Multifocal motor neuropathy: a trial of therapeutic complement inhibition, and investigation of serological factors

Immune-mediated neuropathies cause inflammation of the peripheral nerve, with disruption of the axon, myelin sheath or both. In the acute setting, immune-mediated neuropathy can lead to respiratory muscle weakness, in the group of Guillain-Barré syndrome (GBS). In the chronic setting, immune-mediated neuropathies, which can be sensorimotor (CIDP, MADSAM), sensory predominant (anti-MAG neuropathy, others) and purely motor (MMN), cause permanent and progressive disability and impairment in activities of daily living. Anti-gangliosides antibodies have been detected with varying frequencies in the immune-mediated neuropathies, with the highest prevalence being anti-GQ1b antibodies in Miller-Fisher syndrome and anti-GM1 antibodies in MMN and AMAN (axonal variant of GBS). There is evidence that the inflammatory potential of these antibodies is reliant upon complement activation, and the resultant formation of the MAC (membrane attack complex). In experimental models of anti-ganglioside mediated neuropathy, inhibition of the complement cascade results in the complete prevention of inflammatory damage, and preserved nerve function. Multifocal motor neuropathy is a chronic, progressive purely motor neuropathy which causes weakness and wasting. IgM anti-GM1 antibodies are found in between 50 – 80% of affected cases. The only current treatment for MMN is high dose IVIg (intravenous immunoglobulin). The response rate to IVIg is around 80%, and cases who are antibody negative can also respond to this treatment. However, the effect is temporary, and further doses are usually re-administered at around 4 weekly intervals. Since it is a human blood product which is pooled from donated blood products, it is in short supply and does carry some important side effects. The main focus of this study was to test a novel therapy for immune-mediated neuropathy. The treatment tested was the first complement inhibitor licensed for human use, eculizumab. In this study it has been tested in the treatment of MMN, in patients who may also be receiving treatment with IVIg. The aim was to collect safety information regarding the concurrent use of these biological products, and to test for any neutralising effect between them. Any beneficial effect of complement inhibition in MMN was investigated by various outcome measures, clinical, functional and electrophysiological. The results of the clinical trial showed that eculizumab treatment was associated with a higher rate of adverse events, in patients who were or were not receiving IVIg. Most adverse events were mild to moderate in severity, none were unexpected, and more occurred during the induction phase of treatment than during the maintenance phase. The most common adverse event was headache, which 69% of patients experienced at any time. Two thirds of all headaches occurred in the induction phase. IVIg did lower the serum concentration of eculizumab, however eculizumab activity was not compromised. There were significant changes to subjective scores overall, and some objective scores also displayed significant improvement. However repeated IVIg doses were still required by those who were regularly using it prior to the study, albeit perhaps at slightly longer intervals. Electrophysiology showed small significant improvement in two parameters in keeping with improved nerve conduction. Overall it was felt that complement inhibition was associated with some potential benefits in MMN however did not substitute the therapeutic mechanism of action of IVIg. Aspects of the study design meant that evidence of efficacy could not be concluded from this study, and further trials are necessary to elucidate this. In addition, this thesis presents a laboratory-based study in which further information about the binding characteristics of the IgM GM1 antibody were sought using different methods than the standard ELISA technique. Using a combinatorial glycolipid microarray, MMN sera were screened against a large range of glycolipid pairs, to test for novel epitopes in the ‘antibody negative’ MMN patients without anti-GM1 antibody. It was found that in patients who did not have an antibody to GM1 or any other single ganglioside on ELISA or microarray, there was presence of an antibody to the glycolipid pair, GM1:GalC. It was shown that the IgM GM1 antibody in MMN is also inhibited from binding to GM1 in a solid phase and live membrane due to the local presence of GD1a. These findings lead to greater understanding of the pathogenesis of MMN and possibility of a more sensitive diagnostic test

Secondary use of data recorded in primary care: insights from human computer interaction field studies

Introduction: Electronic health records from primary care, are now aggregated in a number of large datasets from primary care settings, containing both coded data and free-text. Secondary users can easily undertake analyses using coded data. However although the balance of information between these codes and free text is variable, they rarely use the information contained in doctors’ free-text notes - because of their ‘messy’ nature and the costs of ensuring anonymity. Our epidemiological studies within the Patient Records Enhancement Project has demonstrated that free text contains important information, that is often ignored. Method: Human computer interaction (HCI) studies, using qualitative approaches, can help us understand the reasons for variability in the balance of coded and free text data. We undertook field studies in six GP surgeries which included observations of record use across the surgery, video analysis of real patient consultations and interviews with a range of surgery staff. We also undertook ‘simulated’ consultations, with two medical actors playing the part of the patient, allowing us to standarise the patient across doctors and software systems. Results: Preliminary results suggest several reasons for variation in data recording. Doctors create notes in order to best manage patients with little consideration for use by others, and reported limited awareness of secondary uses of the information. Doctors often record and “read” a picture painted by the overall record of a consultation or record symptoms and signs in free text notes, and choose not to code a definite diagnosis. If coding, they often choose a more general non specific code, even when they have inferred and acted on a clear diagnosis. These approaches reflect processes of progressing from differential to definite diagnosis, and the surgery’s administrative and consultation processes. Conclusion: Our findings may explain apparent delays in diagnosis often observed in epidemiological analyses. The picture portrayed within records may not be at all clear to researchers relying on coded data. Our results have implications for secondary users of data and assessment of data for quality of care. Follow on work might result in typologies of diseases liable to coded data deficits and support software development

Causality in Contemporary American Sociology: An Empirical Assessment and Critique

Using a unique data set of causal usage drawn from research articles published between 2006–2008 in the American Journal of Sociology and American Sociological Review, this article offers an empirical assessment of causality in American sociology. Testing various aspects of what we consider the conventional wisdom on causality in the discipline, we find that (1) “variablistic” or “covering law” models are not the dominant way of making causal claims, (2) research methods affect but do not determine causal usage, and (3) the use of explicit causal language and the concept of “mechanisms” to make causal claims is limited. Instead, we find that metaphors and metaphoric reasoning are fundamental for causal claims‐making in the discipline. On this basis, we define three dominant causal types used in sociology today, which we label the Probabilistic, Initiating and Conditioning types. We theorize this outcome as demonstrating the primary role that cognitive models play in providing inference‐rich metaphors that allow sociologists to map causal relationships on to empirical processes

Vestibular Evoked Myogenic Potential (VEMP) Test-Retest Reliability in Children

Objective—Vestibular evoked myogenic potentials (VEMPs) are short-latency muscle potentials measured from the neck (cervical VEMP; cVEMP) or under the eyes (ocular VEMP; oVEMP), which provide information regarding function of the saccule and utricle, respectively. VEMPs are reliable when performed in adults; however, reliability of VEMPs in children is unknown. Therefore, the purpose of the study was to determine the test-retest reliability of c- and oVEMP testing in normal control children. Study Design—Prospective. Setting—Hospital. Patients—Ten adults, 14 adolescent children and 13 young children with normal hearing. Interventions—c- and oVEMP testing were completed across two test sessions in response to air-conduction 500 Hz tone-burst and impulse hammer stimuli. Additionally, oVEMP was completed using eyes-open and eyes-closed conditions. Main Outcome Measures—Intraclass correlation coefficients were calculated to determine the reliability of c- and oVEMP outcomes. Results—When using air-conduction stimuli, c- and oVEMP amplitudes are reliable across test sessions in normal control children and adults. With impulse hammer stimuli, cVEMP amplitudes showed high reliability; however, oVEMP amplitudes showed low reliability in both eyes-open and eyes-closed conditions. Comparison between eyes-open and eyes-closed oVEMP conditions revealed shorter latencies and higher peak-to-peak amplitudes in the eyes-open condition. Conclusions—In this small cohort of normal control children, cVEMPs are reliable using air-conduction and impulse hammer stimuli and oVEMPs are reliable using air-conduction stimuli in the eyes-open condition. oVEMP in eyes-closed conditions were less reliable compared to eyes-open conditions and resulted in a large number of absent responses

The Forum: Fall 2002

Fall 2002 journal of the Honors Program at the University of North Dakota. The issue includes stories, poems, essays and art by undergraduate students.https://commons.und.edu/und-books/1050/thumbnail.jp

Size and conformation limits to secretion of disulfide-bonded loops in autotransporter proteins

Autotransporters are a superfamily of virulence factors typified by a channel-forming C terminus that facilitates translocation of the functional N-terminal passenger domain across the outer membrane of Gram-negative bacteria. This final step in the secretion of autotransporters requires a translocation-competent conformation for the passenger domain that differs markedly from the structure of the fully folded secreted protein. The nature of the translocation-competent conformation remains controversial, in particular whether the passenger domain can adopt secondary structural motifs, such as disulfide- bonded segments, while maintaining a secretion-competent state. Here, we used the endogenous and closely spaced cysteine residues of the plasmid-encoded toxin (Pet) from enteroaggregative Escherichia coli to investigate the effect of disulfide bond-induced folding on translocation of an auto-transporter passenger domain. We reveal that rigid structural elements within disulfide-bonded segments are resistant to autotransporter-mediated secretion. We define the size limit of disulfide-bonded segments tolerated by the autotransporter system demonstrating that, when present, cysteine pairs are intrinsically closely spaced to prevent congestion of the translocator pore by large disulfide-bonded regions. These latter data strongly support the hairpin mode of autotransporter biogenesis

Atlas of Lobular Breast Cancer Models: Challenges and Strategic Directions

Invasive lobular carcinoma (ILC) accounts for up to 15% of all breast cancer (BC) cases and responds well to endocrine treatment when estrogen receptor α-positive (ER+) yet differs in many biological aspects from other ER+ BC subtypes. Up to 30% of patients with ILC will develop late-onset metastatic disease up to ten years after initial tumor diagnosis and may experience failure of systemic therapy. Unfortunately, preclinical models to study ILC progression and predict the efficacy of novel therapeutics are scarce. Here, we review the current advances in ILC modeling, including cell lines and organotypic models, genetically engineered mouse models, and patient-derived xenografts. We also underscore four critical challenges that can be addressed using ILC models: drug resistance, lobular tumor microenvironment, tumor dormancy, and metastasis. Finally, we highlight the advantages of shared experimental ILC resources and provide essential considerations from the perspective of the European Lobular Breast Cancer Consortium (ELBCC), which is devoted to better understanding and translating the molecular cues that underpin ILC to clinical diagnosis and intervention. This review will guide investigators who are considering the implementation of ILC models in their research programs

Size and conformation limits to secretion of disulfide-bonded loops in autotransporter proteins

Autotransporters are a superfamily of virulence factors typified by a channel-forming C terminus that facilitates translocation of the functional N-terminal passenger domain across the outer membrane of Gram-negative bacteria. This final step in the secretion of autotransporters requires a translocation-competent conformation for the passenger domain that differs markedly from the structure of the fully folded secreted protein. The nature of the translocation-competent conformation remains controversial, in particular whether the passenger domain can adopt secondary structural motifs, such as disulfide- bonded segments, while maintaining a secretion-competent state. Here, we used the endogenous and closely spaced cysteine residues of the plasmid-encoded toxin (Pet) from enteroaggregative Escherichia coli to investigate the effect of disulfide bond-induced folding on translocation of an auto-transporter passenger domain. We reveal that rigid structural elements within disulfide-bonded segments are resistant to autotransporter-mediated secretion. We define the size limit of disulfide-bonded segments tolerated by the autotransporter system demonstrating that, when present, cysteine pairs are intrinsically closely spaced to prevent congestion of the translocator pore by large disulfide-bonded regions. These latter data strongly support the hairpin mode of autotransporter biogenesis