Patients with sporadic FTLD exhibit similar increases in lysosomal proteins and storage material as patients with FTD due to GRN mutations.

Loss of function progranulin (GRN) mutations are a major autosomal dominant cause of frontotemporal dementia (FTD). Patients with FTD due to GRN mutations (FTD-GRN) develop frontotemporal lobar degeneration with TDP-43 pathology type A (FTLD-TDP type A) and exhibit elevated levels of lysosomal proteins and storage material in frontal cortex, perhaps indicating lysosomal dysfunction as a mechanism of disease. To investigate whether patients with sporadic FTLD exhibit similar signs of lysosomal dysfunction, we compared lysosomal protein levels, transcript levels, and storage material in patients with FTD-GRN or sporadic FTLD-TDP type A. We analyzed samples from frontal cortex, a degenerated brain region, and occipital cortex, a relatively spared brain region. In frontal cortex, patients with sporadic FTLD-TDP type A exhibited similar increases in lysosomal protein levels, transcript levels, and storage material as patients with FTD-GRN. In occipital cortex of both patient groups, most lysosomal measures did not differ from controls. Frontal cortex from a transgenic mouse model of TDP-opathy had similar increases in cathepsin D and lysosomal storage material, showing that TDP-opathy and neurodegeneration can drive these changes independently of progranulin. To investigate these changes in additional FTLD subtypes, we analyzed frontal cortical samples from patients with sporadic FTLD-TDP type C or Pick's disease, an FTLD-tau subtype. All sporadic FTLD groups had similar increases in cathepsin D activity, lysosomal membrane proteins, and storage material as FTD-GRN patients. However, patients with FTLD-TDP type C or Pick's disease did not have similar increases in lysosomal transcripts as patients with FTD-GRN or sporadic FTLD-TDP type A. Based on these data, accumulation of lysosomal proteins and storage material may be a common aspect of end-stage FTLD. However, the unique changes in gene expression in patients with FTD-GRN or sporadic FTLD-TDP type A may indicate distinct underlying lysosomal changes among FTLD subtypes.

Loop arteriovenous graft of the chest wall as a viable option for dialysis.

The search for a reliable, complication-free vascular access is crucial among dialysis patients. The creation of a long-term access site for hemodialysis is dependent on several factors that mandate forming a life-plan for dialysis access, with upper extremity vascular access being the preferred route. However, complications including poor maturation, venous anastomosis lesions, and thrombosis are all associated with poor survival of these accesses. As a result, numerous patients within the dialysis population have exhausted access sites in the upper and lower extremities, requiring the search for other access options including chest wall arteriovenous graft (AVG). However, limited data is available about the outcomes of these chest wall grafts. Here, we describe two 62-year-old female dialysis patients who exhausted other dialysis access sites and subsequently underwent arteriovenous loop graft of the chest wall that connected the axillary artery with the ipsilateral axillary vein. These AVGs remained functional during the follow up period. This report highlights the viability of chest wall AVG access in the unique subset of hemodialysis patients who exhausted all other access sites.

Chest wall arteriovenous graft for dialysis: A case report.

Upper extremity access sites are the preferred access sites for hemodialysis. With the improvement of the survival in dialysis population, most patients outlive the dialysis access lifespan. As such, some patients exhaust the vascular access options of the upper extremities, which necessitates the search for new access sites. While lower extremity grafts and hemodialysis reliable outflow devices are potential alternatives, these access sites are plagued with recurrent lesions at the venous anastomosis and subsequent thrombosis leading to poor access survival. Within this framework, the axillary-based dialysis access was developed to address these challenges. In this report, we describe a 70-year-old woman who exhausted her upper extremity access sites and eventually underwent a chest wall arteriovenous graft (AVG) that connected the right axillary artery to the right axillary vein. This chest wall AVG remained functional without any intervention for more than 3 years. In conclusion, chest wall AVG access can be a viable option for hemodialysis patients who have exhausted the access sites of the upper extremities, while potentially minimizing complications seen in other methods of vascular access.

Delivering progranulin to neuronal lysosomes protects against excitotoxicity.

Loss-of-function mutations in progranulin (GRN) are a major genetic cause of frontotemporal dementia (FTD), possibly due to loss of progranulin's neurotrophic and anti-inflammatory effects. Progranulin promotes neuronal growth and protects against excitotoxicity and other forms of injury. It is unclear if these neurotrophic effects are mediated through cellular signaling or through promotion of lysosomal function. Progranulin is a secreted proprotein that may activate neurotrophic signaling through cell-surface receptors. However, progranulin is efficiently trafficked to lysosomes and is necessary for maintaining lysosomal function. To determine which of these mechanisms mediates progranulin's protection against excitotoxicity, we generated lentiviral vectors expressing progranulin (PGRN) or lysosome-targeted progranulin (L-PGRN). L-PGRN was generated by fusing the LAMP-1 transmembrane and cytosolic domains to the C-terminus of progranulin. L-PGRN exhibited no detectable secretion, but was delivered to lysosomes and processed into granulins. PGRN and L-PGRN protected against NMDA excitotoxicity in rat primary cortical neurons, but L-PGRN had more consistent protective effects than PGRN. L-PGRN's protective effects were likely mediated through the autophagy-lysosomal pathway. In control neurons, an excitotoxic dose of NMDA stimulated autophagy, and inhibiting autophagy with 3-methyladenine reduced excitotoxic cell death. L-PGRN blunted the autophagic response to NMDA and occluded the protective effect of 3-methyladenine. This was not due to a general impairment of autophagy, as L-PGRN increased basal autophagy and did not alter autophagy after nutrient starvation. These data show that progranulin's protection against excitotoxicity does not require extracellular progranulin, but is mediated through lysosomes, providing a mechanistic link between progranulin's lysosomal and neurotrophic effects.

Independent and Combined Effects of All-Out Sprint and Low-Intensity Continuous Exercise on Plasma Oxidative Stress Biomarkers in Trained Judokas.

The purpose of this study was to assess oxidative stress biomarkers prior to and following different forms of exercise. Ten elite male judokas (age: 18.1 ± 1.7 years, athletic experience: 6 years with a training frequency of 6 Judo-sessions/week) performed three cycle ergometry sessions comprising a 30 s Wingate test (MAX), 30 min at 60% maximal-aerobic-power-output (LOW) or these two exercise protocols combined (COMBINED) in a repeated-measures design. Venous blood-samples were collected before, and 0(P0), 5(P5), 10(P10) and 20(P20) min after each exercise protocol and assessed for malondialdehyde concentration ([MDA]), glutathione peroxidase (GPX), superoxide dismutase (SOD) and glutathione reductase (GR) content, and total-antioxidant-status (TAS). Plasma [MDA] was found to be increased above baseline at P0 and P5 in the MAX, LOW and COMBINED conditions (p < 0.05), but was greater at P10 and P20 in the LOW condition compared to MAX and COMBINED conditions (p < 0.05). Blood GPX and SOD content increased above baseline at P0 in MAX and COMBINED and at P5 in LOW (p < 0.05), with GR content being similar between groups at P0 and P5 (p > 0.05). 20 min post-exercise, GPX, SOD, GR content and TAS were lower in the MAX compared to the LOW and COMBINED conditions (p < 0.05). In conclusion, the findings from this study reveal that redox-related biomarkers exhibited divergent response dynamics following different forms of exercise, which might have implications for understanding the mechanisms of exercise-induced skeletal muscle fatigue and adaptive remodeling.

Combined ultrafiltration-electrodeionization technique for production of high purity water.

Electrodeionization (EDI) is the most common method to produce high purity water used for boiler feed water, microelectronic, and pharmaceutical industries. Commonly, EDI is combined with reverse osmosis (RO) to meet the requirement of EDI feed water, with hardness less than 1 ppm. However, RO requires a relatively high operating pressure and ultrafiltration (UF) as pretreatment which results in high energy consumption and high complexity in piping and instrumentation. In this work, UF was used as the sole pretreatment of EDI to produce high purity water. Tap water with conductivity 248 µS/cm was fed to UF-EDI system. The UF-EDI system showed good performance with ion removal more than 99.4% and produced water with low conductivity from 0.2 to 1 µS/cm and total organic compounds less than 0.3 ppm. Generally, product conductivity decreased with the increase of current density of EDI and the decrease of feed velocity and UF pressure. The energy consumption for UF-EDI system in this work was 0.89-2.36 kWh/m3. These results proved that UF-EDI system meets the standards of high purity water for pharmaceutical and boiler feed water with lower investment and energy consumption than RO-EDI system.

Life threatening angioedema in a patient on ACE inhibitor (ACEI) confined to the upper airway.

INTRODUCTION: ACE inhibitors accounts for 8% of all cases of angioneurotic edema and the overall incidence is 0.1 to 0.7% of patients on ACE inhibitors. It is a leading cause (20-40%) of emergency room visits in the US with angioedema. We report a case of angioedema caused by ACE inhibitors confined to the upper airway after four years on treatment with Lisinopril which persisted for three weeks and required endotracheal intubation and subsequent tracheostomy due to delayed resolution. This case is one of the rare cases presented as upper airway edema which persisted for a long time. PRESENTATION: A 60-year-old Sudanese male patient with osteoarthritis in both knees underwent bilateral total knee replacement under single-shot epidural anesthesia. He had significant past medical history of type II diabetes, bipolar affective disorder and hypertension managed with Lisinopril for the past four years. Postoperatively after 10 hours the patient desaturated and developed airway obstruction requiring intubation. Laryngoscopy revealed an edematous tongue and upper airway and vocal cords were not visualized. In view of this clinical picture a provisional diagnosis of angioedema secondary to Lisinopril was made and it was discontinued. CT scan of the neck and soft tissues revealed severe airway edema with snugly fitting endotracheal tube with no peritubal air. A repeat CT neck on the tenth postoperative day showed no signs of resolution and an elective tracheostomy was performed on the eleventh postoperative day. C1 inhibitor protein and C4 levels were assayed to exclude hereditary angioedema and were found to be within normal range. Decannulation of tracheostomy was done after airway edema resolved on the twenty-fourth postoperative day as confirmed by CT scan. Subsequently he was transferred to the ward and discharged home. CONCLUSION: ACEI induced angioedema is a well-recognized condition. Early diagnosis based on a high index of suspicion, immediate withdrawal of the offending drug followed by supportive therapy is the cornerstone of management.