Mecp2 deficiency leads to delayed maturation and altered gene expression in hippocampal neurons

It is well known that Rett Syndrome, a severe postnatal childhood neurological disorder, is mostly caused by mutations in the MECP2 gene. However, how deficiencies in MeCP2 contribute to the neurological dysfunction of Rett Syndrome is not clear. We aimed to resolve the role of MeCP2 epigenetic regulation in postnatal brain development in an Mecp2-deficient mouse model. We found that, while Mecp2 was not critical for the production of immature neurons in the dentate gyrus (DG) of the hippocampus, the newly generated neurons exhibited pronounced deficits in neuronal maturation, including delayed transition into a more mature stage, altered expression of presynaptic proteins and reduced dendritic spine density. Furthermore, analysis of gene expression profiles of isolated DG granule neurons revealed abnormal expression levels of a number of genes previously shown to be important for synaptogenesis. Our studies suggest that MeCP2 plays a central role in neuronal maturation, which might be mediated through epigenetic control of expression pathways that are instrumental in both dendritic development and synaptogenesis.     

Identification of astrocyte-expressed factors that modulate neural stem/progenitor cell differentiation

Multipotent neural stem/progenitor cells (NSPCs) can be isolated from many regions of the adult central nervous system (CNS), yet neurogenesis is restricted to the hippocampus and subventricular zone in vivo. Identification of the molecular cues that modulate NSPC fate choice is a prerequisite for their therapeutic applications. Previously, we demonstrated that primary astrocytes isolated from regions with higher neuroplasticity, such as newborn and adult hippocampus and newborn spinal cord, promoted neuronal differentiation of adult NSPCs, whereas astrocytes isolated from the nonneurogenic region of the adult spinal cord inhibited neural differentiation. To identify the factors expressed by these astrocytes that could modulate NSPC differentiation, we performed gene expression profiling analysis using Affymetrix rat genome arrays. Our results demonstrated that these astrocytes had distinct gene expression profiles. We further tested the functional effects of candidate factors that were differentially expressed in neurogenesis-promoting and -inhibiting astrocytes using in vitro NSPC differentiation assays. Our results indicated that two interleukins, IL-1beta and IL-6, and a combination of factors that included these two interleukins could promote NSPC neuronal differentiation, whereas insulin-like growth factor binding protein 6 (IGFBP6) and decorin inhibited neuronal differentiation of adult NSPCs. Our results have provided further evidence to support the ongoing hypothesis that, in adult mammalian brains, astrocytes play critical roles in modulating NSPC differentiation. The finding that cytokines and chemokines expressed by astrocytes could promote NSPC neuronal differentiation may help us to understand how injuries induce neurogenesis in adult brains.     

Use of fibrin glue (Tissucol) for mesh fixation in laparoscopic transabdominal hernia repair

The aim of this study was to demonstrate the efficacy and safety and report the results of prosthesis fixation by means of fibrin glue during laparoscopic treatment of inguinal and femoral hernias. From September 2001 to December 2004 we employed fibrin glue (Tissucol, Baxter, Maurepas) as a means of fixation during a transabdominal preperitoneal procedure in 230 patients (225 M, 5 F) with an average age of 45 years (range: 20-75) presenting a total of 320 hernias: 140/230 (60.8%) were monolateral and 90 (39.2%) bilateral; 267/320 hernias (83.6%) were primary and 53 (16.4%) recurrent. We had no perioperative complications. After an average follow-up of 26 months (range: 1-40) the only postoperative complications we encountered were 6 seromas (1.8%) and 1 trocar-site haematoma (0.3%). None of the patients developed scrotal haematomas. None of the patients complained of immediate or subsequent paraesthesia or cruralgia. No recurrences have occurred to date. The mean operative time was 30 minutes for monolateral hernias (range: 15-45) and about 50 minutes for bilateral hernias (range: 30-75). This was true of both primary and recurrent hernias. Patients are usually discharged on day 1 postoperatively. In the absence of pain, working activities are resumed after 5 days and sports can be practiced after 10 days. In our experience, fibrin glue (Tissucol) is the best way of fixing the mesh during a transabdominal preperitoneal procedure. It is better than mechanical devices because, though guaranteeing prosthetic stability, it is completely non-traumatic and presents none of the problems of metal clips.     

Unbiased characterization of high-density oligonucleotide microarrays using probe-level statistics

Affymetrix GeneChips are being used increasingly for quantitative monitoring of gene expression in a variety of biological systems. Depending on the experiment, the analysis of Affymetrix results can have several different goals ranging from calculation of signal strength for a variety of inter-gene comparisons to the determination of which genes show significant differential expression between sample conditions. There have been several proposed methods for precise quantification of expression signal with promising results; however the question of what constitutes a significant change between replicate groups still remains. We have designed a method which performs statistical analysis on the differential expression of genes in the Affymetrix GeneChip system at the probe level in order to bypass the assumptions made in other analysis techniques. Validation using both spike-in data and real experimental data proves the method is effective at isolating differentially expressed genes statistically, thereby eliminating the need for arbitrary restrictions such as fold change. Application to an existing neural stem cell data set demonstrates the method's applicability to highly complex systems and its ability to detect very low expression differences (<1.2-fold change), providing resolution which may be of significant interest in neural systems such as this.     

Fine-needle aspiration of breast lesions: role and accuracy in a review of 7,495 cases

In the past 10 years, 7,495 cytological breast fine-needle aspirations (FNAs) were performed (4,756 FNAs of solid nodes and 2,739 of cystic nodes). Of these, 2,099 cases underwent surgery; 650 (31%) had histologically proven carcinoma. Sensitivity was 83.9%, specificity was 99.5%, the predictive value for negative results was 93.2% and for positive results was 98.6%, and the accuracy was 94.6%. Inadequate (13.3%) and doubtful samples (8.1%) were excluded from calculation. False-negative results (82 cases) mainly resulted from sampling errors. False suspicious results (six cases) lessened with increasing experience in breast pathology and with the application of strict diagnostic criteria, but most likely they will never reach zero. Frozen-section diagnosis could be bypassed only in selected cases. Guidelines on the role of FNA in management of solid breast lesions are given. FNA deserves further evaluation in diagnosing early stages of breast carcinoma: sensitivity was 7.5% in 57 carcinomas in situ, 67.5% in 55 minimally invasive carcinoma, and 92.7% in 538 nonminimally invasive carcinomas.     

Armodafinil, the R-enantiomer of modafinil: wake-promoting effects and pharmacokinetic profile in the rat

Modafinil reduces the excessive sleepiness associated with narcolepsy, obstructive sleep apnea/hypopnea syndrome, and shift work sleep disorder. In rats, modafinil promotes dose-dependent increases in wake duration. The wake-promoting activity of the R-enantiomer of modafinil (armodafinil) was evaluated in WKY rats and compared to the classical stimulant, D-methamphetamine. Electroencephalographic and electromyographic signals were assessed via a tethered cranial implant. Body temperature and locomotor activity were assessed by telemetry via intraperitoneal implant. Rats (n=60, 12 per group) were subjected to one of five parallel treatments: armodafinil at 30, 100 and 300 mg/kg i.p.; D-methamphetamine, 1 mg/kg i.p. and vehicle. Armodafinil and D-methamphetamine increased time spent awake relative to vehicle. Armodafinil-evoked increases in wake duration were dose-dependent and proportional to plasma compound exposure. Induction of wakefulness by D-methamphetamine was associated with an approximately two-fold increase in locomotor activity during the 2-h period immediately following administration relative to vehicle. D-methamphetamine also increased body temperature over the same time interval. The dose of armodafinil (100 mg/kg, i.p.) that was closest to D-methamphetamine in its wake-promoting efficacy did not produce changes in either body temperature or the intensity of locomotor activity relative to vehicle. Acute rebound hypersomnolence, characterized by increases in non-rapid eye movement sleep (NREMS) as a percentage of time and NREMS bout duration and by a decreased frequency of brief awakenings following sleep deprivation, occurred following D-methamphetamine-but not armodafinil-induced wake in this rat model which has been shown to be predictive of human drug responses.     

Prognostic factors and effectiveness of treatment in acute renal failure due to multiple myeloma: a review of 50 cases. Report of the Italien Renal Immunopathology Group

We studied 50 patients with myeloma acute renal failure to investigate possible prognostic factors and to evaluate the effectiveness of the various treatment schedules used. Renal failure was reversible 1 month after the onset in 50% of the patients considered. The patients treated with chemotherapy and plasma exchange recovered renal function more frequently (61% of the cases) than those treated only with chemotherapy (27%). The most important clinical prognostic factors were total proteins, serum creatinine values and myeloma type. Considering the histological findings, the prognosis correlated with the severity of the lesions and number of tubular casts. Survival at 1 year was higher in the patients who regained renal function than in those in whom renal function did not improve.