Mechanisms of NSAID-induced ulcerogenesis: structural properties of drugs, focus on the microvascular factors, and novel approaches for gastro-intestinal protection.

The multifactorial ulcer-producing actions of non-steroidal anti-inflammatory drugs (NSAIDs) are briefly reviewed and the main actions highlighted as the focus for potential strategies for reducing the ulcerogenic effects of these drugs. While some clinical benefits are evident from long-term clinical studies from application of PG analogues (misoprostol) and H+/K(+)-ATP-ase inhibitors (omeprazole) these are, ultimately, expensive approaches. Chemical structural properties of the NSAIDs underlying differences in their ulcerogenicity are analyzed with the objective of establishing the reasons for the low ulcerogenicity of some of these drugs (e.g. azapropazone). These studies serve as a basis for developing less gastrotoxic drugs in the future. In the studies we have undertaken analysis of the benefits of micronutrients and of modulating eicosanoid metabolism have been considered. The results of some clinical trials with micronutrients have proven encouraging. These and other approaches and pitfalls reported give further encouragement to explore the mechanisms of the protective effects of these latter agents and serve as a basis for future developments.     

Effect of using protocols on medical care: randomised trial of three methods of taking an antenatal history.

OBJECTIVE--To compare the effectiveness of three methods of taking an antenatal history on the quality of obstetric care. DESIGN--Randomised controlled trial. SETTING--Antenatal clinic of St James''s University Hospital, Leeds. SUBJECTS--2424 women attending the hospital for the first (booking) visit. INTERVENTIONS--Histories were taken by midwives using an unstructured paper questionnaire, a structured paper questionnaire (incorporating a checklist), or an interactive computerised questionnaire (incorporating 101 clinical reminders). MAIN OUTCOME MEASURES--The number of clinical responses to factors arising from the antenatal booking history according to method of taking the history. Actions were categorised as medical and surgical, obstetric, personal, current symptoms and treatment, related to maternal age, and related to two common actions (cervical smear testing and dental hygiene) and were weighted for clinical importance by 10 obstetricians. RESULTS--Overall the unstructured questionnaire generated 1063 actions, the structured questionnaire 1146, and the computerised questionnaire 1122. The clinical importance of these actions was lowest for the unstructured questionnaire (overall total value score 1987 v 2182 and 2110 for the structured and computerised questionnaires respectively). The structured questionnaire was better than the computerised questionnaire in the medical and surgical (total value score 191 v 184), obstetric (275 v 241), and personal (430 v 360) categories but inferior in the current symptoms category (179 v 191). CONCLUSION--Structured questionnaires (computerised or paper) provide more and better information, and their use improves clinical response to risk factors. Computerised systems offer no further advantage in antenatal clinics.     

Neural activation and functional connectivity during motor imagery of bimanual everyday actions

Bimanual actions impose intermanual coordination demands not present during unimanual actions. We investigated the functional neuroanatomical correlates of these coordination demands in motor imagery (MI) of everyday actions using functional magnetic resonance imaging (fMRI). For this, 17 participants imagined unimanual actions with the left and right hand as well as bimanual actions while undergoing fMRI. A univariate fMRI analysis showed no reliable cortical activations specific to bimanual MI, indicating that intermanual coordination demands in MI are not associated with increased neural processing. A functional connectivity analysis based on psychophysiological interactions (PPI), however, revealed marked increases in connectivity between parietal and premotor areas within and between hemispheres. We conclude that in MI of everyday actions intermanual coordination demands are primarily met by changes in connectivity between areas and only moderately, if at all, by changes in the amount of neural activity. These results are the first characterization of the neuroanatomical correlates of bimanual coordination demands in MI. Our findings support the assumed equivalence of overt and imagined actions and highlight the differences between uni- and bimanual actions. The findings extent our understanding of the motor system and may aid the development of clinical neurorehabilitation approaches based on mental practice.     

Determinants of evolving metabolic and cardiovascular benefit/risk profiles of rosiglitazone therapy during the natural history of diabetes: molecular mechanisms in the context of integrated pathophysiology

Rosiglitazone is a thiazolidinedione, a synthetic PPARγ receptor agonist with insulin-sensitizing properties that is used as an antidiabetic drug. In addition to improving glycemic control through actions in metabolic target tissues, rosiglitazone has numerous biological actions that impact on cardiovascular homeostasis. Some of these actions are helpful (e.g., improving endothelial function), whereas others are potentially harmful (e.g., promoting fluid retention). Since cardiovascular morbidity and mortality are major endpoints for diabetes, it is essential to understand how the natural history of diabetes alters the net benefits and risks of rosiglitazone therapy. This complex issue is an important determinant of optimal use of rosiglitazone and is critical for understanding cardiovascular safety issues. We give special attention to the effects of rosiglitazone in diabetic patients with stable coronary artery disease and the impact of rosiglitazone actions on atherosclerosis and plaque instability. This provides a rational conceptual framework for predicting evolving benefit/risk profiles that inform optimal use of rosiglitazone in the clinical setting and help explain the results of recent large clinical intervention trials where rosiglitazone had disappointing cardiovascular outcomes. Thus, in this perspective, we describe what is known about the molecular mechanisms of action of rosiglitazone on cardiovascular targets in the context of the evolving pathophysiology of diabetes over its natural history.     

Cognitive Problem Solving Patterns of Medical Students Correlate with Success in Diagnostic Case Solutions

Context

Problem-solving in terms of clinical reasoning is regarded as a key competence of medical doctors. Little is known about the general cognitive actions underlying the strategies of problem-solving among medical students. In this study, a theory-based model was used and adapted in order to investigate the cognitive actions in which medical students are engaged when dealing with a case and how patterns of these actions are related to the correct solution.

Methods

Twenty-three medical students worked on three cases on clinical nephrology using the think-aloud method. The transcribed recordings were coded using a theory-based model consisting of eight different cognitive actions. The coded data was analysed using time sequences in a graphical representation software. Furthermore the relationship between the coded data and accuracy of diagnosis was investigated with inferential statistical methods.

Results

The observation of all main actions in a case elaboration, including evaluation, representation and integration, was considered a complete model and was found in the majority of cases (56%). This pattern significantly related to the accuracy of the case solution (φ = 0.55; p<.001). Extent of prior knowledge was neither related to the complete model nor to the correct solution.

Conclusions

The proposed model is suitable to empirically verify the cognitive actions of problem-solving of medical students. The cognitive actions evaluation, representation and integration are crucial for the complete model and therefore for the accuracy of the solution. The educational implication which may be drawn from this study is to foster students reasoning by focusing on higher level reasoning.     

Mechanisms of action of green tea catechins, with a focus on ischemia-induced neurodegeneration

Catechins are dietary polyphenolic compounds associated with a wide variety of beneficial health effects in vitro, in vivo and clinically. These therapeutic properties have long been attributed to the catechins' antioxidant and free radical scavenging effects. Emerging evidence has shown that catechins and their metabolites have many additional mechanisms of action by affecting numerous sites, potentiating endogenous antioxidants and eliciting dual actions during oxidative stress, ischemia and inflammation. Catechins have proven to modulate apoptosis at various points in the sequence, including altering expression of anti- and proapoptotic genes. Their anti-inflammatory effects are activated through a variety of different mechanisms, including modulation of nitric oxide synthase isoforms. Catechins' actions of attenuating oxidative stress and the inflammatory response may, in part, account for their confirmed neuroprotective capabilities following cerebral ischemia. The versatility of the mechanisms of action of catechins increases their therapeutic potential as interventions for numerous clinical disorders. However, more epidemiological and clinical studies need to be undertaken for their efficacy to be fully elucidated.     

Insulin and insulin resistance

As obesity and diabetes reach epidemic proportions in the developed world, the role of insulin resistance and its consequences are gaining prominence. Understanding the role of insulin in wide-ranging physiological processes and the influences on its synthesis and secretion, alongside its actions from the molecular to the whole body level, has significant implications for much chronic disease seen in Westernised populations today. This review provides an overview of insulin, its history, structure, synthesis, secretion, actions and interactions followed by a discussion of insulin resistance and its associated clinical manifestations. Specific areas of focus include the actions of insulin and manifestations of insulin resistance in specific organs and tissues, physiological, environmental and pharmacological influences on insulin action and insulin resistance as well as clinical syndromes associated with insulin resistance. Clinical and functional measures of insulin resistance are also covered. Despite our incomplete understanding of the complex biological mechanisms of insulin action and insulin resistance, we need to consider the dramatic social changes of the past century with respect to physical activity, diet, work, socialisation and sleep patterns. Rapid globalization, urbanisation and industrialization have spawned epidemics of obesity, diabetes and their attendant co-morbidities, as physical inactivity and dietary imbalance unmask latent predisposing genetic traits.     

GABA-benzodiazepine receptor complex and drug actions

This short review describes the benzodiazepine receptors, their interplay with GABAergic transmission and chloride ionophore, the search for endogenous ligands, and the drug responses that can be evoked through these receptors. Benzodiazepine receptors offer a unique pathway through which opposite drug actions e.g., anxiogenic and anxiolytic effects can be exerted, and these actions can be inhibited with competitive receptor antagonists. The most plausible endogenous ligand for benzodiazepine receptors discovered so far, a polypeptide DBI, exerts actions opposite to those of the benzodiazepines used in clinical therapy. This has been the stimulus for a new look at the physiological role for these receptors.     

Audit of compliance with antenatal protocols.

OBJECTIVE--To assess the implementation of action protocols dictated by antenatal risk factors noted at the initial (booking) antenatal visit. DESIGN--Retrospective study of 2000 women delivered between 1 March 1990 and 29 March 1991. SETTING--Maternity department of a district general hospital supporting a multiethnic population in inner London. MAIN OUTCOME MEASURES--Comparison of clinical actions performed against those dictated by the department''s protocols. Analysis according to clinical importance, gestation at booking, maternal age, parity, birth order, ethnic origin, and certainty of gestational age. RESULTS--Interobserver agreement between the two auditors was good (kappa statistic for risk factors detected, 0.78; for actions generated, 0.80). Of the 15,658 actions dictated by department protocols, 3673 (23.5%) were actually performed by the clinicians. The 63 combinations of risk factors and actions believed by consultants to be of particular clinical importance had an action rate of 28.3% compared with 18.6% for those considered less important (p < 0.001). Mothers who first visited the hospital antenatal clinic at or before 24 weeks'' gestation had 25.2% of relevant protocols fulfilled (p < 0.001). Compliance was significantly improved in women aged 36 or over (32.4%), black women (24.9%), and cases of uncertain gestation (24.5%). Parity and birth order were not associated with an altered action rate. Ethnic origin deemed as "other" (than white, black, Asian, or oriental) or "unknown" was associated with poor compliance (19.3%). CONCLUSIONS--Compliance to a set of agreed protocols was poor even though a computer system was available and a protocol manual had been distributed. Protocols were more likely to be implemented in women who booked early and in some groups of women deemed at high risk including older mothers, black women, and those denoted as having uncertain gestational age.     

Cytokines and acute neurodegeneration

Cytokines have been implicated as mediators and inhibitors of diverse forms of neurodegeneration. They are induced in response to brain injury and have diverse actions that can cause, exacerbate, mediate and/or inhibit cellular injury and repair. Here we review evidence for the contribution of cytokines to acute neurodegeneration, focusing primarily on interleukin 1 (IL-1), tumour necrosis factor-alpha (TNFalpha) and transforming growth factor-beta (TGFbeta). TGFbeta seems to exert primarily neuroprotective actions, whereas TNFalpha might contribute to neuronal injury and exert protective effects. IL-1 mediates ischaemic, excitotoxic and traumatic brain injury, probably through multiple actions on glia, neurons and the vasculature. Understanding cytokine action in acute neurodegeneration could lead to novel and effective therapeutic strategies, some of which are already in clinical trials.     

Delivery of molecular genetic services within a health care system: time analysis of the clinical workload. The Molecular Genetic Study Group.

The most recent discoveries in molecular genetics today are rapidly incorporated into clinical practice and have resulted in an unprecedented expansion of medical options. Despite this, the impact of molecular genetics on health care services has yet to be evaluated. In order to begin this assessment, clinical genetic workload was prospectively collected from cases where molecular genetic testing was considered. Participation involved all 16 urban and outreach genetic centers regionalized to service the entire population of 10 million within the Canadian province of Ontario. Molecular genetic testing has been clinically available for > 5 years, as part of a publicly supported genetic network in which there are no direct costs to residents. Cross-sectional data were collected on 1,101 clients from 544 families involving 1,742 clinical actions relating to diseases in which molecular (DNA) tests were considered. Median times per clinical genetic action were as follows: formal counseling (60 min), case review (15 min), phone call (10 min), letter (15 min), specimen arrangement (15 min), and interpretation of molecular test results (10 min). Times varied significantly with the inheritance pattern of the disease, topics involved, and location. For any given genetic case, multiple clinical actions resulted in substantial time spent by the genetic professional. Clerical and administrative times were not captured. Workload unit measurements similar to those currently employed in hospital laboratories may be helpful for predicting the clinical resources and personnel that will be required as the use of molecular genetics by other medical specialties increases.     

Partial role of nitric oxide in infarct size limiting effect of quercetin and rutin against ischemia-reperfusion injury in normal and diabetic rats

Reperfusion injury is remarkable clinical issue that needs to be resolved as ischemia-reperfusion is a common phenomenon encountered in numerous clinical situations. The present communication report the involvement of nitric oxide (NO) in cardioprotection offered by flavonoids (rutin and quercetin) against myocardial ischemia reperfusion. Rutin produced better cardioprotection than quercetin in normal and diabetic rats. The observed cardioprotection offered with quercetin and rutin was partially abolished by prior administration of nitric oxide synthase inhibitor, L-NAME (N-nitro-L-arginine methyl ester) in both normal and diabetic rats. L-NAME abolished the cardioprotective actions of rutin more strongly than the cardioprotective actions of quercetin. However, mechanistic study with NOS inhibitor implied the possible partial role of nitric oxide in infarct size limiting effect of quercetin and rutin     

A review of clinical and experimental observations about antidepressant actions and side effects produced by Hypericum perforatum extracts

Hypericum perforatum is an herbaceous perennial plant, also known as "St. John's wort", used popularly as a natural antidepressant. Although some clinical and experimental studies suggest it has some properties similar to conventional antidepressants, the proposed mechanism of action seems to be multiple: a non-selective blockade of the reuptake of serotonin, noradrenaline and dopamine; an increase in density of serotonergic and dopaminergic receptors and an increased affinity for GABAergic receptors; moreover, the inhibition of monoaminoxidase enzyme activity has been involved. In any case, the increase of monoamine concentrations in the synaptic cleft resembles several actions exerted by clinically effective antidepressants. In the present article, we review some of the controversial evidence derived from clinical and experimental studies suggesting that H. perforatum exerts antidepressant-like actions, and we also review some of its side effects, such as nausea, rash, fatigue, restlessness, photosensitivity, acute neuropathy, and even episodes of mania and serotonergic syndrome when administered simultaneously with other antidepressant drugs. All of the foregoing suggests that H. perforatum extracts appear to exert potentially significant pharmacological activity involving several neurotransmission systems supposed to be involved in the pathophysiology of depression. However, little information regarding the safety of H. perforatum is available, including potential herb-drug interactions. There is a need for additional research on the pharmacological and biochemical activity of H. perforatum, as well as its side-effects and its several bioactive constituents to further elucidate the mechanisms of antidepressant actions.     

Neurohumoral changes in chronic heart failure

Background: Humoral systems play an important role in the patophysiology and development of chronic heart failure (CHF). Methods: We conducted a search of neurohumoral activation in heart failure and its risk in the development of CHF. Results and conclusion: Neurohumoral factors may be divided into vasoconstrictive, vasodilative and cytokines. The main vasoconstrictive systems are the renin-angiotensin-aldosterone system (RAAS) and the sympathoadrenal system (SAS). Cytokines include tumour necrosis factor (TNF) alpha and interleukins. The systems of actions are interconnected and they mutually influence their secretion and activities. The possibilities of their detection and assessment for clinical purposes depend on their changes and kinetics in the organism and on the activity of individual metabolites. Apart from their vasoactive effects, the majority of humoral actions also interfere in the process of remodelling, function of the endothelium, blood elements, cardiomyocytes, cells of the smooth muscles, and in immunity as well as inflammatory processes. The rapid development of knowledge on the humoral actions in recent years has made possible their utilisation in diagnostics, treatment and prognosis.     

Coronary arterial perforation during endovascular intervention

The paper deals with the timely detection and treatment of a menacing complication during endovascular interventions, such as coronary arterial perforation. It describes the causes of perforations, their classification, and an algorithm of actions to eliminate this complication. A clinical example demonstrates the sequence of operations for the detection and correction of coronary arterial perforation.     

Role of epigallocatechin gallate (EGCG) in the treatment of breast and prostate cancer

Green tea and its major constituent epigallocatechin gallate (EGCG) have been extensively studied as a potential treatment for a variety of diseases, including cancer. Epidemiological data have suggested that EGCG may provide protective effects against hormone related cancers, namely breast or prostate cancer. Extensive in vitro investigations using both hormone responsive and non-responsive cell lines have shown that EGCG induces apoptosis and alters the expression of cell cycle regulatory proteins that are critical for cell survival and apoptosis. This review will highlight the important in vitro mechanistic actions elicited by EGCG in various breast and prostate cancer cell lines. Additionally, the actions of green tea/EGCG in in vivo models for these cancers as well as in clinical trials will be discussed.     

STUDIES ON ENZYME ACTION : XXXIII. LIPASE ACTIONS OF EXTRACTS OF THE WHOLE RAT AT DIFFERENT AGES.

The ester-hydrolyzing or lipase actions of extracts of whole rats whose ages ranged from 3 days before birth to 3 years 15 days were tested on ten simple esters by the method described in previous papers. The results are presented in the form of curves, both as absolute actions and as relative actions on the different substrates. The "pictures" of the relative actions changed progressively with increasing age of the rat. For the embryo and the youngest rats, the curves approached those given by the Flexner-Jobling rat carcinoma and by a number of tumors of human origin, changing to a type characteristic of the adult rat, and appearing to revert again to some extent to the embryonic type for the oldest rats. The changes in the actions on individual esters and the relative changes in the actions on different esters are discussed in detail. The greatest increases in actions as the rats became older were found with methyl and ethyl butyrates; at the same time that the actions on some of the other esters were also found to change in characteristic ways. Similar experiments with the protease actions of the extracts of whole rats of different ages on three protein preparations did not give differences similar to those found for the lipase actions. The probable reasons for these observed differences in the two sets of enzyme actions are discussed.     

Cellular and molecular actions of adrenomedullin in glomerular mesangial cells.

Adrenomedullin (AM), a potent vasodilatory and hypotensive peptide produces several biological outcomes in glomerular mesangial cells. Mesangial cells are important in the pathogenesis of glomerulonephritis, and therefore the actions of AM on mesangial cells have important clinical and therapeutic implications. This minireview describes the various actions of AM on mesangial cell function and the signal transduction mechanisms involved. As in other systems, most actions of AM can be explained by increase in cAMP levels in the cell, although a few exceptions remain. The fact that most data obtained to date has been in culture, the physiological significance of the actions of AM in mesangial cells is discussed.     

The value of glucocorticoid co-therapy in different rheumatic diseases - positive and adverse effects

Glucocorticoids play a pivotal role in the management of many inflammatory rheumatic diseases. The therapeutic effects range from pain relief in arthritides, to disease-modifying effects in early rheumatoid arthritis, and to strong immunosuppressive actions in vasculitides and systemic lupus erythematosus. There are multiple indications that adverse effects are more frequent with the longer use of glucocorticoids and use of higher dosages, but high-quality data on the occurrence of adverse effects are scarce especially for dosages above 10 mg prednisone daily. The underlying rheumatic disease, disease activity, risk factors and individual responsiveness of the patient should guide treatment decisions. Monitoring for adverse effects should also be tailored to the patient. Continuously balancing the benefits and risks of glucocorticoid therapy is recommended. There is an ongoing quest for new drugs with glucocorticoid actions without the potential to cause harmful effects, such as selective glucocorticoid receptor agonists, but the application of a new compound in clinical practice will probably not occur within the next few years. In the meantime, basic research on glucocorticoid effects and detailed reports on therapeutic efficacy and occurrence of adverse effects will be valuable in weighing benefits and risks in clinical practice.