Efficacy of tolvaptan on advanced chronic kidney disease with heart failure: a randomized controlled trial

Clinical and Experimental Nephrology - Tolvaptan (TLV) is reported to improve diuretic effects in patients with chronic kidney disease (CKD) when furosemide (FUR) is not sufficiently effective....     

Comparison of oral flora before and after triple therapy for Helicobacter pylori eradication in patient with gastric disease

Odontology - The oral cavity is recognized as a major route for infection by Helicobacter pylori, which colonizes the gastric mucosa. Therapeutic options for elimination in patients with digestive...     

Analysis of Metal Contamination and Bioindicator Potential of Predatory Fish Species Along Contas River Basin in Northeastern Brazil

Samples of two carnivore fish species (Hoplias malabaricus and Serrasalmus brandtii) were collected along Contas River, northeastern Brazil, to determine the levels of Co, Cr, Cu, Fe, Mn, Ni and Pb in edible and non-edible tissues of these important local fisheries resources. Lead could not be quantified in most of the samples, while the other metals were detected in both species. In edible parts, Cr levels were above Brazilian threshold limits in all specimens and Ni was at high concentration in S. brandtii individuals from one collection site. In non-edible parts (viscera), besides Cr, Cu concentration was higher than that recommended by Brazilian laws. Both fish species proved to be sensitive to environmental contamination. Despite the different ecological characteristics, such as vagility and feeding strategy, these fish showed that aquatic predators are efficient bioindicators of water quality and biomagnification.     

The role of percutaneous balloon compression in the treatment of trigeminal neuralgia recurring after other surgical procedures

Trigeminal neuralgia (TN) recurring after surgery can be difficult to treat. Treatment algorithms have not been standardized or universally accepted. Here we investigated the effectiveness of percutaneous balloon compression (PBC) in the treatment of patients with TN recurrence after other surgical techniques and analyzed the role of some clinical and operative factors in determining the prognosis. The records of 22 patients (13 M and 9 F) suffering recurrent TN after one (2 gamma knife surgery, 5 percutaneous radiofrequency rhizotomy, 6 percutaneous retrogasserian glycerol rhizotomy, 3 microvascular decompression) or more (6 patients) procedures and submitted to PBC at our institution from January 2003 to February 2012 were reviewed. Seven patients had TN related to multiple sclerosis (MS). Mean follow-up was 51.81 ± 26.63 months. 81.81 % of patients reported an acute pain relief. No major complication was observed after PBC. Eight patients (36.36 %) experienced pain recurrence and underwent one (five patients) or more (three patients) PBC. At the last follow-up, we obtained an excellent outcome (BNI I–II) in 16 patients out of 22 (72.72 %) and a good outcome (BNI III) in the remaining six. No patients had an uncontrolled pain. The lack of history of MS (p = 0.0174), the pear-like shape of the balloon at the operation (p = 0.0234) and a compression time <5 min (p < 0.05) were associated to higher pain-free survival. Considering these results PBC could be considered a useful technique for patients whose pain recurs after other procedures.     

Estimating the seroprevalence of chikungunya virus exposure in Shimoga district,Karnataka state: A hospital-based study during 2014-2018

Chikungunya fever is a viral disease transmitted to humans by the bite of infected mosquitoes. The disease is characterized by fever, headache, rash, severe joint, and muscle pain. To evaluate the disease burden in the population and the effectiveness of public health measures, periodic seroprevalence surveys are essential. Chikungunya outbreaks were reported from many Asian countries since 2005, after more than three decades of disappearance. The study aimed to estimate the seroprevalence of the chikungunya virus in southern parts of Karnataka state, through demonstrating chikungunya virus-specific neutralizing antibodies. A cross-sectional study was carried out using 509 archived blood samples from a hospital-based acute febrile illness surveillance project, representative of the period between June 2014 and 2018. The study reported a 3.7% seroprevalence of chikungunya virus-neutralizing antibodies in Thirthahalli and Hosanagara taluks of South Karnataka. The low prevalence of chikungunya-neutralizing antibodies indicates that a major population is unexposed and prone to future outbreaks.     

Structure-guided engineering of tick evasins for targeting chemokines in inflammatory diseases

As natural chemokine inhibitors, evasin proteins produced in tick saliva are potential therapeutic agents for numerous inflammatory diseases. Engineering evasins to block the desired chemokines and avoid off-target side effects requires structural understanding of their target selectivity. Structures of the class A evasin EVA-P974 bound to human CC chemokine ligands 7 and 17 (CCL7 and CCL17) and to a CCL8-CCL7 chimera reveal that the specificity of class A evasins for chemokines of the CC subfamily is defined by conserved, rigid backbone–backbone interactions, whereas the preference for a subset of CC chemokines is controlled by side-chain interactions at four hotspots in flexible structural elements. Hotspot mutations alter target preference, enabling inhibition of selected chemokines. The structure of an engineered EVA-P974 bound to CCL2 reveals an underlying molecular mechanism of EVA-P974 target preference. These results provide a structure-based framework for engineering evasins as targeted antiinflammatory therapeutics.

While some proteins exhibit absolute specificity for a unique binding partner, many others display “multispecificity,” whereby they interact with several, but not all, members of a partner protein family (1, 2). Understanding how proteins achieve such selectivity provides a basis for rational engineering to regulate alternative targets. In this study, we investigated the structural basis for multispecific recognition of human proinflammatory chemokines by tick evasin proteins.Chemokines are the master regulators of leukocyte-trafficking, the unifying feature of immune homeostasis and all inflammatory diseases (3). Chemokines stimulate leukocyte migration via activation of chemokine receptors, G protein–coupled receptors expressed on the surfaces of leukocytes. Chemokines are classified into two major families (CCL and CXCL) and two minor families (XCL and CX₃CL) based on the arrangement of conserved cysteine residues near the N termini of their amino acid sequences. Chemokine receptors are classified (CCR, CXCR, XCR, and CX₃CR) based on their chemokine selectivity. The types of leukocytes recruited to specific tissues depend on the array of chemokines expressed in those tissues and the selectivity of those chemokines for the receptors expressed on different leukocyte subsets. For example, in vascular inflammation associated with hypertension, elevated levels of the chemokines CCL2, CCL7, and CCL8 act via the receptor CCR2 (and possibly also CCR1) to stimulate migration of monocytes into the blood vessel wall (4).To suppress leukocyte recruitment in inflammatory diseases, numerous antagonists of specific chemokine receptors have been evaluated in clinical trials. However, these trials have not yielded any new antiinflammatory therapeutics (5), in part because most leukocytes can utilize multiple chemokine receptors, thus circumventing the specific antagonists. The alternative approach of targeting chemokines has not generally been favored, because it would require agents that bind with high affinity to multiple chemokines. However, the natural chemokine-binding proteins of ticks, helminths, and viruses (6–8) display multispecificity for mammalian chemokines, suggesting that they could potentially be deployed as antiinflammatory therapeutics.Evasins are two families of chemokine-binding, antiinflammatory proteins from tick saliva (6). Class A evasins each inhibit multiple CC chemokines of their mammalian hosts but none of the closely related CXC chemokines. Conversely, class B evasins are specific for CXC over CC chemokines but exhibit variable selectivity among CXC chemokines. Typically, each tick species secretes a mixture of evasins, thereby accomplishing broad-spectrum suppression of the host inflammatory response, presumably enabling the tick to feed on the host for extended periods.The in vivo antiinflammatory activity of tick evasins has been demonstrated using a variety of animal models of inflammatory diseases, including lung fibrosis, skin inflammation, arthritis, colitis, pancreatitis, ischemic reperfusion injury, postinfarction myocardial injury, and Leishmania major infection (9–13). However, deploying evasins as effective antiinflammatory therapeutics in humans would require engineering the natural evasins to selectively target the relevant array of chemokines for any given indication while minimizing off-target inhibition (14). Such engineering requires understanding both the specificity of evasins for a single chemokine subfamily and their target preference among chemokines within that subfamily.Previously, only a single structure has been reported for an evasin:chemokine complex, class A evasin EVA-1 bound to CCL3 (15), so it has not been possible to identify the conserved and variable features of the interactions. Nevertheless, the structure revealed that EVA-1 binds to several receptor recognition elements of CCL3, explaining its inhibitory activity. Moreover, limited mutational data (15, 16) have confirmed that residues in the N- and C-terminal regions of EVA-1 and the homologous EVA-4, respectively, contribute to binding affinity, raising the question of whether the structural basis of CC chemokine recognition varies across the class A evasin family.To establish a structure-based platform for engineering the chemokine selectivity of class A evasins, we now report the structures of EVA-P974 (previously called ACA-01) (17, 18), from the Cayenne tick (Amblyomma cajennense), bound to each of two wild-type chemokines and one chimeric CC chemokine. Structural comparisons and extensive evasin and chemokine mutational data revealed the structural basis for CC chemokine specificity and identified several “hotspots” that define target preference among CC chemokines. These insights enabled EVA-P974 to be engineered to modify its target preference. We further verified the molecular basis of the modified selectivity by solving the chemokine-bound structure of the engineered evasin. Finally, by inhibiting a chemokine mixture, we provide proof of principle for applying engineered evasins as multichemokine inhibitors.     

犀角地黄汤合银翘散及其单方对小鼠流感病毒性肺炎治疗作用的比较

目的 比较截断疗法经典方犀角地黄汤合银翘散及其单方对小鼠流感病毒性肺炎的治疗作用,探究犀角地黄汤和银翘散在截断疗法中的不同作用.方法 ICR小鼠和BALB/c小鼠,随机分为正常组、模型组、犀角地黄汤合银翘散组(简称合方组)、犀角地黄汤组、银翘散组、达菲组,除正常组外其余小鼠以流感病毒滴鼻感染,1 h后给药.各组分别以对...     

Combined administration of lauric acid and glucose improved cancer‐derived cardiac atrophy in a mouse cachexia model

Cancer‐derived myocardial damage is an important cause of death in cancer patients. However, the development of dietary interventions for treating such damage has not been advanced. Here, we investigated the effect of dietary intervention with lauric acid (LAA) and glucose, which was effective against skeletal muscle sarcopenia in a mouse cachexia model, on myocardial damage. Treatment of H9c2 rat cardiomyoblasts with lauric acid promoted mitochondrial respiration and increased ATP production by Seahorse flux analysis, but did not increase oxidative stress. Glycolysis was also promoted by LAA. In contrast, mitochondrial respiration and ATP production were suppressed, and oxidative stress was increased in an in vitro cachexia model in which cardiomyoblasts were treated with mouse cachexia ascites. Ascites‐treated H9c2 cells with concurrent treatment with LAA and high glucose showed that mitochondrial respiration and glycolysis were promoted more than that of the control, and ATP was restored to the level of the control. Oxidative stress was also reduced by the combined treatment. In the mouse cachexia model, myocardiac atrophy and decreased levels of a marker of muscle maturity, SDS‐soluble MYL1, were observed. When LAA in CE‐2 diet was orally administered alone, no significant rescue was observed in the cancer‐derived myocardial disorder. In contrast, combined oral administration of LAA and glucose recovered myocardial atrophy and MYL1 to levels observed in the control without increase in the cancer weight. Therefore, it is suggested that dietary intervention using a combination of LAA and glucose for cancer cachexia might improve cancer‐derived myocardial damage.     

Inverse relationship between nitric oxide synthases and endothelin-1 synthesis in bovine corpus luteum: interactions at the level of luteal endothelial cell

Endothelin-1 (ET-1) and nitric oxide (NO) play pivotal roles in corpus luteum (CL) function. The present study examined the interplay between NO and ET-1 synthesis in the bovine CL. We found similar inducible and endothelial NO synthase (iNOS and eNOS, respectively) activities in the young CL (d 1-5) expressing the highest levels of both eNOS and iNOS mRNA. These values later declined at mid-cycle (d 8-15) and remained low at later stages (d 16-18). Luteolysis, initiated by prostaglandin F2alpha analog administration, further reduced NOS mRNA and by 24 h, NOS values dropped to approximately 15% of those at mid-cycle. eNOS protein levels followed a similar pattern to its mRNA. Because endothelial cells (ECs) are the main site for ET-1 and NO production in the CL, we examined the direct effects of the NO donor, NONOate on luteal ECs (LECs). Elevated NO levels markedly decreased ET-1 mRNA, and peptide concentrations in cultured and freshly isolated LECs in a dose-dependent manner. In agreement, NOS inhibitor, NG-nitro-l-arginine methyl ester, stimulated ET-1 mRNA expression in these cells. Interestingly, NO also up-regulated prostaglandin F2alpha receptors in LECs. These data show that there is an inverse relationship between NOS and ET-1 throughout the CL life span, and imply that this pattern may be the result of their interaction within the resident LECs. NOS are expressed in a physiologically relevant manner: elevated NO at an early luteal stage is likely to play an important role in angiogenesis, whereas reduced levels of NO during luteal regression may facilitate the sustained up-regulation of ET-1 levels during luteolysis.