Pili prove pertinent to enterococcal endocarditis

Enterococcus faecalis is an important agent of endocarditis and urinary tract infections, which occur frequently in hospitals. Antimicrobial therapy is complicated by the emergence of drug-resistant strains, which contribute significantly to mortality associated with E. faecalis infection. In this issue of the JCI, Nallapareddy and colleagues report that E. faecalis produces pili on its surface and that these proteinaceous fibers are used for bacterial adherence to host tissues and for the establishment of biofilms and endocarditis (see the related article beginning on page 2799). This information may enable new vaccine strategies for the prevention of E. faecalis infections.     

Single nucleotide polymorphisms in the regulatory region of gonadotropin-releasing hormone receptor gene and breast cancer susceptibility

It is known that exposure to estrogens affects the pathophysiology of breast cancer. The key role of gonadotropin-releasing hormone (GnRH) in the regulation of female steroid hormone metabolism raises the question of whether polymorphisms in its receptor, GnRHR, might influence breast cancer risk. To test this hypothesis, we analyzed three single nucleotide polymorphisms (SNPs) in the 5'-regulatory region of the GnRHR gene in a total of 565 women, 254 women with breast cancer and 311 women without any malignancy by allele-specific PCR. No significant differences were observed between the breast cancer and control group in terms of genotype, allele frequency or allele positivity. In contrast, different frequencies of the SNPs rs13138607, rs12644822 and rs3756159 were observed after sub-grouping the breast cancer cases according to tumor grading. Our data suggest a potential role of GnRHR gene polymorphisms in the development of breast cancer.     

Phase I trial to investigate the safety, pharmacokinetics and efficacy of sorafenib combined with docetaxel in patients with advanced refractory solid tumours

AimThe safety, pharmacokinetics and efficacy of sorafenib plus docetaxel in patients with advanced refractory cancer were investigated in a Phase I, dose-escalation trial.MethodsTwenty-seven patients in four Cohorts received docetaxel on Day 1 (Cohorts 1 and 4: 75 mg/m²; Cohorts 2 and 3: 100 mg/m²) plus sorafenib on Days 2–19 (Cohorts 1 and 2: 200 mg twice-daily (bid); Cohorts 3 and 4: 400 mg bid) in 21-day cycles.ResultsMost common adverse events (AEs) (Grade 3–5) included neutropenia (89%), leucopaenia (81%), hand–foot skin reaction (30%) and fatigue (30%). The most common drug-related AEs leading to dose reduction/interruption or permanent discontinuation were dermatologic (41%), gastrointestinal (26%) and constitutional (22%). Coadministration of sorafenib altered the pharmacokinetics of docetaxel. On average, docetaxel area under the concentration–time curve (AUC)_0–24 increased by 5% (Cohort 1), 54% (Cohort 2), 36% (Cohort 3) and 80% (Cohort 4) with docetaxel plus sorafenib, while C_max increased by 16–32%, independent of sorafenib/docetaxel doses. Three of 25 evaluable patients (11%) had partial responses; 14 (52%) had stable disease.ConclusionDose-limiting dermatologic AEs were more common than expected for either therapy alone. A starting dose of docetaxel 75 mg/m² plus sorafenib 400 mg bid (with dose reductions for dermatological toxicities) is proposed for Phase II.     

Effects of a combined treatment with GPR30 agonist G-1 and herceptin on growth and gene expression of human breast cancer cell lines

Expression of G-protein-coupled receptor 30 (GPR30) is present in HER2-overexpressing breast cancer. In this study, we examined to what extent GPR30-agonist G-1 would affect the antitumoral action of trastuzumab (Herceptin). Combined treatment with both drugs exerted an additive growth-inhibitory effect on breast cancer cells which was accompanied by a significant decline of cyclin A2 expression both on the protein and the mRNA level. Combined treatment also resulted in expression changes of c-fos, cyclin D1, or p21/WAF-1. The results of our study encourage further attempts to test the relevance of these in vitro data in the clinical setting.     

Plasma exchange in neuroimmunological disorders: Part 1: Rationale and treatment of inflammatory central nervous system disorders

Plasma exchange is a well-established therapeutic procedure commonly used in many neurological disorders of autoimmune etiology. It is thought that the beneficial effects of plasma exchange occur through the elimination of pathognomonic inflammatory mediators, including autoantibodies, complement components, and cytokines. In various neurological disorders, randomized controlled studies have demonstrated the efficacy of plasma exchange (eg, in Guillain-Barré syndrome and other forms of immune neuropathies). Although widely used, the potential benefit of plasma exchange in the treatment of multiple sclerosis, myasthenia gravis, and Lambert-Eaton syndrome is less clear.     

Inhibition by mitoxantrone of in vitro migration of immunocompetent cells: a possible mechanism for therapeutic efficacy in the treatment of multiple sclerosis

BACKGROUND: Damage of the blood-brain barrier and invasion of immunocompetent cells into the central nervous system represent key events in the immunopathogenesis of multiple sclerosis. Mitoxantrone hydrochloride reduces progression of disability and clinical exacerbations in patients with multiple sclerosis. Its precise mode of action is unclear. OBJECTIVE: To investigate the effects of mitoxantrone on the migratory capacity of immunocompetent cells ex vivo and in vitro. DESIGN: Case-control study. SETTING: Department of Neurology, Heinrich Heine University, Düsseldorf, Germany. PARTICIPANTS: Peripheral blood mononuclear cells (PBMCs) were obtained from 11 patients with multiple sclerosis before and after intravenous mitoxantrone treatment; PBMCs from 5 healthy control donors were treated with mitoxantrone in vitro. MAIN OUTCOME MEASURES: The migratory capacity was studied in an in vitro Boyden chamber assay; cells and their rates of migration were analyzed by light microscopy and flow cytometry. To determine the specificity of our findings, PBMCs were treated with perfosfamide in vitro. RESULTS: Mitoxantrone decreased the migratory capacity of CD14(+) monocytes and (to a lesser degree) of CD4(+) and CD8(+) T lymphocytes. These observations were confirmed when control PBMCs were treated with an equivalent dose of mitoxantrone in vitro. Similar effects were seen when PBMCs were preincubated with perfosfamide. The inhibitory effects of mitoxantrone on the migratory capacity of PBMCs were mediated by reduced matrix metalloproteinase 9 activity, as demonstrated by zymography, polymerase chain reaction, and inhibitory studies. CONCLUSION: Mitoxantrone may inhibit the migration of inflammatory cells into and within the central nervous system.     

Onset of action of levetiracetam: a RCT trial using therapeutic intensive seizure analysis (TISA)

OBJECTIVES: To correlate the onset of clinical effects of add-on levetiracetam (LEV) therapy with daily serum LEV concentration, in pharmaco-resistant focal epilepsies, using the TISA method. METHODS: 25 adult patients (aged>6 years) with pharmaco-resistant focal epilepsies undergoing presurgical evaluation at the Epilepsy Center Erlangen were enrolled in the study. Eligible patients on a maximum of one other antiepileptic drug (AED) were recruited into the 48-hour baseline phase. Those who had at least two seizures during this phase were randomized into the seven-day treatment phase, when they received either LEV or placebo, under continuous day-and-night video-EEG monitoring. The starting daily dose of LEV was 500 mg bid, titrated from the second treatment day to 1,000 mg bid. The peak serum concentration of LEV was monitored daily at 8:00 am (one hour after drug administration) for every patient. The number and duration of seizures per 24h (N/24h and D/24h respectively) were investigated. RESULTS: 23 patients completed the study (LEV group n=11 and placebo group n=12). Seven patients in the LEV group and two patients in the placebo group achieved seizure-freedom during the treatment phase. The intergroup comparison of the decrease in N/24h and D/24h from the baseline phase to the treatment phase was in favor of the LEV group (p<0.05). A significant effect of LEV on D/24h was seen as early as the second treatment day (p=0.013), becoming more apparent on the third treatment day (p=0.009). CONCLUSION: The present study objectively quantified the correlation between the anticonvulsant effects of LEV in focal epilepsies and the peak serum concentration of the drug. For the first time, direct measurement was used to demonstrate the onset of action of LEV to be two days after drug initiation.     

Motor activation in SPG4-linked hereditary spastic paraplegia

OBJECTIVE: The aim of this study was to investigate the extent of motor cortical functional reorganisation in patients with SPG4-linked hereditary spastic paraplegia by exploring cortical motor activation related to movements of clinically affected (lower) and unaffected (upper) limbs. METHODS: Thirteen patients and 13 normal controls matched for age, gender and handedness underwent O15-labelled water positron emission tomography during (1) right ankle flexion-extension, (2) right shoulder flexion-extension and (3) rest. Within-group comparisons of movement vs. rest (simple main effects) and between-group comparisons of movement vs. rest (group x behavioural state interaction) were performed using a random effects approach and statistical parametric mapping (SPM99). RESULTS: Patterns of motor activation were generally comparable between groups during both tasks, although patients had a tendency towards more widespread activation in sensorimotor cortical and cerebellar regions. Statistically significant differences were restricted to the ankle movement response, however, where patients showed significantly increased regional cerebral blood flow in the right and left primary motor cortices, the supplementary motor areas and the right premotor cortex compared to controls. CONCLUSIONS: Motor cortical reorganisation may explain this result, but as no significant differences were recognised in the motor response of the unaffected limb, differences in functional demands should also be considered.