Megan M. Jack

Role of advanced glycation endproducts and glyoxalase I in diabetic peripheral sensory neuropathy

Diabetic neuropathy is the most common and debilitating complication of diabetes mellitus with more than half of all patients developing altered sensation as a result of damage to peripheral sensory neurons. Hyperglycemia results in altered nerve conduction velocities, loss of epidermal innervation, and development of painful or painless signs and symptoms in the feet and hands. Current research has been unable to determine whether a patient will develop insensate or painful neuropathy or be protected from peripheral nerve damage all together. One mechanism that has been recognized to have a role in the pathogenesis of sensory neuron damage is the process of reactive dicarbonyls forming advanced glycation endproducts (AGEs) as a direct result of hyperglycemia. The glyoxalase system, composed of the enzymes glyoxalase I (GLO1) and glyoxalase II, is the main detoxification pathway involved in breaking down toxic reactive dicarbonyls before producing carbonyl stress and forming AGEs on proteins, lipids, or nucleic acids. This review discusses AGEs, GLO1, their role in diabetic neuropathy, and potential therapeutic targets of the AGE pathway.

Characterisation of glyoxalase I in a streptozocin-induced mouse model of diabetes with painful and insensate neuropathy

Aims/hypothesisDiabetic peripheral neuropathy (DN) is a common complication of diabetes; however, the mechanisms producing positive or negative symptoms are not well understood. The enzyme glyoxalase I (GLO1) detoxifies reactive dicarbonyls that form AGEs and may affect the way sensory neurons respond to heightened AGE levels in DN. We hypothesised that differential GLO1 levels in sensory neurons may lead to differences in AGE formation and modulate the phenotype of DN.MethodsInbred strains of mice were used to assess the variability of Glo1 expression by quantitative RT-PCR. Non-diabetic C57BL/6 mice were used to characterise the distribution of GLO1 in neural tissues by immunofluorescence. Behavioural assessments were conducted in diabetic A/J and C57BL/6 mice to determine mechanical sensitivity, and GLO1 abundance was determined by western blot.ResultsGLO1immunoreactivity was found throughout the nervous system, but selectively in small, unmyelinated peptidergic dorsal root ganglia (DRG) neurons that are involved in pain transmission. GLO1 protein was present at various levels in DRG from different inbred mice strains. Diabetic A/J and C57BL/6 mice, two mouse strains with different levels of GLO1, displayed dramatically different behavioural responses to mechanical stimuli. Diabetic C57BL/6 mice also had a reduced abundance of GLO1 following diabetes induction.Conclusions/interpretationThese findings reveal that the abundance of GLO1 varies between different murine strains and within different sensory neuron populations. These differences could lead to different responses of sensory neurons to the toxic effects of hyperglycaemia and reactive dicarbonyls associated with diabetes.

Protection from diabetes-induced peripheral sensory neuropathy — A role for elevated glyoxalase I?

Diabetic neuropathy is a common complication of diabetes mellitus with over half of all patients developing neuropathy symptoms due to sensory nerve damage. Diabetes-induced hyperglycemia leads to the accelerated production of advanced glycation end products (AGEs) that alter proteins, thereby leading to neuronal dysfunction. The glyoxalase enzyme system, specifically glyoxalase I (GLO1), is responsible for detoxifying precursors of AGEs, such as methylglyoxal and other reactive dicarbonyls. The purpose of our studies was to determine if expression differences of GLO1 may play a role in the development of diabetic sensory neuropathy. BALB/cJ mice naturally express low levels of GLO1, while BALB/cByJ express approximately 10-fold higher levels on a similar genetic background due to increased copy numbers of GLO1. Five weeks following STZ injection, diabetic BALB/cJ mice developed a 68% increase in mechanical thresholds, characteristic of insensate neuropathy or loss of mechanical sensitivity. This behavior change correlated with a 38% reduction in intraepidermal nerve fiber density (IENFD). Diabetic BALB/cJ mice also had reduced expression of mitochondrial oxidative phosphorylation proteins in Complexes I and V by 83% and 47%, respectively. Conversely, diabetic BALB/cByJ mice did not develop signs of neuropathy, changes in IENFD, or alterations in mitochondrial protein expression. Reduced expression of GLO1 paired with diabetes-induced hyperglycemia may lead to neuronal mitochondrial damage and symptoms of diabetic neuropathy. Therefore, AGEs, the glyoxalase system, and mitochondrial dysfunction may play a role in the development and modulation of diabetic peripheral neuropathy.

Screw Placement Accuracy and Outcomes Following O-Arm-Navigated Atlantoaxial Fusion: A Feasibility Study

Study Design Case series of seven patients. Objective C2 stabilization can be challenging due to the complex anatomy of the upper cervical vertebrae. We describe seven cases of C1–C2 fusion using intraoperative navigation to aid in the screw placement at the atlantoaxial (C1–C2) junction. Methods Between 2011 and 2014, seven patients underwent posterior atlantoaxial fusion using intraoperative frameless stereotactic O-arm Surgical Imaging and StealthStation Surgical Navigation System (Medtronic, Inc., Minneapolis, Minnesota, United States). Outcome measures included screw accuracy, neurologic status, radiation dosing, and surgical complications. Results Four patients had fusion at C1–C2 only, and in the remaining three, fixation extended down to C3 due to anatomical considerations for screw placement recognized on intraoperative imaging. Out of 30 screws placed, all demonstrated minimal divergence from desired placement in either C1 lateral mass, C2 pedicle, or C3 lateral mass. No neurovascular compromise was seen following the use of intraoperative guided screw placement. The average radiation dosing due to intraoperative imaging was 39.0 mGy. All patients were followed for a minimum of 12 months. All patients went on to solid fusion. Conclusion C1–C2 fusion using computed tomography-guided navigation is a safe and effective way to treat atlantoaxial instability. Intraoperative neuronavigation allows for high accuracy of screw placement, limits complications by sparing injury to the critical structures in the upper cervical spine, and can help surgeons make intraoperative decisions regarding complex pathology.

Intrinsic Activity of C57BL/6 Substrains Associates with High-Fat Diet-Induced Mechanical Sensitivity in Mice

Pain is significantly impacted by the increasing epidemic of obesity and the metabolic syndrome. Our understanding of how these features impact pain is only beginning to be developed. Herein, we have investigated how small genetic differences among C57BL/6 mice from 2 different commercial vendors lead to important differences in the development of high-fat diet-induced mechanical sensitivity. Two substrains of C57BL/6 mice from Jackson Laboratories (Bar Harbor, ME; C57BL/6J and C57BL/6NIH), as well as C57BL/6 from Charles Rivers Laboratories (Wilmington, MA; C57BL/6CR) were placed on high-fat diets and analyzed for changes in metabolic features influenced by high-fat diet and obesity, as well as measures of pain-related behaviors. All 3 substrains responded to the high-fat diet; however, C57BL/6CR mice had the highest weights, fat mass, and impaired glucose tolerance of the 3 substrains. In addition, the C57BL/6CR mice were the only strain to develop significant mechanical sensitivity over the course of 8 weeks. Importantly, the C57BL/6J mice were protected from mechanical sensitivity, which may be based on increased physical activity compared with the other 2 substrains. These findings suggest that activity may play a powerful role in protecting metabolic changes associated with a high-fat diet and that these may also be protective in pain-associated changes as a result of a high-fat diet. These findings also emphasize the importance of selection and transparency in choosing C57BL/6 substrains in pain-related research. PERSPECTIVE: Obesity and the metabolic syndrome play an important role in pain. This study identifies key differences in the response to a high-fat diet among substrains of C57BL/6 mice and differences in intrinsic physical activity that may influence pain sensitivity. The results emphasize physical activity as a powerful modulator of obesity-related pain sensitivity.

A ketogenic diet reduces metabolic syndrome-induced allodynia and promotes peripheral nerve growth in mice

ABSTRACT Current experiments investigated whether a ketogenic diet impacts neuropathy associated with obesity and prediabetes. Mice challenged with a ketogenic diet were compared to mice fed a high‐fat diet or a high‐fat diet plus exercise. Additionally, an intervention switching to a ketogenic diet following 8weeks of high‐fat diet was performed to compare how a control diet, exercise, or a ketogenic diet affects metabolic syndrome‐induced neural complications. When challenged with a ketogenic diet, mice had reduced bodyweight and fat mass compared to high‐fat‐fed mice, and were similar to exercised, high‐fat‐fed mice. High‐fat‐fed, exercised and ketogenic‐fed mice had mildly elevated blood glucose; conversely, ketogenic diet‐fed mice were unique in having reduced serum insulin levels. Ketogenic diet‐fed mice never developed mechanical allodynia contrary to mice fed a high‐fat diet. Ketogenic diet fed mice also had increased epidermal axon density compared all other groups. When a ketogenic diet was used as an intervention, a ketogenic diet was unable to reverse high‐fat fed‐induced metabolic changes but was able to significantly reverse a high‐fat diet‐induced mechanical allodynia. As an intervention, a ketogenic diet also increased epidermal axon density. In vitro studies revealed increased neurite outgrowth in sensory neurons from mice fed a ketogenic diet and in neurons from normal diet‐fed mice given ketone bodies in the culture medium. These results suggest a ketogenic diet can prevent certain complications of prediabetes and provides significant benefits to peripheral axons and sensory dysfunction. HIGHLIGHTSA ketogenic diet can reverse high‐fat‐induced mechanical allodynia.Peripheral nerves are sensitive to metabolic change that may not mirror systemic metabolism.A ketogenic diet and ketones stimulate sensory axon growth in vitro and in vivo.

Safety, Efficacy, and Cost-Analysis of Percutaneous Endoscopic Gastrostomy and Ventriculoperitoneal Shunt Placement in a Simultaneous Surgery

BACKGROUND Limited historical data suggest that concomitant placement of both a ventriculoperitoneal (VP) shunt and percutaneous endoscopic gastrostomy (PEG) tube is associated with an increased risk of complications, including VP shunt infections. Here we compare the outcomes and cost difference between 2 groups of patients, one in which a VP shunt and PEG tube were placed in the same operation and the other in which separate operations were performed. METHODS A total of 10 patients underwent simultaneous placement of a VP shunt and PEG tube. This group was compared with a group of 18 patients that underwent separate placements. Hospital billing charges were used to compare the total cost of the procedures in the 2 groups. RESULTS Eight of the 10 patients presented with aneurysmal subarachnoid hemorrhage. The average length of stay was 25 ± 2 days for the simultaneous procedure group and 43 ± 7 days for the separate procedures group. The average duration of follow-up was 12 ± 3 months after simultaneous placement. No patient in the simultaneous surgery group had signs of infection or shunt malfunction at last follow-up. The overall complication rate was significantly lower in the simultaneous surgery group. A cost analysis demonstrated significant cost savings by completing both procedures in the same surgical procedure. CONCLUSIONS Simultaneous placement of a PEG tube and VP shunt is safe, efficacious, and cost-effective. Thus, in patients requiring both a VP shunt and PEG tube, placement of both devices in a single surgical procedure should be considered.

Herniated gyrus rectus causing idiopathic compression of the optic chiasm

Anomalies in the frontal lobe can interfere with visual function by compression of the optic chiasm and nerve. The gyrus rectus is located at the anterior cranial fossa floor superior to the intracranial optic nerves and chiasm. Compression of these structures by the gyrus rectus is often caused by neoplastic or dysplastic growth in the area. We report a rare case of a herniated gyrus rectus impinged on the optic chiasm and nerve without a clear pathological cause for the herniation.

Rats bred for low and high running capacity display alterations in peripheral tissues and nerves relevant to neuropathy and pain

Diet and activity are recognized as modulators of nervous system disease, including pain. Studies of exercise consistently reveal a benefit on pain. This study focused on female rats to understand differences related to metabolic status and peripheral nerve function in females.