Melatonin: a hormone,a tissue factor,an autocoid,a paracoid,and an antioxidant vitamin

Melatonin, a derivative of an essential amino acid, tryptophan, was first identified in bovine pineal tissue and subsequently it has been portrayed exclusively as a hormone. Recently accumulated evidence has challenged this concept. Melatonin is present in the earliest life forms and is found in all organisms including bacteria, algae, fungi, plants, insects, and vertebrates including humans. Several characteristics of melatonin distinguish it from a classic hormone such as its direct, non-receptor-mediated free radical scavenging activity. As melatonin is also ingested in foodstuffs such as vegetables, fruits, rice, wheat and herbal medicines, from the nutritional point of view, melatonin can also be classified as a vitamin. It seems likely that melatonin initially evolved as an antioxidant, becoming a vitamin in the food chain, and in multicellular organisms, where it is produced, it has acquired autocoid, paracoid and hormonal properties.     

Guidelines for hospital-acquired pneumonia and health-care-associated pneumonia: a vulnerability, a pitfall, and a fatal flaw

The 2005 American Thoracic Society and Infectious Disease Society of America's guidelines for pneumonia introduced the new category of health-care-associated pneumonia, which increased the number of people to whom the guidelines for multidrug-resistant pathogens applied. Three fundamental issues inherent in the definition of hospital-acquired pneumonia and health-care-associated pneumonia undermined the credibility of these guidelines and the applicability of their recommendations: a vulnerability, a pitfall, and a fatal flaw. The vulnerability is the extreme heterogeneity of the population of patients. The fatal flaw is the failure to accurately diagnose hospital-acquired pneumonia and ventilator-associated pneumonia; inability to distinguish colonisation from infection in respiratory-tract cultures renders the guidelines inherently unstable. The pitfall is spiralling empiricism of antibiotic use for severely ill patients in whom infection might not be present. A vicious circle of antibiotic overuse leading to emergence of resistant microflora can become established, leading to unnecessary use of empirical broad-spectrum combination antibiotics and increased mortality. Controlled studies now show that administration of broad-spectrum combination antibiotic therapy can lead to increased mortality in uninfected patients. Proposed solutions include the use of individualised assessment of patients. Health-care-associated pneumonia should be broken down into several distinct subgroups so narrow-spectrum antibiotic therapy can be used. Emphasis should be placed on defining the microbial cause of the pneumonia rather than reflex administration of empirical combination therapy.     

Dyslipidemia,statins, and venous thromboembolism: a potential risk factor and a potential treatment

The optimal drug for the prevention of venous thromboembolism is one that is efficacious, associated with minimal bleeding risk, and easy to administer. Statins fulfill the latter two criteria, but their efficacy remains unproved. By examining the association between dyslipidemia and venous thromboembolism, as well as the evidence that statins might prevent venous thromboembolism, there may be a new rationale for the use of this class of drugs. There may be a common link between arterial and venous thrombosis. Dyslipidemia may be one of the many systemic factors associated not only with arterial thrombosis, but with venous thromboembolism as well. This may occur through the effects of circulating lipid molecules on the vascular endothelium, platelet function, and coagulation factors. By impeding these mechanisms, statins may be protective against venous thrombosis, but epidemiologic studies are few in number, and no randomized clinical trials have been conducted. Better epidemiologic evidence is required to establish whether dyslipidemia is a risk factor for venous thromboembolism. If future observational studies can demonstrate that statins are associated with a lower risk of venous thromboembolism, then consideration should be given to conducting a randomized clinical trial comparing statins with placebo for the prevention of venous thromboembolism. Until then, the efficacy of statins for the prevention or treatment of venous thromboembolism remains uncertain.     

Melatonin,energy metabolism,and obesity: a review

Melatonin is an old and ubiquitous molecule in nature showing multiple mechanisms of action and functions in practically every living organism. In mammals, pineal melatonin functions as a hormone and a chronobiotic, playing a major role in the regulation of the circadian temporal internal order. The anti‐obesogen and the weight‐reducing effects of melatonin depend on several mechanisms and actions. Experimental evidence demonstrates that melatonin is necessary for the proper synthesis, secretion, and action of insulin. Melatonin acts by regulating GLUT4 expression and/or triggering, via its G‐protein‐coupled membrane receptors, the phosphorylation of the insulin receptor and its intracellular substrates mobilizing the insulin‐signaling pathway. Melatonin is a powerful chronobiotic being responsible, in part, by the daily distribution of metabolic processes so that the activity/feeding phase of the day is associated with high insulin sensitivity, and the rest/fasting is synchronized to the insulin‐resistant metabolic phase of the day. Furthermore, melatonin is responsible for the establishment of an adequate energy balance mainly by regulating energy flow to and from the stores and directly regulating the energy expenditure through the activation of brown adipose tissue and participating in the browning process of white adipose tissue. The reduction in melatonin production, as during aging, shift‐work or illuminated environments during the night, induces insulin resistance, glucose intolerance, sleep disturbance, and metabolic circadian disorganization characterizing a state of chronodisruption leading to obesity. The available evidence supports the suggestion that melatonin replacement therapy might contribute to restore a more healthy state of the organism.     

Sarcoidosis and sacroiliitis, a case report

Sarcoidosis is a multisystem disorder of unknown etiology characterized by the presence of non-caseating granulomas in the organs affected. Sarcoid arthropathy is a rare manifestation, and sacroiliitis is an unusual first manifestation of the disorder.     

Anal fissures,fistulas, abscesses,and hemorrhoids in a tropical population

Summary Anal fissures, fistulas, abscesses, and hemorrhoids over a seven-year period in a tropical environment are reviewed. It is suggested that these diseases may be commoner in urban and city dwellers than in villagers. Increasing sophistication and changing food habits in the cities and towns and the attendant limitations on defecating at will are suggested as responsible etiologic factors. If diet, transversal gut time, and bowel habits contribute to large-bowel oncogenesis, cancer of the large bowel should increase in cities and towns faster than in villages. The marked male predominance in the diseases under discussion here is not explained, except that the incidence of perianal abscesses in females could have been higher if “pelvic inflammatory disease” had been taken into consideration. In an area where tuberculosis is very common, it is not considered an important cause of fistulas and abscesses. In an area where amebic ulcers of the rectum are common (third commones side in the large bowel), one would expect perianal abscess and fistula formation to benmuch more prevalent than these findings seem to indicate.     

Striking a Balance: Autophagy, Apoptosis, and Necrosis in a Normal and Failing Heart

Despite the progress that has been made over the past two decades in cardiovascular research, heart failure remains a major cause of morbidity and mortality worldwide. Insight into the cellular and molecular mechanisms that underlie the heart failure in individuals with ischemic heart disease have identified defects in cellular processes that govern autophagy, apoptosis and necrosis as a prevailing underlying cause. Indeed, programmed cell death of cardiac cells by apoptosis or necrosis is believed to involve the intrinsic mitochondrial pathway and/or extrinsic death receptor pathway by certain Bcl-2 family members as well as components of the TNF?? signaling pathway. In this review, we discuss recent advances in the molecular signaling factors that govern cardiac cell fate under normal and disease conditions.     

Genes, environments, development and asthma: a reappraisal.

Significant advances have been made in our understanding of the role of genetic variation in determining complex human phenotypes such as asthma. It is now well established that there is no single "gene for asthma", in the way that the cystic fibrosis transmembrane receptor is the "gene for cystic fibrosis". It is also clear that among all genetic variants eventually found to be associated with asthma, only a few will be replicated, and in the same direction, in the majority of well-performed studies. Current evidence suggests that most asthma-related polymorphisms determine risk for the disease in a context-dependent manner, i.e. they interact with environmental factors, with polymorphisms in other genes and with the specific developmental phase of the disease in which the association is tested. Elucidating these complex interactions will allow us to understand better the heterogeneity of the disease and thus to develop therapeutic tools tailored to the specific form of the disease in each patient.     

Clusters, superclusters, and large-scale structure: a consistent picture

Observations of the large-scale structure in the universe using different tracers and techniques, including the spatial distribution of galaxies, clusters of galaxies, narrow pencil-beam surveys, and quasars, appear to be yielding a consistent picture of the universal structure. A network of large-scale superclusters with scales up to approximately 150h-1 Mpc is suggested (where h approximately 0.5-1 is the Hubble constant in units of 100 km.s-1.Mpc-1; 1 pc = 3.09 x 10(16) m; h = 1 is used throughout this paper). The supercluster network surrounds low-density regions, suggesting a "cellular" structure of the universe. The universal dimensionless cluster correlation function, supported by new data from automated cluster surveys, is consistent with this picture. The "standard" Omega = 1 cold dark matter (CDM) model for the universe appears to be inconsistent with the details of the observed large-scale structure distribution; a low-density, Omega approximately 0.2-0.3, CDM model provides a considerably better fit to the observations.     

Temperance, alcohol, and the American evangelical: a reassessment

Abstinence from alcohol is a way of life for many American evangelicals, with rates of abstention running at over 70% among some Pentecostal denominations. This paper examines the religious beliefs that, historically, have supported teetotalism. The most notable of these is Christian perfection, a doctrine that originated in 18th-century England, that was then radicalized in America in the early 19th century. Abstinence from alcohol is highest among denominations that make Christian perfection the cornerstone of their teachings, and lowest among those that discount human agency. The paper also argues that 19th-century American evangelicals were by no means committed uniformly to temperance as a way of life, and that this was especially true of the various Methodist churches.     

Design, synthesis, and biological characterization of a peptide-mimetic antagonist for a tethered-ligand receptor

Protease-activated receptors (PARs) represent a unique family of seven-transmembrane G protein-coupled receptors, which are enzymatically cleaved to expose a truncated extracellular N terminus that acts as a tethered activating ligand. PAR-1 is cleaved and activated by the serine protease alpha-thrombin, is expressed in various tissues (e.g., platelets and vascular cells), and is involved in cellular responses associated with hemostasis, proliferation, and tissue injury. We have discovered a series of potent peptide-mimetic antagonists of PAR-1, exemplified by RWJ-56110. Spatial relationships between important functional groups of the PAR-1 agonist peptide epitope SFLLRN were employed to design and synthesize candidate ligands with appropriate groups attached to a rigid molecular scaffold. Prototype RWJ-53052 was identified and optimized via solid-phase parallel synthesis of chemical libraries. RWJ-56110 emerged as a potent, selective PAR-1 antagonist, devoid of PAR-1 agonist and thrombin inhibitory activity. It binds to PAR-1, interferes with PAR-1 calcium mobilization and cellular function (platelet aggregation; cell proliferation), and has no effect on PAR-2, PAR-3, or PAR-4. By flow cytometry, RWJ-56110 was confirmed as a direct inhibitor of PAR-1 activation and internalization, without affecting N-terminal cleavage. At high concentrations of alpha-thrombin, RWJ-56110 fully blocked activation responses in human vascular cells, albeit not in human platelets; whereas, at high concentrations of SFLLRN-NH(2), RWJ-56110 blocked activation responses in both cell types. Thus, thrombin activates human platelets independently of PAR-1, i.e., through PAR-4, which we confirmed by PCR analysis. Selective PAR-1 antagonists, such as RWJ-56110, should serve as useful tools to study PARs and may have therapeutic potential for treating thrombosis and restenosis.     

The athlete, cocaine, and lactic acidosis: a hypothesis

The muscular makeup of the sprint-trained athlete may make him especially susceptible to severe lactic acidosis from cocaine-induced seizures. Because of a high percentage of glycolytic muscle fibers (compared to the muscle fiber type of the endurance-trained athlete), the lactic acidosis and heat generated from muscular activity is much greater in the sprint-trained athlete than in the endurance-trained athlete. The role of cocaine in producing seizures and increasing glycolysis, both of which produce lactic acidosis, is discussed. The hypothesis is presented that the elite athlete may be at greater risk of death than the general population from lactic acidosis produced as a result of cocaine-induced seizures.     

Hemoglobin Knossos: a clinical, laboratory, and epidemiological study

Hb Knossos is a beta-chain variant (beta 27 Ser----Ala) that is unrecognizable by conventional separation methods but detectable by globin electrophoresis on urea-Triton X-acrylamide gels or by IEF. Hb Knossos is characterized by reduced synthesis and by interaction with beta-thalassemia, in which the double heterozygotes display typical features of thalassemia intermedia. The present paper summarizes the salient genetic, clinical, and biochemical characteristics of five such cases hitherto identified in three families along with the same features on 12 heterozygous Hb Knossos carriers. Hb Knossos displays a slightly decreased oxygen affinity; this factor may compensate in part for the severe anemia of the double heterozygotes. Hb Knossos is relatively rare in our population, since a prospective survey on 610 individuals has failed to disclose any heterozygotes. However, the mutation appears to have spread over the Mediterranean countries and may be more common elsewhere.     

Theophylline intoxication, clinical features, treatment and outcome: a case report and a review of the literature

Severe theophylline intoxication is a medical emergency that can lead to cardiac arrhythmias, convulsions and cardiovascular collapse not infrequently leading to permanent morbidity or mortality. We describe a 30-yr-old patient with a peak serum theophylline level of 87 mg/l treated with haemoperfusion using a coated charcoal-filled column. A review of the literature concerning theophylline toxicity, supportive care, outcome and the possible indications for the use of extracorporeal haemoperfusion is given. A summary of possible conservative measures is given. It is concluded that haemoperfusion is the extracorporeal treatment of choice and should be considered in case of theophylline serum levels above 80 mg/l even without signs of major toxicity. For certain patients with conditions increasing the risks of prolonged or severe toxicity even lower serum theophylline levels may warrant the use of haemoperfusion.     

Curcumin, a cancer chemopreventive and chemotherapeutic agent, is a biologically active iron chelator

Curcumin is a natural product currently in human clinical trials for a variety of neoplastic, preneoplastic, and inflammatory conditions. We previously observed that, in cultured cells, curcumin exhibits properties of an iron chelator. To test whether the chelator activity of curcumin is sufficient to induce iron deficiency in vivo, mice were placed on diets containing graded concentrations of both iron and curcumin for 26 weeks. Mice receiving the lowest level of dietary iron exhibited borderline iron deficiency, with reductions in spleen and liver iron, but little effect on hemoglobin, hematocrit, transferrin saturation, or plasma iron. Against this backdrop of subclinical iron deficiency, curcumin exerted profound 2 effects on systemic iron, inducing a dose-dependent decline in hematocrit, hemoglobin, serum iron, and transferrin saturation, the appearance of microcytic anisocytotic red blood cells, and decreases in spleen and liver iron content. Curcumin repressed synthesis of hepcidin, a peptide that plays a central role in regulation of systemic iron balance. These results demonstrate that curcumin has the potential to affect systemic iron metabolism, particularly in a setting of subclinical iron deficiency. This may affect the use of curcumin in patients with marginal iron stores or those exhibiting the anemia of cancer and chronic disease.     

Aging, religiosity, and adjustment: a longitudinal analysis

The relationships between church attendance, self-rated religiosity, and private prayer with aging are investigated with longitudinal data on older Mexican-Americans and Anglos. It is found that church attendance and practice of private prayer remained relatively stable over time (4 years) and that self-rated religiosity increased somewhat. Of the three measures only church attendance showed a significant effect on life satisfaction (net of other important predictors of life satisfaction) for both ethnic groups and at both points of observation. Among Anglos the effect of church attendance on life satisfaction increased significantly during the study interval.