Metabolic syndrome: what, why, how and who?

Although first knowledge on the joint onset of cardiovascular risk factors had been gained earlier, the first systematic review of this condition was made by G. Reaven in 1988 with his thesis on syndrome X, today known as the metabolic syndrome, with insulin resistance as the common denominator. Four elements have been identified: central obesity, dyslipoproteinemia (increased triglycerides, reduced HDL cholesterol), hypertension and glucose intolerance. There are two most influential definitions: one by the National Cholesterol Education Program (NCEP) and the other by the International Diabetes Federation (/IDF). NCEP requires the presence of at least three of the following factors: abdominal obesity as assessed by waist circumference >102 cm (m) or >88 cm (f), dyslipoproteinemia defined as triglyceridemia > or =1.7 mmol/L and/or HDL cholesterol <1.03 mmol/L (m); <1.29 mmol/L (f), hypertension (blood pressure > or =30/85 mmHg) and fasting glycemia > or =5.6 mmol/L (previously 6.1). IDF focuses on central obesity defined as waist circumference, taking into consideration sex and ethnic group specificities, with the presence of at least two additional factors (dyslipoproteinemia, hypertension, or increased fasting glycemia - all criteria virtually the same as in NCEP definition). Both IDF and NCEP define abdominal obesity by waist circumference, taking account of sex differences, and, in case of IDF, ethnic ones as well. The idea is to identify the simplest measure to indirectly determine the accumulation of visceral fat, which is, contrary to subcutaneous fat, a significant cardiovascular risk factor. However, waist circumference as the only criterion seems to be less specific than the waist-to-hip circumference ratio, which defines the risk more specifically and also better reflects insulin resistance. There is broad discussion as to whether the term metabolic syndrome contributes to the identification of persons at risk of cardiovascular disease better than its components, and, if so, which is the right set of components. It is being recommended that the discussion on the metabolic syndrome be limited to persons without diabetes or already diagnosed cardiovascular disease, as the primary goal for these individuals is to prevent these diseases. It has already been shown that this was possible, primarily by intensive change in lifestyle - healthy diet and exercise. In conclusion, further basic research is necessary to explain the pathophysiologic mechanisms, which might serve to develop new therapies. Moreover, epidemiological and public health aspects are extremely important in the creation of a prevention program. Preliminary results of the Croatian Health Survey (2003) indicate that the metabolic syndrome according to the IDF criteria is present even in the youngest age group, with expected age-dependent increase in both men and women. This is even an underestimate since in this survey only blood pressure and waist circumference were actually measured, and data on dislipidemia and blood glucose were based on a questionnaire. It is already obvious that a wide action with two main goals aimed primarily at the youngest population is necessary: an increase in regular physical activity and the promotion of healthy and energy-adequate diet in the population at large.     

In vivo EPR: when, how and why?

This special issue is aimed at providing the readers of this journal with an indication of the exciting and important areas in which in vivo electron paramagnetic resonance (EPR) [or equivalently electron spin resonance (ESR)] is making contributions to experimental progress and to provide perspectives on future developments, including the potential for in vivo EPR to be an important new clinical tool. There also are many situations where the combination of in vivo EPR with NMR may be very synergistic. EPR (ESR) is a magnetic resonance-based technique that detects species with unpaired electrons. The technique has become a major tool in diverse fields ranging from biology and chemistry to solid-state physics. In the last few years, many publications have demonstrated that EPR measurements in living animals (in vivo EPR) can provide very significant new insights to physiology, pathophysiology and pharmacology. The most successful applications of in vivo EPR have been non-invasive measurements of oxygen, nitric oxide, bioradicals, pH and redox state, with applications in oncology, cardiology, neuroscience and toxicology. EPR also appears to be the method of choice for measuring radiation dose retrospectively, including the potential to do this in vivo in human subjects. While far from comprehensive, the reviews, original contributions and viewpoints provided in this issue by several leaders in the field of in vivo EPR should provide the readers with confirmation that in vivo EPR is an exciting field that is likely to provide very valuable complementary information for many NMR-based studies in experimental animals and, probably, also for clinical studies.     

Allelic exclusion of immunoglobulin gene rearrangement and expression: why and how?

Since the discovery of the allelic exclusion of immunoglobulin (Ig) gene expression by Pervis in the 1960s [J. Exp. Med. 122 (1965) 853], much attention has been focused on its mechanism. Much less attention has been paid, however, to the question of why B cells demonstrate such unusual genetic regulation of antigen receptor gene expression. A large body of literature implicates the Ig gene products as feedback regulators of their own genetic rearrangement [Adv. Immunol.78 (2001)169; Science 236 (1987)816]. While a role for Ig gene products in the regulation of V(D)J recombination is beyond debate, it is extremely unlikely that such a feedback mechanism would be fast enough to avoid occasional near-simultaneous rearrangement of allelic loci leading to dual receptor gene expression. This review will suggest an hypothesis to answer the 'why bother' aspect of allelic exclusion and then go on to propose a mechanism, distinct from feedback regulation, which may contribute to the allelic exclusion of Ig gene expression.     

Comparative karyotype using bidirectional chromosome painting: how and why?

Rat is widely used in biomedical and pharmaceutical research but its genome has been significantly less studied than that of the mouse. This represents a major limitation for studying cytogenetic and molecular mechanisms in the rat model. As Muridae species underwent an intense chromosome evolution it is not possible to directly transpose knowledge of the mouse genome to that of the rat. For establishing a comparative karyotype between rat and mouse, painting probes of both species were prepared by PARM-PCR (Priming Authorizing Random Mismatches PCR) from a low copy number of sorted chromosomes, the mouse and rat specific painting probes being then hybridized on rat and mouse metaphases, respectively. The availability of rodent species chromosome painting probes as well as the information obtained by the comparative karyotype and comparative gene mapping data are of great interest to improve knowledge on species evolution but also to better understand carcinogenesis process, as illustrated by our data concerning the cytogenetic characterization of radon-induced rat lung tumors. Detailed methods for obtaining painting probes by PARM-PCR from sorted mouse and rat chromosomes and for their hybridization in homologous or heterologous conditions are described. Usefulness of chromosome painting is illustrated by the characterization of chromosomal abnormalities in a radon-induced rat lung tumor. Advantages and limitations of this technique as compared to classical cytogenetics, FISH and CGH are discussed.     

Chemotherapy of Chagas’ disease: the how and the why

Current developments in experimental chemotherapy of Chagas’ disease are reviewed, in particular the demonstration that fourth-generation azole derivatives (inhibitors of sterol C14α demethylase), with particular selectivity against Trypanosoma cruzi and special pharmacokinetic properties, are capable of inducing radical parasitological cures in murine models of both acute and chronic disease. These are the first reports of parasitological cure of this disease in its chronic phase. We also discuss the relevance of etiological treatment in the clinical outcome of patients with chronic Chagas’ disease. Although previous studies have suggested an important autoimmune component in the pathogenesis of this disease, recent results obtained using highly sensitive polymerase chain reaction based detection methods and detailed immunological characterization of the inflammatory process associated with chagasic cardiomyopathy indicate a positive correlation between tissue parasitism and the severity of cardiac pathological findings. Effective antiparasitic treatment can lead to regression of the inflammatory heart lesions and fibrosis in experimental animals and to stop the progression of the disease in humans. Taken together, these findings support the notion that the presence of the parasite is a necessary and sufficient condition for chagasic cardiomyopathy and confirm the importance of specific etiological treatment in the management of chronic chagasic patients. Received: 30 March 1998 / Accepted: 6 November 1998     

Why, why, why?: Reason-giving and rumination as predictors of response to activation- and insight-oriented treatment rationales

This study examines the relationships among the reasons a person offers for depression, the tendency to ruminate in response to depression, and reactions to activation-oriented (AO) or insight-oriented (IO) treatment rationales. Adults from the community (N=51) completed self-report measures of reason-giving and rumination and rated the credibility of, and personal reactions to, AO and IO rationales presented in written and videotape formats. Participants who gave more reasons for depression also tended to ruminate more in response to depressed mood. Reason-giving and rumination predicted lower credibility ratings and more negative personal reactions to the AO rationale. Although no relationship was found between these variables and response to the IO rationale, specific reasons were associated with different reactions to the two rationales. We discuss the roles of reason-giving and rumination in predicting responses to psychotherapies for depression.     

A clinical and molecular review of inverted papilloma of the urinary tract: how to handle?

Inverted papilloma (IP) of the urinary tract is classified by the World Health Organisation as a non‐invasive urothelial tumour with normal to minimal cytological atypia of the neoplastic cells. During the 1980s, it came under suspicion of having a premalignant or malignant potential and of being concurrent with urothelial cell carcinoma (UCC). This quandary has been proven difficult to solve, due to the fact that IP is very rare and literature mostly consists of case reports with varying levels of information, making strong meta‐analyses problematic. New immunohistochemical techniques and genetic approaches are more frequently being used in the attempt to achieve better classifications, prognosis and treatment of lesions hereunder IP. This review will, in our awareness, be the first to combine the knowledge from retrospective studies with these new approaches for determining a possible premalignant potential and concurrency with UCC and subsequently outline a recommendation for follow‐up.     

Compartmentalization of cyclic nucleotide signaling: a question of when, where, and why?

Preciseness of cellular behavior depends upon how an extracellular cue mobilizes a correct orchestra of cellular messengers and effector proteins spatially and temporally. This concept, termed compartmentalization of cellular signaling, is now known to form the molecular basis of many aspects of cellular behavior in health and disease. The cyclic nucleotides cyclic adenosine monophosphate and cyclic guanosine monophosphate are ubiquitous cellular messengers that can be compartmentalized in three ways: first, by their physical containment; second, by formation of multiple protein signaling complexes; and third, by their selective depletion. Compartmentalized cyclic nucleotide signaling is a very prevalent response among all cell types. In order to understand how it becomes relevant to cellular behavior, it is important to know how it is executed in cells to regulate physiological responses and, also, how its execution or dysregulation can lead to a pathophysiological condition, which forms the scope of the presented review.     

GABAAreceptor subtypes: which,where and why?

Synaptic inhibition in the vertebrate central nervous system is mediated predominantly by subtypes of the GABA_Areceptor, which comprise different pentameric combinations of the products of 13 genes. In this article, we review the results of recent experiments that are helping to define binding-site determinants, on GABA_Areceptors, for various ligands and some clinically-important modulators. New and sometimes conflicting data, on the polypeptide compositions of native subtypes, will also be discussed. Studies such as those described here should ultimately lead to a molecular understanding of receptor–ligand interactions, and the biological basis for the large number of subtypes that appear to exist in brain.