NAD+ Precursors Reverse Experimental Diabetic Neuropathy in Mice.

Abnormal NAD+ signaling has been implicated in axonal degeneration in diabetic peripheral neuropathy (DPN). We hypothesized that supplementing NAD+ precursors could alleviate DPN symptoms through increasing the NAD+ levels and activating the sirtuin-1 (SIRT1) protein. To test this, we exposed cultured Dorsal Root Ganglion neurons (DRGs) to Nicotinamide Riboside (NR) or Nicotinamide Mononucleotide (NMN), which increased the levels of NAD+, the SIRT1 protein, and the deacetylation activity that is associated with increased neurite growth. A SIRT1 inhibitor blocked the neurite growth induced via NR or NMN. We then induced neuropathy in C57BL6 mice with streptozotocin (STZ) or a high fat diet (HFD) and administered NR or NMN for two months. Both the STZ and HFD mice developed neuropathy, which was reversed through the NR or NMN administration: sensory function improved, nerve conduction velocities normalized, and intraepidermal nerve fibers were restored. The NAD+ levels and SIRT1 activity were reduced in the DRGs from diabetic mice but were preserved with the NR or NMN treatment. We also tested the effect of NR or NMN administration in mice that overexpress the SIRT1 protein in neurons (nSIRT1 OE) and found no additional benefit from the addition of the drug. These findings suggest that supplementing with NAD+ precursors or activating SIRT1 may be a promising treatment for DPN.

NAD+ Precursors Repair Mitochondrial Function in Diabetes and Prevent Experimental Diabetic Neuropathy.

Axon degeneration in diabetic peripheral neuropathy (DPN) is associated with impaired NAD+ metabolism. We tested whether the administration of NAD+ precursors, nicotinamide mononucleotide (NMN) or nicotinamide riboside (NR), prevents DPN in models of Type 1 and Type 2 diabetes. NMN was administered to streptozotocin (STZ)-induced diabetic rats and STZ-induced diabetic mice by intraperitoneal injection at 50 or 100 mg/kg on alternate days for 2 months. mice The were fed with a high fat diet (HFD) for 2 months with or without added NR at 150 or 300 mg/kg for 2 months. The administration of NMN to STZ-induced diabetic rats or mice or dietary addition of NR to HFD-fed mice improved sensory function, normalized sciatic and tail nerve conduction velocities, and prevented loss of intraepidermal nerve fibers in skin samples from the hind-paw. In adult dorsal root ganglion (DRG) neurons isolated from HFD-fed mice, there was a decrease in NAD+ levels and mitochondrial maximum reserve capacity. These impairments were normalized in isolated DRG neurons from NR-treated mice. The results indicate that the correction of NAD+ depletion in DRG may be sufficient to prevent DPN but does not significantly affect glucose tolerance, insulin levels, or insulin resistance.

Comparison of expiratory pressures generated by four different EPAP devices in a laboratory bench setting.

OBJECTIVE/BACKGROUND: Expiratory positive airway pressure (EPAP) has been a treatment option for patients with obstructive sleep apnea (OSA). ULTepap is a new FDA-cleared EPAP device that seals the nares with a nasal pillow interface. Comparisons of expiratory pressures generated by ULTepap and other EPAP devices like Provent, Bongo Rx, and Theravent are not available. We aimed to compare the backpressures created by these devices in an in vitro laboratory bench setting. METHODS: A test rig was designed and fabricated to test the expiratory pressures generated by ULTepap, Provent, Bongo Rx, and Theravent. Airflow was generated by a linear actuator-driven piston in a syringe, and a range of flow rates was provided by varying the voltage input to the actuator. The resulting expiratory and inspiratory pressures were measured and resistances were calculated. RESULTS: The backpressures generated by ULTepap and Provent were comparable at all flow rates. For flow rates at 99/142/212 ml/s, the expiratory pressures were 3.5/7.5/13.8 cmH2O for ULTepap and 4.5/8.5/14.5 cmH2O for Provent. Bongo Rx and Theravent devices produced substantially lower backpressures compared to ULTepap devices (0.8/1.8/3.5 cmH2O for Bongo Rx and 0.9/2.2/5.3 cmH2O for Theravent at flow rates of 99/142/212 ml/s). All four devices presented very low inspiratory flow resistance, with all generating 0.5 cmH2O or less at all flow rates. CONCLUSION: Not all FDA-cleared EPAP devices produce similar expiratory pressure profiles. ULTepap generated backpressures closest to that of Provent. Clinical trials comparing the efficacy, tolerance, and adherence of these EPAP devices in patients with OSA are warranted.

mGluR2/3 activation of the SIRT1 axis preserves mitochondrial function in diabetic neuropathy.

Objectives: There is a critical need to develop effective treatments for diabetic neuropathy. This study determined if a selective mGluR2/3 receptor agonist prevented or treated experimental diabetic peripheral neuropathy (DPN) through glutamate recycling and improved mitochondrial function. Methods: Adult male streptozotocin treated Sprague-Dawley rats with features of type 1 diabetes mellitus (T1DM) or Low Capacity Running (LCR) rats with insulin resistance or glucose intolerance were treated with 3 or 10 mg/kg/day LY379268. Neuropathy end points included mechanical allodynia, nerve conduction velocities (NCV), and intraepidermal nerve fiber density (IENFD). Markers of oxidative stress, antioxidant response, glutamate recycling pathways, and mitochondrial oxidative phosphorylation (OXPHOS) associated proteins were measured in dorsal root ganglia (DRG). Results: In diabetic rats, NCV and IENFD were decreased. Diabetic rats treated with an mGluR2/3 agonist did not develop neuropathy despite remaining diabetic. Diabetic DRG showed increased levels of oxidized proteins, decreased levels of glutathione, decreased levels of mitochondrial DNA (mtDNA) and OXPHOS proteins. In addition, there was a 20-fold increase in levels of glial fibrillary acidic protein (GFAP) and the levels of glutamine synthetase and glutamate transporter proteins were decreased. When treated with a specific mGluR2/3 agonist, levels of glutathione, GFAP and oxidized proteins were normalized and levels of superoxide dismutase 2 (SOD2), SIRT1, PGC-1α, TFAM, glutamate transporter proteins, and glutamine synthetase were increased in DRG neurons. Interpretation: Activation of glutamate recycling pathways protects diabetic DRG and this is associated with activation of the SIRT1-PGC-1α-TFAM axis and preservation of mitochondrial OXPHOS function.

Serum uric acid level in acute stroke patients.

BACKGROUND: The role of uric acid as a risk factor for vascular disease and acute stroke is controversial and there is little information about it. In this study, we determined serum uric acid levels in patients with acute stroke and assessed its relationship with cerebrovascular risk factors. METHODS: In this cross sectional study, we assessed patients with acute stroke who were admitted in Firoozgar Hospital from September 2010 to March 2011. Clinical records of patients and their serum uric acid level was investigated. Finally, collected data were analyzed using SPSS software Ver.16. RESULTS: Fifty five patients with acute stroke were evaluated who 25 of these patients (45.5%) were female and 30 of them (54.5%) were male. The mean age of patients was 67±14 years. Mean serum uric acid levels in the patients studied 5.94±1.70 mg/dl, and about half of the patients (47.3%) were hyperuricemic. There was a significant negative correlation between age of patients and their serum uric acid level (p=0.04, R =-0.27). Uric acid level was significantly higher in men than women (p=0.03). Hyperuricemia was associated with increased amounts of triglycerides and Low-density lipoprotein (LDL) cholesterol (p=0.03, p=0.02). In patients with acute stroke, there was no significant association between serum uric acid level and diabetes mellitus, hypertension, history of ischemic heart disease, smoking, prescription rTPA, and type of stroke. CONCLUSION: Due to the high prevalence of hyperuricemia in patients with acute stroke, and its accompanying increase in triglyceride and LDL cholesterol levels, it can be considered as a risk factor for acute stroke.

Does bleeding during percutaneous nephrolithotomy necessitate keeping the nephrostomy tube? A randomized controlled clinical trial.

PURPOSE: To compare outcomes in two groups of patients with kept and discarded nephrostomy tube after percutaneous nephrolithotomy (PCNL) complicated with bleeding. MATERIALS AND METHODS: Two hundred patients who had undergone PCNL complicated with hemorrhage were recruited in this study. Patients were randomly allocated to two groups: group A, who underwent tubeless PCNL and tract port was packed for 3 to 4 minutes after removing Amplatz sheath, and group B, for whom a 24-F nephrostomy tube was left in place at the end of the procedure. Patients were followed up for 3 months to check if bleeding occurred. RESULTS: The mean operation time was 68 ± 4.3 minutes in group A and 74 ± 5.6 minutes in group B (P = .098). The mean stone size was similar in groups A and B (36.26 ± 5.3 mm versus 35.35 ± 5.85 mm; P = .613). The mean hemoglobin drop was 3.65 ± 1.20 g/dL in group A and 3.13 ± 1.06 g/dL in group B. There was no significant difference between the mean of stone free rate in groups A and B (92.58% ± 5.97 versus 89.60% ± 8.3; P = .210). Patients in group A experienced a significantly less duration of hospitalization than group B (2.42 ± 0.84 days versus 3.70 ± 0.80 days; P < .001). CONCLUSION: In the absence of clear indication, nephrostomy tube insertion after PCNL does not seem to be beneficial, and its removal does not pose patients at any additional risk.

Objective measurement of nasal airway dimensions and resistance using acoustic rhinometry and rhinomanometry in habitual snorers compared with non-snorers.

Snorers represent a heterogeneous group that requires adequate assessment before recommending surgical treatment. Most studies of the pathophysiology of snoring and obstructive sleep apnea have emphasized anatomical abnormalities in the oropharyngeal and hypopharyngeal airways. It is still unclear if nasal airway restriction plays an important role in sleep-disordered breathing and there is no general consensus if treatment of nasal pathology should be included in the management of patients with snoring or sleep apnea. The aim of this study was to compare nasal dimensions and airflow resistance of habitual snorers with non-snoring individuals by means of acoustic rhinometry and rhinomanometry. Sixty individuals were enrolled in this analytical cross-sectional study. They were divided in two groups: group A (case) consisted of 30 patients with a main complaint of chronic snoring referred to ear, nose, and throat (ENT) clinic of Hazrat-e-Rasoul University Hospital, Tehran, Iran. Group B (control) consisted of 30 individuals without any complaint of snoring. The subjects were assessed objectively with acoustic rhinometry and rhinomanometry. Nasal dimensions and airflow resistance were recorded for all individuals. The most common site of minimum cross-sectional area (MCA) was at the left concha-notch in both snoring and non-snoring individuals. Significant reduction of cross-sectional area of both isthmus and concha notches was seen in habitual snorers (P < 0.05). The mean total airflow resistances in both pressures of 75 and 150 Pa was higher in habitual snorers. Whereas, these differences were not statistically significant (P > 0.05). The results of our study illustrate that acoustic rhinometry, rhinomanometry may be helpful methods for quantitative assessments of nasal airway respiratory function, and configuration in snorers; especially to evaluate site of MCA, decreased nasal cross-sectional area and increased nasal airflow resistance in habitual snorers which may lead to OSA.

The effect of interferon-beta1a on relapses and progression of disability in patients with clinically isolated syndromes (CIS) suggestive of multiple sclerosis.

OBJECTIVES: In 85% of young adults with multiple sclerosis (MS), onset is a subacute clinically isolated syndrome (CIS) of the optic nerves, brain stem or spinal cord. The advent of disease-modifying treatments for MS has increased attention on early stages of the disease. Therefore, the aim of this study was to evaluate the effect of interferon on relapses and progression of disability in patients with a CIS. PATIENTS AND METHODS: This randomized, clinical trial was conducted in 25 patients who presented with a CIS indicative of MS. They were evaluated in two groups: 11 patients who were receiving interferon-beta(1a) (Rebif, Serono) subcutaneous injections three times a week (group A), and 14 patients who were not receiving disease-modifying treatment (group B). The progression of disability was determined using the Kurtzke Expanded Disability Status Scale (EDSS) and the numbers of new relapses were recorded during 21 months of follow-up. RESULTS: The mean numbers of new relapses and changes in EDSS at the end of study period were 0.68 (standard deviation [S.D.]=0.80) and -1.09 (S.D.=0.49), and 1.79 (S.D.=1.05) and -0.64 (S.D.=0.49) in groups A and B, respectively. Statistical analysis showed that disease-modifying treatment with interferon-beta(1a) may reduce relapses (P=0.007) and prevent progressive disability (P=0.034). CONCLUSION: Interferon-beta(1a) significantly delayed progression to disability and incidence of new relapses.