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Pain is a under-recognized association of leucine-rich glioma-inactivated 1 (LGI1) and contactin-associated protein-like 2 (CASPR2) antibodies. Of 147 patients with these autoantibodies, pain was experienced by 17 of 33 (52%) with CASPR2- versus 20 of 108 (19%) with LGI1 antibodies (p = 0.0005), and identified as neuropathic in 89% versus 58% of these, respectively. Typically, in both cohorts, normal nerve conduction studies and reduced intraepidermal nerve fiber densities were observed in the sampled patient subsets. In LGI1 antibody patients, pain responded to immunotherapy (p = 0.008), often rapidly, with greater residual patient-rated impairment observed in CASPR2 antibody patients (p = 0.019). Serum CASPR2 antibodies, but not LGI1 antibodies, bound in vitro to unmyelinated human sensory neurons and rodent dorsal root ganglia, suggesting pathophysiological differences that may underlie our clinical observations. ANN NEUROL 2021;90:683-690.

Paraneoplastic neurological syndromes (PNS) are the immune-mediated effects of a remote cancer and are characterised by an autoantibody response against antigens expressed by the tumour. Classically, well-characterised ‘onconeuronal’ antibodies target intracellular antigens and hence cannot access their antigens across intact cell membranes. The pathogenic mediators are likely to be neuronal-specific T cells. There is a variable response to immunotherapies and the clinical syndrome helps to direct the search for a specific set of tumours. By contrast, many newly emerging autoantibodies with oncological associations target cell surface epitopes and can exert direct pathogenic effects on both the central and peripheral nervous systems. Patients with these cell-surface directed autoantibodies often clearly respond to immunotherapies. Overall, the clinical, serological and oncological features in an individual patient help to determine the clinical relevance of the syndrome and hence guide its management. We summarise current knowledge and a practical approach to the investigation, diagnosis, treatment and outcomes of patients with suspected PNS.

Background/objective:A Canadian Stroke Best Practices consensus statement on Acute Stroke Management during pregnancy was published in 2018. The state of individual practice, however, is unknown.Methods:A survey on treatment of acute stroke in pregnant and post-partum women was distributed via the Canadian Stroke Consortium email list. Descriptive statistics (frequencies and proportions) were calculated for demographic and response variables and free-text responses were coded for thematic content.Results:Thirty-five participants completed the survey; 12 had experience with intravenous tissue plasminogen activator (IV-tPA), endovascular therapy (EVT), or both in pregnant patients. None had treatment-related complications. The majority (92%) of those who had not yet encountered the issue in practice expressed some reservation about giving IV-tPA to an otherwise eligible pregnant woman. In a theoretical scenario where an otherwise eligible pregnant woman was a candidate for both IV-tPA and EVT, 58% of respondents would have opted for EVT alone. Amongst this cohort comprised mainly of stroke sub-specialists, more than a third had treated pregnant patients with reperfusion therapy.Conclusions:The reported safety experience with both IV-tPA and EVT was reassuring. Overall, there was a hesitancy towards use of IV-tPA in pregnancy that is discordant with the recent consensus statement. Possible barriers to uptake identified through thematic analysis were concerns regarding risks of bleeding in the pregnant patient, presence of EVT as a perceived alternative, and the need for express consent from the patient and family.

New findings • What is the central question of this study? Does overexpression of peroxisome proliferator-activated receptor α (PPARα) specifically in pancreatic β-cells of diet-induced obese mice preserve pancreatic β-cell function and delay the onset of obesity-induced diabetes? • What is the main finding and its importance? This study reports the phenotype of the first in vivo model of β-cell-specific PPARα overexpression in a murine model of diet-induced obesity. We show that pancreatic β-cell-specific overexpression of PPARα significantly improves glucose tolerance in diet-induced obese mice. These results suggest that activation of β-cell PPARα may be an appropriate target to preserve β-cell function in obesity-induced diabetes. Lipotoxicity is implicated in pancreatic β-cell dysfunction in obesity-induced type 2 diabetes. In vitro, activation of peroxisome proliferator-activated receptor α (PPARα) has been shown to protect pancreatic β-cells from the lipotoxic effects of palmitate, thereby preserving insulin secretion. Utilizing an adeno-associated virus (dsAAV8), overexpression of PPARα was induced specifically in pancreatic β-cells of adult, C57Bl/6 mice fed a high-fat diet for 20 weeks and carbohydrate metabolism and β-cell mass assessed. We show that overexpression of PPARα in pancreatic β-cells in vivo preserves β-cell function in obesity, and this improves glucose tolerance by preserving insulin secretion in comparison to control mice with diet-induced obesity. No changes in β-cell mass were observed in PPARα-overexpressing mice compared with diet-induced obese control animals. This model of β-cell-specific PPARα overexpression provides a useful in vivo model for elucidating the mechanisms underlying β-cell lipotoxicity in obesity-induced type 2 diabetes.

A n 88-year-old, HIV-negative, non-diabetic man developed right facial pain, swelling and redness one day after right upper molar extraction. Despite outpatient therapy with amoxicillin and valacyclovir, he developed serous drainage and swelling of the right eyelid. The next day he presented with extensive right facial erythema, edema, patches of crusting and black eschar, but no vesicles, in the V2 distribution (Fig. 1). Oral examination showed small vesicles and ulcers on the right hard and soft palates (Fig. 2). Lesion distribution was sharply demarcated at the midline. Swabs showed co-infection with herpes simplex virus type 1 (HSV1), varicella-zoster virus (VZV) and methicillinsensitive Staphylococcus aureus. Ophthalmologic consultation excluded corneal involvement. The patient received intravenous acyclovir and antibiotics. Three weeks later, his facial and palatal lesions had resolved. In immune-competent patients, concurrent reactivation with VZVand HSV is rare in the same cutaneous site. Co-infection cases tend to be more severe than single-infection cases, are more common in the elderly, and demonstrate a predilection for head involvement. In our patient, co-reactivation in a vulnerable area was further complicated by bacterial superinfection which was unresponsive to initial outpatient treatment. Awareness of the possibility and severity of co-infection may facilitate earlier diagnosis and appropriate interventions.

The contribution of peroxisomal proliferator-activated receptor (PPAR)-γ agonism in pancreatic β-cells to the antidiabetic actions of thiazolidinediones has not been clearly elucidated. Genetic models of pancreatic β-cell PPARγ ablation have revealed a potential role for PPARγ in β-cell expansion in obesity but a limited role in normal β-cell physiology. Here we overexpressed PPARγ1 or PPARγ2 specifically in pancreatic β-cells of mice subjected to high-fat feeding using an associated adenovirus (β-PPARγ1-HFD and β-PPARγ2-HFD mice). We show β-cell-specific PPARγ1 or PPARγ2 overexpression in diet-induced obese mice exacerbated obesity-induced glucose intolerance with decreased β-cell mass, increased islet cell apoptosis, and decreased plasma insulin compared with obese control mice (β-eGFP-HFD mice). Analysis of islet lipid composition in β-PPARγ2-HFD mice revealed no significant changes in islet triglyceride content and an increase in only one of eight ceramide species measured. Interestingly β-PPARγ2-HFD islets had significantly lower levels of lysophosphatidylcholines, lipid species shown to enhance insulin secretion in β-cells. Gene expression profiling revealed increased expression of uncoupling protein 2 and genes involved in fatty acid transport and β-oxidation. In summary, transgenic overexpression of PPARγ in β-cells in diet-induced obesity negatively impacts whole-animal carbohydrate metabolism associated with altered islet lipid content, increased expression of β-oxidative genes, and reduced β-cell mass., Funding agencies:Canadian Diabetes Association University of Northern British Columbia Research Project Awards

Lipotoxicity is implicated in pancreatic β-cell dysfunction in obesity-induced type 2 diabetes. In vitro, activation of peroxisome proliferator-activated receptor α (PPARα) has been shown to protect pancreatic β-cells from the lipotoxic effects of palmitate, thereby preserving insulin secretion. Utilizing an adeno-associated virus (dsAAV8), overexpression of PPARα was induced specifically in pancreatic β-cells of adult, C57Bl/6 mice fed a high-fat diet for 20 weeks and carbohydrate metabolism and β-cell mass assessed. We show that overexpression of PPARα in pancreatic β-cells in vivo preserves β-cell function in obesity, and this improves glucose tolerance by preserving insulin secretion in comparison to control mice with diet-induced obesity. No changes in β-cell mass were observed in PPARα-overexpressing mice compared with diet-induced obese control animals. This model of β-cell-specific PPARα overexpression provides a useful in vivo model for elucidating the mechanisms underlying β-cell lipotoxicity in obesity-induced type 2 diabetes.

Apurinic/apyrimidinic endonuclease 1 (APE1) is the major mammalian enzyme in DNA base excision repair that cleaves the DNA phosphodiester backbone immediately 5′ to abasic sites. Recently, we identified APE1 as an endoribonuclease that cleaves a specific coding region of c-myc mRNA in vitro, regulating c-myc mRNA level and half-life in cells. Here, we further characterized the endoribonuclease activity of APE1, focusing on the active-site center of the enzyme previously defined for DNA nuclease activities. We found that most site-directed APE1 mutant proteins (N68A, D70A, Y171F, D210N, F266A, D308A, and H309S), which target amino acid residues constituting the abasic DNA endonuclease active-site pocket, showed significant decreases in endoribonuclease activity. Intriguingly, the D283N APE1 mutant protein retained endoribonuclease and abasic single-stranded RNA cleavage activities, with concurrent loss of apurinic/apyrimidinic (AP) site cleavage activities on double-stranded DNA and single-stranded DNA (ssDNA). The mutant proteins bound c-myc RNA equally well as wild-type (WT) APE1, with the exception of H309N, suggesting that most of these residues contributed primarily to RNA catalysis and not to RNA binding. Interestingly, both the endoribonuclease and the ssRNA AP site cleavage activities of WT APE1 were present in the absence of Mg2+, while ssDNA AP site cleavage required Mg2+ (optimally at 0.5–2.0 mM). We also found that a 2′-OH on the sugar moiety was absolutely required for RNA cleavage by WT APE1, consistent with APE1 leaving a 3′-PO42− group following cleavage of RNA. Altogether, our data support the notion that a common active site is shared for the endoribonuclease and other nuclease activities of APE1; however, we provide evidence that the mechanisms for cleaving RNA, abasic single-stranded RNA, and abasic DNA by APE1 are not identical, an observation that has implications for unraveling the endoribonuclease function of APE1 in vivo.

This 68-year-old Caucasian male presented with fever of 39.8°C, rigours, hypotension, urinary retention and 2 weeks of abdominal pain. Medical background included colonisation with methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE), hypertension, remote ischaemic stroke, coronary bypass, peripheral vascular disease with toe amputation and anterior resection 9 months prior for rectosigmoid mass (benign tubulovillous adenoma). Abdominal/pelvic CT demonstrated severe faecal impaction and focal perforation at the posterolateral rectosigmoid junction. A large collection posterior to the perforation extended into the presacral musculature. Debris and gas bubbles further extended into the epidural space at L3 (figure 1A–C). Subsequent MRI confirmed intraspinal gas, sacral osteomyelitis and posterior L3 epidural abscess extending inferiorly into the sacrum. Figure 1 (A) Sagittal section. …

s / Can J Diabetes 36 (2012) S24eS76 S62 glucolipotoxicity and chronic ER stress. Interestingly, double BaxBak knockout resulted in an acute and transient up-regulation of the islet ER stress response. Together, these data suggest that Bax and Bak, both separately and in combination, are important for beta-cell loss in diabetes and have novel roles in the regulation of beta-cell organelle stress upstream of apoptosis execution.