Astrocyte activation and altered metabolism in normal aging,age-related CNS diseases,and HAND

Journal of NeuroVirology - Astrocytes regulate local cerebral blood flow, maintain ion and neurotransmitter homeostasis, provide metabolic support, regulate synaptic activity, and respond to brain...     

Biperiden and mepazine effectively inhibit MALT1 activity and tumor growth in pancreatic cancer

MALT1 is a key mediator of NF-κB signaling and a main driver of B-cell lymphomas. Remarkably, MALT1 is expressed in the majority of pancreatic ductal adenocarcinomas (PDACs) as well, but absent from normal exocrine pancreatic tissue. Following, MALT1 shows off to be a specific target in cancer cells of PDAC without affecting regular pancreatic cells. Therefore, we studied the impact of pharmacological MALT1 inhibition in pancreatic cancer and showed promising effects on tumor progression. Mepazine (Mep), a phenothiazine derivative, is a known potent MALT1 inhibitor. Newly, we described that biperiden (Bip) is a potent MALT1 inhibitor with even less pharmacological side effects. Thus, Bip is a promising drug leading to reduced proliferation and increased apoptosis in PDAC cells in vitro and in vivo. By compromising MALT1 activity, nuclear translocation of c-Rel is prevented. c-Rel is critical for NF-κB-dependent inhibition of apoptosis. Hence, off-label use of Bip or Mep represents a promising new therapeutic approach to PDAC treatment. Regularly, the Anticholinergicum Bip is used to treat neurological side effects of Phenothiazines, like extrapyramidal symptoms.     

Diagnostic challenges for a novel SH2D1A mutation associated with X‐linked lymphoproliferative disease

Mutations in SH2D1A, encoding the intracellular adaptor signaling lymphocyte activation molecule associated protein (SAP), are associated with X‐linked lymphoproliferative disease type 1 (XLP1). We identified a novel hemizygous SH2D1A c.49G > A (p.E17K) variant in a 21‐year‐old patient with fatal Epstein‐Barr virus infection–associated hemophagocytic lymphohistiocytosis. Cellular and biochemical assays revealed normal expression of the SAP variant protein, yet binding to phosphorylated CD244 receptor was reduced by >95%. Three healthy brothers carried the SH2D1A c.49G > A variant. Thus, data suggest that this variant represents a pathogenic mutation, but with variable expressivity. Importantly, our results highlight challenges in the clinical interpretation of SH2D1A variants and caution in using functional flow cytometry assays for the diagnosis of XLP1.     

Human papillomavirus infection in the oromaxillofacial area: Clinical anatomy and histological considerations

Clinical manifestations of human papillomavirus (HPV) infection in the head and neck can range from benign lesions, which are the most frequent, to malignant lesions. The prevalence of head and neck cancer is increasing, despite currently decreasing trends in known risk factors such as smoking and alcohol use. A new patient profile has appeared in recent practice: most frequently a middle‐aged male patient who does not smoke or drink alcohol, is sexually active (possibly having multiple partners), and presents with oral or cervicofacial lesions requiring diagnosis and treatment. Another risk factor that should be considered in these patients is HPV infection. The association of oral potentially malignant disorders (OPMD) with HPV is a challenge for the medical practitioner. The gold standard for diagnosis is histopathological examination, which can also yield evidence suggesting HPV infection. Determination of the viral genotype provides additional data for assessing the oncological risk of an HPV infection. Treatment of these patients is aimed at removing the lesions, in association or not with antiviral treatment and recurrence control. Clin. Anat. 28:1002–1007, 2015. © 2015 Wiley Periodicals, Inc.     

Development of a biochemical marker to detect current breast milk intake

The WHO recommends exclusive breastfeeding for 6 months, but despite interventions, breastfeeding rates remain stubbornly low. Financial voucher incentives have shown promise but require a biomarker for validation of intake. This study aimed to develop a simple biochemical assay of infant urine that would tell if an infant was receiving any breast milk to validate maternal report. Urine samples were collected and snap frozen from 34 infants attending with minor illness or feeding problems, of whom 12 infants were exclusively breastfed, nine exclusively formula fed, and 11 mixed breast/formula fed. High‐performance anion exchange chromatography was used to identify discriminating patterns of monosaccharide composition of unconjugated glycans in a sequence of three experiments. The absolute concentration of all human milk oligosaccharides measured blind could detect “any breastfeeding” only with a sensitivity of 48% and specificity of 78%. Unblinded examination of N‐acetylglucosamine (GlcNAc) measured as GlcNH₂ after hydrolysis of GlcNAc improved sensitivity to 75% at the expense of a specificity of 28%. Estimation of the relative abundance of GlcNH2 (GlcNH2[%]) or the ratio of GlcNH2 to endogenous mannose (Man) improved accuracy. In a further blind experiment, the GlcNH2/Man ratio with a cut‐off of 1.5 correctly identified all those receiving “any breast milk,” while excluding exclusively formula fed infants. The GlcNH2/Man ratio in infant urine is a promising test to provide biochemical confirmation of any breastfeeding for trials of breastfeeding promotion.     

Attachment,Sexual Assertiveness,and Sexual Outcomes in Women with Provoked Vestibulodynia and Their Partners: A Mediation Model

Provoked vestibulodynia (PVD) is a prevalent women’s sexual pain disorder, which is associated with sexual function difficulties. Attachment theory has been used to understand adult sexual outcomes, providing a useful framework for examining sexual adaptation in couples confronted with PVD. Research to date indicates that anxious and avoidant attachment dimensions correlate with worse sexual outcomes in community and clinical samples. The present study examined the association between attachment, pain, sexual function, and sexual satisfaction in a sample of 101 couples in which the women presented with PVD. The actor–partner interdependence model was used in order to investigate both actor and partner effects. This study also examined the role of sexual assertiveness as a mediator of these associations via structural equation modeling. Women completed measures of pain intensity and both members of the couple completed measures of romantic attachment, sexual assertiveness, sexual function, and satisfaction. Results indicated that attachment dimensions did not predict pain intensity. Both anxious and avoidant attachment were associated with lower sexual satisfaction. Only attachment avoidance predicted lower sexual function in women. Partner effects indicated that higher sexual assertiveness in women predicted higher sexual satisfaction in men. Finally, women’s sexual assertiveness was found to be a significant mediator of the relationship between their attachment dimensions, sexual function, and satisfaction. Findings highlight the importance of examining how anxious and avoidant attachment may lead to difficulties in sexual assertiveness and to less satisfying sexual interactions in couples where women suffer from PVD.