Pendrin as a novel target for diuretic therapy

The Cl(-)/HCO(3)(-) exchanger pendrin (SLC26A4, PDS) and the thiazide-sensitive NaCl cotransporter NCC (SLC12A3) are expressed on the apical membranes of distal nephron segments and mediate salt absorption, with pendrin working in tandem with the epithelial Na channel (ENaC) and NCC working by itself. Pendrin is expressed on the apical membrane of intercalated cells in late distal convoluted tubule (DCT), connecting tubule (CNT) and the cortical collecting duct (CCD) whereas the thiazide-sensitive NaCl cotransporter NCC is primarily detected on the apical membrane of DCT cells. Recent studies indicate that pendrin expression is increased in kidneys of NCC knockout mice, raising the possibility that pendrin and NCC can compensate for loss of the other by increasing their expression and activity. Current investigations in our laboratories demonstrate that pendrin plays an important role in compensatory salt absorption in response to the loop diuretics and the thiazide derivatives. These studies further demonstrate that whereas single deletion of pendrin or NCC does not cause salt wasting in mutant mice under baseline conditions, double knockout of pendrin and NCC causes profound polyuria and polydipsia, along with salt wasting under basal conditions. As a result, animals develop significant dehydration. We propose that pharmacologic inhibition of pendrin and NCC can provide a novel and strong diuretic regimen for patients with fluid overload, including those with congestive heart failure, nephrotic syndrome or renal failure.     

Effects of playing surface (hard and clay courts) on heart rate and blood lactate during tennis matches played by high-level players

The aim of this study was to compare tennis matches played on clay (CL) and resin (R) courts. Six matches were played (3 on CL courts and 3 on R courts) by 6 high-level players. Heart rate (HR) was monitored continuously while running time (4.66 m), and blood lactate concentration ([La]) were measured every 4 games. Mean duration of points and effective playing time (EPT) were measured for each match. Mean HR (154 ± 12 vs. 141 ± 9 b · min(-1)) and [La] values (5.7 ± 1.8 vs. 3.6 ± 1.2 mmol · L(-1)) were significantly higher on CL (p < 0.05). The [La] increased significantly during the match on CL court. Mean duration of rallies (8.5 ± 0.2 vs. 5.9 ± 0.5 seconds) and EPT (26.2 ± 1.9 vs. 19.5 ± 2.0%) were significantly longer (p < 0.05) on CL. Running time values in speed tests were not significantly different between CL and R. Running time performance was not significantly decreased during the match, whatever the playing surface. This study shows that the court surface influences the characteristics of the match and the player's physiological responses. The court surface should be a key factor for consideration when coaches determine specific training programs for high-level tennis players.     

Diversity of response to Trypanosoma brucei gambiense infections in the Forecariah mangrove focus (Guinea): perspectives for a better control of sleeping sickness

At a time when human African trypanosomiasis (HAT) elimination again seems a reachable goal in many parts of sub-Saharan Africa, it is becoming increasingly important to characterise the factors involved in disease resurgence or maintenance to develop sustainable control strategies. In this study conducted in the Forecariah mangrove focus in Guinea, HAT patients and serological suspects (SERO) were identified through mass screening of the population with the Card Agglutination Test for Trypanosomiasis (CATT) and were followed up for up to 2 years. Analysis of the samples collected during the follow-up of HAT patients and SERO was performed with PCR (TBR1/TBR2) and the trypanolysis serological test (TL) in order to clarify the role played by these individuals in the epidemiology of HAT. PCR positivity was higher in TL⁺ than in SERO TL⁻ (50% vs. 18%, respectively). Whereas CATT plasma titres decreased both in treated HAT patients and SERO TL⁻, SERO TL⁺ maintained high CATT titres. Four out of 17 SERO TL⁺ developed HAT during the study. These results strongly suggest that SERO TL⁺ individuals are asymptomatic carriers. In the context where disease prevalence is sufficiently low, treating SERO TL⁺ individual may thus be of crucial importance in order to cut transmission.     

West African Cattle Farmers’ Perception of Tick-Borne Diseases

Worldwide, cattle production is struggling to face the negative impacts caused by ticks and Rhipicephalus (Boophilus) microplus is one of the most harmful ticks for livestock. Most of the people in West Africa depend on cattle farming and subsistence agriculture. The presence of ticks on cattle is a major problem faced by smallholder farmers who fight for their livelihood. National and regional tick control programs could assist these rural communities in protecting their livelihoods against ticks and tick-borne diseases, but only if they take into account the targeted herders and their perception on cattle management and tick control. This paper aims to provide a better insight in the socio-economic characteristics of Beninese cattle farmers, and their perception on tick burden, as well as to document common tick control strategies. Different tick species and their seasonality are well understood by cattle herders. For tick control, many still use manual tick removal, especially in the north of the country. The high cost of acaricides, the lack of financial means of African farmers, and of the local stockbreeders in particular, limits the use of acaricides in livestock breeding in Benin. While aiming to increase the meat or milk production of their animals, stockbreeders who can afford it sometimes turn to an abusive use of acaricides, which might in time lead to an increase in tick resistance. This study remains one of the rare studies to report extensively on the perceptions of West African cattle herders.     

Conformational motion of the ABC transporter MsbA induced by ATP hydrolysis

We measured the amplitude of conformational motion in the ATP-binding cassette (ABC) transporter MsbA upon lipopolysaccharide (LPS) binding and following ATP turnover by pulse double electron-electron resonance and fluorescence homotransfer. The distance constraints from both methods reveal large-scale movement of opposite signs in the periplasmic and cytoplasmic part of the transporter upon ATP hydrolysis. LPS induces distinct structural changes that are inhibited by trapping of the transporter in an ATP post-hydrolysis intermediate. The formation of this intermediate involves a 33-Å distance change between the two ABCs, which is consistent with a dimerization-dissociation cycle during transport that leads to their substantial separation in the absence of nucleotides. Our results suggest that ATP-powered transport entails LPS sequestering into the open cytoplasmic chamber prior to its translocation by alternating access of the chamber, made possible by 10–20-Å conformational changes.     

Effects of Acute Supramaximal Cycle Exercise on Plasma FFA Concentration in Obese Adolescent Boys

Aims

The aims of the present study are 1) to evaluate the free fatty acid (FFA) profile and 2) to determine the relative anaerobic and aerobic contributions to total energy consumption during repeated supramaximal cycling bouts (SCE) in adolescent boys with different body weight statuses.

Materials and Methods

Normal-weight (NW), overweight (OW), and obese (OB) adolescent boys (n =15 per group) completed a SCE sessions consisted of 6 x 6s maximal sprints with 2 min of passive rest between each repetition. Plasma FFA levels were determined at rest, immediately after a 10 min warm-up, and immediately at the end of SCE. The anaerobic and aerobic contributions (%) were measured via repeated SCE bouts. Insulin resistance was calculated using the homoeostatic model assessment (HOMA-IR) index.

Results

The FFA concentrations measured immediately after SCE were higher in the OB group than in the OW and NW (p<0.01 and p<0.01, respectively) groups. Moreover, the anaerobic contributions to SCE were significantly lower in obese adolescents (p<0.01) and decreased significantly during the 2^nd, 3^rd and 4^th repetitions. The FFA levels were significantly associated with the HOMA-IR index and aerobic contribution among adolescent boys (r=0.83 and r=0.91, respectively, p<0.01).

Conclusion

In contrast to the NW and OW groups, there is an increase in lipid mobilization and sift to aerobic energy metabolism during SCE in the OB group.     

Novel 3-chloro-6-nitro-1H-indazole derivatives as promising antileishmanial candidates: synthesis,biological activity,and molecular modelling studies

An efficient pathway was disclosed for the synthesis of 3-chloro-6-nitro-1H-indazole derivatives by 1,3-dipolar cycloaddition on dipolarophile compounds 2 and 3. Faced the problem of separation of two regioisomers, a click chemistry method has allowed us to obtain regioisomers of triazole-1,4 with good yields from 82 to 90% were employed. Also, the antileishmanial biological potency of the compounds was achieved using an MTT assay that reported compound 13 as a promising growth inhibitor of Leishmania major. Molecular docking demonstrated highly stable binding with the Leishmania trypanothione reductase enzyme and produced a network of hydrophobic and hydrophilic interactions. Molecular dynamics simulations were performed for TryR-13 complex to understand its structural and intermolecular affinity stability in a biological environment. The studied complex remained in good equilibrium with a structure deviation of ∼1–3 Å. MM/GBSA binding free energies illustrated the high stability of TryR-13 complex. The studied compounds are promising leads for structural optimisation to enhance the antileishmanial activity.     

ANG II controls Na+-K+(NH+4)-2Cl- cotransport via 20-HETE and PKC in medullary thick ascending limb

Cell pH was monitored in medullary thick ascending limbs todetermine effects of ANG II onNa⁺-K⁺(NH⁺₄)-2Clcotransport. ANG II at 10¹⁶to 10¹² M inhibited30-50% (P < 0.005),but higher ANG II concentrations were stimulatory compared with the10¹² M ANG II levelcotransport activity; eventually,10⁶ M ANG II stimulated34% cotransport activity (P < 0.003). Inhibition by 10¹²M ANG II was abolished by phospholipase C (PLC), diacylglycerol lipase,or cytochrome P-450-dependentmonooxygenase blockade; 10¹² M ANG II had no effectadditive to inhibition by 20-hydroxyeicosatetranoic acid (20-HETE).Stimulation by 10⁶ M ANG IIwas abolished by PLC and protein kinase C (PKC) blockade and waspartially suppressed when the rise in cytosolicCa²⁺ was prevented. All ANG IIeffects were abolished by DUP-753 (losartan) but not by PD-123319. Thus10¹² M ANG II inhibitsvia 20-HETE, whereas 5 × 10¹¹ M ANG II stimulatesvia PKCNa⁺-K⁺(NH⁺₄)-2Clcotransport; all ANG II effects involveAT₁ receptors and PLC activation.