Differential Mechanisms of Tenofovir and Tenofovir Disoproxil Fumarate Cellular Transport and Implications for Topical Preexposure Prophylaxis

Intravaginal rings releasing tenofovir (TFV) or its prodrug, tenofovir disoproxil fumarate (TDF), are being evaluated for HIV and herpes simplex virus (HSV) prevention. The current studies were designed to determine the mechanisms of drug accumulation in human vaginal and immune cells. The exposure of vaginal epithelial or T cells to equimolar concentrations of radiolabeled TDF resulted in over 10-fold higher intracellular drug levels than exposure to TFV. Permeability studies demonstrated that TDF, but not TFV, entered cells by passive diffusion. TDF uptake was energy independent but its accumulation followed nonlinear kinetics, and excess unlabeled TDF inhibited radiolabeled TDF uptake in competition studies. The carboxylesterase inhibitor bis-nitrophenyl phosphate reduced TDF uptake, suggesting saturability of intracellular carboxylesterases. In contrast, although TFV uptake was energy dependent, no competition between unlabeled and radiolabeled TFV was observed, and the previously identified transporters, organic anion transporters (OATs) 1 and 3, were not expressed in human vaginal or T cells. The intracellular accumulation of TFV was reduced by the addition of endocytosis inhibitors, and this resulted in the loss of TFV antiviral activity. Kinetics of drug transport and metabolism were monitored by quantifying the parent drugs and their metabolites by high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS). Results were consistent with the identified mechanisms of transport, and the exposure of vaginal epithelial cells to equimolar concentrations of TDF compared to TFV resulted in ∼40-fold higher levels of the active metabolite, tenofovir diphosphate. Together, these findings indicate that substantially lower concentrations of TDF than TFV are needed to protect cells from HIV and HSV-2.     

Food Intolerance,Diet Composition,and Eating Patterns in Functional Dyspepsia Patients

The aims of this study are to investigate dietary factors, food intolerance, and the body mass index data, as an indicator of nutritional status, in functional dyspepsia patients. Forty-one functional dyspepsia patients and 30 healthy volunteers answered a standardized questionnaire to identify eating habits and food intolerance, and then completed a 7-day alimentary diary. There was no significant difference in daily total caloric intake between patients and controls. Patients associated their symptoms with the ingestion of several foods, but in general maintained their regular intake, with the exception of a small reduction in the proportion of fat in comparison with controls (median 28 vs. 34%; P = 0.001). No patient was underweight. In conclusion, our results suggest that food intolerance has no remarkable influence on food pattern and nutritional status in most functional dyspepsia patients. Further studies are necessary to clarify the role of fat in the generation of dyspeptic symptoms.     

Electroencephalographic evidence of brainstem recruitment during scorpion envenomation

Scorpion envenomation is a public health problem in Brazil, with most severe cases occuring in children under the age of 5 years (0.6% lethality). In fact, the toxic fractions of the Tityus serrulatus scorpion venom (TSSV) have greater permeability across the BBB of weanling rats when compared to adults. Although EEG alterations have been reported in up to 75% of pediatric severe cases, the role of the CNS in envenomation morbidity is still in debate. Our working hypothesis is that the neural substrates that play a major role in morbidity generate activity undetectable from EEG scalp leads. Twenty one-day-old rats (n=18) were injected s.c. with the deadliest toxic fraction of the TSSV, tityustoxin (TsTX; 2xDL50=6 mg/kg). EEG leads were stereotaxicaly implanted in the nucleus of the solitary tract (NTS) and left parietal cortex. EEG and ECG were continuously monitored by a video EEG system until death or for a maximum period of 240 min. An experimental group pre-treated with carbamazepine (CBZ) was added in order to better access the cause-effect relationship between neural discharges and the systemic ECG alterations. High amplitude discharges in the NTS, which correlated to cardiac alterations, were recorded soon after administration of TsTX. Abnormal electrographic activity spread throughout the cortex only later in the recording. As expected, the CBZ treatment increased the latency for the first epileptiform discharge, decreased EEG/ECG alterations and increased the general survival time. In summary: peripheral scorpion toxin inoculation recruits brainstem involved in cardiovascular control and initial electrographic activity was undetectable from the cortical electrode.     

Central granular cell odontogenic tumor: a histopathologic and immunohistochemical study

The central granular cell odontogenic tumor (CGCOT) is a rare lesion that usually affects the posterior region of the mandible of young adults. We present a case of CGCOT involving the mandible of a 20-year-old white woman, emphasizing the immunohistochemical characteristics using a large panel of antibodies. The lesion was removed surgically, and after 4 years of follow-up, there are no evidences of recurrences. The odontogenic epithelium (OE) showed positivity for cytokeratins (CKs) AE1/AE3, 34βE12, CK5, CK7, CK8, CK14, CK19, E-cadherin, β-catenin, CD138, and p63. The granular cells were positive for vimentin, CD68, lysozyme, muscle-specific actin, α-smooth muscle actin, calponin, neuron-specific enolase (NSE), CD138, and bcl-2. Dendritic-like cells surrounding the OE displayed positivity for vimentin, CD1a, S100, CD68, and bcl-2, but it was negative for factor XIIIa, supporting a Langerhans cell phenotype. Ki-67 labeling index was 1.8%, whereas p53 was negative. These data confirm the benign nature of CGCOT, the association of OE with Langerhans cells, and a variable phenotype of the granular cells.     

Home Advantage in High-Level Volleyball Varies According to Set Number

The aim of the present study was to identify the probability of winning each Volleyball set according to game location (home, away). Archival data was obtained from 275 sets in the 2005 Men’s Senior World League and 65,949 actions were analysed. Set result (win, loss), game location (home, away), set number (first, second, third, fourth and fifth) and performance indicators (serve, reception, set, attack, dig and block) were the variables considered in this study. In a first moment, performance indicators were used in a logistic model of set result, by binary logistic regression analysis. After finding the adjusted logistic model, the log-odds of winning the set were analysed according to game location and set number. The results showed that winning a set is significantly related to performance indicators (Chisquare₍₁₈₎=660.97, p<0.01). Analyses of log-odds of winning a set demonstrate that home teams always have more probability of winning the game than away teams, regardless of the set number. Home teams have more advantage at the beginning of the game (first set) and in the two last sets of the game (fourth and fifth sets), probably due to facilities familiarity and crowd effects. Different game actions explain these advantages and showed that to win the first set is more important to take risk, through a better performance in the attack and block, and to win the final set is important to manage the risk through a better performance on the reception. These results may suggest intra-game variation in home advantage and can be most useful to better prepare and direct the competition.

Key points

• Home teams always have more probability of winning the game than away teams.
• Home teams have higher performance in reception, set and attack in the total of the sets.
• The advantage of home teams is more pronounced at the beginning of the game (first set) and in two last sets of the game (fourth and fifth sets) suggesting intra-game variation in home advantage.
• Analysis by sets showed that home teams have a better performance in the attack and block in the first set and in the reception in the third and fifth sets.

Key words: Performance indicators, binary logistic regression, game analysis, team sport     

Evaluation of the In Vivo Activity of Different Concentrations of Clerodendrum Umbellatum Poir Against Schistosoma Mansoni Infection in Mice

Clerodendrum umbellatum Poir (Verbenaceae) is traditionally used in Cameroon for the treatment of many diseases including intestinal helminthiasis. This study was undertaken to assess the in vivo antischistosomal activity of its leaves aqueous extract on a Schistosoma mansoni mice model and to determine the most effective dose of this extract. Mice showing a patent infection of S. mansoni were daily treated with C. umbellatum leaves aqueous extract at the doses of 40, 80 or 160 mg/kg body weight for 14 days. Seven days after administration of the extract, schistosomicidal activity was evaluated on the liver and spleen weights, faecal eggs releasing, liver egg count and worm burden. Treatment using C. umbellatum leaves aqueous extract resulted in an important reduction in faecal egg output by 75.49 % and 85.14 % for 80 mg/kg and 160 mg/kg of the extract respectively. These reduction rates did not differ significantly from the 100 % obtained in the group of infected mice treated with 100 mg/kg of praziquantel. C. umbellatum leaves aqueous extract was lethal to S. mansoni worm. A 100 % reduction rate was recorded in the group of infected mice treated with 160 mg/kg of the extract, as well as in praziquantel-treated mice. An amelioration of the hepatosplenomegaly was noticed in both the extract-treated mice and the praziquantel-treated mice. From these results, we can conclude that C. umbellatum leaves aqueous extract demonstrated schistosomicidal properties in S. mansoni model at doses of at least 80 mg/kg body weight.     

Role of endoglin and VEGF family expression in colorectal cancer prognosis and anti-angiogenic therapies

Colorectal cancer (CRC) is one of the cancer models and most of the carcinogenic steps are presently well understood. Therefore, successful preventive measures are currently used in medical practice. However, CRC is still an important public health problem as it is the third most common cancer and the fourth most frequent cause of cancer death worldwide. Nowadays, pathologic stage is a unique and well-recognized prognostic indicator, however, more accurate indicators of the biologic behavior of CRC are expected to improve the specificity of medical treatment. Angiogenesis plays an important role in the growth and progression of cancer but its role as a prognostic factor is still controversial. Probably the most important clinical implication of tumor angiogenesis is the development of anti-angiogenic therapy. The goal of this review is to critically evaluate the role of angiogenic markers, assessed by either endoglin-related microvessel density or expression of vascular endothelial growth factor family members in the CRC setting and discuss the role of these angiogenic markers in anti-angiogenic therapies.