Congenital nystagmus: randomized, controlled, double-masked trial of memantine/gabapentin

OBJECTIVE: Nystagmus consists of involuntary to and fro movements of the eyes. Although studies have shown that memantine and gabapentin can reduce acquired nystagmus, no drug treatment has been systematically investigated in congenital nystagmus. METHODS: We performed a randomized, double-masked, placebo-controlled study investigating the effects of memantine and gabapentin on congenital nystagmus over a period of 56 days. The primary outcome measure was logarithmic minimum angle of resolution (logMAR) visual acuity; the secondary outcome measures were nystagmus intensity and foveation, subjective questionnaires about visual function (VF-14) and social function. Analyses were by intention to treat. RESULTS: Forty-eight patients were included in the study. One patient in the placebo group dropped out. Patients were randomized into either a memantine group (n=16), gabapentin group (n=16), or placebo group (n=15). Mean visual acuity improvements showed a significant effect between treatment groups (F=6.2; p=0.004, analysis of variance) with improvement in both memantine and gabapentin groups. Participants with afferent visual defects showed poorer improvements in visual acuity to medication than those with apparently normal visual systems. However, eye movement recordings showed that both nystagmus forms improved in nystagmus intensity (F=7.7; p=0.001) and foveation (F=8.7; p=0.0007). Participants subjectively reported an improvement in vision after memantine and gabapentin treatment more often than in the placebo group (p=0.03). However, there were no significant differences between the treatment groups with visual function (VF-14) or social function questionnaires because all groups reported improvements. INTERPRETATION: Our findings show that pharmacological agents such as memantine and gabapentin can improve visual acuity, reduce nystagmus intensity, and improve foveation in congenital nystagmus.     

Progressive GAA expansions in dorsal root ganglia of Friedreich's ataxia patients

OBJECTIVE: Friedreich's ataxia patients are homozygous for expanded alleles of a GAA triplet-repeat sequence in the FXN gene. Patients develop progressive ataxia due to primary neurodegeneration involving the dorsal root ganglia (DRGs). The selective neurodegeneration is due to the sensitivity of DRGs to frataxin deficiency; however, the progressive nature of the disease remains unexplained. Our objective was to test whether the expanded GAA triplet-repeat sequence undergoes further expansion in DRGs as a possible mechanism underlying the progressive pathology seen in patients. METHODS: Small-pool polymerase chain reaction analysis, a sensitive technique that allows the measurement of repeat length in individual FXN genes, was used to analyze somatic instability of the expanded GAA triplet-repeat sequence in multiple tissues obtained from six autopsies of Friedreich's ataxia patients. RESULTS: DRGs showed a significantly greater frequency of large expansions (p < 0.001) and a relative paucity of large contractions compared with all other tissues. There was a significant age-dependent increase in the frequency of large expansions in DRGs, which ranged from 0.5% at 17 years to 13.9% at 47 years (r = 0.78; p = 0.028). INTERPRETATION: Progressive pathology involving the DRGs is likely due to age-dependent accumulation of large expansions of the GAA triplet-repeat sequence. Thus, somatic instability of the expanded GAA triplet-repeat sequence may contribute directly to disease pathogenesis and progression. Progressive repeat expansion in specific tissues is a common theme in the pathogenesis of triplet-repeat diseases.     

The effect of respiratory muscle endurance training in patients with myasthenia gravis

We tested the effect of a home-based respiratory muscle endurance training in patients with mild to moderate generalized myasthenia gravis (MG) on Besinger score, lung function and respiratory muscle endurance. Ten patients performed respiratory muscle endurance training in form of normocapnic hyperpnea training at 50-60% of their maximal voluntary ventilation over 4-6 weeks. MG score, lung function and respiratory endurance were assessed before and after training period. The training significantly increased respiratory endurance from 8.4+/-0.9 min to 17.1+/-1.3 min (p<0.001) and total ventilatory volume from 555+/-87 L to 1081+/-127 L (p=0.004). About 25% of this gain was lost after 3-5 months of detraining. The remaining 75% gain might result from improved neuromuscular coordination rather than muscular training. MG score and lung function, however, did not change. Patients assessed the training effects on physical fitness and respiration as positive. In conclusion, respiratory muscle endurance training can be useful for MG patients as it is enhancing respiratory muscle endurance.     

Genotoxicity of glyphosate assessed by the comet assay and cytogenetic tests

It was evaluated the genotoxicity of glyphosate which up to now has heterogeneous results. The comet assay was performed in Hep-2 cells. The level of DNA damage in the control group (5.42±1.83 arbitrary units) for tail moment (TM) measurements has shown a significant increase (p<0.01) with glyphosate at a range concentration from 3.00 to 7.50mM. In the chromosome aberrations (CA) test in human lymphocytes the herbicide (0.20-6.00mM) showed no significant effects in comparison with the control group. In vivo, the micronucleus test (MNT) was evaluated in mice at three doses rendering statistical significant increases at 400mg/kg (13.0±3.08 micronucleated erythrocytes/1000 cells, p<0.01). In the present study glyphosate was genotoxic in the comet assay in Hep-2 cells and in the MNT test at 400mg/kg in mice. Thiobarbituric acid reactive substances (TBARs) levels, superoxide dismutase (SOD) and catalase (CAT) activities were quantified in their organs. The results showed an increase in these enzyme activities.     

Phosphodiesterase 5A inhibition induces Na+/H+ exchanger blockade and protection against myocardial infarction

Acute phosphodiesterase 5A inhibition by sildenafil or EMD360527/5 promoted profound inhibition of the cardiac Na(+)/H(+) exchanger (NHE-1), detected by the almost null intracellular pH recovery from an acute acid load (ammonium prepulse) in isolated papillary muscles from Wistar rats. Inhibition of phosphoglycerate kinase-1 (KT5823) restored normal NHE-1 activity, suggesting a causal link between phosphoglycerate kinase-1 increase and NHE-1 inhibition. We then tested whether the beneficial effects of NHE-1 inhibitors against the deleterious postmyocardial infarction (MI) remodeling can be detected after sildenafil-mediated NHE-1 inhibition. MI was induced by left anterior descending coronary artery ligation in Wistar rats, which were randomized to placebo or sildenafil (100 mg kg(-1) day(-1)) for 6 weeks. Sildenafil significantly increased left ventricular phosphoglycerate kinase-1 activity in the post-MI group without affecting its expression. MI increased heart weight/body weight ratio, left ventricular myocyte cross-sectional area, interstitial fibrosis, and brain natriuretic peptide and NHE-1 expression. Sildenafil blunted these effects. Neither a significant change in infarct size nor a change in arterial or left ventricular systolic pressure was detected after sildenafil. MI decreased fractional shortening and the ratio of the maximum rate of rise of LVP divided by the pressure at the moment such maximum occurs, effects that were prevented by sildenafil. Intracellular pH recovery after an acid load was faster in papillary muscles from post-MI hearts (versus sham), whereas sildenafil significantly inhibited NHE-1 activity in both post-MI and sildenafil-treated sham groups. We conclude that increased phosphoglycerate kinase-1 activity after acute phosphodiesterase 5A inhibition blunts NHE-1 activity and protects the heart against post-MI remodeling and dysfunction.     

A-803467, a potent and selective Nav1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat

Activation of tetrodotoxin-resistant sodium channels contributes to action potential electrogenesis in neurons. Antisense oligonucleotide studies directed against Na(v)1.8 have shown that this channel contributes to experimental inflammatory and neuropathic pain. We report here the discovery of A-803467, a sodium channel blocker that potently blocks tetrodotoxin-resistant currents (IC(50) = 140 nM) and the generation of spontaneous and electrically evoked action potentials in vitro in rat dorsal root ganglion neurons. In recombinant cell lines, A-803467 potently blocked human Na(v)1.8 (IC(50) = 8 nM) and was >100-fold selective vs. human Na(v)1.2, Na(v)1.3, Na(v)1.5, and Na(v)1.7 (IC(50) values >or=1 microM). A-803467 (20 mg/kg, i.v.) blocked mechanically evoked firing of wide dynamic range neurons in the rat spinal dorsal horn. A-803467 also dose-dependently reduced mechanical allodynia in a variety of rat pain models including: spinal nerve ligation (ED(50) = 47 mg/kg, i.p.), sciatic nerve injury (ED(50) = 85 mg/kg, i.p.), capsaicin-induced secondary mechanical allodynia (ED(50) approximately 100 mg/kg, i.p.), and thermal hyperalgesia after intraplantar complete Freund's adjuvant injection (ED(50) = 41 mg/kg, i.p.). A-803467 was inactive against formalin-induced nociception and acute thermal and postoperative pain. These data demonstrate that acute and selective pharmacological blockade of Na(v)1.8 sodium channels in vivo produces significant antinociception in animal models of neuropathic and inflammatory pain.     

TNF-alpha suppresses the expression of clock genes by interfering with E-box-mediated transcription

Production of TNF-alpha and IL-1 in infectious and autoimmune diseases is associated with fever, fatigue, and sleep disturbances, which are collectively referred to as sickness behavior syndrome. In mice TNF-alpha and IL-1 increase nonrapid eye movement sleep. Because clock genes regulate the circadian rhythm and thereby locomotor activity and may alter sleep architecture we assessed the influence of TNF-alpha on the circadian timing system. TNF-alpha is shown here to suppress the expression of the PAR bZip clock-controlled genes Dbp, Tef, and Hlf and of the period genes Per1, Per2, and Per3 in fibroblasts in vitro and in vivo in the liver of mice infused with the cytokine. The effect of TNF-alpha on clock genes is shared by IL-1beta, but not by IFN-alpha, and IL-6. Furthermore, TNF-alpha interferes with the expression of Dbp in the suprachiasmatic nucleus and causes prolonged rest periods in the dark when mice show spontaneous locomotor activity. Using clock reporter genes TNF-alpha is found here to inhibit CLOCK-BMAL1-induced activation of E-box regulatory elements-dependent clock gene promoters. We suggest that the increase of TNF-alpha and IL-1beta, as seen in infectious and autoimmune diseases, impairs clock gene functions and causes fatigue.     

The interplay between microRNAs and the neurotrophin receptor tropomyosin-related kinase C controls proliferation of human neuroblastoma cells

MicroRNAs (miRNAs) are tiny noncoding RNAs whose function as modulators of gene expression is crucial for the proper control of cell growth and differentiation. Although the profile of miRNA expression has been defined for many different cellular systems, the elucidation of the regulatory networks in which they are involved is only just emerging. In this work, we identify a crucial role for three neuronal miRNAs (9, 125a, and 125b) in controlling human neuroblastoma cell proliferation. We show that these molecules act in an additive manner by repressing a common target, the truncated isoform of the neurotrophin receptor tropomyosin-related kinase C, and we demonstrate that the down-regulation of this isoform is critical for regulating neuroblastoma cell growth. Consistently with their function, these miRNAs were found to be down-modulated in primary neuroblastoma tumors.