Expression of concentrative nucleoside transporters SLC28 (CNT1, CNT2, and CNT3) along the rat nephron: effect of diabetes

BACKGROUND: The renal reabsorption of natural nucleosides and a variety of nucleoside-derived drugs relies on the function of the apically located, Na(+)-dependent, concentrative nucleoside transporters CNT1, CNT2, and CNT3 (SLC28A1, SLC28A2, and SLC28A3). The aims of this study were to determine the segmental localization of the three SLC28 family members and to establish whether streptozotocin-induced diabetes alters their expression. METHODS: SLC28 expression was measured by real-time polymerase chain reaction (PCR) on microdissected sections of rat nephrons. Diabetes was induced by streptozotocin treatment and the biochemical profiles of control, diabetic, and insulin-treated rats were established. The effect of diabetes on SLC28 expression was assessed in those segments that significantly express SLC28 genes. RESULTS: CNT1-3 mRNAs were expressed in the proximal tubule and glomerulus. In addition, CNT2 and CNT3 mRNAs were expressed in the outer medullary and cortical collecting duct, respectively. Diabetes reduced expression of the three CNTs in almost all nephron segments, and this effect was not prevented by an insulin treatment that normalized all blood and urine parameters. Diabetes increased CNT1 and CNT3 expression in the glomerulus and insulin treatment decreased it. CONCLUSION: The relative distribution of SLC28 gene expression suggests a role for the proximal tubule in renal nucleoside clearance and an accessory role for CNT2 and CNT3, in adenosine-mediated regulation of collecting duct functions. Diabetes probably may impair nucleoside clearance independently of insulin.     

Partial Portal Vein Ligation Plus Thioacetamide: A Method to Obtain a New Model of Cirrhosis and Chronic Portal Hypertension in the Rat

To obtain a new model of chronic portal hypertension in the rat, two classical methods to produce portal hypertension, partial portal vein ligation and the oral administration of thioacetamide (TAA), have been combined. Male Wistar rats were divided into four groups: 1 (control; n?=?10), 2 [triple partial portal vein ligation (TPVL); n?=?9], 3 (TAA; n?=?11), and 4 (TPVL plus TAA; n?=?9). After 3 months, portal pressure, types of portosystemic collateral circulation, laboratory hepatic function tests (aspartate aminotransferase, alanine aminotransferase, bilirubin, alkaline phosphatase, and gamma-glutamyl transpeptidase) and liver histology were studied. The animals belonging to group 2 (TPVL) developed extrahepatic portosystemic collateral circulation, associated with mesenteric venous vasculopathy without hepatic destructurization or portal hypertension. Animals from group 3 (TAA) developed cirrhosis and portal hypertension but not extrahepatic portosystemic collateral circulation, or mesenteric venous vasculopathy. Finally, the animals from group 4 (TPVL?+?TAA) developed cirrhosis, portal hypertension, portosystemic collateral circulation, and mesenteric venous vasculopathy. The association of TPVL and TAA can be used to obtain a model of chronic portal hypertension in the rat that includes all the alterations that patients with hepatic cirrhosis usually have. This could, therefore, prove to be a useful tool to study the pathophysiological mechanisms involved in these alterations.     

Efficacy, Tolerance, and Safety of Mammalian Target of Rapamycin Inhibitors as Rescue Immunosuppressants in Liver Transplantation

Background

Mammalian target of rapamycin (mTOR) inhibitors behave as potent immunosuppressants which have the advantages, with respect to calcineurin inhibitors (CNI: cyclosporine or tacrolimus), of no nephrotoxicity and inhibition of cell proliferation. They are particularly suitable for patients with renal insufficiency or neoplasias.

Materials and Methods

Twenty-two liver transplant patients were immunosuppressed with everolimus or sirolimus as rescue therapy after CNI treatment: 7 hepatocellular carcinomas; 5 de novo malignancies; 4 renal insufficiencies; 4 chronic rejections; and 2 acute rejection episodes.

Results

There were 16.7% tumor recurrences, and 25% improvements in renal function, 75% in chronic rejection, and 50% in acute rejection. There was no incidence of rejection, kidney failure, gastrointestinal intolerance, hydrocarbon intolerance, hypertension, or arterial or venous thrombosis. We observed incidences of 50% for hypercholesterolemia, 31.8% for hypertriglyceridemia, 22.7% for thrombocytopenia, 18.2% for leukopenia, and 9.1% for anemia. The intercurrent infection rate was 13.6%, including oral thrush in 13.6%. Lower limb edema occurred in 13.6%, with 1 case of facial edema and 1 of alopecia.

Conclusions

mTOR inhibitors were safe immunosuppressive drugs whose side effects were controlled and easily managed. They have advantages with respect to CNI due to their slight effects on kidney function and lack of promotion of diabetes mellitus. Although their long-term effectiveness for control of neoplastic diseases is yet to be seen, they can be used safely in these patients with no incidence of rejection. Their effectiveness to control chronic rejection seems significant, but it is doubtful for steroid-resistant acute rejection episodes.     

Dolutegravir plus rilpivirine as dual regimen in virologically suppressed HIV-1 infected patients in a clinical setting

Objectives: There are scarce data on the combination of dolutegravir (DTG) plus rilpivirine (RPV) in the real world, including patients with hepatitis C virus (HCV) coinfection, toxicity or previous failure, or at risk for severe drug–drug interactions (DDIs).

Methods: Prospective cohort study of virologically suppressed HIV-1 infected patients, without resistance to DTG or RPV, switched to this dual regimen because of toxicity or risk of DDIs (NCT02491242).

Results: Overall, 102 patients (mean age 54 years, 28% women) were included. Fifty-seven were coinfected with HCV (fibrosis grade 4 in 27 cases, 1 liver transplantation). Seven patients had chronic kidney disease (1 renal transplantation). At week 48, only 1 virologic failure occurred (<1%), and 6 patients (6%) left the regimen (3 with central nervous system adverse events, 1 each due to pregnancy, metformin interaction, and lost to follow up). Thus, the overall treatment success rates were 93% (95% CI, 88%–98%; ITT-e, snapshot analysis) and 96% (95% CI, 92%–99%; per protocol analysis). The CD4/CD8 ratio increased slightly (median, +0.03). Triglycerides levels improved significantly (?18.8%, p?<?0.01). The creatinine-based estimated glomerular filtration rate decreased by a mean of ?8.4?ml/min/1.73 m², but tubular renal parameters improved. A paired dual X-ray absorptiometry scan showed a mild improvement in spine (mean, +1.15%; ?0.57 to +3.3%) and in femoral neck bone mineral density (mean, +0.4%; ?3.3% to +2.57%).

Conclusions: In the clinical setting, switching to the combination of DTG plus rilpivirine in virologically suppressed HIV-1 patients is effective and safe, and improves lipid, renal and bone evolution.

Trial registration: ClinicalTrials.gov identifier: NCT02491242.     

Review: Head and neck squamous cell carcinoma in sub-Saharan Africa

Aim

Review the literature from 1990 to 2013 to determine known anatomic sites, risk factors, treatments, and outcomes of head and neck squamous cell carcinoma (HNSCC) in sub-Saharan Africa.

Methods

Using a systematic search strategy, literature pertaining to HNSCC in sub-Saharan Africa was reviewed and patient demographics, anatomic sites, histology, stage, treatment, and outcomes were abstracted. The contributions of human immunodeficiency virus (HIV), human papillomavirus (HPV) and behavioural risk factors to HNSCC in the region were assessed.

Results

Of the 342 papers identified, 46 were utilized for review, including 8611 patients. In sub-Saharan Africa, the oropharyngeal/oral cavity was found to be the most common site, with 7750 cases (90% of all cases). Few papers distinguished oropharyngeal from oral cavity, making identification of possible HPV-associated oropharyngeal squamous cell carcinoma (SCC) difficult. SCC of the nasopharynx, nasal cavity, or paranasal sinuses was identified in 410 patients (4.8% of all cases). Laryngeal SCC was found in 385 patients (4.5% of all cases), and only 66 patients (0.8% of all cases) with hypopharyngeal SCC were identified. In 862 patients with data available, 43% used tobacco and 42% used alcohol, and reported use varied widely and was more common in laryngeal SCC than that of the oropharyngeal/oral cavity. Toombak and kola nut use was reported to be higher in patients with HNSCC. Several papers reported HIV-positive patients with HNSCC, but it was not possible to determine HNSCC prevalence in HIV-positive compared to negative patients. Reports of treatment and outcomes were rare.

Conclusions

The oropharyngeal/oral cavity was by far the most commonly reported site of HNSCC reported in sub-Saharan Africa. The roles of risk factors in HNSCC incidence in sub-Saharan Africa were difficult to delineate from the available studies, but a majority of patients did not use tobacco and alcohol.     

Situating language in a minimal social context: how seeing a picture of the speaker’s face affects language comprehension

Natural use of language involves at least two individuals. Some studies have focused on the interaction between senders in communicative situations and how the knowledge about the speaker can bias language comprehension. However, the mere effect of a face as a social context on language processing remains unknown. In the present study, we used event-related potentials to investigate the semantic and morphosyntactic processing of speech in the presence of a photographic portrait of the speaker. In Experiment 1, we show that the N400, a component related to semantic comprehension, increased its amplitude when processed within this minimal social context compared to a scrambled face control condition. Hence, the semantic neural processing of speech is sensitive to the concomitant perception of a picture of the speaker’s face, even if irrelevant to the content of the sentences. Moreover, a late posterior negativity effect was found to the presentation of the speaker’s face compared to control stimuli. In contrast, in Experiment 2, we found that morphosyntactic processing, as reflected in left anterior negativity and P600 effects, is not notably affected by the presence of the speaker’s portrait. Overall, the present findings suggest that the mere presence of the speaker’s image seems to trigger a minimal communicative context, increasing processing resources for language comprehension at the semantic level.     

Caffeine increases striatal dopamine D2/D3 receptor availability in the human brain

Caffeine, the most widely consumed psychoactive substance in the world, is used to promote wakefulness and enhance alertness. Like other wake-promoting drugs (stimulants and modafinil), caffeine enhances dopamine (DA) signaling in the brain, which it does predominantly by antagonizing adenosine A_2A receptors (A_2AR). However, it is unclear if caffeine, at the doses consumed by humans, increases DA release or whether it modulates the functions of postsynaptic DA receptors through its interaction with adenosine receptors, which modulate them. We used positron emission tomography and [¹¹C]raclopride (DA D₂/D₃ receptor radioligand sensitive to endogenous DA) to assess if caffeine increased DA release in striatum in 20 healthy controls. Caffeine (300 mg p.o.) significantly increased the availability of D₂/D₃ receptors in putamen and ventral striatum, but not in caudate, when compared with placebo. In addition, caffeine-induced increases in D₂/D₃ receptor availability in the ventral striatum were associated with caffeine-induced increases in alertness. Our findings indicate that in the human brain, caffeine, at doses typically consumed, increases the availability of DA D₂/D₃ receptors, which indicates that caffeine does not increase DA in the striatum for this would have decreased D₂/D₃ receptor availability. Instead, we interpret our findings to reflect an increase in D₂/D₃ receptor levels in striatum with caffeine (or changes in affinity). The association between increases in D₂/D₃ receptor availability in ventral striatum and alertness suggests that caffeine might enhance arousal, in part, by upregulating D₂/D₃ receptors.