Use of fMRI to predict psychiatric adverse effects of interferon treatment for Hepatitis C – preliminary report

Interferon alfa2 (IFN-α2) is a parenterally administered cytokine used to treat patients with Hepatitis C and B, and malignancy. Interferon (INF) has a relatively high rate of central nervous system (CNS) adverse effects, including agitation, depression, fatigue, cognitive dysfunction, suicidal thought and drug craving. Using functional magnetic resonance imaging (fMRI) we studied patients with Hepatitis C virus (HCV) infection who were not more than mildly clinically depressed at baseline for their CNS reaction to IFN-α2. During fMRI, patients underwent visual stimulation with pictures designed to induce feelings of depression. In the two patients who became clinically depressed or markedly anxious while on treatment with interferon, but not in patients who did not experience these effects, there was a significant activation in specific areas of the brain known to be involved with depression, along with an increase above baseline in the Beck Depression Scale for the patient who developed INF-induced depression. The activation pattern differed from that previously observed for endogenous depression, indicating that INF-induced depression may differ in its underlying neuropathology. Functional magnetic resonance imaging can be an important tool in understanding and monitoring for (INF and other) medication-induced CNS effects, and response to treatment.     

In vitro cytotoxicity and phototoxicity of N-piperazinyl quinolone derivatives with a 2-thienyl group.

We examined the cytotoxic potential of nine N-[2-substituted-2-(2-thienyl)ethyl] piperazinyl quinolone derivatives on human oral epithelial mouth carcinoma (KB) and human squamous carcinoma (A431) cell lines. Phototoxic properties of these compounds were also evaluated by mouse 3T3 fibroblast under ultraviolet-A (UVA) irradiation. The percent of cell viability was evaluated by MTT assay. Compound 6 having a 4-[2-(phenylmethoxyimino)-2-(2-thienyl)ethyl] group attached to N4 position of piperazine ring of enoxacin showed the highest cytotoxicity potential on both A431 and KB cell lines (IC50 of 3.11+/-0.52 and 4.91+/-1.94 microg/ml, respectively). While some of the other tested compounds exhibited clear phototoxic potential in 3T3 cell line, compound 6 showed only a minor potential of phototoxicity. These findings suggest the high potential of 4-[2-(phenylmethoxyimino)-2-(2-thienyl)ethyl] derivative of enoxacin as a cytotoxic compound with low potency of phototoxic reactions. The mentioned chemical was identified to be of special interest for further characterization.     

Coronary stenting for coronary artery narrowing in a heart transplant recipient

Transplant atherosclerotic coronary disease remains the leading cause of death in heart transplant recipients. We report the first case of coronary stent implantation in a heart graft for epicardial focal stenosis. Due to the lower rate of restenosis after stenting in the native coronary artery, we suggest that coronary stenting be considered an acceptable, first intention therapeutic option instead of angioplasty alone whenever possible.     

Changes in the lipid composition and activities of isocitrate dehydrogenase and isocitrate lyase during encystation of Acanthamoeba culbertsoni strain A-1

The contents of total lipids, total sterols, total and individual phospholipids: lysophosphatidyl choline, lysophosphatidyl ethanolamine, phosphatidyl choline, phosphatidyl ethanolamine and alkali-stable phospholipids I and II, were significantly lower in mature cysts of Acanthamoeba culbertsoni strain A-1 than in trophozoites. The major constituent sterols of trophozoites, viz. ergosterol, 7-dehydrostigmasterol and 7,22,25-tridehydrostigmasterol which resolved as a single spot on thin-layer chromatography, disappeared in the cysts. When trophozoites grown in the presence of [14C]acetate were transferred to encystation medium, there was a steady decrease in the radioactivity in the lipids and acid-soluble fraction (glycogen) of the encysting cells while the radioactivity increased in the akali-insoluble fraction (cellulose). The activity of isocitrate lyase in the encysting cells steadily increased up to 24 h of encystation, followed by a slight decrease during 24-32 h, but the activity of isocitrate dehydrogenase steadily decreased up to 32 h of encystation, beyond which time no enzyme activity was detected. Inhibitors of isocitrate lyase, glycolate and maleate at 8.5 to 34 mM concentration inhibited encystation by 18-67%.     

Proliferation of Nb2 lymphoma cells in vitro in response to interleukin-7.

An attempt was made to investigate the proliferative effect of interleukin-7 (IL-7) on a rat Nb2 T-cell lymphoma line. It was demonstrated that both human and mouse IL-7 stimulated these cells to proliferate in a dose dependent fashion in culture medium containing 10% horse serum. The maximum activities of mIL-7 and hIL-7 were observed at 100 and 1000 units/ml with their half-maximal response of 10 and 50 units/ml, respectively. In a totally serum-free culture condition, mIL-7 produced a similar cellular proliferation, whereas hIL-7 was much less effective. The effectiveness of IL-7 on Nb2 cells was completely abolished by antibody to IL-7, but not by antibody to IL-2. Therefore, Nb2 cells may serve as a simple, convenient and sensitive assay for monitoring the biological activity of IL-7 in vitro. In addition, these cells are also useful for studying the lymphopoiesis of T-cell lineage regulated by IL-7.     

Protective effects of calcium-magnesium soft gels in morphine tolerant and dependent mice.

The present study was aimed at evaluating the acute effects of Calcium-Magnesium soft gels (CalMag) in morphine tolerant and dependent mice. Mice were rendered tolerant and dependent on morphine by subcutaneous injection of morphine over a fixed time period. Withdrawal signs were precipitated by injecting naloxone 2 h after the final injection of morphine. The tail-pinch assay was used to investigate the effects of various compounds on the development and reversal of morphine tolerance. Acute injection of CalMag (containing 50 mg/kg calcium and 25 mg/kg magnesium) significantly reduced the number of jumps, stands and fast breathing in morphine dependent mice. Co-administration of calcium (50 mg/kg) and magnesium (25 mg/kg) was also effective in preventing the development of morphine tolerance and dependence. Administration of calcium (up to 50 mg/kg) alone did not significantly block the development of tolerance and dependence. The mean latency to pain was significantly increased in animals pretreated with CalMag (containing 50 mg/kg calcium and 25 mg/kg magnesium). The mixture of calcium and magnesium at specific concentrations seem to be critical for preventing the development of morphine tolerance and dependence.     

Striatal delivery of CERE-120, an AAV2 vector encoding human neurturin, enhances activity of the dopaminergic nigrostriatal system in aged monkeys.

Neurturin (NTN) is a potent survival factor for midbrain dopaminergic neurons. CERE-120, an adeno-associated virus type 2 (AAV2) vector encoding human NTN (AAV2-NTN), is currently being developed as a potential therapy for Parkinson's disease. This study examined the bioactivity and safety/tolerability of AAV2-NTN in the aged monkey model of nigrostriatal dopamine insufficiency. Aged rhesus monkeys received unilateral injections of AAV2-NTN into the caudate and putamen, with each animal therefore serving as its own control. Robust expression of NTN within the nigrostriatal system was observed 8 months postadministration. (18)F-fluorodopa imaging using positron emission tomography revealed statistically significant increases in (18)F-fluorodopa uptake in the injected striatum compared with the uninjected side at 4 and 8 months. In addition, at 8 months postadministration, a significant enhancement in tyrosine hydroxylase immunoreactive fibers and an increase in the number of tyrosine hydroxylase immunoreactive cells was observed in the AAV2-NTN injected striatum compared with the uninjected side. Robust activation of phosphorylated extracellular signal-regulated kinase immunoreactivity in the substantia nigra was also observed. Histopathological analyses revealed no adverse effects of AAV2-NTN in the brain. Collectively, these results are consistent with the neurotrophic effects of NTN on the dopaminergic nigrostriatal system and extend the growing body of evidence supporting the concept that AAV2-NTN may have therapeutic benefit for Parkinson's disease.