Tenofovir disoproxil fumarate induces peripheral neuropathy and alters inflammation and mitochondrial biogenesis in the brains of mice.

Mounting evidence suggests that antiretroviral therapy (ART) drugs may contribute to the prevalence of HIV-associated neurological dysfunction. The HIV envelope glycoprotein (gp120) is neurotoxic and has been linked to alterations in mitochondrial function and increased inflammatory gene expression, which are common neuropathological findings in HIV+ cases on ART with neurological disorders. Tenofovir disproxil fumarate (TDF) has been shown to affect neurogenesis in brains of mice and mitochondria in neurons. In this study, we hypothesized that TDF contributes to neurotoxicity by modulating mitochondrial biogenesis and inflammatory pathways. TDF administered to wild-type (wt) and GFAP-gp120 transgenic (tg) mice caused peripheral neuropathy, as indicated by nerve conduction slowing and thermal hyperalgesia. Conversely TDF protected gp120-tg mice from cognitive dysfunction. In the brains of wt and gp120-tg mice, TDF decreased expression of mitochondrial transcription factor A (TFAM). However, double immunolabelling revealed that TFAM was reduced in neurons and increased in astroglia in the hippocampi of TDF-treated wt and gp120-tg mice. TDF also increased expression of GFAP and decreased expression of IBA1 in the wt and gp120-tg mice. TDF increased tumor necrosis factor (TNF) α in wt mice. However, TDF reduced interleukin (IL) 1β and TNFα mRNA in gp120-tg mouse brains. Primary human astroglia were exposed to increasing doses of TDF for 24 hours and then analyzed for mitochondrial alterations and inflammatory gene expression. In astroglia, TDF caused a dose-dependent increase in oxygen consumption rate, extracellular acidification rate and spare respiratory capacity, changes consistent with increased metabolism. TDF also reduced IL-1β-mediated increases in IL-1β and TNFα mRNA. These data demonstrate that TDF causes peripheral neuropathy in mice and alterations in inflammatory signaling and mitochondrial activity in the brain

Preliminary study of kaonic deuterium X-rays by the SIDDHARTA experiment at DAFNE

The study of the KbarN system at very low energies plays a key role for the understanding of the strong interaction between hadrons in the strangeness sector. At the DAFNE electron-positron collider of Laboratori Nazionali di Frascati we studied kaonic atoms with Z=1 and Z=2, taking advantage of the low-energy charged kaons from Phi-mesons decaying nearly at rest. The SIDDHARTA experiment used X-ray spectroscopy of the kaonic atoms to determine the transition yields and the strong interaction induced shift and width of the lowest experimentally accessible level (1s for H and D and 2p for He). Shift and width are connected to the real and imaginary part of the scattering length. To disentangle the isospin dependent scattering lengths of the antikaon-nucleon interaction, measurements of Kp and of Kd are needed. We report here on an exploratory deuterium measurement, from which a limit for the yield of the K-series transitions was derived: Y(K_tot)<0.0143 and Y(K_alpha)<0.0039 (CL 90%). Also, the upcoming SIDDHARTA-2 kaonic deuterium experiment is introduced.Comment: Accepted by Nuclear Physics

First measurement of kaonic helium-3 X-rays

The first observation of the kaonic 3He 3d - 2p transition was made using slow K- mesons stopped in a gaseous 3He target. The kaonic atom X-rays were detected with large-area silicon drift detectors using the timing information of the K+K- pairs of phi-meson decays produced by the DAFNE e+e- collider. The strong interaction shift of the kaonic 3He 2p state was determined to be -2+-2 (stat)+-4 (syst) eV.Comment: Accepted for publication in Phys. Lett.

Which Drug to Discontinue 3 Months After Combination Therapy of Tadalafil plus Tamsulosin for Men with Lower Urinary Tract Symptom and Erectile Dysfunction? Results of a Prospective Observational Trial

Background: Safety and efficacy of tamsulosin and tadalafil for men with benign prostatic enlargement (BPE) and/or erectile dysfunction (ED) are defined. However, there are only a few pilot studies on combination therapy with these drugs for men with lower urinary tract symptom (LUTS)/BPE and ED. Moreover, preliminary reports are limited to 12 wk, without any information about subsequent therapies. Objective: To evaluate the impact of discontinuation of tamsulosin versus tadalafil 12 wk after combination therapy. Design, setting, and participants: Fifty consecutive patients with moderate-to-severe LUTS (International Prostate Symptom Score [IPSS] &gt; 7) and mild-to-severe ED (International Index of Erectile Function-5 [IIEF-5] &lt; 22) were treated with combination therapy (tamsulosin 0.4 mg/d plus tadalafil 5 mg/d) for 12 wk. After 12 wk, 25 patients discontinued tamsulosin (Group TAD), while 25 patients discontinued tadalafil (Group TAM). Outcome measurements and statistical analysis: Efficacy variables were IPSS (total, voiding, storage) and IIEF-5. Paired samples t test and analysis of variance were used. Results and limitations: Groups TAD and TAM presented similar features (age, BMI, metabolic profile) including symptoms scores at baseline. Similar and significant improvements in IPSS (total, voiding, and storage) and IIEF-5 were recorded in both groups after 12 wk of combination therapy (all p &lt; 0.001). Total IPSS was similar between the two groups at the end of the trial. However, we found between-group significant differences from baseline to 24 wk and from 12 to 24 wk in storage-IPSS (Group TAD: –3.32 vs Group TAM: –1.24, p = 0.002; Group TAD: +0.24 vs Group TAM: +1.20, p = 0.040, respectively) and in IIEF-5 (Group TAD: +4.64 vs Group TAM: +0.16, p &lt; 0.001; Group TAD: –1.64 vs Group TAM: –4.40, p = 0.003). No significant treatment-related adverse event was recorded in both groups. Conclusions: After 12 wk of combination therapy, monotherapy with tadalafil for further 12 wk allows to preserve the improvement of storage IPSS and IIEF-5, in addition to total IPSS. Patient summary: In this report we evaluated the discontinuation of tamsulosin or tadalafil after 12 wk of combination therapy. We found that tadalafil monotherapy, for a further 12 wk, aids in retaining the improvement of storage symptoms and erectile function