Rare mutations predisposing to familial adenomatous polyposis in Greek FAP patients

BACKGROUND: Familial Adenomatous Polyposis (FAP) is caused by germline mutations in the APC (Adenomatous Polyposis Coli) gene. The vast majority of APC mutations are point mutations or small insertions / deletions which lead to truncated protein products. Splicing mutations or gross genomic rearrangements are less common inactivating events of the APC gene. METHODS: In the current study genomic DNA or RNA from ten unrelated FAP suspected patients was examined for germline mutations in the APC gene. Family history and phenotype were used in order to select the patients. Methods used for testing were dHPLC (denaturing High Performance Liquid Chromatography), sequencing, MLPA (Multiplex Ligation – dependent Probe Amplification), Karyotyping, FISH (Fluorescence In Situ Hybridization) and RT-PCR (Reverse Transcription – Polymerase Chain Reaction). RESULTS: A 250 Kbp deletion in the APC gene starting from intron 5 and extending beyond exon 15 was identified in one patient. A substitution of the +5 conserved nucleotide at the splice donor site of intron 9 in the APC gene was shown to produce frameshift and inefficient exon skipping in a second patient. Four frameshift mutations (1577insT, 1973delAG, 3180delAAAA, 3212delA) and a nonsense mutation (C1690T) were identified in the rest of the patients. CONCLUSION: Screening for APC mutations in FAP patients should include testing for splicing defects and gross genomic alterations

Recurring Ethanol Exposure Induces Disinhibited Courtship in Drosophila

Alcohol has a strong causal relationship with sexual arousal and disinhibited sexual behavior in humans; however, the physiological support for this notion is largely lacking and thus a suitable animal model to address this issue is instrumental. We investigated the effect of ethanol on sexual behavior in Drosophila. Wild-type males typically court females but not males; however, upon daily administration of ethanol, they exhibited active intermale courtship, which represents a novel type of behavioral disinhibition. The ethanol-treated males also developed behavioral sensitization, a form of plasticity associated with addiction, since their intermale courtship activity was progressively increased with additional ethanol experience. We identified three components crucial for the ethanol-induced courtship disinhibition: the transcription factor regulating male sex behavior Fruitless, the ABC guanine/tryptophan transporter White and the neuromodulator dopamine. fruitless mutant males normally display conspicuous intermale courtship; however, their courtship activity was not enhanced under ethanol. Likewise, white males showed negligible ethanol-induced intermale courtship, which was not only reinstated but also augmented by transgenic White expression. Moreover, inhibition of dopamine neurotransmission during ethanol exposure dramatically decreased ethanol-induced intermale courtship. Chronic ethanol exposure also affected a male's sexual behavior toward females: it enhanced sexual arousal but reduced sexual performance. These findings provide novel insights into the physiological effects of ethanol on sexual behavior and behavioral plasticity

Chronic Obstructive Pulmonary Disease and Lung Cancer: Underlying Pathophysiology and New Therapeutic Modalities

Chronic obstructive pulmonary disease (COPD) and lung cancer are major lung diseases affecting millions worldwide. Both diseases have links to cigarette smoking and exert a considerable societal burden. People suffering from COPD are at higher risk of developing lung cancer than those without, and are more susceptible to poor outcomes after diagnosis and treatment. Lung cancer and COPD are closely associated, possibly sharing common traits such as an underlying genetic predisposition, epithelial and endothelial cell plasticity, dysfunctional inflammatory mechanisms including the deposition of excessive extracellular matrix, angiogenesis, susceptibility to DNA damage and cellular mutagenesis. In fact, COPD could be the driving factor for lung cancer, providing a conducive environment that propagates its evolution. In the early stages of smoking, body defences provide a combative immune/oxidative response and DNA repair mechanisms are likely to subdue these changes to a certain extent; however, in patients with COPD with lung cancer the consequences could be devastating, potentially contributing to slower postoperative recovery after lung resection and increased resistance to radiotherapy and chemotherapy. Vital to the development of new-targeted therapies is an in-depth understanding of various molecular mechanisms that are associated with both pathologies. In this comprehensive review, we provide a detailed overview of possible underlying factors that link COPD and lung cancer, and current therapeutic advances from both human and preclinical animal models that can effectively mitigate this unholy relationship

The significance of defining the levels of medical evidence in medicolegal practice

The practice of presenting a medical expert testimony to judges, juries and laymen could be improved by adopting the concept of ‘Levels of Medical Evidence’. Clinicians exchange the levels of evidence, between themselves, for valuing the significance of such evidence in matters of medical research, practice and guidelines. The expert witness has a duty to refer to both supportive and contradictive publications. S/he should provide an objective weighting of the publication, by referring to ‘the level of evidence’. Measuring the levels of medical evidence against a grid provide medical experts with an objective way of communication, for clarifying the relevance and quantifying its significance to a non-medical audience. The scarcity of some medical conditions, the rarity of their reporting in literature, and the conflict of medical consensus make the expert opinion of level four. The failure of a medical expert witness to explain where his/her opinion falls in the scale is a potential for misunderstanding, misrepresentation and misquotation. </jats:p

Persistent genital arousal and restless genitalia: sexual dysfunction or subtype of vulvodynia?

We conducted a literature review of patients’ conditions described under persistent genital arousal disorder and restless genital syndrome, vulvodynia and male genital skin pain of unknown aetiology (penoscrotodynia). Our aim is to improve the understanding of the condition, unify nomenclature and promote evidence-based practice. The most prominent symptom in persistent genital arousal disorder and restless genital syndrome is a spontaneous, unwelcomed, intrusive and distressing vulval sensation. There are similarities between the clinical presentation of vulvodynia, penoscrotodynia, persistent genital arousal disorder and restless genital syndrome patients. The aetiology of persistent genital arousal disorder and restless genital syndrome, similar to vulvodynia, could be better explained in terms of neuro-vascular dysfunction, genital peripheral neuropathy and/or dysfunctional micro-vascular arterio-venous shunting. Erythromelalgia lends itself to explain some cases of restless genital syndrome, who have concurrent restless legs syndrome; and therefore draw parallels with the red scrotum syndrome. The published literature supports the concept of classifying restless genital syndrome as a sub-type of vulvodynia rather than sexual dysfunction. </jats:p

Endothelial to mesenchymal transition (EndMT) and vascular remodeling in pulmonary hypertension and idiopathic pulmonary fibrosis

Introduction: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and irreversible fibrotic disease associated with respiratory failure. The disease remains idiopathic, but repeated alveolar epithelium injury, disruption of alveolar-capillary integrity, abnormal vascular repair, and pulmonary vascular remodeling are considered possible pathogenic mechanisms. Also, the development of comorbidities such as pulmonary hypertension (PH) could further impact disease outcome, quality of life and survival rates in IPF. Areas covered: The current review provides a comprehensive literature survey of the mechanisms involved in the development and manifestations of IPF and their links to PH pathology. This review also provides the current understanding of molecular mechanisms that link the two pathologies and will specifically decipher the role of endothelial to mesenchymal transition (EndMT) along with the possible triggers of EndMT. The possibility of targeting EndMT as a therapeutic option in IPF is discussed. Expert opinion: With a steady increase in prevalence and mortality, IPF is no longer considered a rare disease. Thus, it is of utmost importance and urgency that the underlying profibrotic pathways and mechanisms are fully understood, to enable the development of novel therapeutic strategies.</p