The gene expression profile of extraskeletal myxoid chondrosarcoma

Extraskeletal myxoid chondrosarcoma (EMC) is a soft tissue tumour that occurs primarily in the extremities and is characterized by a balanced translocation most commonly involving t(9;22) (q22;q12). The morphological spectrum of EMC is broad and thus a diagnosis based on histology alone can be difficult. Currently, no systemic therapy exists that improves survival in patients with EMC. In the present study, gene expression profiling has been performed to discover new diagnostic markers and potential therapeutic targets for this tumour type. Global gene expression profiling of ten EMCs and 26 other sarcomas using 42,000 spot cDNA microarrays revealed that the cases of EMC were closely related to each other and distinct from the other tumours profiled. Significance analysis of microarrays (SAM) identified 86 genes that distinguished EMC from the other sarcomas with 0.25% likelihood of false significance. NMB, DKK1, DNER, CLCN3, and DEF6 were the top five genes in this analysis. In situ hybridization for NMB gene expression on tissue microarrays (TMAs) containing a total of 1164 specimens representing 62 different sarcoma types and 15 different carcinoma types showed that NMB was highly expressed in 17 of 22 EMC cases and very rarely expressed in other tumours and thus could function as a novel diagnostic marker. High levels of expression of PPARG and the gene encoding its interacting protein, PPARGC1A, in most EMCs suggest activation of lipid metabolism pathways in this tumour. Small molecule inhibitors for PPARG exist and PPARG could be a potential therapeutic target for EMC.     

Decreased firing frequency of midbrain dopamine neurons in mice lacking mu opioid receptors

Dopamine neurons originating in the midbrain and projecting to cortico-limbic and motor structures are one of the major neuronal substrates implicated in the reinforcing properties of drugs of abuse. The output of this system is largely determined by its impulse activity (amount and pattern of firing activity). Several intrinsic and synaptic factors can influence dopamine neuronal activity and, consequently, addiction liability. Pharmacological studies indicate that mu-opioid receptors and their activation by endogenous opioids may play an important role. In the present study, we use a genetic approach to better understand the role of mu-opioid receptors in modulating dopamine neuronal activity in vivo. Using in vivo extracellular single-unit recordings, we show that mice lacking mu-opioid receptors exhibit lower firing rates of dopamine neurons compared with their wild-type littermates. Although we observed no overall changes in bursting activity compared with wild-type mice, animals lacking mu-opioid receptors exhibited a higher proportion of regular-spiking cells that lacked bursting activity. These findings are the first to emphasize the critical role of mu-opioid receptors in modulating action potential output of dopamine neurons in vivo using a genetic approach. They also provide a possible underlying mechanism for the decreased reinforcing properties of drugs of abuse that was previously observed in mice lacking mu-opioid receptors.     

Dyskinesias predict the onset of motor response fluctuations in patients with Parkinson's disease on L-dopa monotherapy

The aim of the study was to investigate the relationship between dyskinesias and motor fluctuations in patients with Parkinson's disease on l-dopa monotherapy. We identified 116 patients on l-dopa monotherapy treated between 1965 and 1992 and followed until death. Dyskinesias occurred in 102 patients. Of these, 48 only developed dyskinesias while 54 had both dyskinesias and motor fluctuations. Among patients with both complications, 49 developed dyskinesias before fluctuations, and only five had dyskinesias after the onset of fluctuations. Our findings suggest that dyskinesias predict the onset of motor fluctuations, and may share a common pathophysiological mechanism.     

The combined maternal administration of magnesium sulfate and aminophylline reduces intraventricular hemorrhage in very preterm neonates

OBJECTIVE: To determine whether the adjunctive administration of aminophylline and magnesium sulfate to mothers at risk for preterm birth can reduce the rate of intraventricular hemorrhage in neonates born at less than 30 weeks of gestation. STUDY DESIGN: A prospective study was conducted to determine whether the rate of intraventricular hemorrhage was different in patients at risk for preterm delivery treated with ritodrine, magnesium sulfate, aminophylline, and corticosteroids (group A) versus patients treated with ritodrine and corticosteroids (group B). During the study period (January 1996 to December 2001), 125 patients enrolled in the study. Treatment was assigned by alternative allocation, and the study was designed to compare the rate of intraventricular hemorrhage in neonates born before the 30th week of gestation (primary outcome), 78 newborns in group A and 68 in group B. The proportion of neonates with intraventricular hemorrhage was calculated, and data were analyzed with Student t test, chi 2 , and logistic regression analysis. RESULTS: The frequency of severe respiratory distress syndrome needing surfactant replacement and high-pressure positive ventilation, patent ductus arteriosus, and retinopathy of prematurity was not different between the 2 groups. However, the rate of intraventricular hemorrhage was lower in neonates born before 30 weeks whose mothers received adjunctive aminophylline and magnesium sulphate (group A) than in the group that did not receive these 2 agents (group B). The overall frequency of intraventricular hemorrhage was 5.1% (4/78) versus 20.6% (14/68) ( P < .001), and the frequency of intraventricular hemorrhage grade 3-4 was 1.3% (1/78) versus 10.3 % (7/68; P < .001), respectively. CONCLUSION: Adjunctive maternal administration of aminophylline and magnesium sulfate was associated with a significant reduction in the rate of intraventricular hemorrhage in neonates born before 30 completed weeks.     

Dopamine-containing neurons are silenced by energy deprivation: a defensive response or beginning of cell death?

Metabolic stress associated to mitochondrial dysfunction has been put forward as an important factor causing degeneration of mesencephalic dopamine-containing neurons in Parkinson's disease (PD). Here we overview how these neurons react to acute hypoxia or hypoglycemia, that are conditions of energy deprivation causing a reduced production of ATP by mitochondria. These neurons, which show a tonic firing discharge under normal condition, undergo into membrane hyperpolarization during hypoxia or hypoglycemia that silence their spontaneous activity. We outline the cellular mechanisms causing membrane hyperpolarization and the accompanied disturbances of intracellular calcium and sodium homeostasis. A better understanding of the changes occurring during transient energy deprivation might contribute to understand the physiopathology of these neurons that derives from mitochondrial dysfunction.     

The treatment of bone defects in primary arthroplasty of the knee

The authors reviewed the literature as well as their own cases in order to discuss the indications, advantages and disadvantages relative to the methods used to treat bone defects in primary knee arthroplasty. An analysis shows that the use of cement represents the most unfavorable method from a mechanical point of view and it should thus be limited to defects that are not too deep and extensive. Bone grafts, both homoplastic and autoplastic, are preferred in younger patients. The former in lesions that are smaller, the latter in those that are larger. Currently, modular prostheses are diffusedly used because of their versatility and relatively low cost if we compare them with prostheses that are custom made. Finally, the authors emphasize the need to use intramedullary stems in bone defect with the purpose of reducing stress in the metaphyseal region.     

XPD gene polymorphism and host characteristics in the association with cutaneous malignant melanoma risk

We recently reported an association between low DNA repair capacity, measured through the host-cell reactivation assay, and melanoma risk in subjects with dysplastic naevi or low tanning ability. We investigated the genetic basis for these findings by analysing the Asp312Asn and Lys751Gln polymorphisms of the XPD (ERCC2) DNA repair gene in the same subjects. Similar to our previous report, no significant association between XPD polymorphisms and melanoma risk was found in 176 melanoma cases and 177 controls (odds ratio (OR)=1.5, 95% confidence interval (CI)=0.9-2.5 for 312Asn; OR=1.3, 95% CI=0.8-2.1 for 751Gln, adjusted for age, gender, dysplastic naevi and pigmentation characteristics). However, XPD variants were associated with increased risk in older (>50 years) subjects (OR=3.4, 95% CI=1.6-7.3 for 312Asn; OR=2.3, 95% CI=1.1-4.9 for 751Gln). The 751Gln allele was associated with elevated melanoma risk among subjects without dysplastic naevi (OR=2.6, 95% CI=1.1-6.4). Subjects with low tanning ability and XPD variants exhibited a nonsignificant increase of melanoma risk (OR=2.3, 95% CI=0.7-7.0 for 312Asn; OR=3.0, 95% CI=1.0-8.8 for 751Gln). DNA repair capacity was slightly decreased in subjects carrying 751Gln alleles. XPD variants may modify melanoma risk in subjects with specific host characteristics, such as older age, lack of dysplastic naevi or low tanning ability.     

Aquaporin water channels in central nervous system

Aquaporins (AQPs) are a family of water-selective channels that provide a major pathway for osmotically driven water transport through cell membranes. Some members of the aquaporin family have been identified in the central nervous system (CNS). The water channel aquaporin 1 (AQP1) is restricted to the apical domain of the choroid plexus epithelial cells. The AQP4 is abundantly expressed in astrocyte foot processes and ependymocytes facing capillaries and brain-cerebrospinal fluid (CSF) interfaces, whereas AQP9 is localized in tanycytes and astrocytes processes. The mRNA for other aquaporin homologs (i.e., AQP3, 5, and 8) have been recently found in cultured astrocytes. Based on their subcellular localization and data obtained from functional studies, it is assumed that aquaporins are implicated in water movements in nervous tissue and may play a role in central osmoreception, K+ siphoning, and cerebrospinal fluid formation. There have been recent reports describing different aquaporin-responses under pathologic states leading to brain edema. The data available provide a better understanding of the mechanisms responsible for brain edema and indicate that aquaporins are potential targets for drug development.     

Corticosteroids treatment

Corticosteroids (Cs) are widely used for treatment of multiple sclerosis (MS) acute relapses because of the potent immunosuppressive and anti-inflammatory properties. As for patients with relapsing-remitting (RR) MS, short-term administrations of Cs markedly less severity of symptoms and promote faster recovery of clinical attacks. Chronic administrations of Cs significantly diminish the formation of T1 hypointense lesions and the progression of brain atrophy. As for patients with secondary progressive MS treatment with Cs delays the time to onset of sustained disability. Finally the association between methylprednisolone and interferon beta (IFNbeta) leads the recovery of active lesions at greater extent and reduces the formation of neutralizing antibodies (NABs) against IFNbeta in patients with RRMS.