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.     

A resuscitation “dilemma” theory–practice–ethics. Is there a theory–practice–ethics gap?

The theory–practice–ethics gap – a new paradigm to contemplate.Practices based on tradition, rituals and outdated information are placed into a nonscientific paradigm called the theory–practice gap. Within this paradigm there is often a gap between theoretical knowledge and its application in practice.This theory–practice gap has always existed [Allmark, P., 1995. A classical view of the theory–practice gap in nursing. J. Adv. Nurs. 22 (1), 18–23; Hewison, A. et al., 1996. The theory–practice gap in nursing: a new dimension. J. Adv. Nurs. 24 (4), 754–761]. Its creation is often sited as a culmination of theory being idealistic and impractical, even if practical and beneficial, are often ignored. Most of the evidence relating to the non integration of theory and practice makes the assumption that environmental factors are responsible and will affect learning and practice outcomes, hence the “gap”.In fact, it is the author’s belief, that to “bridge the gap” between theory and practice an additional component is required, called ethics. A moral duty and obligation ensuring theory and practice integrate. In order to effectively implement new practices, one must deem these practices are worthy and relevant to their role as healthcare providers. Otherwise, we fall victims to providing nothing more than a lip service.This introduces a new concept which the author refers to as the theory–practice–ethics gap. This theory–practice–ethics gap must be considered when reviewing some of the unacceptable outcomes in health care practice. The author believes that there is a crisis of ethics where theory and practice integrate, and as a consequence, malfeasance. We are failing to fulfill our duty as healthcare providers and as patient advocates.One practice of major concern, which the author will endeavor to unfold relates to adult and pediatric resuscitation.     

The hypothalamic–pituitary–adrenal axis in critical illness

Hypothalamic-pituitary-adrenal (HPA) axis function is crucial to maintain and restore homeostasis. The HPA axis does not function in isolation. Rather, the HPA axis modulates and reacts to signals from endocrine, neural, and immune systems. Cortisol is the major glucocorticoid secreted by the human adrenal cortex. Its actions are largely mediated by the glucocorticoid receptor. The potent anti-inflammatory actions of glucocorticoids led to their use in critically ill patients. Metaanalyses of these early studies (before 1985) concluded that large glucocorticoid doses had no effect and were potentially detrimental. More recently, the pendulum has swung in the opposite direction based on the concept that critically ill patients may have relative adrenal insufficiency and/or acquired glucocorticoid resistance. However, inconsistent diagnostic criteria, heterogeneity of subjects, variable nutritional status, and pre-existing conditions preclude formulating definitive conclusions regarding glucocorticoid use among critically patients. Diagnosing adrenal insufficiency in the critically ill patient remains challenging. To resolve the issue, our challenge is to develop physiologically relevant tools to assess glucocorticoid action and GR function at the cellular level.     

The Na–K–Cl Co-transporter in astrocyte swelling

Ion channels, exchangers and transporters are known to be involved in cell volume regulation. A disturbance in one or more of these systems may result in loss of ion homeostasis and cell swelling. In particular, activation of the Na⁺–K⁺–Cl⁻ cotransporters has been shown to regulate cell volume in many conditions. The Na⁺–K⁺–Cl− cotransporters (NKCC) are a class of membrane proteins that transport Na, K, and Cl ions into and out of a wide variety of epithelial and nonepithelial cells. Studies have established the role of NKCC1 in astrocyte swelling/brain edema in ischemia and trauma. Our recent studies suggest that NKCC1 activation is also involved in astrocyte swelling induced by ammonia and in the brain edema in the thioacetamide model of acute liver failure. This review will focus on mechanisms of NKCC1 activation and its contribution to astrocyte swelling/brain edema in neurological disorders, with particular emphasis on ammonia neurotoxicity and acute liver failure.     

Sleep–wake regulation and hypocretin–melatonin interaction in zebrafish

In mammals, hypocretin/orexin (HCRT) neuropeptides are important sleep–wake regulators and HCRT deficiency causes narcolepsy. In addition to fragmented wakefulness, narcoleptic mammals also display sleep fragmentation, a less understood phenotype recapitulated in the zebrafish HCRT receptor mutant (hcrtr−/−). We therefore used zebrafish to study the potential mediators of HCRT-mediated sleep consolidation. Similar to mammals, zebrafish HCRT neurons express vesicular glutamate transporters indicating conservation of the excitatory phenotype. Visualization of the entire HCRT circuit in zebrafish stably expressing hcrt:EGFP revealed parallels with established mammalian HCRT neuroanatomy, including projections to the pineal gland, where hcrtr mRNA is expressed. As pineal-produced melatonin is a major sleep-inducing hormone in zebrafish, we further studied how the HCRT and melatonin systems interact functionally. mRNA level of arylalkylamine-N-acetyltransferase (AANAT2), a key enzyme of melatonin synthesis, is reduced in hcrtr−/− pineal gland during the night. Moreover, HCRT perfusion of cultured zebrafish pineal glands induces melatonin release. Together these data indicate that HCRT can modulate melatonin production at night. Furthermore, hcrtr−/− fish are hypersensitive to melatonin, but not other hypnotic compounds. Subthreshold doses of melatonin increased the amount of sleep and consolidated sleep in hcrtr−/− fish, but not in the wild-type siblings. These results demonstrate the existence of a functional HCRT neurons-pineal gland circuit able to modulate melatonin production and sleep consolidation.     

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.     

Ileal Pouch–Anal Anastomosis–Vaginal Fistula: A Review

BACKGROUND Fistula between an ileal pouch and the vagina is an uncommon complication of ileal pouch–anal anastomosis. Its optimal management has not been determined because of its low incidence.METHODS The literature describing such fistulas was reviewed to determine the incidence, cause, and appropriate investigation and repair of these lesions. A literature search was performed with the PubMed, MEDLINE, and EMBASE databases. Through this search we located English-language articles from 1970 to 2003 on pouch-vaginal fistulas following ileal pouch–anal anastomosis. References from these articles were searched manually for further references.RESULTS AND CONCLUSION Pouch-vaginal fistula occurs in 6.3 (range, 3.3–15.8) percent of female patients with an ileal pouch–anal anastomosis. Sepsis and technical factors are the most common contributors. It is the cause of considerable morbidity. Management depends on the level of the fistula, the amount of pelvic scar tissue, and previous treatments. An algorithm for surgical treatment is suggested.Reprints are not available.     

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.     

Erdheim–Chester disease

Erdheim–Chester disease is characterized by long bone pain and symmetric sclerosis of the diametaphyseal portions of the long bones. It is an important differential diagnosis of sclerotic disease of the bones.     

Thrombomodulin and GFC levels in Legg–Calve–Perthes disease

Abstract

Legg–Calve–Perthes disease (LCPD) is a self-limited microvascular disorder leading to the occlusion of the femoral blood supply, which results in bone necrosis. Endothelial injury and hemostatic alterations may play a role in the microvascular compromise and decreased blood flow, which occur during the course of LCPD. Global fibrinolytic capacity (GFC) is a novel assay reflecting the overall fibrinolysis response resulting from the dynamic interactions of numerous stimulatory and inhibitory fibrinolytic molecules. Circulating soluble thrombomodulin (TM) reflects endothelial activation and/or injury. It is a cofactor in the clinically important protein C natural anticoagulant system. Beyond the coagulation pathway it is shown to have effects on biological events, especially inflammation. The aim of this study was to determine GFC and TM levels in LCPD patients. The study included 77 children in two groups. Group I consisted of 42 patients with LCPD and Group II (control) comprised 35 healthy children. Median (interquartile ratios) GFC and TM levels were significantly higher in the LCPD patients (Group I) (p<0·0001 and p=0·049, respectively). Circulating high levels of soluble TM may be associated with ongoing endothelial injury or ongoing inflammation during the disease course. Along with increased overall fibrinolytic response, increased TM may be a compensatory reaction to thrombosis. Further investigations are needed to elucidate the endothelial, anticoagulant, and fibrinolytic kinetics associated with the microvascular compromise and self-limiting nature of LCPD.     

Erdheim–Chester disease

Erdheim–Chester disease (ECD) is a rare but increasingly recognized multi-system disorder. Its diagnosis and treatment require integration of clinical information, imaging studies, and pathology studies. Of note, ECD can now be defined as a clonal myeloid disorder due to mutations which activate mitogen-activated protein kinase (MAPK) pathways and where an inflammatory milieu is important in the pathogenesis and clinical manifestations of the disease. Biopsy demonstrating characteristic histopathologic features in addition to clinical and radiographic features, most often sclerosing long bone involvement, is required to establish a diagnosis. Detection of somatic MAPK pathway mutations can also assist in the differential diagnosis of ECD and related histiocytic neoplasms. Also, genetic analysis establishing BRAF and RAS mutational status is critical in all ECD patients, as these features will impact therapy with MAPK inhibition. Therapy is recommended at diagnosis in all patients, except for those patients with minimally symptomatic disease. Prospective therapeutic trials are essential to furthering therapeutic progress in ECD.     

Left ventricular pressure–volume measurements in mice: Comparison of closed–chest versus open–chest approach

Objective We investigated whether in vivo closed–chest left ventricular pressure–volume measurements would yield similar values for LV hemodynamics compared with open–chest PV measurements under several anesthetics. Methods The right common carotid of C57Bl/6 mice was cannulated with a combined pressure–conductance catheter and inserted retrogradely into the left ventricle in the closed–chest model. The open–chest model consisted of an abdominal approach involving the opening of the thoracic cavity by transverse opening of the diaphragm and ventricular catheterization by apical stab. Measurements were performed under urethane or pentobarbital intraperitoneal injection anesthesia. Results Cardiac function in the open–chest model was characterized by larger ejection fraction and stroke volume with a leftward shift in ventricular volume compared to the closed–chest model. Further observed characteristics include low endsystolic pressure and arterial–ventricular coupling mismatch in the openchest model. Arrhythmias were not detected in either model. Conclusion Murine cardiac function determination via open–chest or closed–chest protocols is sensitive, reproducible and comparable. The choice for open– or closed–chest pressure–volume measurements in mice depends on the aims of the study.     

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.     

Effect of rhBMP–2 sustained–release nanocapsules on the ectopic osteogenesis process in Sprague–Dawley rats

ObjectiveTo explore the effect of sustained–release recombinant human bone morphogenetic protein–2 (rhBMP–2) on ectopic osteogenesis in the muscle pouches of rats through preparing rhBMP–2 sustained–release capsules by wrapping morphogenesis protein bones–2 (BMP–2) using chitosan nanoparticles, and compositing collagen materials.MethodsTwenty four Sprague–Dawley rats were randomly divided into four groups with six rats in each group, that is Group A (control group), Group B (only treated with collagen), Group C (rhBMP–2+collagen treated group) and Group D (rhBMP–2/cs+collagen treated group). The composite materials for each group were implanted in the bilateral peroneal muscle pouches in rats. The peroneal muscles were only separated without implanting any materials in control group. Rats were sacrificed 2 weeks and 4 weeks post treatment and samples were cut off for general observation, Micro CT scans and histological observation.ResultsGeneral observation showed no new bone formation in Groups A and B mice, while new bones were formed in Groups C and D mice. Two weeks after treatment Micro CT scans showed that The bone volume fraction (BVF), trabecular thickness (Tb.Th), bone mineral density (BMD) in Group C mice were all higher than that in Group D (P<0.05). At the fourth week, the BVF, Tb.Th and BMD were significantly higher than that at the second week (P<0.01).ConclusionsThe slow-release effect of rhBMP–2/cs sustained–release capsules can significantly promote ectopic osteogenesis. Its bone formation effect is better than that of rhBMP–2 burst-release group.