Skeletal muscle secretome in Duchenne muscular dystrophy: a pivotal anti-inflammatory role of adiponectin.

BACKGROUND: Persistent inflammation exacerbates the progression of Duchenne muscular dystrophy (DMD). The hormone, adiponectin (ApN), which is decreased in the metabolic syndrome, exhibits anti-inflammatory properties on skeletal muscle and alleviates the dystrophic phenotype of mdx mice. Here, we investigate whether ApN retains its anti-inflammatory action in myotubes obtained from DMD patients. We unravel the underlying mechanisms by studying the secretome and the early events of ApN. METHODS: Primary cultures of myotubes from DMD and control patients were treated or not by ApN after an inflammatory challenge. Myokines secreted in medium were identified by cytokine antibody-arrays and ELISAs. The early events of ApN signaling were assessed by abrogating selected genes. RESULTS: ApN retained its anti-inflammatory properties in both dystrophic and control myotubes. Profiling of secretory products revealed that ApN downregulated the secretion of two pro-inflammatory factors (TNFα and IL-17A), one soluble receptor (sTNFRII), and one chemokine (CCL28) in DMD myotubes, while upregulating IL-6 that exerts some anti-inflammatory effects. These changes were explained by pretranslational mechanisms. Earlier events of the ApN cascade involved AdipoR1, the main receptor for muscle, and the AMPK-SIRT1-PGC-1α axis leading, besides alteration of the myokine profile, to the upregulation of utrophin A (a dystrophin analog). CONCLUSION: ApN retains its beneficial properties in dystrophic muscles by activating the AdipoR1-AMPK-SIRT1-PGC-1α pathway, thereby inducing a shift in the secretion of downstream myokines toward a less inflammatory profile while upregulating utrophin. ApN, the early events of the cascade and downstream myokines may be therapeutic targets for the management of DMD.

Formulation and hypoglycemic activity of pioglitazone-cyclodextrin inclusion complexes.

Pioglitazone is a thiazolidinedione derivative used for the treatment of type 2 diabetes. The drug's poor aqueous solubility and slow dissolution rate are the main causes of its limited therapeutic action in some cases. The aim of the present study is to formulate a more soluble product of pioglitazone at physiological pH. The potential interaction of pioglitazone with cyclodextrins and water-soluble polymers was investigated to enhance the drug's bioavailability and improve its efficacy. The interaction of pioglitazone with ß-cyclodextrin, HP-ß-cyclodextrin, and dimethyl-ß- cyclodextrin was evaluated by spectrophotometric and solubility methods. Both methods revealed the formation of 1:1 inclusion complexes. The phase solubility diagram of pioglitazone-cyclodextrin systems with or without water-soluble polymers was classified as the AL type. The solubilization strength of cyclodextrins and the apparent stability constant of systems increased upon addition of water-soluble polymers. Inclusion complexes of pioglitazone in cyclodextrins with or without watersoluble polymers were prepared by the kneading method. Binary systems were characterized and confirmed by IR spectroscopy, X-ray diffractometry, and thermogravimetric analysis. The dissolution rates of pioglitazone, pioglitazone-cyclodextrin physical mixtures, pioglitazone-cyclodextrin complexes, and ternary systems containing watersoluble polymers were determined using a USP dissolution tester; results revealed enhanced dissolution properties of cyclodextrin complexes compared to drug and physical mixtures, and all of the ternary systems displayed higher dissolution efficiency than corresponding binary systems. The permeation of pioglitazone and pioglitazonecyclodextrin complexes through a cellulose membrane with and without water-soluble polymers (PVP and HPMC) present increased and the release pattern follows the kinetics of a Higuchi equation. Assessment of the hypoglycemic effect of the free drug and its cyclodextrin complexes in normal rats via measurement of blood glucose levels (BGL) after administration of a single oral dose revealed that the hypoglycemic effect of pioglitazone-cyclodextrin complexes was greater than that of the free drug and that a pioglitazone-DM ß-cyclodextrin complex had the greatest effect. In conclusion, the physicochemical and biological properties of pioglitazone improved as a result of complexation with cyclodextrins, and the improvement of physicochemical properties was more prominent after water-soluble polymers were associated with pioglitazone-cyclodextrin systems.

Luteal function in hypophysectomized rhesus monkeys.

Experiments were designed to study the maintenance of corpus luteum function in the rhesus monkey. The experiments used a transfrontal microsurgical approach for total hypophysectomy. This proved to be a reliable and safe procedure for the complete removal of the pituitary gland. Luteal function was not affected by either complete hypophysectomy or sham surgery performed 1 day after ovulation. The concentrations of PRL in serum became undetectable during the luteal phase in hypophysectomized animals. Serum LH levels in the first postoperative cycle were detectable, but were just above the lower limits of sensitivity of the bioassay. Ovulation was induced with human menopausal gonadotropin and hCG or human menopausal gonadotropin and human LH at least 6 months after hypophysectomy, at which time endogenous LH was undetectable. These animals displayed normal luteal function, for approximately 10 days suggesting that the corpus luteum, once formed, can function independently of circulating LH and in the absence of the pituitary gland.

Extracranial surgical procedures in the management of vertebrobasilar insufficiency.

Vertebrobasilar insufficiency is an important syndrome in the spectrum of cerebrovascular disease. Its clinical importance and the frequency of its clinical manifestations are often underestimated. Our experience with a large population of patients having extensive cerebrovascular disease has led us to recognize two classes of vertebrobasilar insufficiency--simple and complex--and, also, to recognize that vertebrobasilar insufficiency is often associated with disease in multiple extracranial vessels. Until recently, direct approaches to the vertebral artery have been underutilized for these patients. In fact, there has been a tendency either to relegate patients with vertebrobasilar disease to medical follow-up or to surgical procedures upon the carotid system. We believe that the resurgence of neurosurgical interest in the vertebrobasilar system is most appropriate. Furthermore, the active interest that neurosurgeons are now taking in developing procedures for managing extracranial vertebral artery problems is in the best interest of patients with cerebrovascular disease. We believe that careful neurosurgical evaluation of patients with simple and complex vertebrobasilar insufficiency will lead to appropriate selection of candidates for vascular reconstruction of the vertebral system. Finally, we believe that vertebral artery to common carotid artery transposition, and its variations, is a procedure that has an important role in the management of cerebrovascular disease.

Cranial epidermoid tumor associated with subacute extradural hematoma. Case report.

The authors present a case of cranial epidermoid tumor that caused a subacute epidural hematoma after minor trauma. The radiological, operative, and pathological findings are described, and indications for elective excision of cranial epidermoid tumor are discussed.

Melatonin concentration in human blood and cerebrospinal fluid: relationship to stress.

In 35 daytime paired blood and cerebrospinal fluid (CSF) samples from 15 patients, melatonin levels in CSF were undetectable or detectable but not higher than blood levels. During pneumoencephalography in 6 patients, no significant elevation of blood melatonin levels was observed, whereas cortisol concentration increased.