Role of P-Glycoprotein in the Distribution of the HIV Protease Inhibitor Atazanavir in the Brain and Male Genital Tract

The blood-testis barrier and blood-brain barrier are responsible for protecting the male genital tract and central nervous system from xenobiotic exposure. In HIV-infected patients, low concentrations of antiretroviral drugs in cerebrospinal fluid and seminal fluid have been reported. One mechanism that may contribute to reduced concentrations is the expression of ATP-binding cassette drug efflux transporters, such as P-glycoprotein (P-gp). The objective of this study was to investigate in vivo the tissue distribution of the HIV protease inhibitor atazanavir in wild-type (WT) mice, P-gp/breast cancer resistance protein (Bcrp)-knockout (Mdr1a^−/−, Mdr1b^−/−, and Abcg2^−/− triple-knockout [TKO]) mice, and Cyp3a^−/− (Cyp) mice. WT mice and Cyp mice were pretreated with a P-gp/Bcrp inhibitor, elacridar (5 mg/kg of body weight), and the HIV protease inhibitor and boosting agent ritonavir (2 mg/kg intravenously [i.v.]), respectively. Atazanavir (10 mg/kg) was administered i.v. Atazanavir concentrations in plasma (C_plasma), brain (C_brain), and testes (C_testes) were quantified at various times by liquid chromatography-tandem mass spectrometry. In TKO mice, we demonstrated a significant increase in atazanavir C_brain/C_plasma (5.4-fold) and C_testes/C_plasma (4.6-fold) ratios compared to those in WT mice (P < 0.05). Elacridar-treated WT mice showed a significant increase in atazanavir C_brain/C_plasma (12.3-fold) and C_testes/C_plasma (13.5-fold) ratios compared to those in vehicle-treated WT mice. In Cyp mice pretreated with ritonavir, significant (P < 0.05) increases in atazanavir C_brain/C_plasma (1.8-fold) and C_testes/C_plasma (9.5-fold) ratios compared to those in vehicle-treated WT mice were observed. These data suggest that drug efflux transporters, i.e., P-gp, are involved in limiting the ability of atazanavir to permeate the rodent brain and genital tract. Since these transporters are known to be expressed in humans, they could contribute to the low cerebrospinal and seminal fluid antiretroviral concentrations reported in the clinic.     

3D reconstruction of peripheral nerves from optical projection tomography images: A method for studying fascicular interconnections and intraneural plexuses

The general microscopic characteristics of nerves are described in several textbooks of histology, but the specific microanatomies of most nerves that can be blocked by anesthesiologists are usually less well known. Our objective was to evaluate the 3D reconstruction of nerve fascicles from optical projection tomography images (OPT) and the ability to undertake an internal navigation exploring the morphology in detail, more specifically the fascicular interconnections. Median and lingual nerve samples were obtained from five euthanized piglets. OPT images of the samples were acquired and 3D reconstruction was performed. The OPT technique revealed the inner structure of the nerves at high resolution, including large and small fascicles, perineurium, interfascicular tissue, and epineurium. The fascicles were loosely packed inside the median nerve and more densely so in the lingual nerve. Analysis of the 3D models demonstrated that the nerve fascicles can show six general spatial patterns. Fascicular interconnections were clearly identified. The 3D reconstruction of nerve fascicles from OPT images opens a new path for research into the microstructure of the inner contents of fascicular nerve groups and their spatial disposition within the nerve including their interconnections. These techniques enable 3D images of partial areas of nerves to be produced and could became an excellent tool for obtaining data concerning the 3D microanatomy of nerves, essential for better interpretation of ultrasound images in clinical practice and thus avoiding possible neurological complications. Clin. Anat. 31:424–431, 2018. © 2017 Wiley Periodicals, Inc.     

Maximum Standard Uptake Value at the Biopsy Site during F-Fluorodeoxyglucose Positron Emission Tomography Does Not Predict the Proliferation Potential of Tumor Cells in Extranodal Natural Killer/T Cell Lymphoma, Nasal Type

No abstract available.     

Another (Internal) Epineurium: Beyond the Anatomical Barriers of Nerves

The epineurium has been accepted as the outer anatomical barrier of the peripheral nerves. Our objective was to characterize the microanatomy of the layers surrounding nerves using different tissue-specific staining methods. Two hundred forty-two cross sections of human sciatic and median nerves, and brachial plexuses of eight fresh unembalmed cadavers, were examined. The samples were fixed in formaldehyde solution and stained with hematoxylin–eosin, Masson's trichrome, or epithelial membrane antigen under standard conditions. Because epithelial membrane antigen only stains the perineurium, we demonstrated using hematoxylin–eosin and Masson's trichrome that there were different collagen layers inside and outside the nerves. All fascicles had a collagen layer that surrounded the perineurium and were in close contact with it, with no adipose tissue between them. Unlike the perineurium, this layer, an “internal epineurium,” contained no cells, and it surrounded one or a small group of fascicles. Bundling these fascicles or small groups of fascicles together was the true epineurium, and between the true and internal epineurium, we consistently found an adipose-containing compartment. More proximal to this, the tibial and common peroneal nerves were bundled together by another collagen layer, the circumneurium, which also had a fat-cell-containing compartment deep to it. There were scattered collagen fibers among the adipocytes. Using tissue-specific staining, we were able to demonstrate a collagen layer, the “internal epineurium.” Outside the nerves, we identified several fat-containing concentric compartments. Those compartments were limited by collagen fiber layers that were also similar to the epineurium. Clin. Anat. 33:199–206, 2020. © 2019 Wiley Periodicals, Inc.     

Desarrollo y validación de la versión abreviada del Transsexual Voice Questionnaire for Male-to-Female Transsexuals en español

ObjectiveThe aim of this study was to create and validate an abbreviated version of the Spanish Transsexual Voice Questionnaire for Male-to-Female Transsexuals (SvTVQ^MtF).SettingThe study was conducted by two referral hospitals for voice feminization surgery and by a university department of psychology and speech therapy, all in Spain.Subjects and methodsWe prospectively studied 51 male-to-female transsexuals who underwent voice feminization surgery between January 2017 and December 2018. The SvTVQ^MtF was completed before and after surgery, and the 10 items with the greatest variation were selected by clinical consensus of an expert panel to develop the short version of the SvTVQ^MtF (SvTVQ^MtF-10). The correlation between the total score and the score for each item on the SvTVQ^MtF and the SvTVQMtF-10 was studied. The internal consistency of the SvTVQ^MtF-10 was analysed.ResultsGood correlation (Pearson coefficient above .90) was found between the two questionnaires. A significant correlation was found between the total SvTVQ^MtF-10 score and the score for each item. A significant negative correlation was found between the SvTVQ^MtF and fundamental frequency after voice feminization surgery. Cronbach's α was .79.ConclusionThe SvTVQ^MtF-10 is a valid short version of the SvTVQ^MtF and can be used to quantify voice-related quality of life in MtF transsexuals.     

Seizure control in Unverricht‐Lundborg disease: a single‐centre study

New antiepileptic drug (AED) options for generalised seizure types have been adopted for use as treatment for Unverricht‐Lundborg disease. Whether this has led to improved seizure control or functional outcome in ULD patients remains obscure. We retrospectively identified all patients seen at Helsinki University Hospital due to Unverricht‐Lundborg disease during 2003–2008 in order to determine which AED treatments had been retained for long‐term use. The majority of the patients had severe functional disabilities. In the year preceding the last hospital visit, all patients (n=20) were receiving polytherapy and 14 patients had been free of tonic‐clonic seizures. During follow‐up, improvement in myoclonia had been recorded for the majority of patients with either add‐on piracetam, topiramate, or levetiracetam, but valproate was still in use by all patients. Treatment with lamotrigine had been started and retained less often relative to other AEDs. Add‐on AED treatment was often associated with significant adverse effects. Unverricht‐Lundborg disease patients may benefit from add‐on treatment with levetiracetam or topiramate for seizure control. Treatment of eventual comorbidities with other than AEDs is also discussed.