[Ultrastructural and clinical findings of mitochondrial encephalomyopathy:report of 27 cases].

Objective: To investigate the ultrastructural features of muscle in patients with mitochondrial encephalomyopathy for its diagnosis and differential diagnosis. Methods: The clinical data of 27 mitochondrial encephalomyopathy patients who underwent left or right biceps brachii muscle biopsy at Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University from July 2006 to August 2017 were analyzed retrospectively. The muscle biopsy specimens were examined underlight microscope and transmission electron microscope. Results: There were 27 patients (17 males, 10 females) with an age range of 12 to 62 years (mean 29 years). The age of onset ranged from 3 to 38 years. The course of disease ranged from 1 month to 24 years. Twenty-two cases presented with lactic acidosis and stroke-like episodes (MELAS) syndrome, four with myoclonic epilepsy with ragged red fibers (MERRF) syndrome, and one with chronic progressive paralysis of extraocular muscle (CPEO) syndrome. Skeletal muscle biopsy showed abundant ragged red fibers and strongly SDH-reactive vessel. Genetic studies showed 17 of 22 cases of MELAS syndrome had A3243G mutation, and the other 5 cases had no abnormality. A8344G mutation was found in 3 of 4 cases of MERRF syndrome. No single or multiple mtDNA mutations were found in the single case of CPEO. Transmission electron microscopy of all 27 cases showed diffuse proliferation of mitochondria between the myofibrils and beneath the sarcolemma, with increased spacing between muscle cells. Seven cases showed numerous glycogen and four showed subsarcolemmal lipid droplets, 13 cases showed unusual mitochondrial morphology, including mitochondrial electron-dense substances and paracrystal line inclusions ("parking lot" change)in eight cases. Conclusions: Transmission electron microscopy shows significant differences in ultrastructural pathological changes among different patients with mitochondrial encephalomyopathy. Some patients with mild clinical symptoms have increased mitochondrial number, increased metabolism of glycogen and lipid droplets, while others with severe clinical symptoms have abnormal mitochondrial morphology. Typical crystalloid inclusions are found in mitochondria, which are of great value in the diagnosis of this disease.

Sorafenib inhibits activation of human peripheral blood T cells by targeting LCK phosphorylation.

Sorafenib, a novel drug for metastatic renal cancer, has broad-spectrum activity against multiple tyrosine kinases, including Raf-1, vascular endothelial growth factor receptor and platelet-derived growth factor receptor. However, little is known about its effects on the immune system. In this report, we examine the effects of sorafenib on the proliferation and activation of human peripheral blood T cells, as well as its effects on T-cell-mediated immune response in mice. At concentrations similar to those used in patients, sorafenib inhibited the proliferation of primary human T cells in vitro. At more than 10 microM, sorafenib caused an irrecoverable inhibition of proliferation, even after drug withdrawal. In addition, sorafenib induced T-cell apoptosis at concentrations higher than 10 muM. sorafenib also caused G(0)/G(1) phase arrest, inhibition of CD25 and CD69 expression, interleukin-2 production and LCK phosphorylation in the T cells; all of these effects exhibited dose and time dependence. When tested against contact dermatitis in mice, sorafenib significantly reduced the ear swelling induced by picryl chloride. These findings suggest that sorafenib may cause the loss of T-cell immune response by inducing apoptosis and targeting LCK. This could potentially lead to immunosuppression in patients with cancer.

Neurotoxic effect of high dose of L-(+)-2-amino-3-phosphonopropionic acid in rats after intracaudatal injection.

AIM: To investigate neurotoxic effect of L-(+)-2-amino-3-phosphonopropionic acid (L-AP3), a partial agonist/antagonist of metabotropic glutamate receptors (mGluRs), and explore the underlying mechanisms. METHODS: Consciousness and behavior of rats were evaluated after injection of L-AP3, D-(+)-2-amino-3-phosphonopropionic acid (D-AP3, an isomer of L-AP3) or L-(+)-2-amino-4-phosphonobutyric acid (L-AP4, an agonist of mGluRs) into right caudatum. Brain water, Na+, K+, and Ca2+ contents as well as the permeability of blood brain barrier (BBB) were determined 6 h after treatment of these chemicals. Histological changes at the same time point were also observed. RESULTS: Rats treated with L-AP3 600 nmol but not 60 nmol became somnolentia. Inject ion of L-AP3 600 nmol induced a great increase of brain water, Na+, and Ca2+ contents, and a decrease of brain K+ content (P < 0.01). Meanwhile, the permeability of BBB was also increased (P < 0.01). Electron microscopic study revealed remarkable swelling of astrocytes and degenerative changes of neurons in chemical-treated caudatum. The neurotoxic effect of L-AP3 was not mimicked by D-AP3 or L-AP4 (P < 0.05). DL-2-Amino-5-phosphonovaleric acid, an antagonist of N-methyl-D-aspartate (NMDA) receptors, attenuated the changes induced by L-AP3 (P < 0.05), whereas (+/-)-alpha-methyl-(4-carboxyphenyl)glycine, a non-subtype specific antagonist of mGluRs, failed to block the effect of L-AP3. CONCLUSION: Intracaudatal injection of L-AP3 induced neurotoxic effect characterized by vasogenic brain edema, neuronal degeneration, and high brain Ca2+ content. Neurotoxic effect of L-AP3 was stereoselective and might be mediated by phospholipase C activation and partially involvement of NMDA receptors.