The molecular basis and clinical aspects of Peutz-Jeghers syndrome

Peutz-Jeghers syndrome (PJS) is a classic, but not widely known hereditary trait. Its clinical hallmarks are intestinal hamartomatous polyposis and melanin pigmentation of the skin and mucous membranes. In addition, PJS predisposes to cancer . The most common malignancies are small intestinal, colorectal, stomach and pancreatic adenocarcinomas. Other cancer types that probably occur in excess in PJS families include breast and uterine cervical cancer, as well as testicular and ovarian sex cord tumors. The relative risk of cancer may be as high as 18 times that of the general population, and the cancer patients' prognosis is reduced. Recently, the predisposing locus was mapped to 19p13.3 using a novel method. Subsequently, the causative gene was shown to be LKB1 (a.k.a. STK11), a serine/threonine kinase of unknown function. Although preliminary reports seem to suggest a minor role for LKB1 in sporadic tumorigenesis, further investigations are needed. Received 12 October 1998; received after revision 30 November 1998; accepted 30 November 1998     

Introduction: molecular and biomechanical basis of osteoarthritis

Osteoarthritis has developed into the most common chronic disease in the highly industrialized nations. Moreover, because of the prevalence of the disease in the elderly, this trend occurs worldwide as a consequence of increasing longevity due to the overall improvement in living conditions and health status. In contrast, research on osteoarthritis is still financially marginalized within biomedical research, so that the molecular and biophysical bases for disease initiation and progression are largely unmapped. The following sequence of five reviews highlights a remarkable change in that body of knowledge taking place at the beginning of the World Health Organization (WHO) 'Bone and Joint Decade 2001-2010'. The data and ideas presented in these articles reflect to some extent the guidelines set up by the WHO and by the National Institutes of Health of the USA and therefore allow a glimpse into the directions that research in osteoarthritis will take in the future.     

Colitis-associated neoplasia: molecular basis and clinical translation

Crohn’s disease and ulcerative colitis are both associated with an increased risk of inflammation-associated colorectal carcinoma. Colitis-associated cancer (CAC) is one of the most important causes for morbidity and mortality in patients with inflammatory bowel diseases (IBD). Colitis-associated neoplasia distinctly differs from sporadic colorectal cancer in its biology and the underlying mechanisms. This review discusses the molecular mechanisms of CAC and summarizes the most important genetic alterations and signaling pathways involved in inflammatory carcinogenesis. Then, clinical translation is evaluated by discussing new endoscopic techniques and their contribution to surveillance and early detection of CAC. Last, we briefly address different types of concepts for prevention (i.e., anti-inflammatory therapeutics) and treatment (i.e., surgical intervention) of CAC and give an outlook on this important aspect of IBD.     

Bacterial aging: from mechanistic basis to evolutionary perspective

Aging—defined as the progressive impairment of an organism’s functional capacity, resulting from deleterious changes in cells, organs, and biological systems—is one of the most fundamental features of Eukaryotes, from humans to the unicellular budding yeast Saccharomyces cerevisiae. It has recently been reported that this may also be the case for certain (if not all) types of bacteria. In this paper, the current view on the mechanistic background and evolutionary significance of bacterial kind of aging is presented, with particular emphasis on the role of asymmetric cell division, the characteristics of stationary growth phase, and the role of oxidative protein damage.     

Peutz-Jeghers syndrome: clinicopathology and molecular alterations

Peutz-Jeghers syndrome (PJS, OMIM 175200) is an unusual inherited intestinal polyposis syndrome associated with distinct peri-oral blue/black freckling [1–9]. Variable penetrance and clinical heterogeneity make it difficult to determine the exact frequency of PJS [4]. PJS is a cancer predisposition syndrome. Affected individuals are at high risk for intestinal and extra-intestinal cancers. In 1997, linkage studies mapped PJS to chromosome 19p [10, 11], and subsequently a serine/threonine kinase gene defect (LKB1) was noted in a majority of PJS cases [12, 13]. A phenotypically similar syndrome has been produced in an LKB1 mouse knockout model [14–18]. Several PJS kindred without LKB1 mutations have been described, suggesting other PJS loci [19–22]. The management of PJS is complex and evolving. New endoscopic technologies may improve management of intestinal polyposis. Identification of specific genetic mutations and their targets will more accurately assess the clinical course, and help gage the magnitude of cancer risk for affected individuals. Received 20 February 2006; received after revision 5 May 2006; accepted 15 June 2006     

Review¶Psychrophilic enzymes: molecular basis of cold adaptation

Psychrophilic organisms have successfully colonized polar and alpine regions and are able to grow efficiently at sub-zero temperatures. At the enzymatic level, such organisms have to cope with the reduction of chemical reaction rates induced by low temperatures in order to maintain adequate metabolic fluxes. Thermal compensation in cold-adapted enzymes is reached through improved turnover number and catalytic efficiency. This optimization of the catalytic parameters can originate from a highly flexible structure which provides enhanced abilities to undergo conformational changes during catalysis. Thermal instability of cold-adapted enzymes is therefore regarded as a consequence of their conformational flexibility. A survey of the psychrophilic enzymes studied so far reveals only minor alterations of the primary structure when compared to mesophilic or thermophilic homologues. However, all known structural factors and weak interactions involved in protein stability are either reduced in number or modified in order to increase their flexibility.     

Sexual behavior mutants revisited: molecular and cellular basis of Drosophila mating

The study of Drosophila melanogaster by a combination of forward genetics with specific mutants, and reverse genetics, in which a given gene is expressed in an appropriate brain area to test its effect on behavior, provides a unique opportunity to explore the causal relationship between a particular gene, its function in the cell and the behavioral outcome at the organismic level. Enhanced male-to-male courtship has been shown to occur as a result of mutations in several different genes. For example, the Voila mutant exhibits intense GAL4 reporter expression in the tarsal gustatory sensilla, suggesting the importance of tapping by a male on the female abdomen with his forelegs. Feminization of parts of the antennal lobe and mushroom body by targeted expression of a female-determining gene transformer ⁺ (tra ⁺) drives the male to court other males. Mutations in the tra target gene fruitless (fru), which is expressed in the antennal lobe as well as the suboesophageal ganglion (the gustatory inputs are processed here), also induce homosexual courtship in males. These results suggest that sensory inputs mediated and/or processed by the tarsal receptors, suboesophageal ganglion, antennal lobe and mushroom body contribute to the regulation of male–female courtship. Mosaic analysis localized the neural center for male courtship behavior to the posterior dorsal brain, in which the sensory information processed by the aforementioned neural structures may be integrated. Another mosaic study mapped the neural center for female sexual behavior, as measured by her receptiveness to copulation, to the anterior dorsal brain. The issue as to how the mutations that reduce female sexual receptiveness, e.g. dissatisfaction (dsf), spinster (spin) and chaste (cht), affect the structure and/or function of this neural center deserves to be addressed urgently. Received 27 April 1999; received after revision 21 June 1999; accepted 8 July 1999     

Collagen synthesis of cultured fibroblast from Werner's syndromes of premature aging

Summary The difference of collagen producibility between 2 groups of skin fibroblasts from patients with Werner's syndrome with skin change and with normal skin, and the difference of collagen accumulation to cell layer between skin fibroblast from Werner's syndrome and controls were studied.Acknowledgments. We are grateful to Dr M. Ohkido and Dr I. Matsuo of the Department of Dermatology of Tokai University for their supply of materials and generous advice and Mr K. Takeichi of the Department of Pathology of Tokai University for his technical assistance.     

Endothelial signaling and the molecular basis of arteriovenous malformation

Arteriovenous malformations occur when abnormalities of vascular patterning result in the flow of blood from arteries to veins without an intervening capillary bed. Recent work has revealed the importance of the Notch and TGF-β signaling pathways in vascular patterning. Specifically, Notch signaling has an increasingly apparent role in arterial specification and suppression of branching, whereas TGF-β is implicated in vascular smooth muscle development and remodeling under angiogenic stimuli. These physiologic roles, consequently, have implicated both pathways in the pathogenesis of arteriovenous malformation. In this review, we summarize the studies of endothelial signaling that contribute to arteriovenous malformation and the roles of genes implicated in their pathogenesis. We further discuss how endothelial signaling may contribute to vascular smooth muscle development and how knowledge of signaling pathways may provide us targets for medical therapy in these vascular lesions.     

The genetic and evolutionary basis of colour variation in vertebrates

Variation in pigmentation is one of the most conspicuous phenotypic traits in vertebrates. Although mammals show less variation in body pigmentation than other vertebrate groups, the genetics of colour determination and variation is best understood for them. More than 150 genes have been identified that influence pigmentation, and in many cases, the cause for variation in pigmentation has been identified down to the underlying nucleotide changes. These studies show that while some genes are often responsible for deviating pigmentation, similar or almost identical phenotypes even in the same species may be due to mutations in different genes. In this review we will first discuss the current knowledge about the genes and their functions underlying the biochemical pathways that determine pigmentation and then give examples where the mutations responsible for colour variation have been determined. Finally, we will discuss potential evolutionary causes for and consequences of differences in pigmentation between individuals.     

Insights into the genetic basis of congenital heart disease

Cardiovascular malformations are the most common type of birth defect and result in significant mortality worldwide. The etiology for the majority of these anomalies remains unknown. Advances in the characterization of the molecular pathways critical for normal cardiac development have led to the identification of numerous genes necessary for this complex morphogenetic process. This work has aided the discovery of an increasing number of single genes being implicated as the cause of human cardiovascular malformations. This review summarizes normal cardiac development and outlines the recent discoveries of the genetic causes of congenital heart disease. Received 4 November 2005; received after revision 14 January 2006; accepted 1 February 2006     

Human progeroid syndromes,aging and cancer: new genetic and epigenetic insights into old questions

Disorders in which individuals exhibit certain features of aging early in life are referred to as segmental progeroid syndromes. With the progress that has been made in understanding the etiologies of these conditions in the past decade, potential therapeutic options have begun to move from the realm of improbability to initial stages of testing. Among these syndromes, relevant advances have recently been made in Werner syndrome, one of several progeroid syndromes characterized by defective DNA helicases, and Hutchinson-Gilford progeria syndrome, which is characterized by aberrant processing of the nuclear envelope protein lamin A. Although best known for their causative roles in these illnesses, Werner protein and lamin A have also recently emerged as key players vulnerable to epigenetic changes that contribute to tumorigenesis and aging. These advances further demonstrate that understanding progeroid syndromes and introducing adequate treatments will not only prove beneficial to patients suffering from these dramatic diseases, but will also provide new mechanistic insights into cancer and normal aging processes. Received 28 July 2006; received after revision 5 September 2006; accepted 13 October 2006     

New insights into the metabolic and molecular basis for diabetic neuropathy

Diabetic polyneuropathy is the most common complication of diabetes mellitus. Several interactive pathogenetic mechanisms have been identified mainly in streptozotocin-induced diabetes in rats and have been ascribed to hyperglycemia. Over the last number of years it is becoming increasingly clear that diabetic neuropathy differs in type 1 and type 2 diabetes in humans and in murine models that more accurately mimic the human disorders. Beside hyperglycemia, attention is increasingly being paid to the pathogenetic roles of insulin and C-peptide deficiencies, particularly in type 1 diabetic neuropathy. There is now evidence to suggest that insulin and C-peptide deficiencies are mainly responsible for perturbations of neurotrophic factors and contribute to oxidative stress in diabetic nerve. This may also be true for apoptotic phenomena afflicting both the peripheral and central nervous systems in diabetes. The new data have lead to re-evaluations of pathogenetic components in this complex disorder, and their further exploration is likely to form a more refined basis for future therapeutic and preventive measures.Received 25 February 2003; received after revision 12 May 2003; accepted 19 May 2003