Differential expression of microRNAs miR-21, miR-31, miR-203, miR-125a-5p and miR-125b and proteins PTEN and p63 in verrucous carcinoma of the head and neck

Odar K, Bo?tjan?i? E, Gale N, Glava? D & Zidar N
(2012) Histopathology  61, 257–265 Differential expression of microRNAs miR‐21, miR‐31, miR‐203, miR‐125a‐5p and miR‐125b and proteins PTEN and p63 in verrucous carcinoma of the head and neck Aims: To investigate the expression of microRNAs miR‐21, miR‐31, miR‐203, miR‐125a‐5p and miR‐125b and proteins phosphatase and tensin homologue (PTEN) and p63 in verrucous carcinoma (VC) of the head and neck. Methods and results: Thirty cases of VC, 50 cases of conventional squamous cell carcinoma (SCC) and 30 samples of normal epithelium of the head and neck were included. Real‐time polymerase chain reaction and immunohistochemistry were used to analyse the expression of microRNAs and proteins, respectively. In comparison to normal epithelium, miR‐21 was overexpressed in both VC and SCC and miR‐31 was overexpressed in VC and in well‐ and moderately differentiated SCC. Levels of miR‐203 were elevated in VC but unaltered or reduced in SCC, and levels of miR‐125a‐5p and miR‐125b were reduced in VC but unaltered in SCC. PTEN was down‐regulated in both VC and SCC, whereas p63 was down‐regulated in VC but up‐regulated in SCC. Differential expression of p63 in VC correlated inversely with the expression of miR‐21 and miR‐203. Conclusions: Differences between VC, SCC and normal epithelium in expression profiles of investigated molecules indicate their association with the pathogenesis and clinicopathological characteristics of VC. Our results suggest that some microRNAs and proteins, particularly miR‐125b, miR‐203 and p63, might be useful in the diagnosis of VC.     

Striatal and cortical midline activation and connectivity associated with suicidal ideation and depression in bipolar II disorder

Background

Considerable evidence implicates dysfunction of striatal and cortical midline structure (CMS) circuitry in mood disorders. Whether such aberrations exist in bipolar II depression is unknown.

Methods

Sixteen unmedicated subjects with bipolar II depression and 19 healthy controls were studied using functional MRI and a motor activation paradigm. Analyses of both activation and functional connectivity were conducted.

Results

A history of suicidal ideation (SI) was negatively correlated with activation of the left putamen while depression severity was positively correlated with activation of the left thalamus. The superior bilateral putamen was simultaneously correlated with depression severity and anti-correlated with SI. Striatal functional connectivity was altered with the bilateral CMS and right inferior parietal lobule. Depression severity was correlated with strength of connectivity between the bilateral striatum and the right lingual gyrus and left cerebellum.

Limitations

Only males experiencing an episode of major depression were studied.

Conclusions

Striatal and CMS circuit abnormalities likely contribute to the neurobiology of bipolar II depression. Altered connectivity of the striatum may directly impact depression severity. Further, dissociable components of activation associated with depression severity and suicidal ideation may exist. Finally, the motor activation paradigm used in this study appears to be a useful probe of some neural processes underlying bipolar II depression.     

Factors associated with junior doctors’ decisions to apply for general practice training programmes in the UK: secondary analysis of data from the UKMED project

Background

The UK, like many high-income countries, is experiencing a worsening shortfall of general practitioners (GPs) alongside an increasing demand for their services. At the same time, factors influencing junior doctors’ decisions to apply for GP training are only partially understood and research in this area has been hampered by the difficulties in connecting the datasets that map the journey from student to qualified GP. The UK Medical Education Database (UKMED) has been established to ameliorate this problem by linking institutional data across the spectrum of medical education from school to specialty training. Our study aimed to use UKMED to investigate which demographic and educational factors are associated with junior doctors’ decisions to apply for GP training.

Methods

Study data, provided by the UKMED Development Group and accessed remotely, contained longitudinal educational and sociodemographic information on all doctors who entered UK medical schools in the 2007/2008 academic year and who made first-time specialty training applications in 2015. We used multivariable logistic regression models to investigate two binary outcomes, namely (1) application to GP training, possibly alongside applications to other specialties, and (2) application solely to GP training.

Results

Of 7634 doctors in the sample, 43% applied to GP training possibly alongside other specialities and 26% applied solely to GP training. The odds of applying to GP training were associated with particular demographic factors (being female, non-white or secondary educated in the UK increased the odds of application) and educational factors (non-graduate entry, intercalation and above-median academic performance during medical school all decreased the odds of application). After adjusting for these factors, both the medical school and the foundation school attended were independently associated with the odds of applying to GP training.

Conclusions

Our findings suggest that the supply and demand imbalance in UK primary care might be improved by (1) efforts to attract greater numbers of female, non-white and UK secondary-educated students into medical schools, and (2) targeting resources at medical and foundation schools that deliver doctors likely to fill significant gaps in the workforce. Further research is required to better understand inter-school differences and to develop strategies to improve recruitment of GP trainees.

     

Systemic Infection Following Intravenous Inoculation of Mice with Candida albicans int1 Mutant Strains

The Candida albicans gene INT1 is associated with epithelial adhesion, hyphal formation, and virulence. C. albicans strains carrying two, one, or no functional INT1 alleles were used to assess the association between mortality and C. albicans persistence in the liver and kidney of intravenously inoculated mice. Mice were injected with 10⁵C. albicans CAF2 (parent strain, INT1/INT1), C. albicans CAG3 (homozygous disruptant, Int1/int1), or C. albicans CAG5 (heterozygous reintegrant, int1/int1 + INT1). Mortality was monitored and mice were sacrificed on Days 1, 7, 14, and 21 for quantitative analysis of kidney and liver microbes, with histologic analysis of these tissues as well. Mortality was highest for mice injected with the wild-type strain CAF2 (INT1/INT1) and lowest for mice injected with the homozygous disruptant CAG3 (int/int1). Yeast were readily cleared from the liver of all mice injected with any of the three C. albicans strains. Although the mutant strains CAG3 and CAG5 are defective for hyphal formation in vitro, there was histological evidence of abundant hyphal formation in the renal pelvis of mice injected with these strains. Compared to the wild-type strain, mutant strains were associated with reduced mortality but increased C. albicans persistence in the kidney. Thus, the absolute ability to form hyphae in the kidney did not appear to modulate either C. albicans-induced mortality or the course of progressive infection in the kidney. In addition, reduced virulence was paradoxically associated with increased, not decreased, persistence of C. albicans in the kidney.     

Systemic infection following intravenous inoculation of mice with Candida albicans int1 mutant strains.

The Candida albicans gene INT1 is associated with epithelial adhesion, hyphal formation, and virulence. C. albicans strains carrying two, one, or no functional INT1 alleles were used to assess the association between mortality and C. albicans persistence in the liver and kidney of intravenously inoculated mice. Mice were injected with 10(5) C. albicans CAF2 (parent strain, INT1/INT1), C. albicans CAG3 (homozygous disruptant, Int1/int1), or C. albicans CAG5 (heterozygous reintegrant, int1/int1 + INT1). Mortality was monitored and mice were sacrificed on Days 1, 7, 14, and 21 for quantitative analysis of kidney and liver microbes, with histologic analysis of these tissues as well. Mortality was highest for mice injected with the wild-type strain CAF2 (INT1/INT1) and lowest for mice injected with the homozygous disruptant CAG3 (int/int1). Yeast were readily cleared from the liver of all mice injected with any of the three C. albicans strains. Although the mutant strains CAG3 and CAG5 are defective for hyphal formation in vitro, there was histological evidence of abundant hyphal formation in the renal pelvis of mice injected with these strains. Compared to the wild-type strain, mutant strains were associated with reduced mortality but increased C. albicans persistence in the kidney. Thus, the absolute ability to form hyphae in the kidney did not appear to modulate either C. albicans-induced mortality or the course of progressive infection in the kidney. In addition, reduced virulence was paradoxically associated with increased, not decreased, persistence of C. albicans in the kidney.     

Differences in functional connectivity in major depression versus bipolar II depression

Background

Objective methods of differentiating unipolar versus bipolar depression would enhance our ability to treat these disorders by providing more accurate diagnoses. One first step towards developing diagnostic methodology is determining whether brain function as assessed by functional MRI (fMRI) and functional connectivity analyses might differentiate the two disorders.

Methods

Fourteen subjects with bipolar II depression and 26 subjects with recurrent unipolar depression were studied using fMRI and functional connectivity analyses.

Results

The first key finding of this study was that functional connectivity of the right posterior cingulate cortex differentiates bipolar II and unipolar depression. Additionally, results suggest that functional connectivity of this region is associated with suicidal ideation and depression severity in unipolar but not bipolar II depression.

Limitations

The primary limitation is the relatively small sample size, particularly for the correlational analyses.

Conclusions

The functional connectivity of right posterior cingulate cortex may differential unipolar from bipolar II depression. Further, connectivity of this region may be associated with depression severity and suicide risk in unipolar but not bipolar depression.     

Metacarpophalangeal pattern profile analysis in Noonan syndrome

Metacarpophalangeal pattern (MCPP) analysis is an application of an anthropometric technique that provides a quantitative assessment of the amount and direction of abnormality in the hand skeleton. MCPP analysis was undertaken on 15 individuals (9 males, 6 females) with Noonan syndrome ranging in age from 0.1 to 36 years with a mean age at 11.6 years. The overall average Z score for the MCPP variables was -2.1 and the range was -2.5 (for metacarpal two) and -1.5 (for middle phalanx 5). The average hand pattern variability index, a measure of hand bone length relationships, was abnormal. A Pearsonian correlation analysis was used to assess similarity between the mean pattern and each of the 15 individual patterns. Nine (60%) of the fifteen individuals with Noonan syndrome had significant positive correlations (P < 0.05), indicating homogeneity or similarity in the hand patterns. A stepwise discriminant analysis was performed on Z score data from the individual hand bone measurements on the 15 subjects with Noonan syndrome and 41 healthy controls (24 females, 17 males; mean age = 13.1 years with age range of 9.6 to 18 years). This analysis produced a discriminant function with two MCPP variables (metacarpal 1 and middle phalanx 3) entering into the function and producing a correct classification rate of 93%. The two MCPP variables contributed to the overall difference between individuals with Noonan syndrome and the normative sample. The hand pattern variability index was outside of the normal range, indicating an abnormal MCPP with multivariate analysis. The MCPP analysis may be useful as a tool for diagnosis in screening subjects for Noonan syndrome.     

Disruption of Eph/ephrin signaling affects migration and proliferation in the adult subventricular zone

The subventricular zone (SVZ) of the lateral ventricles, the largest remaining germinal zone of the adult mammalian brain, contains an extensive network of neuroblasts migrating rostrally to the olfactory bulb. Little is known about the endogenous proliferation signals for SVZ neural stem cells or guidance cues along the migration pathway. Here we show that the receptor tyrosine kinases EphB1-3 and EphA4 and their transmembrane ligands, ephrins-B2/3, are expressed by cells of the SVZ. Electron microscopy revealed ephrin-B ligands associated with SVZ astrocytes, which function as stem cells in this germinal zone. A three-day infusion of the ectodomain of either EphB2 or ephrin-B2 into the lateral ventricle disrupted migration of neuroblasts and increased cell proliferation. These results suggest that Eph/ephrin signaling is involved in the migration of neuroblasts in the adult SVZ and in either direct or indirect regulation of cell proliferation.     

DICOM Modality Worklist: An essential component in a PACS environment

The development and acceptance of the digital communication in medicine (DICOM) standard has become a basic requirement for the implementation of electronic imaging in radiology. DICOM is now evolving to provide a standard for electronic communication between radiology and other parts of the hospital enterprise. In a completely integrated filmless radiology department, there are 3 core computer systems, the picture archiving and communication system (PACS), the hospital or radiology information system (HIS, RIS), and the acquisition modality. Ideally, each would have bidirectional communication with the other 2 systems. At a minimum, a PACS must be able to receive and acknowledge receipt of image and demographic data from the modalities. Similarly, the modalities must be able to send images and demographic data to the PACS. Now that basic DICOM communication protocols for query or retrieval, storage, and print classes have become established through both conformance statements and intervendor testing, there has been an increase in interest in enhancing the functionality of communication between the 3 computers. Historically, demographic data passed to the PACS have been generated manually at the modality despite the existence of the same data on the HIS or RIS. In more current sophisticated implementations, acquisition modalities are able to receive patient and study-related data from the HIS or RIS. DICOM Modality Worklist is the missing electronic link that transfers this critical information between the acquisition modalities and the HIS or RIS. This report describes the concepts, issues, and impact of DICOM Modality Worklist implementation in a PACS environment.