Carrier detection in Duchenne and Becker muscular dystrophy Argentine families

In order to offer carrier detection, genetic counseling, and prenatal diagnosis to families with Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) in our country, segregation analysis of highly polymorphic short tandem repeats (STR) (dC-dA)n: (dG-dT)n loci was utilized. The risks to females of 15 DMD/BMD families (9 familial and 6 sporadic) were evaluated on STR, pedigree and serum creatine kinase (SCK) data. From the 36 females at risk of being carriers (not including 8 obligate carriers), results of STR analysis were compatible with carrier status in 7 and not compatible in 20. In 9 females, no information regarding carriership was derived from the STR analysis. Prenatal diagnosis is now possible on the carrier females. Previously identified deletions in the central part of the gene were confirmed by STR analysis in 3 families. Five new alleles were identified in Argentine individuals; allele frequencies differed from those of North American people. Results derived from this study are useful for carrier detection and genetic counseling in DMD/BMD. One case of probable mosaicism in an unaffected father was detected on a pedigree basis in a family with DMD patients.     

Evaluation of urinary and general symptoms and correlation with other clinical parameters in interstitial cystitis patients

AIMS: Interstitial cystitis (IC) has been deemed by some authors as a local manifestation of a systemic disease, particularly one of the autoimmune disorders. In order to provide an answer to the question whether IC patients do or do not indiscriminately report high scores for various somatic symptoms, we compared University of Wisconsin scores (U-W scores), including both urinary and non-urinary symptoms, for 30 IC female patients and 30 female controls. MATERIALS AND METHODS: A total of 30 female patients with IC and 30 healthy female controls were recruited for the study. All patients had to meet the symptom criteria established by the National Institute for Diabetes and Digestive and Kidney Diseases. Each patient completed a University of Wisconsin symptom scale, after translation (WICS). RESULTS: In the IC group median score was zero for all, but two of the reference symptoms: abdominal cramps and dizziness. All urinary symptoms were significantly increased in IC patients compared to controls. In the control group, the median value of urinary symptoms was zero. The duration of the disease was then related to IC symptoms in the patient group. Among the bladder-related symptoms, a good correlation was found for several specific symptoms and urinary symptoms as a whole. An association could be found between a positive potassium sensitivity test (PST) and burning bladder sensation, as well as pelvic discomfort. CONCLUSIONS: IC patients had significantly higher scores for the seven urinary symptoms compared to controls. The duration of disease was found to be correlated with the group of seven urinary symptoms.     

Bilateral ureteral compression by multiple abdominal desmoid tumors in Gardner syndrome: case report and literature review

A 28-year-old man with Gardner syndrome was admitted to our Department because of multiple abdominal masses. Abdominal computed tomography revealed severe hydronephrosis of both kidneys due to ureteral compression against the pelvic bones exerted by multiple solid abdominal masses. The patient developed oligoanuria. Right percutaneous nephrostomy tube placement was followed by restoration of diuresis and progressive recovery of renal function of the left side. The patient then underwent median laparotomy and removal of five large desmoid tumors originating from the abdominal wall. Bilateral ureteral obstruction due to abdominal desmoid tumors can be a rare urologic complication of Gardner syndrome.     

Spinal epidural hematoma following coronary thrombolysis. A case report

A case of cervicothoracic spontaneous spinal epidural hematoma (SSEH) following coronary thrombolysis with r-TPA and intravenous heparin is reported. The clinical picture is discussed, as well as the importance of rapid neuroradiological diagnosis (with spinal MRI being the method of choice) and surgical treatment. Anyway, in these patients, thorough cardiac function evaluation and rapid correction of any clotting disorder is necessary prior to surgery. With the increasing use of fibrinolytic therapy this complication would be more frequent. This underlines the importance of prompt recognition and adequate treatment.     

Biodegradable PLGA microparticles for sustained release of a new GnRH antagonist: part II. In vivo performance.

Poly (DL-lactide-co-glycolide) microparticles (MP) containing a highly potent peptidic gonadotropin releasing hormone antagonist (degarelix) of interest in the prostate cancer indication were screened for biological performance. Efficacy was tested in a castrated male rat model at 3 doses (0.4, 1.0 and 1.5 mg/kg) and assessed as inhibition of luteinizing hormone (LH) secretion. When increasing the dose, onset of inhibition was faster, inhibition was more intense, and duration of action was prolonged. The MP type was also highly influent. If spray-dried and microextrusion particles exhibited comparable potencies, double emulsion microspheres were significantly less potent, both for onset and duration of inhibition. Interestingly, for the latter type it was found that the degarelix fraction released upon reconstitution in the solution for injection was significantly lower (max 0.3%), in comparison to spray-dried MP (max 2%) or microextrusion (max 4%). With the three types of particles, increasing peptide content was detrimental for duration of action, but only little difference was noticed between particles based on different polymers. At 1.5 mg/kg, LH inhibition was achieved over 36 days with spray-dried MP based on 75/25 lactate/glycolate copolymer. This was superior by 1 week to the performance of unformulated degarelix given at the same dose.     

JNK and ERK1/2 pathways have a dual opposite effect on the expression of BACE1

The activity of beta-secretase (BACE1), the endo-protease essential for the production of amyloid beta (Abeta) peptides, is increased in brain of late-onset sporadic Alzheimer's disease (AD), and oxidative stress is the potential cause of this event. Oxidative stress up-regulates the expression and the activity of BACE1 in cellular and animal models, through a mechanism that involves the increase of gamma-secretase cleavage on APP and the activation of c-jun N-terminal kinase/activator protein 1 (JNK/AP1) pathway. We further characterized the cellular pathways that control BACE1 expression under oxidative stress. We investigated the involvement of extracellular signal regulated MAP kinase (ERK1/2) pathway in the regulation of BACE1 expression, since it has been recently shown that ERK1/2 is an endogenous regulator of the gamma-secretase activity. We found that ERK1/2 pathway negatively modulates BACE1 expression and activity. Moreover, we observed that conditions that abrogate the gamma-secretase activity favor the activation of signalling pathways that promote cell survival, such as ERK1/2 and the serine/threonine kinase Akt/protein kinase B (Akt). These data suggest that the positive or negative cellular responses to oxidative stress parallel the activities of the beta- and the gamma-secretase. ERK1/2 and JNK pathways are involved in this bipartite response, which can lead to neurodegeneration or neuroprotection depending on the cellular and environmental conditions or cooperation with other signalling pathways such as Akt cascade.     

Advantages of bilayered vascular grafts for surgical applicability and tissue regeneration

Nanofibrous scaffolds are part of an intense research effort to design the next generation of vascular grafts. With electrospinning, the production of micro- and nano-fiber-based prostheses is simple and cost effective. An important parameter for tissue regeneration in such scaffolds is pore size. Too small pores will impede cell infiltration, but too large pores can lead to problems such as blood leakage. In this study, bilayered grafts were made by electrospinning a high-porosity graft with a low-porosity layer on either the luminal or the adventitial side. Grafts were characterized in vitro for fiber size, pore size, total porosity, water and blood leakage, mechanical strength, burst pressure and suture retention strength, and were evaluated in vivo in the rat abdominal aorta replacement model for 3 and 12 weeks. In vitro blood leakage through these bilayered grafts was significantly reduced compared with a high-porosity graft. All grafts had an excellent in vivo outcome, with perfect patency and no thrombosis. Cell invasion and neovascularization were significantly reduced in the grafts with a low-porosity layer on the adventitial side, and there was no significant difference between the grafts in endothelialization rate or intimal hyperplasia. By tailoring the microarchitecture of biodegradable vascular prostheses, it is therefore possible to optimize the scaffold for tissue regeneration while preventing blood leakage, and thus facilitating applicability in the clinic.     

Distribution of interleukin-1 receptor complex at the synaptic membrane driven by interleukin-1β and NMDA stimulation

Interleukin-1β (IL-1β) is a pro-inflammatory cytokine that contributes to neuronal injury in various degenerative diseases, and is therefore a potential therapeutic target. It exerts its biological effect by activating the interleukin-1 receptor type I (IL-1RI) and recruiting a signalling core complex consisting of the myeloid differentiation primary response protein 88 (MyD88) and the IL-1R accessory protein (IL-1RAcP). This pathway has been clearly described in the peripheral immune system, but only scattered information is available concerning the molecular composition and distribution of its members in neuronal cells. The findings of this study show that IL-1RI and its accessory proteins MyD88 and IL-1RAcP are differently distributed in the hippocampus and in the subcellular compartments of primary hippocampal neurons. In particular, only IL-1RI is enriched at synaptic sites, where it co-localises with, and binds to the GluN2B subunit of NMDA receptors. Furthermore, treatment with NMDA increases IL-1RI interaction with NMDA receptors, as well as the surface expression and localization of IL-1RI at synaptic membranes. IL-1β also increases IL-1RI levels at synaptic sites, without affecting the total amount of the receptor in the plasma membrane. Our results reveal for the first time the existence of a dynamic and functional interaction between NMDA receptor and IL-1RI systems that could provide a molecular basis for IL-1β as a neuromodulator in physiological and pathological events relying on NMDA receptor activation.