Therapeutic Potentials of Ecto‐Nucleoside Triphosphate Diphosphohydrolase,Ecto‐Nucleotide Pyrophosphatase/Phosphodiesterase,Ecto‐5′‐Nucleotidase,and Alkaline Phosphatase Inhibitors

The modulatory role of extracellular nucleotides and adenosine in relevance to purinergic cell signaling mechanisms has long been known and is an object of much research worldwide. These extracellular nucleotides are released by a variety of cell types either innately or as a response to patho‐physiological stress or injury. A variety of surface‐located ecto‐nucleotidases (of four major types; nucleoside triphosphate diphosphohydrolases or NTPDases, nucleotide pyrophosphatase/phosphodiesterases or NPPs, alkaline phosphatases APs or ALPs, and ecto‐5′‐nucleotidase or e5NT) are responsible for meticulously controlling the availability of these important signaling molecules (at their respective receptors) in extracellular environment and are therefore crucial for maintaining the integrity of normal cell functioning. Overexpression of many of these ubiquitous ecto‐enzymes has been implicated in a variety of disorders including cell adhesion, activation, proliferation, apoptosis, and degenerative neurological and immunological responses. Selective inhibition of these ecto‐enzymes is an area that is currently being explored with great interest and hopes remain high that development of selective ecto‐nucleotidase inhibitors will prove to have many beneficial therapeutic implications. The aim of this review is to emphasize and focus on recent developments made in the field of inhibitors of ecto‐nucleotidases and to highlight their structure activity relationships wherever possible. Most recent and significant advances in field of NTPDase, NPP, AP, and e5NT inhibitors is being discussed in detail in anticipation of providing prolific leads and relevant background for research groups interested in synthesis of selective ecto‐nucleotidase inhibitors.     

Comparison of behavioral,neuroprotective, and proinflammatory cytokine modulating effects exercised by (+)‐cis‐EC and (−)‐cis‐EC stereoisomers in a PTZ‐induced kindling test in mice

Epoxy‐carvone (EC) has chiral centers that allow generation of stereoisomers, including (+)‐cis‐EC and (?)‐cis‐EC, whose effects in the kindling tests have never been studied. Accordingly, this study aims to comparatively investigate the effect of stereoisomers (+)‐cis‐epoxy‐carvone and (?)‐cis‐epoxy‐carvone on behavioral changes measured in scores, in the levels of cytokines (IL‐1β, IL‐6, and TNFα) and neuronal protection in the face of continuous treatment with pentylenetetrazol. Swiss mice were divided into five groups (n = 10), receiving vehicle, (+) – cis‐EC, (?) – cis‐EC (both at the dose of 30 mg/kg), and diazepam (4 mg/kg). Thirty minutes after the respective treatment was administered to the animals one subconvulsive dose of PTZ (35 mg/kg). Seven subconvulsives treatments were made on alternate days, in which each treatment several parameters were recorded. In the eighth treatment, the animals receiving the highest dose of PTZ (75 mg/kg) and were sacrificed for quantification of cytokines and histopathologic analysis. All drugs were administered by intraperitoneal route. In the kindling test, (+)‐cis‐EC and (?)‐cis‐EC reduced the average scores. The stereoisomer (+)‐cis‐EC decreased levels of proinflammatory cytokines IL‐1β, IL‐6, and TNFα, whereas comparatively (?)‐cis‐EC did not reduce IL‐1β levels. Histopathological analysis of the mice hippocampi undergoing this methodology showed neural protection for treated with (+)‐cis‐EC. The results suggest that the anticonvulsant effect of (+)‐cis‐EC possibly takes place due to reduction of proinflammatory cytokines involved in the epileptogenic process, besides neuronal protection, yet further investigation of the mechanisms involved is required.     

Self‐harm in young people: Prevalence,associated factors,and help‐seeking in school‐going adolescents

Adolescent self‐harm is recognized as a serious public health problem; however, there is little reliable comparative data on its prevalence or characteristics, or on the extent of help‐seeking for self‐harm. The aims of the present study were to determine the prevalence and associated factors of adolescent self‐harm in an urban region in Ireland, and to investigate help‐seeking behaviours for self‐harm. This was a cross‐sectional study of 856 school‐going adolescents, employing an anonymous self‐report questionnaire. A lifetime history of self‐harm was reported by 12.1% of adolescents. Factors independently associated with self‐harm included exposure to self‐harm of a friend/family member. Professional help‐seeking was uncommon prior to (9%) and after (12%) self‐harm. Furthermore, only 6.9% of adolescents presented to hospital as a result of their last self‐harm act. These findings indicate that self‐harm is common in adolescents; however, seeking professional help is not a common phenomenon, and those who present to hospital represent the ‘tip of the iceberg’ of adolescent self‐harm. Identifying the prevalence of self‐harm and associated factors, in addition to help‐seeking behaviours, in young people is important to determine the preventative programmes to target ‘at‐risk’ groups. Mental health nurses have an important and increasing role to play in such school‐based initiatives.     

New measures of diabetes self‐care agency,diabetes self‐efficacy,and diabetes self‐management for insulin‐treated individuals with type 2 diabetes

Aims and objectives. To develop and refine three new scales that measure diabetes self‐care agency, diabetes self‐efficacy and diabetes self‐management to reflect the American Diabetes Association current standards of diabetes care and the American Association of Diabetes Educators self‐care behaviours. And, to establish the clarity, consistency and content validity of the scales. Background. There is a need to have valid and reliable instruments or scales to assess an individual’s diabetes self‐care agency, self‐efficacy and self‐management to plan appropriate interventions that can be effective in improving glycaemic control and delaying or preventing diabetes‐related complications. Design. A methodological design was used to conduct this study. Methods. Ten clinicians and 10 insulin‐treated individuals with type 2 diabetes (T2DM) from a diabetes care center in the southern USA participated in this study. Analysis consisted of inter‐rater agreement to determine clarity and consistency with standards of diabetes care and content validity of individual items on the scales (I‐CVI) and the overall scales (S‐CVI/Ave) to determine relevance for current diabetes care practice. Results. All I‐CVI and S‐CVI/Ave of the DSES exceeded the minimum acceptable criteria. All I‐CVI and the S‐CVI of the DSMS also exceeded the minimum accepted criteria, except for one item that had I‐CVI = 0·70. Evaluation of the items and the directions of the scales by the sample of insulin‐treated individuals with T2DM exceeded the minimum criteria of 80% inter‐rater agreement. Relevance to research and clinical practice. Further psychometric testing of the scales with samples of insulin‐treated individuals with diabetes is warranted and will lay the groundwork for further research and clinical practice to enhance the capability, confidence and actual performance of diabetes self‐management activities among insulin‐treated individuals with T2DM. Conclusions. The scales can be used by diabetes care providers to assess and follow‐up individuals with diabetes who need intense case management. They also can be the measures of choice to conduct future research to test the effects of interventions among insulin‐treated individuals with T2DM.     

Effect of the small molecule plasminogen activator inhibitor‐1 (PAI‐1) inhibitor,PAI‐749, in clinical models of fibrinolysis

Summary. Background: The principal inhibitor of fibrinolysis in vivo is plasminogen activator inhibitor‐1 (PAI‐1). PAI‐749 is a small molecule inhibitor of PAI‐1 with proven antithrombotic efficacy in several preclinical models. Objective: To assess the effect of PAI‐749, by using an established ex vivo clinical model of thrombosis and a range of complementary in vitro human plasma‐based and whole blood‐based models of fibrinolysis. Methods: In a double‐blind, randomized, crossover study, ex vivo thrombus formation was assessed using the Badimon chamber in 12 healthy volunteers during extracorporeal administration of tissue‐type plasminogen activator (t‐PA) in the presence of PAI‐749 or control. t‐PA‐mediated lysis of plasma clots and of whole blood model thrombi were assessed in vitro. The role of vitronectin was examined by assessing lysis of fibrin clots generated from purified plasma proteins. Results: There was a dose‐dependent reduction in ex vivo thrombus formation by t‐PA (P < 0.0001). PAI‐749 had no effect on in vitro or ex vivo thrombus formation or fibrinolysis in the presence or absence of t‐PA. Inhibition of PAI‐1 with a blocking antibody enhanced fibrinolysis in vitro (P < 0.05). Conclusions: Despite its efficacy in a purified human system and in preclinical models of thrombosis, the current study suggests that PAI‐749 does not affect thrombus formation or fibrinolysis in a range of established human plasma and whole blood‐based systems.     

Describing Self‐Care Self‐Efficacy: Definition,Measurement, Outcomes,and Implications

PURPOSE

The pragmatic utility method of concept analysis was used to explore the usefulness of the concept self‐care self‐efficacy.

DATA SOURCES

Empirical studies across disciplines published between 1996 and 2015 were used as data.

DATA SYNTHESIS

A data matrix was developed. Analytical questions and responses were derived from the data to understand patterns, develop new knowledge and achieve synthesis.

CONCLUSION

Usefulness of the concept is contingent on how it is defined and measured. Self‐care self‐efficacy is associated with performance of self‐care activities and positive health outcomes in diverse populations.

IMPLICATIONS

Research can guide development of targeted interventions to increase patients' self‐care self‐efficacy, thus reducing costs, and assisting people to achieve optimal health.     

Implementation of a diabetes clinic‐in‐a‐clinic project in a family practice setting: using the plan,do, study,act model

Objectives. The American Association of Diabetic Educators suggests that educating patients about their diabetes management facilitates problem solving and coping skills. This paper will describe a clinic‐in‐a‐clinic model of care delivery founded on the principles of the Chronic Care Model and focused towards the outcomes proposed by the American Association of Diabetic Educators. The reader will be introduced to the use of the ‘plan, do, study, act’ process used to develop this model in a clinical setting. Background. Self‐management support, a key component of the Chronic Care Model, focuses on providing patients with the skills to make healthcare decisions. Self‐management encourages patient to be responsible for his/her own health care. Because diabetes outcomes and complication prevalence are related to the degree of self involvement in illness care, self‐management support is an important component of disease management. Design. Plan, do, study, act model for program development. Methods. The ‘plan, do, study, act’ cycles outlined the steps needed to implement the clinic‐in‐a‐clinic program with success related to coordination of all components and continual assessment and revision. Each cycle was initiated in a sequential order allowing for evaluation and goal adjustment before the next cycle was implemented. Conclusions. The majority of patients seen were middle‐aged, obese, females with HbA1cs greatly above the recommended 7·0. Patients selected a variety of topics related to diabetes management for their clinical session. Participation rates were consistent with regular clinic visit attendance. Barriers to success of the program were related to both structure and process. Relevance to clinical practice. The clinic‐in‐a‐clinic design moves disease management from individual practice into a property of the health systems and places importance on the collaboration of patient, provider and delivery system in reducing the consequences of chronic illness. Use of the ‘plan, do, study, act’ cycle model offers a method for changing the process of care delivery in a structured, sequential approach.     

Endothelium‐dependent and endothelium‐independent effects of 1‐nitro‐2‐propylbenzene on rat aorta

A group of nitro compounds contains a benzene ring in a short aliphatic chain with the NO₂ group, property that supposedly favors its vasodilator profile. In this study, we evaluated in isolated rat aorta the effects of 1‐nitro‐2‐propylbenzene (NPB), a nitro compound containing the NO₂ in the aromatic ring. In aorta precontracted with KCl, NPB (1‐3000 μm ) induced full endothelium‐independent relaxation. In endothelium‐intact preparations, phenylephrine‐induced contractions were fully relaxed by NPB, effect unaltered by N(ω)‐nitro‐L‐arginine methyl ester (L‐NAME) or 1H‐[1,2,4]oxadiazolo[4,3‐a]quinoxalin‐1‐one (ODQ). In the concentration range of 30–300 μm , NPB slightly but significantly potentiated the phenylephrine‐induced contraction. Such potentiation was unaltered by the thromboxane‐prostanoid receptor antagonist seratrodast, but was abolished by endothelium removal or by preincubation of endothelium‐intact preparations with L‐NAME, ODQ or by ruthenium red and HC‐030031, blockers of subtype 1 of ankyrin transient receptor potential (TRPA₁) channels. Verapamil exacerbated the potentiating effect of NPB. The potentiating effect was undetectable in preparations precontracted by 9,11‐dideoxy‐11α,9α‐epoxymethanoprostaglandin F2α (U‐46619). Relaxation was reduced by ruthenium red while it was enhanced by HC‐030031. In conclusion, NPB has vasodilator properties but with a mechanism of action distinct from its analogues. Contrary to other nitro compounds, its relaxing effects did not involve recruitment of the guanylyl cyclase pathway. NPB has also endothelium‐dependent potentiating properties on phenylephrine‐induced contractions, a phenomenon that putatively required a role of endothelial TRPA₁ channels. The present findings reinforce the notion that the functional group NO₂ in the aliphatic chain of these nitro compounds determines favorably their vasodilator properties.