Synthesis and antibacterial evaluation of 2–substituted–4,5–diphenyl–N–alkyl imidazole derivatives

ObjectiveTo synthesis 2–substituted–4,5–diphenyl–N–alkyl imidazole derivatives. and evaluate their antibacterial activity.MethodsA mixture of benzil (10 mmol) and ammonium acetate (0.1 mol) (immediately fused) in glacial acetic acid (25 mL) was stirred at 80–100 °C for 1 h under nitrogen atmosphere (to prevent incorporation of any atmospheric impurities and moisture). Substituted aldehydes (10 mmol) in glacial acetic acid (5 mL) was added drop-wise over a period of 15–20 min at the same temperature and stirred for another 4 h, the progress of the reaction was monitored by TLC test using ethyl acetate as eluent. The newly synthesized compounds were characterized by IR, ¹HNMR, ¹³CNMR and by mass spectroscopy.ResultsAll the synthesized compounds were confirmed by spectroscopical techniques and evaluated for antimicrobial activity against Staphylococcus aureus(S. aurius), Bacilus subtilus (B. subtilus), and Escheria coli (E. coli). These compounds showed antibacterial activity (zone of inhibition) against S. aurius ranged from 3 mm to 9 mmin diameter, B. subtilus, 4–8 mm, and E. coli 5–12 mm. Out of 2a-2e, only 2a and 2b showed some sort of activity but none of them had considerable activity compared with that of the standard.ConclusionsAll the synthesized compounds show moderate activity against the tested bacteria S. aurius, B. subtilus, and E. coli. So, further structural modification is necessary to improve the antibacterial action of 2-substituted-4,5-diphenyl-N-alkyl imidazole derivatives.     

Recombinant N–terminal fragments of chromogranin–A modulate cardiac function of the Langendorff–perfused rat heart

In this study we tested the hypothesis that vasostatins could act as myocardial modulators in the mammalian heart. Using the Langendorff–perfused rat heart, the cardiac effects of the two recombinant human CGA N–terminal fragments STA–CGA1–78 and STA–CGA1–115, containing the vasostatin–1 (CGA 1–76) and vasostatin–2 (CGA 1–113) sequences, respectively, were evaluated at concentrations of 11 ÷ 165 nM. Cardiac performance was evaluated by analyzing left ventricular pressure (LVP) and the rate pressure product (RPP: HR × LVP), used as indexes of contractile activity and cardiac work, respectively. Under basal conditions, STA–CGA1–78 at all concentrations tested elicited a dose–dependent negative inotropism (LVP variations ranging from –9.6% ± 2 to –23% ± 2.9) without affecting coronary pressure (CP). In contrast, STA–CGA1–115 increased CP at 110 and 165 nM without affecting inotropism. Both STA–CGA1–78 and STA–CGA1–115 counteracted the cardio–stimulatory effects of isoproterenol (ISO). The ISO–dependent positive chronotropism was unaffected by STA–CGA1–78, while being reduced by STA–CGA1–115. Both peptides abolished the ISO–induced positive inotropism without modifying either the β–adrenergic–dependent coronary dilation or the ouabain–induced positive inotropism. The analysis of the percentage of variations of RPP in terms of EC₅₀ values of ISO alone (–8.5 ± 0.3; r² = 0.88) and in presence of STA–CGA1–78 (11, or 33, or 65 nM: –7.7 ± 0.15, r² = 0.97; –7.7 ± 0.15, r² = 0.97; –7.8 ± 0.78, r² = 0.55, respectively) revealed a non–competitive type of antagonism of STA–CGA1–78. Taken together, these data suggest vasostatins as novel cardioregulatory peptides in mammals.     

Management of Budd–Chiari Syndrome

Thrombotic occlusion of the hepatic veins leads to liver dysfunction and liver failure requiring liver transplantation in advanced cases. The cause for the occlusion of the hepatic veins is not completely understood. However, several underlying conditions such as polycytemia, factor V Leiden mutation, and protein C and S deficiency are found in these patients. We here report our single-center experience with 18 consecutive patients with Budd–Chiari Syndrome (BCS) who were treated at our institution between August 1992 and June 2003. Twelve patients underwent liver transplantation, three patients received stents into the hepatic veins or vena cava, another patient was treated with TIPSS (transjugular intrahepatic postosystemic stent shunt), and one patient underwent surgical mesocaval shunting. Three patients, among those the patient with TIPSS, were put on anticoagulant therapy and are scheduled for liver transplantation. We outline the indication for an approach tailored to the stage of the disease and the adaption of the procedures with the deterioration of clinical conditions. Surgical aspects and postoperative management with a focus on liver transplantation are outlined. We conclude from our observations that the management of BCS requires an approach that exhausts conservative approaches until clinical conditions deteriorate with respect to portal hypertension or liver function. Conservative management, i.e., interventional and supportive medical therapy, has been used up to 8 years in our series, until the time for liver transplantation is reached. Liver transplantation for BCS had more complications than transplantation for other liver diseases in our series. Therefore, we propose to keep liver function stable using interventional techniques to maintain venous outflow. If venous outflow cannot be interventionally restored and liver function deteriorates or cirrhosis develops during this time course, liver transplantation is the therapy of choice.     

Systematic review of nephrotoxicity of drugs of abuse, 2005–2016

Background

The United States is faced with an unprecedented epidemic of drug abuse. Every year thousands of Americans visit the emergency departments all over the country with illicit drug related complaints. These drugs have been known to be associated with a range of renal pathologies, from reversible acute kidney injuries to debilitating irreversible conditions like renal infarction. So far, no comprehensive study or systematic review has been published that includes the commonly used street drugs and designer drugs with potential nephrotoxic outcomes.

Methods

We conducted a systematic review of published case reports, case series, and cross sectional studies of nephrotoxicities related to drugs of abuse. Literature review was conducted using PubMed/Medline from January 1, 2005 -December 31, 2016 to search for publications related to drug abuse with a defined renal outcome. Publications which reported renal injury in relation to the use of illicit drugs were selected, specifically those cases with raised creatinine levels, clinically symptomatic patients, for instance those with oliguria and proven renal biopsies.

Results

A total of 4798 publications were reviewed during the search process and PRISMA flow chart and Moose protocol regarding systematic reviews were followed. 110 articles were shortlisted for the review. A total of 169 cases from case reports and case series, and 14 case studies were analyzed. Renal manifestations of specific illicit drug abuse were included in this review.

Conclusion

Based on the evidence presented, a wide range of renal manifestations were found to be associated with drug abuse. If the trend of increasing use of illicit drug use continues, it will put a significant percentage of the population at an elevated risk for poor renal outcomes. This study is limited by the nature of the literature reviewed being primarily case reports and case series.

     

Heart failure and inhibition of renin–angiotensin–aldosterone system

A historical survey is presented of mortality clinical trials focussed on the inhibition of the renin–angiotensin–aldosterone system on different levels in patients with chronic heart failure. The first study, CONSENSUS, was published in 1987 and showed that the ACE-inhibitor enalapril clearly reduced mortality in severe heart failure compared with placebo. This was followed by studies with beta blockers, angiotensin II type 1 receptor blockers, blockers of mineralocorticoid receptors, and direct renin inhibitors.A recent study, PARADIGM, comparing dual inhibitor of neprilysin and antiotensin II receptor (LCZ696) with enalapril, was terminated prematurely for a significant effect of inhibiting neprilysin and valsartan.     

An Information–Motivation–Behavioral Skills Model of PrEP Uptake

Despite documented effectiveness of pre-exposure prophylaxis (PrEP), PrEP uptake remains low among at-risk populations. The 2015 CDC report estimates that about 1.2 million people in the US have indications for PrEP. However, only 49,158 or 4% of the targeted population are currently using PrEP. Efforts to optimize uptake of PrEP may be facilitated by the development of a comprehensive theoretical framework which can be used to understand reasons for poor uptake and to develop interventions to maximize PrEP uptake and adherence. This article reviews research on correlates of PrEP uptake and presents findings organized within an Information-Motivation-Behavioral Skills (IMB) model framework. In the context of PrEP uptake, the IMB model asserts that to the extent that at-risk groups are well-informed about PrEP, motivated to act on their knowledge, and have necessary behavioral skills to seek out and initiate PrEP regimen, they will successfully overcome obstacles to initiate and adhere to PrEP. The article proposes an adaptation the IMB model for PrEP uptake, provides empirical support for the adapted IMB model extracted from related research, and discusses its application in PrEP uptake interventions.     

Photolysis of iron–siderophore chelates promotes bacterial–algal mutualism

Marine microalgae support world fisheries production and influence climate through various mechanisms. They are also responsible for harmful blooms that adversely impact coastal ecosystems and economies. Optimal growth and survival of many bloom-forming microalgae, including climatically important dinoflagellates and coccolithophores, requires the close association of specific bacterial species, but the reasons for these associations are unknown. Here, we report that several clades of Marinobacter ubiquitously found in close association with dinoflagellates and coccolithophores produce an unusual lower-affinity dicitrate siderophore, vibrioferrin (VF). Fe-VF chelates undergo photolysis at rates that are 10–20 times higher than siderophores produced by free-living marine bacteria, and unlike the latter, the VF photoproduct has no measurable affinity for iron. While both an algal-associated bacterium and a representative dinoflagellate partner, Scrippsiella trochoidea, used iron from Fe-VF chelates in the dark, in situ photolysis of the chelates in the presence of attenuated sunlight increased bacterial iron uptake by 70% and algal uptake by >20-fold. These results suggest that the bacteria promote algal assimilation of iron by facilitating photochemical redox cycling of this critical nutrient. Also, binary culture experiments and genomic evidence suggest that the algal cells release organic molecules that are used by the bacteria for growth. Such mutualistic sharing of iron and fixed carbon has important implications toward our understanding of the close beneficial interactions between marine bacteria and phytoplankton, and the effect of these interactions on algal blooms and climate.     

Reaction–diffusion model of hair-bundle morphogenesis

The hair bundle, an apical specialization of the hair cell composed of several rows of regularly organized stereocilia and a kinocilium, is essential for mechanotransduction in the ear. Its precise organization allows the hair bundle to convert mechanical stimuli to electrical signals; mutations that alter the bundle’s morphology often cause deafness. However, little is known about the proteins involved in the process of morphogenesis and how the structure of the bundle arises through interactions between these molecules. We present a mathematical model based on simple reaction–diffusion mechanisms that can reproduce the shape and organization of the hair bundle. This model suggests that the boundary of the cell and the kinocilium act as signaling centers that establish the bundle’s shape. The interaction of two proteins forms a hexagonal Turing pattern—a periodic modulation of the concentrations of the morphogens, sustained by local activation and long-range inhibition of the reactants—that sets a blueprint for the location of the stereocilia. Finally we use this model to predict how different alterations to the system might impact the shape and organization of the hair bundle.Hair cells, which occur in the sensory epithelia of hearing and balance organs of vertebrates, are responsible for mechanotransduction in the inner ear. The specialized mechanoreceptive organelle of each such cell, the hair bundle, is a cluster of 10–300 actin-filled cylinders called stereocilia (1) that occur in a hexagonal pattern on a well-defined, bounded region of the apical cellular surface (Fig. 1). The stereocilia display a monotonic gradient in length along one of the hexagonal axes; at the tall edge stands a single true cilium termed the kinocilium. The mechanical forces initiated by sounds or movements owing to accelerations deflect the hair bundle, bending the stereocilia at their bases. This deflection opens ion channels located at the stereociliary tips and depolarizes the cell, transducing a mechanical stimulus into an electrical output.Open in a separate windowFig. 1.(A) Scanning electron micrograph of a hair bundle protruding from the apical surface of a bullfrog’s saccular hair cell. The bundle is formed by about 60 stereocilia of lengths increasing from left to right. At the tall edge of the bundle stands the kinocilium. (B) Freeze-fracture image of the apical surface of a hair cell from the same organ. The anchoring sites of the stereocilia can be seen in their characteristic hexagonal arrangement. The insertion point of the kinocilium and the cell’s circumference are also visible.The process of hair-bundle morphogenesis starts after a prospective hair cell has differentiated from a population of precursors (2–5). The kinocilium migrates from the center of the apical surface to one edge, providing the first morphological evidence of planar polarity. Microvilli on the apical surface then grow into stereocilia and establish the height gradient of the hair bundle. The numbers, positions, and lengths of the stereocilia are well controlled, producing consistent bundle shapes. In different individuals of the same species the number and dimensions of the stereocilia at a specific location of the cochlea vary by less than 5% (3). A hair bundle is accordingly among the most precisely specified organelles in a vertebrate organism.The structure of the hair bundle, the basic features of which are similar in the organs of all vertebrate species, is essential for its proper functioning as a mechanotransducer. Of the hundreds of mutations that produce deafness in humans, approximately half affect the hair bundle (6, 7). Many of these mutations alter the normal development of hair cells and produce misoriented or misshapen bundles (6, 8–10). Although the effort to understand the molecular mechanisms of hair-bundle morphogenesis has led to the identification of several proteins involved in the process (9–11), we lack a theoretical understanding of how the precise shapes of hair bundles result from interactions among these molecules.In this paper we propose a reaction–diffusion model to explain how the characteristic arrangement of stereocilia emerges through the formation of a Turing pattern (12). A Turing pattern is a spatial arrangement of molecules with a characteristic periodicity that arises and is maintained by a combination of local activation and long-range inhibition between those molecules. The pattern appears autonomously and independently of any preexisting positional information, with a characteristic period determined by the interplay between the rates of diffusion and reaction (13). With this model we examine how the boundaries of the bundle are delimited, how the hexagonal pattern of stereocilia is established, and how the gradient in height is determined.     

Female hypogonadism: evaluation of the hypothalamic–pituitary–ovarian axis

Female hypogonadism refers to deficient or abnormal function of the hypothalamic–pituitary–ovarian axis that clinically presents with menstrual cycle disturbances. Female hypogonadism can be due to a congenital or acquired cause, and the defect can be at the level of the hypothalamus, pituitary or ovary. A careful history, physical exam and selected laboratory testing can often determine the locus of the defect and whether it results from a structural or hormonal problem. Laboratory testing generally relies on basal hormone levels; however, timing of blood sampling in relation to menses is important to interpretation of the data.     

Molecular genetics of intraductal papillary–mucinous neoplasms of the pancreas

Intraductal papillary–mucinous neoplasms of the pancreas show characteristic clinicopathological and molecular pathobiological features which are distinct from those of conventional ductal adenocarcinomas. Alterations of KRAS, AKT/PKB, CDKN2A, TP53, SMAD4, STK11/LKB1, and DUSP6, and other molecular alterations, including global expression studies as well as their clinical implications, are discussed.     

Anti–inflammatory activity of the glandular extracts of Thunnus alalunga

ObjectiveTo evaluate the anti-inflamattory activity of Thunnus alalunga by both in vitro and in vivo methods.MethodsAnti-inflammatory activity of the chloroform water extract of Thunnus alalunga was done by both in vitro and in vivo methods. In vitro method was done by human red blood cells membrane stabilization method (HRBC). In vivo evaluation was estimated on Wister albino rats. Acute toxicity studies were done on the extract and no toxicity was reported.ResultsThe percentage protection exhibited by 300 mg/mL concentration was more when compared to the other ones. The 400 mg/mL concentration showed potent activity on comparison with the standard during in vivo evaluation.ConclusionsIn both means of estimation the extract of Thunnus alalunga was found to possess significant anti-inflammatory activity.     

Antitubercular activity of the semi–polar extractives of Uvaria rufa

ObjectiveTo investigate the inhibitory activity of the chloroform extract, petroleum ether and chloroform sub-extracts, lead-acetate treated chloroform extract, fractions and secondary metabolites of Uvaria rufa (U. rufa) against Mycobacterium tuberculosis (M. tuberculosis) H₃₇Rv.MethodsThe antituberculosis susceptibility assay was carried out using the colorimetric Microplate Alamar blue assay (MABA). In addition, the cytotoxicity of the most active fraction was evaluated using the VERO cell toxicity assay.ResultsThe in vitro inhibitory activity against M. tuberculosis H₃₇Rv increased as purification progressed to fractionation (MIC up to 23 μg/mL). The chloroform extract and its sub-extracts showed moderate toxicity while the most active fraction from chloroform sub-extract exhibited no cytotoxicity against VERO cells. Meanwhile, the lead acetate-treated crude chloroform extract and its fractions showed complete inhibitions (100%) with MIC values up to 8 μg/mL. Phytochemical screening of the most active fraction showed, in general, the presence of terpenoids, steroids and phenolic compounds. Evaluation of the antimycobacterial activity of known secondary metabolites isolated showed no promising inhibitory activity against the test organism.ConclusionsThe present results demonstrate the potential of U. rufa as a phytomedicinal source of compounds that may exhibit promising antituberculosis activity. In addition, elimination of polar pigments revealed enhanced inhibition against M. tuberculosis H₃₇Rv. While several compounds known for this plant did not show antimycobacterial activity, the obtained results are considered sufficient reason for further study to isolate the metabolites from U. rufa responsible for the antitubercular activity.     

Pathophysiology of cardiorenal syndrome in decompensated heart failure: Role of lung–right heart–kidney interaction

Cardiorenal syndrome (CRS) is defined as an interaction of cardiac disease with renal dysfunction that leads to diuretic resistance and renal function worsening, mainly with heart failure (HF) exacerbation.