Effects of Vagus Nerve Stimulation on Progressive Myoclonus Epilepsy of Unverricht-Lundborg Type

Purpose : A 34-year-old woman with progressive myoclonus epilepsy of Unverricht-Lundborg type was considered for vagus nerve stimulation (VNS) therapy. Methods : After demonstration of intractability to multiple antiepileptic regimens and progressive deterioration in cerebellar function, the patient was implanted with a vagus nerve stimulator and followed for 1 year. Neurological status, seizure frequency, and parameter changes were analyzed. Results : VNS therapy resulted in reduction of seizures (more than 90%) and a significant improvement in cerebellar function demonstrated on neurological examination. The patient reported improved quality of life based in part on her ability to perform activities of daily living. Conclusions : VNS therapy may be considered a treatment option for progressive myoclonus epilepsy. The effects of VNS on seizure control and cerebellar dysfunction may provide clues to the underlying mechanism(s) of action.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65549/1/j.1528-1157.2000.tb00293.x.pd

Functional plasticity of antibacterial EndoU toxins.

Bacteria use several different secretion systems to deliver toxic EndoU ribonucleases into neighboring cells. Here, we present the first structure of a prokaryotic EndoU toxin in complex with its cognate immunity protein. The contact-dependent growth inhibition toxin CdiA-CTSTECO31 from Escherichia coli STEC_O31 adopts the eukaryotic EndoU fold and shares greatest structural homology with the nuclease domain of coronavirus Nsp15. The toxin contains a canonical His-His-Lys catalytic triad in the same arrangement as eukaryotic EndoU domains, but lacks the uridylate-specific ribonuclease activity that characterizes the superfamily. Comparative sequence analysis indicates that bacterial EndoU domains segregate into at least three major clades based on structural variations in the N-terminal subdomain. Representative EndoU nucleases from clades I and II degrade tRNA molecules with little specificity. In contrast, CdiA-CTSTECO31 and other clade III toxins are specific anticodon nucleases that cleave tRNAGlu between nucleotides C37 and m2 A38. These findings suggest that the EndoU fold is a versatile scaffold for the evolution of novel substrate specificities. Such functional plasticity may account for the widespread use of EndoU effectors by diverse inter-bacterial toxin delivery systems

Genetic evidence for SecY translocon-mediated import of two 3 contact-dependent growth inhibition (CDI) toxins

The C-terminal (CT) toxin domains of contact-dependent growth inhibition (CDI) CdiA proteins target Gram-negative bacteria and must breach both the outer and inner membranes of target cells to exert growth inhibitory activity. Here, we examine two CdiA-CT toxins that exploit the bacterial general protein secretion machinery after delivery into the periplasm. A Ser281Phe amino acid substitution in transmembrane segment 7 of SecY, the universally conserved channel-forming subunit of the Sec translocon, decreases the cytotoxicity of the membrane depolarizing orphan10 toxin from enterohemorrhagic Escherichia coli EC869. Target cells expressing secY(S281F) and lacking either PpiD or YfgM, two SecY auxiliary factors, are fully protected from CDI-mediated inhibition either by CdiA-CTo10EC869 or by CdiA-CTGN05224, the latter being an EndoU RNase CdiA toxin from Klebsiella aerogenes GN05224 that has a related cytoplasm entry domain. RNase activity of CdiA-CTGN05224 was reduced in secY(S281F) target cells and absent in secY(S281F) Delta ppiD or secY(S281F) Delta yfgM target cells during competition co-cultures. Importantly, an allele-specific mutation in secY (secY(G313W)) renders DppiD or Delta yfgM target cells specifically resistant to CdiA-CTGN05224 but not to CdiA-CTo10EC869, further suggesting a direct interaction between SecY and the CDI toxins. Our results provide genetic evidence of a unique confluence between the primary cellular export route for unfolded polypeptides and the import pathways of two CDI toxins. IMPORTANCE Many bacterial species interact via direct cell-to-cell contact using CDI systems, which provide a mechanism to inject toxins that inhibit bacterial growth into one another. Here, we find that two CDI toxins, one that depolarizes membranes and another that degrades RNA, exploit the universally conserved SecY translocon machinery used to export proteins for target cell entry. Mutations in genes coding for members of the Sec translocon render cells resistant to these CDI toxins by blocking their movement into and through target cell membranes. This work lays the foundation for understanding how CDI toxins interact with the protein export machinery and has direct relevance to development of new antibiotics that can penetrate bacterial cell envelopes

Comparing RADseq and microsatellites for estimating genetic diversity and relatedness - Implications for brown trout conservation

The conservation and management of endangered species requires information on their genetic diversity, relatedness and population structure. The main genetic markers applied for these questions are microsatellites and single nucleotide polymorphisms (SNPs), the latter of which remain the more resource demanding approach in most cases. Here, we compare the performance of two approaches, SNPs obtained by restriction-site-associated DNA sequencing (RADseq) and 16 DNA microsatellite loci, for estimating genetic diversity, relatedness and genetic differentiation of three, small, geographically close wild brown trout (Salmo trutta) populations and a regionally used hatchery strain. The genetic differentiation, quantified as F-ST, was similar when measured using 16 microsatellites and 4,876 SNPs. Based on both marker types, each brown trout population represented a distinct gene pool with a low level of interbreeding. Analysis of SNPs identified half- and full-siblings with a higher probability than the analysis based on microsatellites, and SNPs outperformed microsatellites in estimating individual-level multilocus heterozygosity. Overall, the results indicated that moderately polymorphic microsatellites and SNPs from RADseq agreed on estimates of population genetic structure in moderately diverged, small populations, but RADseq outperformed microsatellites for applications that required individual-level genotype information, such as quantifying relatedness and individual-level heterozygosity. The results can be applied to other small populations with low or moderate levels of genetic diversity.Peer reviewe

Potential risk factors associated with human encephalitis: application of canonical correlation analysis

<p>Abstract</p> <p>Background</p> <p>Infection of the CNS is considered to be the major cause of encephalitis and more than 100 different pathogens have been recognized as causative agents. Despite being identified worldwide as an important public health concern, studies on encephalitis are very few and often focus on particular types (with respect to causative agents) of encephalitis (e.g. West Nile, Japanese, etc.). Moreover, a number of other infectious and non-infectious conditions present with similar symptoms, and distinguishing encephalitis from other disguising conditions continues to a challenging task.</p> <p>Methods</p> <p>We used canonical correlation analysis (CCA) to assess associations between set of exposure variable and set of symptom and diagnostic variables in human encephalitis. Data consists of 208 confirmed cases of encephalitis from a prospective multicenter study conducted in the United Kingdom. We used a covariance matrix based on Gini's measure of similarity and used permutation based approaches to test significance of canonical variates.</p> <p>Results</p> <p>Results show that weak pair-wise correlation exists between the risk factor (exposure and demographic) and symptom/laboratory variables. However, the first canonical variate from CCA revealed strong multivariate correlation (ρ = 0.71, se = 0.03, p = 0.013) between the two sets. We found a moderate correlation (ρ = 0.54, se = 0.02) between the variables in the second canonical variate, however, the value is not statistically significant (p = 0.68). Our results also show that a very small amount of the variation in the symptom sets is explained by the exposure variables. This indicates that host factors, rather than environmental factors might be important towards understanding the etiology of encephalitis and facilitate early diagnosis and treatment of encephalitis patients.</p> <p>Conclusions</p> <p>There is no standard laboratory diagnostic strategy for investigation of encephalitis and even experienced physicians are often uncertain about the cause, appropriate therapy and prognosis of encephalitis. Exploration of human encephalitis data using advanced multivariate statistical modelling approaches that can capture the inherent complexity in the data is, therefore, crucial in understanding the causes of human encephalitis. Moreover, application of multivariate exploratory techniques will generate clinically important hypotheses and offer useful insight into the number and nature of variables worthy of further consideration in a confirmatory statistical analysis.</p

Comparing RADseq and microsatellites for estimating genetic diversity and relatedness Implications for brown trout conservation

The conservation and management of endangered species requires information on their genetic diversity, relatedness and population structure. The main genetic markers applied for these questions are microsatellites and single nucleotide polymorphisms (SNPs), the latter of which remain the more resource demanding approach in most cases. Here, we compare the performance of two approaches, SNPs obtained by restriction-site-associated DNA sequencing (RADseq) and 16 DNA microsatellite loci, for estimating genetic diversity, relatedness and genetic differentiation of three, small, geographically close wild brown trout (Salmo trutta) populations and a regionally used hatchery strain. The genetic differentiation, quantified as F-ST, was similar when measured using 16 microsatellites and 4,876 SNPs. Based on both marker types, each brown trout population represented a distinct gene pool with a low level of interbreeding. Analysis of SNPs identified half- and full-siblings with a higher probability than the analysis based on microsatellites, and SNPs outperformed microsatellites in estimating individual-level multilocus heterozygosity. Overall, the results indicated that moderately polymorphic microsatellites and SNPs from RADseq agreed on estimates of population genetic structure in moderately diverged, small populations, but RADseq outperformed microsatellites for applications that required individual-level genotype information, such as quantifying relatedness and individual-level heterozygosity. The results can be applied to other small populations with low or moderate levels of genetic diversity

Clinical features of culture-proven Mycoplasma pneumoniae infections at King Abdulaziz University Hospital, Jeddah, Saudi Arabia

OBJECTIVE: This retrospective chart review describes the epidemiology and clinical features of 40 patients with culture-proven Mycoplasma pneumoniae infections at King Abdulaziz University Hospital, Jeddah, Saudi Arabia. METHODS: Patients with positive M. pneumoniae cultures from respiratory specimens from January 1997 through December 1998 were identified through the Microbiology records. Charts of patients were reviewed. RESULTS: 40 patients were identified, 33 (82.5%) of whom required admission. Most infections (92.5%) were community-acquired. The infection affected all age groups but was most common in infants (32.5%) and pre-school children (22.5%). It occurred year-round but was most common in the fall (35%) and spring (30%). More than three-quarters of patients (77.5%) had comorbidities. Twenty-four isolates (60%) were associated with pneumonia, 14 (35%) with upper respiratory tract infections, and 2 (5%) with bronchiolitis. Cough (82.5%), fever (75%), and malaise (58.8%) were the most common symptoms, and crepitations (60%), and wheezes (40%) were the most common signs. Most patients with pneumonia had crepitations (79.2%) but only 25% had bronchial breathing. Immunocompromised patients were more likely than non-immunocompromised patients to present with pneumonia (8/9 versus 16/31, P = 0.05). Of the 24 patients with pneumonia, 14 (58.3%) had uneventful recovery, 4 (16.7%) recovered following some complications, 3 (12.5%) died because of M pneumoniae infection, and 3 (12.5%) died due to underlying comorbidities. The 3 patients who died of M pneumoniae pneumonia had other comorbidities. CONCLUSION: our results were similar to published data except for the finding that infections were more common in infants and preschool children and that the mortality rate of pneumonia in patients with comorbidities was high

Two specific mutations are prevalent causes of recessive retinitis pigmentosa in North American patients of Jewish ancestry.

PURPOSE: Retinitis pigmentosa is a Mendelian disease with a very elevated genetic heterogeneity. Most mutations are responsible for less than 1% of cases, making molecular diagnosis a multigene screening procedure. In this study, we assessed whether direct testing of specific alleles could be a valuable screening approach in cases characterized by prevalent founder mutations. METHODS: We screened 275 North American patients with recessive/isolate retinitis pigmentosa for two mutations: an Alu insertion in the MAK gene and the p.Lys42Glu missense in the DHDDS gene. All patients were unrelated; 35 reported Jewish ancestry and the remainder reported mixed ethnicity. RESULTS: We identified the MAK and DHDDS mutations homozygously in only 2.1% and 0.8%, respectively, of patients of mixed ethnicity, but in 25.7% and 8.6%, respectively, of cases reporting Jewish ancestry. Haplotype analyses revealed that inheritance of the MAK mutation was attributable to a founder effect. CONCLUSION: In contrast to most mutations associated with retinitis pigmentosa-which are, in general, extremely rare-the two alleles investigated here cause disease in approximately one-third of North American patients reporting Jewish ancestry. Therefore, their screening constitutes an alternative procedure to large-scale tests for patients belonging to this ethnic group, especially in time-sensitive situations.Genet Med 17 4, 285-290

Burden of herpes zoster requiring hospitalization in Spain during a seven-year period (1998–2004)

<p>Abstract</p> <p>Background</p> <p>A thorough epidemiological surveillance and a good understanding of the burden of diseases associated to VZV are crucial to asses any potential impact of a prevention strategy. A population-based retrospective epidemiological study to estimate the burden of herpes zoster requiring hospitalization in Spain was conducted.</p> <p>Methods</p> <p>This study was conducted by using data from the national surveillance system for hospital data, Conjunto Mínimo Básico de Datos (CMBD). Records of all patients admitted to hospital with a diagnosis of herpes zoster (ICD-9-MC codes 053.0–053.9) during a 7-year period (1998–2004) were selected.</p> <p>Results</p> <p>A total of 23,584 hospitalizations with a primary or secondary diagnosis of herpes zoster in patients ≥ 30 years of age were identified during the study period. Annually there were 13.4 hospitalizations for herpes zoster per 100,000 population in patients ≥ 30 years of age. The rate increases with age reaching a maximum in persons ≥ 80 years of age (54.3 admissions per 100,000 population >80 years of age). The mean cost of a hospitalization for herpes zoster in adult patients was 3,720 €. The estimated annual cost of hospitalizations for herpes zoster in patients ≥ 30 years of age in Spain was 12,731,954 €.</p> <p>Conclusion</p> <p>Herpes zoster imposes an important burden of hospitalizations and result in large cost expenses to the Spanish National Health System, especially in population older than 50 years of age</p

PAAR-repeat proteins sharpen and diversify the Type VI secretion system spike

The bacterial type VI secretion system (T6SS) is a large multi-component, dynamic macromolecular machine that plays an important role in the ecology of many Gram negative bacteria. T6SS is responsible for translocation of a wide range of toxic effector molecules allowing predatory cells to kill both prokaryotic as well as eukaryotic prey cells1-5. The T6SS organelle is functionally analogous to contractile tails of bacteriophages and is thought to attack cells by initially penetrating them with a trimeric protein complex called the VgrG spike6,7. Neither the exact protein composition of the T6SS organelle nor the mechanisms of effector selection and delivery are known. Here we report that proteins from the PAAR (Proline-Alanine-Alanine-aRginine) repeat superfamily form a sharp conical extension on the VgrG spike, which is further involved in attaching effector domains to the spike. The crystal structures of two PAAR-repeat proteins bound to VgrG-like partners show that these proteins function to sharpen the tip of the VgrG spike. We demonstrate that PAAR proteins are essential for T6SS- mediated secretion and target cell killing by Vibrio cholerae and Acinetobacter baylyi. Our results suggest a new model of the T6SS organelle in which the VgrG-PAAR spike complex is decorated with multiple effectors that are delivered simultaneously into target cells in a single contraction-driven translocation event