Characterizing neuroanatomical changes in parvalbumin and perineuronal nets in a rat DISC-1 knock out model

BACKGROUND: Schizophrenia is a debilitating disorder that has a profound impact on quality of life due to the presence of both cognitive deficits and psychotic symptoms. Despite having significant global economic and social costs and a worldwide prevalence of 1%, schizophrenia is still not well understood. Research has been making strides in uncovering the pathophysiology and the etiology that drive this disease, ranging from genetic abnormalities, disrupted circuitry, changes in microarchitecture, to impaired synaptic connectivity. Evidence suggests that disrupted-in-schizophrenia-1 (DISC1) driven genetic disturbances in fast-spiking parvalbumin (PV) neurons and their surrounding perineuronal nets (PNNs) likely contribute to schizophrenia etiology as they are part of the microcircuits required for working memory, a cognitive function that has been consistently impaired in schizophrenic patients. OBJECTIVE: To identify the neuroanatomical changes in PV neurons and surrounding PNNs in the superficial and deep layers of the prelimbic and infralimbic prefrontal cortex of a rat DISC-1 knockout model. METHODS: 19 DISC1-KO male rats and 15 wildtype rats were treated with saline or MK-801. They were sacrificed between P268-269 and brains were extracted and separated at the corpus callosum. After fixing and preserving, the brains were sliced then stained to visualize parvalbumin and perineuronal nets with immunohistochemistry. Slices were imaged and analyzed for PV, PNN, and PV+PNN counts in the superficial and deep regions of the prelimbic and infralimbic cortices. Averages counts within each group were taken and analyzed via 2-way ANOVAs for each brain region and dependent variable. RESULTS: DISC1-KO rats displayed the following trending changes: decreased PV cells in deep layers of infralimbic and decreased PNNs throughout the prelimbic cortex. MK-801 appears to increase the number of unsheathed PV cells in the superficial layers of prelimbic and infralimbic cortex. It decreased the number of PNNs in the prelimbic of wildtype animals but not in the DISC1-KO cohort. MK-801 moderately increased PV counts in DISC1-KO. CONCLUSIONS: This DISC1-KO model is a promising model of schizophrenia as we see the same directionality of decreases in PV and PNN as post mortem human studies. Furthermore, MK-801 is seen to have an increasing trend effect on PV cells, which should be considered when interpreting findings in future studies that look at these markers

Combining general practice with international work: online survey of experiences of UK GPs

Objectives: To conduct an exploratory study to learn about the experiences of GPs who have undertaken international work. Design: Cross-sectional survey. Setting: Online survey of UK-based GPs. Members of all UK RCGP faculties were invited to participate by email and the survey was publicised on the RCGP website. Participants: All UK-based GPs. Main outcome measures: Types of UK and international work undertaken, barriers, competencies gained, influence on career and future plans. Results: The study identified 439 respondents, in a variety of GP roles at all career stages, who had undertaken international work in their role as a doctor. GPs are undertaking international work in both high and low/middle-income countries, engaging in a wide range of clinical and non-clinical activities. Respondents reported gaining a range of competencies from international work, which could be transferred back to the UK setting to a variable degree. Commonly cited barriers to international work were having to leave friends and family, and concerns regarding future employment and pension. Most reported that engaging in international work had influenced the direction of their career, with the largest proportion stating that they wish to work predominantly in the UK, with some international work in the future. Conclusion: The study highlights the variety of ways in which UK GPs are combining UK general practice and international work, competencies gained with such work, and ability to transfer these back to the UK setting. Historical barriers to international work still exist and future research could further examine the value of such work

Rett Syndrome: Revised diagnostic criteria and nomenclature

Objective: Rett syndrome (RTT) is a severe neurodevelopmental disease that affects approximately 1 in 10,000 live female births and is often caused by mutations in Methyl-CpG-binding protein 2 (MECP2). Despite distinct clinical features, the accumulation of clinical and molecular information in recent years has generated considerable confusion regarding the diagnosis of RTT. The purpose of this work was to revise and clarify 2002 consensus criteria for the diagnosis of RTT in anticipation of treatment trials. Method: RettSearch members, representing the majority of the international clinical RTT specialists, participated in an iterative process to come to a consensus on a revised and simplified clinical diagnostic criteria for RTT. Results: The clinical criteria required for the diagnosis of classic and atypical RTT were clarified and simplified. Guidelines for the diagnosis and molecular evaluation of specific variant forms of RTT were developed. Interpretation These revised criteria provide clarity regarding the key features required for the diagnosis of RTT and reinforce the concept that RTT is a clinical diagnosis based on distinct clinical criteria, independent of molecular findings. We recommend that these criteria and guidelines be utilized in any proposed clinical research

Benzylmorpholine Analogs as Selective Inhibitors of Lung Cytochrome P450 2A13 for the Chemoprevention of Lung Cancer in Tobacco Users

The original publication is available at www.springerlink.comPURPOSE 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), one of the most prevalent and procarcinogenic compounds in tobacco, is bioactivated by respiratory cytochrome P450 (CYP) 2A13, forming DNA adducts and initiating lung cancer. CYP2A13 inhibition offers a novel strategy for chemoprevention of tobacco-associated lung cancer. METHODS Twenty-four analogs of a 4-benzylmorpholine scaffold identified by high throughput screening were evaluated for binding and inhibition of both functional human CYP2A enzymes, CYP2A13 and the 94%-identical hepatic CYP2A6, whose inhibition is undesirable. Thus, selectivity is the major challenge in compound design. RESULTS A key feature resulting in CYP2A13-selective binding and inhibition was substitution at the benzyl ortho position, with three analogs being >25-fold selective for CYP2A13 over CYP2A6. CONCLUSIONS Two such analogs were negative for genetic and hERG toxicities and metabolically stable in human lung microsomes, but displayed rapid metabolism in human liver and in mouse and rat lung and liver microsomes, likely due to CYP2B-mediated degradation. A specialized knockout mouse mimicking the human lung demonstrates compound persistence in lung and provides an appropriate test model. Compound delivered by inhalation may be effective in the lung but rapidly cleared otherwise, limiting systemic exposure

Early development and regression in Rett Syndrome

This study utilized developmental profiling to examine symptoms in 14 girls with genetically confirmed Rett syndrome and whose families were participating in the Australian Rett syndrome or InterRett database. Regression was mostly characterized by loss of hand and/or communication skills (13/14) except one girl demonstrated slowing of skill development. Social withdrawal and inconsolable crying often developed simultaneously (9/14), with social withdrawal for shorter duration than inconsolable crying. Previously acquired gross motor skills declined in just over half of the sample (8/14), mostly observed as a loss of balance. Early abnormalities such as vomiting and strabismus were also seen. Our findings provide additional insight into the early clinical profile of Rett syndrome

Three genetically distinct ferlaviruses have varying effects on infected corn snakes (Pantherophis guttatus)

Ferlaviruses are important pathogens in snakes and other reptiles. They cause respiratory and neurological disease in infected animals and can cause severe disease outbreaks. Isolates from this genus can be divided into four genogroups-A, B, and C, as well as a more distantly related sister group, "tortoise". Sequences from large portions (5.3 kb) of the genomes of a variety of ferlavirus isolates from genogroups A, B, and C, including the genes coding the surface glycoproteins F and HN as well as the L protein were determined and compared. In silico analyses of the glycoproteins of genogroup A, B, and C isolates were carried out. Three isolates representing these three genogroups were used in transmission studies with corn snakes (Pantherophis guttatus), and clinical signs, gross and histopathology, electronmicroscopic changes in the lungs, and isolation of bacteria from the lungs were evaluated. Analysis of the sequences supported the previous categorization of ferlaviruses into four genogroups, and criteria for definition of ferlavirus genogroups and species were established based on sequence identities (80% resp. 90%). Analysis of the ferlavirus glycoprotein models showed parallels to corresponding regions of other paramyxoviruses. The transmission studies showed clear differences in the pathogenicities of the three virus isolates used. The genogroup B isolate was the most and the group A virus the least pathogenic. Reasons for these differences were not clear based on the differences in the putative structures of their respective glycoproteins, although e.g. residue and consequential structure variation of an extended cleavage site or changes in electrostatic charges at enzyme binding sites could play a role. The presence of bacteria in the lungs of the infected animals also clearly corresponded to increased pathogenicity. This study contributes to knowledge about the structure and phylogeny of ferlaviruses and lucidly demonstrates differences in pathogenicity between strains of different genogroups

Correlation of Serum Biomarkers and Magnetic Resonance Spectroscopy in Monitoring Disease Progression in Patients With Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Episodes Due to mtDNA A3243G Mutation

Background: Analysis of serum biomarkers and magnetic resonance spectroscopy (MRS) are useful for monitoring disease progression in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). We evaluated the correlation of serum biomarkers and MRS parameters during changes associated with stroke-like episodes.Methods: In 13 symptomatic MELAS patients carrying the A3243G mutation, we retrospectively obtained 207 voxels from 41 MRS studies, which were divided into three groups according to the temporal association with stroke-like episodes. The MRS NAA/Cr, Cho/Cr, NAA/Cho ratios, the presence of a lactate peak, serum biomarkers, serum lactate level and the pyruvate (Lac/Pyr) ratio were determined.Results: In regions with acute infarcts, the severity of serum Lac/Pyr and that of the MRS lactate peak (P = 0.0007) correlated; serum lactate (P = 0.02), severity of elevated serum lactate (P = 0.04), and serum Lac/Pyr (P = 0.02) correlated weakly. In previously infarcted regions, the severity of the MRS lactate peak and serum Lac/Pyr (P = 0.03), as well as the severity of serum Lac/Pyr (P = 0.02) were weakly correlated. In structurally normal regions, we found a weak to moderate negative correlation between serum lactate and MRS NAA/Cr (P = 0.008), and between the severity of elevated serum lactate and MRS NAA/Cr (P = 0.002) as well as MRS NAA/Cho (P = 0.02).Conclusions: MRS parameters correlate with specific serum biomarkers, and are useful for monitoring changes in brain metabolites, particularly as related to stroke-like episodes