Developmental malformations in Huntington disease: neuropathologic evidence of focal neuronal migration defects in a subset of adult brains.

Neuropathologic hallmarks of Huntington Disease (HD) include the progressive neurodegeneration of the striatum and the presence of Huntingtin (HTT) aggregates that result from abnormal polyQ expansion of the HTT gene. Whether the pathogenic trinucleotide repeat expansion of the HTT gene causes neurodevelopmental abnormalities has garnered attention in both murine and human studies; however, documentation of discrete malformations in autopsy brains of HD individuals has yet to be described. We retrospectively searched the New York Brain Bank (discovery cohort) and an independent cohort (validation cohort) to determine whether developmental malformations are more frequently detected in HD versus non-HD brains and to document their neuropathologic features. One-hundred and thirty HD and 1600 non-HD whole brains were included in the discovery cohort and 720 HD and 1989 non-HD half brains were assessed in the validation cohort. Cases with developmental malformations were found at 6.4-8.2 times greater frequency in HD than in non-HD brains (discovery cohort: OR 8.68, 95% CI 3.48-21.63, P=4.8 × 10-5; validation cohort: OR 6.50, 95% CI 1.83-23.17, P=0.0050). Periventricular nodular heterotopias (PNH) were the most frequent malformations and contained HTT and p62 aggregates analogous to the cortex, whereas cortical malformations with immature neuronal populations did not harbor such inclusions. HD individuals with malformations had heterozygous HTT CAG expansions between 40 and 52 repeats, were more frequently women, and all were asymmetric and focal, aside from one midline hypothalamic hamartoma. Using two independent brain bank cohorts, this large neuropathologic series demonstrates an increased occurrence of developmental malformations in HD brains. Since pathogenic HTT gene expansion is associated with genomic instability, one possible explanation is that neuronal precursors are more susceptible to somatic mutation of genes involved in cortical migration. Our findings further support emerging evidence that pathogenic trinucleotide repeat expansions of the HTT gene may impact neurodevelopment.

Reassuringly low carriage of enteropathogens among healthy Swedish children in day care centres.

OBJECTIVES: Infectious gastroenteritis is one of the most common diseases among children and has a considerable impact on health and socio-economy. Day care centres are high-risk environments for infections. The aim of this study was to investigate if asymptomatic preschool children constitute a reservoir for potential enteropathogens. STUDY DESIGN: In total, 438 individual diapers were collected from day care centres in Uppsala, Sweden, during spring and autumn, and molecular techniques were used to estimate the prevalence of asymptomatic carriage of multiple enteropathogens. METHODS: Faecal samples were analysed with multiplex polymerase chain reaction (PCR) (xTAG® Gastrointestinal Pathogen Panel; Luminex Corporation, Toronto, Canada) targeting 21 different pathogens. Samples with a median fluorescence intensity above threshold were re-analysed with a second PCR assay. RESULTS: Sixteen of the 438 samples were positive for enteropathogens, 1.6% for enteric adenovirus, 0.7% for Campylobacter spp., and 0.7% for norovirus. CONCLUSIONS: Preschool children in Uppsala constitute a limited reservoir for potential enteropathogens.

The efficacy and safety of rituximab in a chart review study of 15 patients with systemic lupus erythematosus.

In contrast to randomised clinical trials, open-label studies have suggested that B cell depletion by a course of rituximab is associated with a significant clinical benefit. Our aim was to assess the safety and efficacy of rituximab in 15 refractory lupus patients, particularly those with more than one course of therapy. Disease activity was measured by the classic British Isles Lupus Assessment Group (BILAG) index, anti-DNA antibodies and complement levels. We assessed immunoglobulin levels, functional antibodies and serious adverse events. The mean patient age ± SD was 37.9 ± 7.2 years and mean disease duration was 8.5 ± 3.3 years; 46% were Afro-Caribbean, 27% South Asian, 20% Caucasian and 7% others. Twelve patients responded by 6 months; six avoided major flare for >1 year. Complete absence of disease activity (BILAG D/E) lasted for 5.5 (SD 3.8) months and 4.8 (SD 3.6) months after the first (n = 15) and second (n = 9) rituximab course, respectively. The mean 6-month reduction in daily prednisolone was 10.4 (SD 11.4) mg/day and 10.7 (SD 9.3) mg/day from baseline after the first and second course, respectively. Patients with low C3/C4 normalised their C3 by 6 months. Most patients with raised anti-dsDNA normalised after rituximab courses. Serious adverse events only occurred after more than four courses of rituximab. Rituximab was safe and efficacious for treating patients with refractory systemic lupus erythematosus (SLE) and was associated with significant steroid reduction, but more than four courses of rituximab was associated with an increased risk of serious infection in two patients.

Evaluation of double- and triple-antibiotic combinations for VIM- and NDM-producing Klebsiella pneumoniae by in vitro time-kill experiments.

Combination therapy is recommended for infections with carbapenemase-producing Klebsiella pneumoniae. However, limited data exist on which antibiotic combinations are the most effective. The aim of this study was to find effective antibiotic combinations against metallo-beta-lactamase-producing K. pneumoniae (MBL-KP). Two VIM- and two NDM-producing K. pneumoniae strains, all susceptible to colistin, were exposed to antibiotics at clinically relevant static concentrations during 24-h time-kill experiments. Double- and triple-antibiotic combinations of aztreonam, ciprofloxacin, colistin, daptomycin, fosfomycin, meropenem, rifampin, telavancin, tigecycline, and vancomycin were used. Synergy was defined as a ≥2 log10 decrease in CFU/ml between the combination and its most active drug after 24 h, and bactericidal effect was defined as a ≥3 log10 decrease in CFU/ml after 24 h compared with the starting inoculum. Synergistic or bactericidal activity was demonstrated for aztreonam, fosfomycin, meropenem, and rifampin in double-antibiotic combinations with colistin and also for aztreonam, fosfomycin, and rifampin in triple-antibiotic combinations with meropenem and colistin. Overall, the combination of rifampin-meropenem-colistin was the most effective regimen, demonstrating synergistic and bactericidal effects against all four strains. Meropenem-colistin, meropenem-fosfomycin, and tigecycline-colistin combinations were not bactericidal against the strains used. The findings of this and other studies indicate that there is great potential of antibiotic combinations against carbapenemase-producing K. pneumoniae. However, our results deviate to some extent from those of previous studies, which might be because most studies to date have included KPC-producing rather than MBL-producing strains. More studies addressing MBL-KP are needed.

Cell-wall-inhibiting antibiotic combinations with activity against multidrug-resistant Klebsiella pneumoniae and Escherichia coli.

The increasing prevalence of hospital and community-acquired infections caused by multidrug-resistant (MDR) bacterial pathogens is rapidly limiting the options for effective antibiotic therapy. Systematic studies on combinations of already available antibiotics that could provide an effective treatment against MDR bacteria are needed. We tested combinations of antibiotics that target one important physiological function (peptidoglycan synthesis) at several steps, and studied Enterobacteriaceae (Klebsiella pneumoniae and Escherichia coli) for which multidrug resistance associated with ESBL-producing plasmids has become a major problem. To measure the effectiveness of antibiotics alone and in combination, we used checkerboard assays, static antibiotic concentration time-kill assays, and an improved in-vitro kinetic model that simulates human pharmacokinetics of multiple simultaneously administered antibiotics. The target strains included an MDR K. pneumoniae isolate responsible for a recent major hospital outbreak. A double combination (fosfomycin and aztreonam) and a triple combination (fosfomycin, aztreonam and mecillinam) were both highly effective in reducing bacterial populations in all assays, including the in vitro kinetic model. These combinations were effective even though each of the MDR strains was resistant to aztreonam alone. Our results provide an initial validation of the potential usefulness of a combination of antibiotics targeting peptidoglycan synthesis in the treatment of MDR Gram-negative bacteria. We suggest that a combination of fosfomycin with aztreonam could become a useful treatment option for such infections and should be further studied.

Bilateral retinal vasculitis in a patient with systemic lupus erythematosus and its remission with rituximab therapy.

Severe retinal vasculitis is a rare, but potentially blinding, complication of patients with systemic lupus erythematosus (SLE). We describe here the first reported case of treating severe bilateral SLE-associated retinal vasculitis with the anti-CD20 monoclonal antibody rituximab, a drug which has established its role in rheumatoid arthritis and has shown promise in case series for the treatment of severe SLE that is unresponsive to other therapies. This case suggests that rituximab-induced B-cell depletion may provide an important new therapeutic option for refractory cases of this devastating ocular complication.