Proof-of-concept that network pharmacology is effective to modify development of acquired temporal lobe epilepsy

Epilepsy is a complex network phenomenon that, as yet, cannot be prevented or cured. We recently proposed network-based approaches to prevent epileptogenesis. For proof of concept we combined two drugs (levetiracetam and topiramate) for which in silico analysis of drug-protein interaction networks indicated a synergistic effect on a large functional network of epilepsy-relevant proteins. Using the intrahippocampal kainate mouse model of temporal lobe epilepsy, the drug combination was administered during the latent period before onset of spontaneous recurrent seizures (SRS). When SRS were periodically recorded by video-EEG monitoring after termination of treatment, a significant decrease in incidence and frequency of SRS was determined, indicating antiepileptogenic efficacy. Such efficacy was not observed following single drug treatment. Furthermore, a combination of levetiracetam and phenobarbital, for which in silico analysis of drug-protein interaction networks did not indicate any significant drug-drug interaction, was not effective to modify development of epilepsy. Surprisingly, the promising antiepileptogenic effect of the levetiracetam/topiramate combination was obtained in the absence of any significant neuroprotective or anti-inflammatory effects as indicated by multimodal brain imaging and histopathology. High throughput RNA-sequencing (RNA-seq) of the ipsilateral hippocampus of mice treated with the levetiracetam/topiramate combination showed that several genes that have been linked previously to epileptogenesis, were significantly differentially expressed, providing interesting entry points for future mechanistic studies. Overall, we have discovered a novel combination treatment with promise for prevention of epilepsy

Community-Based Outbreaks in Vulnerable Populations of Invasive Infections Caused by Streptococcus pneumoniae Serotypes 5 and 8 in Calgary, Canada

BACKGROUND: Outbreaks of invasive pneumococcal disease (IPD) typically occur within institutions. Beginning in 2005, we detected an increase in serotype (ST) 5 and ST8 IPD cases, predominantly in homeless persons living in an open community. METHODOLOGY/PRINCIPAL FINDINGS: CASPER (Calgary Area S. pneumoniae Epidemiology Research) surveillance study of all IPD (sterile site isolates) in our region (pop ~1,100,000). Interviews and chart reviews of all cases and all isolates phenotypically analyzed and selected isolated tested by multi-locus sequence typing (MLST). CONCLUSIONS/SIGNIFICANCE: During 2005-2007, 162 cases of ST5 IPD and 45 cases of ST8 IPD were identified. The isolates demonstrated phenotypic and genotypic clonality. The ST5 isolates were sequence type (ST) 289 and demonstrated intermediate susceptibility to TMP-SMX. The ST8 isolates were predominantly ST1268, with a susceptible antimicrobial susceptibility profile. Individuals with ST5 IPD were more likely to be middle aged (OR 2.6), homeless (OR 4.4), using illicit drugs(OR 4.8), and asthmatic(OR 2.6). Those with ST8 were more likely to be male (OR 4.4), homeless (OR 2.6), aboriginal (OR7.3), and a current smoker (OR 2.5). Overlapping outbreaks of ST5 and ST8 IPD occurred in an open community in Calgary, Canada and homelessness was a predominant risk factor. Homelessness represents a unique community in which pneumococcal outbreaks can occur

Efectos de la administración de somatotrofina bovina sobre producción y composición de leche

La inyección regular de somatotrofina bovina en vacas lecheras desde el pico de lactancia incrementó la producción promedio de leche en 28 p.100. Sin afectar a la composición de la leche, aumentó la producción de grasa, proteína, lactosa y sólidos totales. La condición corporal se mantuvo dentro de rangos normales

Efectos de la administración de somatotrofina bovina sobre producción y composición de leche

La inyección regular de somatotrofina bovina en vacas lecheras desde el pico de lactancia incrementó la producción promedio de leche en 28 p.100. Sin afectar a la composición de la leche, aumentó la producción de grasa, proteína, lactosa y sólidos totales. La condición corporal se mantuvo dentro de rangos normales

Methicillin-resistant Staphylococcus aureus endocarditis and de novo development of daptomycin resistance during therapy

Daptomycin resistance in Staphylococcus aureus has been previously reported, but the development of resistance while on therapy with subsequent clinical failure for endocarditis has been infrequently reported. A case of persistent methicillin-resistant S aureus (MRSA) bacteremia in the setting of right-sided endocarditis in a 38-year-old man with a history of intravenous drug use is presented. He developed de novo resistance to daptomycin during therapy after several courses of antibiotics, with subsequent clinical failure. Isolates were identified by molecular characterization to be community-acquired MRSA 10 (USA300). To the authors’ knowledge, the present case was the first in Canada to involve the de novo development of daptomycin resistance with clinical failure due to MRSA during therapy for endocarditis. Clinicians and microbiologists must be aware of this phenomenon given the implications for treatment and transmission of the strain. It also raises questions regarding the use of daptomycin in settings of heavily pretreated patients with persistent MRSA bacteremia

Methicillin-Resistant Staphylococcus aureus Endocarditis and de Novo Development of Daptomycin Resistance during Therapy

Daptomycin resistance in Staphylococcus aureus has been previously reported, but the development of resistance while on therapy with subsequent clinical failure for endocarditis has been infrequently reported. A case of persistent methicillin-resistant S aureus (MRSA) bacteremia in the setting of right-sided endocarditis in a 38-year-old man with a history of intravenous drug use is presented. He developed de novo resistance to daptomycin during therapy after several courses of antibiotics, with subsequent clinical failure. Isolates were identified by molecular characterization to be community-acquired MRSA 10 (USA300). To the authors’ knowledge, the present case was the first in Canada to involve the de novo development of daptomycin resistance with clinical failure due to MRSA during therapy for endocarditis. Clinicians and microbiologists must be aware of this phenomenon given the implications for treatment and transmission of the strain. It also raises questions regarding the use of daptomycin in settings of heavily pretreated patients with persistent MRSA bacteremia.Peer Reviewe