 24 was total-cholesterol 194 ± 5 vs. 176 ± 9 (p=0.07), triglycerides 234 ± 30 vs. 133 ± 27 (p=0.003), and LDL-cholesterol 121 ± 6 vs. 110 ± 8 (p=0.27). There were no serious adverse events (AEs) in either arm. Regimen change occurred in three LPV-r/RAL subjects (n=1, due to LPV-r/RAL-related AEs) vs. 0 in sHAART. There were no differences between arms in bone mineral density, total body fat composition, creatinine clearance, or CD4 T cell counts at week 48. In virologically suppressed patients on HAART, switching therapy to the NRTI-sparing LPV-r/RAL combination produced similar sustained virologic suppression and immunologic profile as sHAART. AEs were comparable between arms, but the LPV-r/RAL arm experienced higher triglyceridemia.

Disseminated Mycobacterium haemophilum infection.

Mycobacterium haemophilum is a slow-growing organism first identified in 1978. Since that time, it has emerged as an unusual pathogen, but one that is identified increasingly, mainly affecting immunocompromised patients and healthy children. The range of disease caused by this organism includes skin and soft-tissue infections, pulmonary infections, lymphadenitis, and frequently, bone and joint infections. Laboratory identification of M haemophilum needs special culture techniques and media and can be difficult in a setting at which these methods are not routinely used. We describe a case of chronic, disseminated M haemophilum infection in a patient with AIDS, and we review published work.

Immune activation mediated change in alpha-1-acid glycoprotein: impact on total and free lopinavir plasma exposure.

BACKGROUND: Immune mediated changes in circulating α-1-acid glycoprotein (AAG), a type 1 acute phase protein, which binds protease inhibitors (PI), may alter protein binding and contribute to PI's pharmacokinetic (PK) variability. METHODS: In a prospective, 2-phase intensive PK study on antiretroviral naive human immunodeficiency virus (HIV)-infected subjects treated with a lopinavir-/ritonavir-based regimen, steady state PK sampling and AAG assays were performed at weeks 2 and 16 of treatment. RESULTS: Median entry age was 43 years (n = 16). Median plasma log(10) HIV-1 RNA, CD4 T-cell counts, and AAG were 5.16 copies/mL, 28 cells/µL, and 143 mg/dL, respectively.The total lopinavir area under the concentration time curve (AUC(12_total)) and maximum concentration (C(max_total)) changed linearly with AAG at mean rates of 16±7 mg*hr/L (slope ± SE); P = .04, and 1.6 ± 0.6 mg/L, P = .02, per 100 mg/dL increase in AAG levels, respectively (n = 15).A 29% drop in AAG levels between week 2 and week 16 was associated with 14% (geometric mean ratio [GMR] = 0.86; 90% confidence interval [CI] = 0.74-0.98) and 13% (GMR = 0.87; 90% CI = 0.79-0.95) reduction in AUC(12_total) and C(max_total), respectively. Neither free lopinavir PK parameters nor antiviral activity (HIV-1 RNA average AUC minus baseline) was affected by change in plasma AAG. CONCLUSIONS: Changes in plasma AAG levels alter total lopinavir concentrations, but not the free lopinavir exposure or antiviral activity. This observation may have implications in therapeutic drug monitoring.

Generalized tetanus despite prior vaccination and a protective level of anti-tetanus antibodies.

Because of the success of widespread vaccination, tetanus rarely occurs in developed countries such as the United States. Vaccination, however, is not entirely protective even if patients develop an adequate antibody response. We discuss a case of generalized tetanus in an individual with both a history of prior vaccination and a measurable level of anti-tetanus antibodies at the time of presentation. We speculate that the patient's preexisting antibodies may have moderated his course of illness.

Syphilis and HIV: old and new foes aligned against us.

Syphilis and HIV infections frequently occur simultaneously because they affect the same risk groups. The declining incidence of syphilis during the 1990s reversed beginning in 2001, with most of the new cases occurring in men who have sex with men. This group is at highest risk of having or acquiring HIV infection. The clinical presentation of syphilis may be altered in persons with HIV infection and the response to therapy may be affected by immunosuppression. Syphilis may also subtly affect HIV infection, at least transiently. This article reviews the epidemiology, clinical manifestations, and treatment of syphilis in the setting of HIV infection.

Beware of the pet dog: a case of Staphylococcus intermedius infection.

Staphylococcus intermedius is a common commensal and pathogen in dogs and cats and only rarely has been identified as causing human infection. We report a human case of postoperative sinus infection caused by methicillin-resistant S. intermedius. A 28-year-old woman with a history of endoscopic pituitary adenoma resection presented with 3 weeks of foul smelling nasal discharge. Nasal endoscopy revealed purulent sinus drainage. Cultures, initially misidentified as coagulase-negative Staphylococcus and then as Staphylococcus aureus, revealed the presence of S. intermedius. Cultures from the patient's pet dog also grew S. intermedius strains that were confirmed to be identical to those of the patient's by pulse field gel electrophoresis analysis. The patient was successfully treated with endoscopic debridement and a prolonged antibiotic regimen with vancomycin and linezolid. Our case illustrates the possibility of transmission of antibiotic-resistant bacteria causing infection from pets to humans.

Dopamine D1 receptors mediate CREB phosphorylation via phosphorylation of the NMDA receptor at Ser897-NR1.

Addictive drugs such as amphetamine and cocaine stimulate the dopaminergic system, activate dopamine receptors and induce gene expression throughout the striatum. The signal transduction pathway leading from dopamine receptor stimulation at the synapse to gene expression in the nucleus has not been fully elucidated. Here, we present evidence that D1 receptor stimulation leads to phosphorylation of the transcription factor Ca2+ and cyclic AMP response element binding protein (CREB) in the nucleus by means of NMDA receptor-mediated Ca2+ signaling. Stimulation of D1 receptors induces the phosphorylation of Ser897 on the NR1 subunit by protein kinase A (PKA). This phosphorylation event is crucial for D1 receptor-mediated CREB phosphorylation. Dopamine cannot induce CRE-mediated gene expression in neurons transfected with a phosphorylation-deficient NR1 construct. Moreover, stimulation of D1 receptors or increase in cyclic AMP levels leads to an increase in cytosolic Ca2+ in the presence of glutamate, but not in the absence of glutamate, indicating the ability of dopamine and cyclic AMP to facilitate NMDA channel activity. The recruitment of the NMDA receptor signal transduction pathway by D1 receptors may provide a general mechanism for gene regulation that is fundamental for mechanisms of drug addiction and long-term memory.

Transcriptome analysis in a rat model of L-DOPA-induced dyskinesia.

We have examined the pattern of striatal messenger RNA expression of over 8000 genes in a rat model of levodopa (L-DOPA)-induced dyskinesia and Parkinson disease (PD). 6-Hydroxydopamine (6-OHDA)-lesioned rats were treated with L-DOPA or physiological saline for 22 days and repeatedly tested for antiakinetic response to L-DOPA and the development of abnormal involuntary movements (AIMs). In a comparison of rats that developed a dyskinetic motor response to rats that did not, we found striking differences in gene expression patterns. In rats that developed dyskinesia, GABA neurons had an increased transcriptional activity, and genes involved in Ca2+ homeostasis, in Ca2+ -dependent signaling, and in structural and synaptic plasticity were upregulated. The gene expression patterns implied that the dyskinetic striatum had increased transcriptional, as well as synaptic activity, and decreased capacity for energy production. Some basic maintenance chores such as ribosome protein biosynthesis were downregulated, possibly a response to expended ATP levels.

Cerebrospinal fluid abnormalities in patients with syphilis: association with clinical and laboratory features.

OBJECTIVE: To define clinical and laboratory features that identify patients with neurosyphilis. METHODS: Subjects (n=326) with syphilis but no previous neurosyphilis who met 1993 Centers for Disease Control and Prevention criteria for lumbar puncture underwent standardized history, neurological examination, venipuncture, and lumbar puncture. Neurosyphilis was defined as a cerebrospinal fluid (CSF) white blood cell count >20 cells/ microL or reactive CSF Venereal Disease Research Laboratory (VDRL) test result. RESULTS: Sixty-five subjects (20.1%) had neurosyphilis. Early syphilis increased the odds of neurosyphilis in univariate but not multivariate analyses. In multivariate analyses, serum rapid plasma reagin (RPR) titer > or =1 : 32 increased the odds of neurosyphilis 10.85-fold in human immunodeficiency virus (HIV)-uninfected subjects and 5.98-fold in HIV-infected subjects. A peripheral blood CD4+ T cell count < or =350 cells/ microL conferred 3.10-fold increased odds of neurosyphilis in HIV-infected subjects. Similar results were obtained when neurosyphilis was more stringently defined as a reactive CSF VDRL test result. CONCLUSION: Serum RPR titer helps predict the likelihood of neurosyphilis. HIV-induced immune impairment may increase the risk of neurosyphilis.