Mitochondrial dysfunction following spinal cord injury (SCI) may be critical for the development of secondary pathophysiology and neuronal cell death. Previous studies have demonstrated a loss of mitochondrial bioenergetics at 24 h following SCI. To begin to understand the evolution and study the contribution of mitochondrial dysfunction in pathophysiology of SCI, we investigated mitochondrial bioenergetics in the mid-thoracic region at 6, 12, and 24 h following contusion SCI. It is widely accepted that increased free radical generation plays a critical role in neuronal damage after SCI. Hence, to ascertain the role of free radicals in SCI-induced mitochondrial dysfunction, markers for oxidative damage, including nitrotyrosine (3-NT), lipid peroxidation byproduct (4-hydroxynonenal [HNE]), and protein oxidation (protein carbonyls) were quantified in the same samples of isolated mitochondria during the 24-h time course. The results demonstrate that a significant decline in mitochondrial function begins to occur 12 h post-injury and persists for a least 24 h following SCI. Furthermore, there was a progressive increase in mitochondrial oxidative damage that preceded the loss of mitochondrial bioenergetics, suggesting that free radical damage may be a major mitochondrial secondary injury process. Based on the present results, the temporal profile of mitochondrial dysfunction indicates that interventions targeting mitochondrial oxidative damage and dysfunction may serve as a beneficial pharmacological treatment for acute SCI.

Objective To assess the possible relationship between erectile dysfunction (ED) and lower urinary tract symptoms (LUTS) in men, and whether treatment of their ED with sildenafil influences their LUTS. Patients and methods In all, 112 men with ED attending the andrology outpatient clinic were offered oral sildenafil and reviewed 1 and 3 months after treatment. They completed the International Index of Erectile Function and the International Prostate Symptom Score (IPSS) questionnaires at baseline and each review. Scores were designated to indicate the visit number and differences between the visits calculated. Results A third of the men had an initial IPSS of > 7; there was no relationship between baseline urinary and sexual function scores. After treatment with sildenafil, the urinary scores at 3 months correlated strongly with the sexual function scores. There was a significant inverse relationship between the baseline IPSS and sexual function scores after treatment. The overall trend in the IPSS was towards improvement after treatment with sildenafil. Conclusions In men with ED there is no relationship between sexual function scores and urinary symptom scores before treating ED. Treatment with sildenafil appears to improve urinary symptom scores. A lower IPSS at baseline appears to predict a better response to ED therapy with sildenafil.

Lobeline is currently being evaluated in clinical trials as a methamphetamine abuse treatment. Lobeline interacts with nicotinic receptor subtypes, dopamine transporters (DATs), and vesicular monoamine transporters (VMAT2s). Methamphetamine inhibits VMAT2 and promotes dopamine (DA) release from synaptic vesicles, resulting ultimately in increased extracellular DA. The present study generated structure-activity relationships by defunctionalizing the lobeline molecule and determining effects on [ H]dihydrotetrabenazine binding, inhibition of [3 H]DA uptake into striatal synaptic vesicles and synaptosomes, the mechanism of VMAT2 inhibition, and inhibition of methamphetamine-evoked DA release. Compared with lobeline, the analogs exhibited greater potency inhibiting DA transporter (DAT) function. Saturated analogs, lobelane and nor-lobelane, exhibited high potency (K i ϭ 45 nM) inhibiting vesicular [ 3 H]DA uptake, and lobelane competitively inhibited VMAT2 function. Lobeline and lobelane exhibited 67-and 35-fold greater potency, respectively, in inhibiting VMAT2 function compared to DAT function. Lobelane potently decreased (IC 50 ϭ 0.65 M; I max ϭ 73%) methamphetamine-evoked DA overflow, and with a greater maximal effect compared with lobeline (IC 50 ϭ 0.42 M, I max ϭ 56.1%). These results provide support for VMAT2 as a target for inhibition of methamphetamine effects. Both transisomers and demethylated analogs of lobelane had reduced or unaltered potency inhibiting VMAT2 function and lower maximal inhibition of methamphetamine-evoked DA release compared with lobelane. Thus, defunctionalization, cis-stereochemistry of the side chains, and presence of the piperidino N-methyl are structural features that afford greatest inhibition of methamphetamine-evoked DA release and enhancement of selectivity for VMAT2. The current results reveal that lobelane, a selective VMAT2 inhibitor, inhibits methamphetamine-evoked DA release and is a promising lead for the development of a pharmacotherapeutic for methamphetamine abuse.

We report measurements of the Raman spectrum of supercooled water in the hindered translational region (20–400 cm−1) down to a temperature of −20 °C. The spectra are analyzed after correcting for the effects of Boltzmann factor and harmonic oscillator coupling, i.e., in the reduced R(ν̄) representation of Shuker and Gammon. Spectral deconvolution shows that in addition to the previously observed 0-0-0 bending mode (≂60 cm−1) and the 0-0 stretching mode (≂190 cm−1), there is a weak feature at 260 cm−1 whose intensity increases by almost an order of magnitude as temperature decreases from 40 to −20 °C. A plausible interpretation of the 260 cm−1 band is that it is analogous to the 310 cm−1 band seen in ice I and probably arises because of differing electrostatic interactions in different configurations of coupled H bonds of neighboring H2O molecules. The 0-0 stretching band at 190 cm−1 changes in many respects as temperature decreases from 40 to −20 °C: (i) Its peak intensity increases almost four times; (ii) integrated intensity increases three times; (iii) bandwidth decreases about 30%; and (iv) peak maximum increases linearly from 176 cm−1 at 40 °C to 202 cm−1 at −20 °C. In contrast, the 0-0-0 bending at 60 cm−1 is quite insensitive to changes in temperature. The increase in the intensity of the 190 and 260 cm−1 bands is consistent with the idea that four-coordinated H2O molecules contribute directly to these spectral features and the fraction of such molecules increases with decreasing temperature. This effect on intensity is further enhanced by the strong coupling of the motion of a few four-coordinated water molecules, as seen in the small-angle x-ray scattering data of Bosio et al. We also observe a limiting value to the width of the 190 cm−1 band at temperatures below the melting point, suggesting that the local structure of supercooled water is approaching some limiting structure.

Objective To determine the prevalence of previously undiagnosed diabetes mellitus (DM) in men presenting with erectile dysfunction (ED), using fasting blood glucose (FBG) compared with urinary dipstick testing for glycosuria. Patients and methods A prospective prevalence study was carried out in an andrology outpatient clinic of a urology department in a district general hospital serving a mixed urban and rural population. In all, 129 consecutive men presenting with ED underwent FBG and urinary dipstick testing to detect undiagnosed DM in those presenting with ED. Results The prevalence of known DM was 17% and the that of undiagnosed DM 4.7% of the 107 remaining men; an abnormal fasting glucose level was found in a further 12%. The sensitivity of urine dipstick test for diagnosing DM was 20%. Conclusions The prevalence of undiagnosed DM is higher in men with ED than in the general population. ED is a marker symptom for DM and DM should be actively sought in men presenting with ED. Urinary dipstick testing for glycosuria, if used as a screening test, will miss the diagnosis in 80% of these men. FBG testing should be undertaken to reliably diagnose DM in men presenting with ED.

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