The origin of life at the origin of ageing?

At first glance, the ageing of unicellular organisms would appear to be different from the ageing of complex, multicellular organisms. In an attempt to describe the nature of ageing in diverse organisms, the intimate links between the origins of life and ageing are examined. Departing from Leslie Orgel’s initial ideas on why organisms age, it is then discussed how the potentially detrimental events characteristic of ageing are continuous, cell-autonomous and universal to all organisms. The manifestation of these alterations relies on the balance between their production and cellular renewal. Renewal is achieved not only by repair and maintenance mechanisms but, importantly, by the process of cell division such that every time cells divide ageing-associated effects are diluted.     

Cranial or postcranial—Dual origin of the pectoral appendage of vertebrates combining the fin-fold and gill-arch theories?

Two main theories have been used to explain the origin of pectoral and pelvic appendages. The “fin-fold theory” proposes that they evolved from a trunk bilateral fin fold, while Gegenbaur's theory assumes they derived from the head branchial arches. However, none of these theories has been fully supported. The “fin-fold” theory is mainly often accepted due to some existing developmental data, but recent developmental studies have revived Gegenbaur's theory by revealing common mechanisms underlying the patterning of branchial arches and paired appendages. Here I review developmental data and many others lines of evidence, which lead to a crucial question: might the apparent contradictions between the two theories be explained by a dual origin of the pectoral appendage, that is, the pectoral girdle and fin/limb being mainly related to the head and trunk, respectively? If this is so then (a) the pectoral and pelvic girdles would not be serial homologues; (b) the term “developmental serial homologues” could only potentially be applied to the pectoral and pelvic fins/limbs. Fascinatingly, in a way this would be similar to what Owen had already suggested, more than 170 years ago: that the pectoral and pelvic girdles are mainly related to the head and trunk, respectively.     

Are proteinases functional molecules of T lymphocytes?

Recent studies have shown that activated T cells possess cytoplasmic granules containing a serine proteinase. In this article Michael Kramer and Markus Simon suggest that the regulated release of this enzyme has an important part to play in the activities of T cells, such as B-cell regulation, cytolysis and migration.     

Are lymphocytes concerned with our definition of idiotypes?

For some, idiotypes are interesting as markers of individual molecules, providing the basis for a taxonomy of B- and T-cell clones. For us, idiotypes are components of a larger network structure of variable regions, and their shapes are of significance because they establish connectivity. Each unique specificity per se is less interesting, for it is interchangeable without altering network organization. These issues are critical for delineating concepts of autoimmunity and for choosing between ‘nonspecific’ and ‘targeted’ approaches of immunoglobulin therapy in autoimmune diseases.     

Assessing ageing of individual T lymphocytes: mission impossible?

Effector T lymphocytes are the progeny of a limited number of antigen-specific precursor cells and it has been estimated that clonotypic human T cells may expand million fold on their way reaching high cell numbers that are sufficient for immune protection. Moreover, memory T cell responses are characterized by repetitive expansion of antigen-specific T cell clonotypes, and limitations in the proliferative capacity could lead to immune senescence. Because telomeres progressively shorten as a function of cell division, telomere length is a powerful indicator of the replicative in vivo history of human T lymphocytes. In this review, we summarize observations made over the last decade on telomere length dynamics of well-defined T cell populations derived from healthy donors and patients with infectious disease or cancer. We focus on T cell differentiation, T cell ageing, and natural and vaccine induced immune responses. We also discuss the scientific evidence for in vivo replicative senescence of antigen-specific T cells, and evaluate the available methods for measuring telomere lengths and telomerase activity, and their potential and limitations to increase our understanding of T cell physiology.     

What happened in the origin of human consciousness?

At some point in its evolutionary history, our species Homo sapiens ceased to be a nonlinguistic, nonsymbolic organism, living in the world as presented to it by Nature, and instead began to exist in a world that it reconstructs in its own mind. Most scientists since Darwin have been content to explain this extraordinary transformation in human consciousness by the operation of natural selection. However, the human fossil and archaeological records indicate that modern human symbolic consciousness is not the culmination of the long trend that natural selection would predict. Instead, it shows that major change in the human past has been episodic and rare and that, as far as can be determined from the archaeological record, the passage from nonsymbolic to symbolic cognition is a recent event as well as an unprecedented one. So recent, indeed, that it significantly postdates the acquisition of modern human anatomy as expressed in skeletal structure. It, thus, appears most likely that the biological (neural) capacity underwriting the radically new behavioral mode arose as an incidental exaptation in the same process that produced the new skeletal structure of Homo sapiens, but that it lay unexpressed until it was "discovered" by means of a cultural innovation, plausibly the invention of language. As in the case of the modern anatomical structure, it appears that the new capacity was initially expressed in Africa and that its various behavioral potentials were sequentially discovered in a drawn-out process that is continuing today. An "accidental" origin of the human capacity helps understand why so many human behaviors have proven self-destructive and contradictory, a feature of our species that reductionist, selection-based scenarios are hard-put to explain.     

Is multiple sclerosis a disease of viral origin?

MS is a multifactorial disease in which host genetic factors as well as environmental factors may interact. Among them, the role of viruses is still debated since none has been directly or indirectly involved in the disease up to now. The latest candidates are HHV6 and MSRV. Recently, HHV6 antigens have been found in MS brain, but these results require further investigation. MSRV is a retroviral sequence isolated from MS tissue and it belongs to the already known ERV9 family of endogenous retroviruses. Its role in MS is only putative. To conclude, "MS virus" is still unidentified. Nevertheless, the search for a virus in MS should be pursued. In that perspective, animal models illustrate how host immune system interacts with viruses to lead to demyelination, a common feature of a multi-step process of diverse origins.     

Are B lymphocytes of importance in severe Staphylococcus aureus infections?

To investigate the role of B cells in experimental, superantigen-mediated Staphylococcus aureus arthritis and sepsis, we used gene-targeted B-cell-deficient mice. The mice were inoculated intravenously with a toxic shock syndrome toxin 1 (TSST-1)-producing S. aureus strain. The B-cell-deficient and thus agamma-globulinemic mice showed striking similarities to the wild-type control animals with respect to the development of arthritis, the mortality rate, and the rate of bacterial clearance. Surprisingly, we found that the levels of gamma interferon in serum were significantly lower (P < 0. 0001) in B-cell-deficient mice than in the controls, possibly due to impaired superantigen presentation and a diminished expression of costimulatory molecules. In contrast, the levels of interleukin-4 (IL-4), IL-6, and IL-10 in serum were equal in both groups. Our findings demonstrate that neither mature B cells nor their products significantly contribute to the course of S. aureus-induced septic arthritis.     

The composition of intrahepatic lymphocytes: shaped by selective recruitment?

Intrahepatic lymphocytes have a distinct subset composition and phenotype. Compared with lymphoid tissues, the frequency of natural killer (NK) cells, NKT cells and gammadelta T cells among total lymphocytes is increased within the liver, and alphabeta T cells are predominantly effector/memory cells. Divergent hypotheses on the origin of intrahepatic T cells have emerged to explain this; in these hypotheses, either local development or selective recruitment of cells into the liver dominates. This Opinion highlights findings showing that the migratory preferences of lymphocyte subsets reflect their representation within the liver surprisingly well, suggesting that the composition of intrahepatic lymphocytes, in the absence of inflammation, is largely shaped by the dynamics of cell entry and exit into and from the liver.     

Is Chlamydia-infected tubal fimbria the origin of ovarian cancer?

Ovarian cancer is a highly lethal disease and its underlying biology is poorly understood. Prophylactic salpingo-oophorectomies in BRCA + women have recently implicated the fimbria as a site of origin for high-grade serous carcinoma and its intraepithelial precursors. This suggests that at least some ovarian cancers, probably the most aggressive ones, may not originate in the ovary itself, but rather may arise in the uterine tubes. Chronic inflammation is associated with carcinogenesis in several tissues, including liver, esophagogastric junction (cardia), and the uterine cervix. The mechanisms underlying the relationship between inflammation and cancer are complex and involve common pathways, in addition to DNA damage. A critical source of uterine tube inflammation is infection with Chlamydia trachomatis. We hypothesize that C.trachomatis infection may be involved in chronic tubal inflammation and subsequent fimbrial carcinogenesis. Fimbrial intraepithelial precursors can evolve into high grade serous carcinomas that spread rapidly to the ovarian surface and peritoneum; such tumors may appear to be primary ovarian neoplasia, though in reality being a secondary malignancy. This hypothesis must be further investigated to understand the intracellular signaling pathways involved in Chlamydia infection and its healing, and their relationship to carcinogenesis in order to discover potential therapeutic molecular targets. If our hypothesis were confirmed, salpingectomy instead of ovariectomy may also become the recommended surgery for high risk women.     

Solitary necrotic nodule of the liver: parasitic origin?

AIMS: To report further cases of solitary necrotic nodule of the liver and to study its nature. METHODS: Seven nodules were retrieved from 4000 necropsy and surgical liver specimens coming to light over the past five years. All of them satisfied the diagnostic criteria of solitary necrotic nodule: a solid lesion with a central necrotic core and a hyalinised fibrotic capsule containing elastic fibres. Their clinicopathological features were reviewed. RESULTS: The nodules were incidental findings at surgery or necropsy in four men and three women whose ages ranged from 48 to 79 years (mean 63.7 years). Four were found in the right lobe and three in the left. Six were subcapsular and only one deep in the parenchyma, with sizes ranging from 0.3-2.5 cm. Each of them was solitary, well demarcated, and round to oval with a firm, whitish rim and a core of yellowish white cheese-like to solid material. In addition to the basic architecture, there were a number of common and undescribed histological features: presence of varying numbers of small mural vessels with intimal fibrosis and obliteration, presence of cholesterol clefts and foamy cells among necrotic material, and sparsity of inflammatory cells. In the two cases where ghosts of degenerated cells and partially preserved liver reticulin pattern were noted, worms were identified, one being Clonorchis sinensis. CONCLUSIONS: The entity is believed to be a "burnt-out phase" of a variety of benign lesions. Parasitic infestation is another possible cause, and presence of ghosts of degenerate cells, partially preserved liver reticulin pattern, cholesterol clefts and foamy cells among necrotic material are auxiliary features pointing to such an aetiology. The variation in morphological fine details reflects both the lesion's diverse pathogenesis and the fact that it can be of varying duration.     

Quantitation of intraepithelial lymphocytes in human duodenum: what is normal?

BACKGROUND: An increase in intraepithelial lymphocytes (IELs) is mandatory for the histological diagnosis of coeliac disease (CD). Currently, duodenal biopsies are used almost exclusively to establish the diagnosis, yet published work continues to cite an upper limit of 40 lymphocytes/100 epithelial cells, a figure derived from jejunal biopsies over 30 years ago. Aim: To establish the normal range for IEL counts in distal duodenal biopsies. MATERIALS/METHODS: Twenty subjects (seven men, 13 women; median age, 34 years; range, 20-65) with a normal sugar permeability test and concurrent distal duodenal biopsies were identified. The number of IELs and epithelial cell nuclei in an uninterrupted length of surface (villous) epithelium (> 500 cells) was counted. An image analysis system was used to assess villous architecture by calculating the villous height to crypt depth ratio. RESULTS: The range of IEL counts in 20 subjects was 1.8-26/100 villous epithelial cells, with a mean value of 11 and SD of 6.8. The mean villous to crypt ratio was 1.82 (SD, 0.38; range, 1.22-2.46). There was no correlation between IEL counts and villous to crypt ratio (Spearman rank correlation, -0.066; p = 0.80). CONCLUSIONS: These results suggest that 25 IELs/100 epithelial cells (mean +2 SD) should be taken as the upper limit of the normal range for duodenal mucosa.     

Extramammary Paget's disease—a proliferation of adnexal origin?

AIM: To investigate a possible follicular origin of extramammary Paget's disease (EPD). EPD is a predominantly intraepidermal tumour with extensive involvement of adnexal structures and high recurrence rates suggesting a follicular stem cell origin. Cytokeratin (CK) 15 and CK19 are considered markers for follicular stem cells located in the hair follicle bulge region. METHODS AND RESULTS: Formalin-fixed paraffin-embedded tissues of 12 cases of primary EPD (three anal, nine vulvar) were studied immunohistochemically with antibodies to CK15 and CK19. All cases of EPD showed polygonal Paget cells in the interfollicular epidermis, hair follicles, sebaceous and apocrine glands distributed individually, in nests and in gland-like areas. The polygonal Paget cells were intimately associated with small, flat, mitotically active, 'compressed' keratinocytes. The large Paget cells uniformly expressed CK19 in 12/12 EPD. The small 'compressed' keratinocytes showed strong cytoplasmic CK15 staining in 9/12 EPD with focal accentuation, while the polygonal Paget cells were negative. CONCLUSIONS: These histological and immunohistochemical observations allow the following conclusions: (i) the small, flat, 'compressed' keratinocytes are an integral part of EPD; (ii) the dual cell population is reminiscent of sebaceous glands with mature sebocytes and germinative keratinocytes; (iii) since both cell types express cytokeratins typical for follicular differentiation, EPD may be a proliferation of adnexal stem cells residing in the infundibulo-sebaceous unit of hair follicles and adnexal structures.     

Gastrointestinal stromal tumors: are they of cajal cell origin?

Recently some reports have suggested that gastrointestinal stromal tumors (GIST) might originate from the interstitial cells of Cajal or differentiate into them because they express c-kit and/or CD34 and indicated that the majority of previously diagnosed smooth muscle tumors (SMT) actually belong to GIST, but are not true SMT. We, therefore, detected c-kit, CD34, SMA, and S-100 in 106 Chinese cases of gastrointestinal tumors, which were histopathologically diagnosed as smooth muscle tumors originally, to demonstrate the immunophenotypes of these tumors. The results showed that 73 cases had immunoreaction with c-kit and/or CD34, of which 48 cases showed coexpression with either SMA or S-100 or with both. A correlation between the immunophenotypes and known histopathological parameters was also shown here based on follow-up data. We suggest that the concept of GIST should not be used as an umbrella to cover all gastrointestinal mesenchymal tumors, but be defined in a narrow term as differing from true smooth muscle tumors.     

Fetal origin of maturity-onset diabetes mellitus: genetic or environmental cause?

Low birthweight is a risk factor for a number of diseases of adult life including non-insulin-dependent diabetes mellitus (NIDDM). This implies that either genetic constitution or factors operating during intrauterine development have a causal role in NIDDM. One reason for rejecting a genetic cause, however, is that there is a rapidly changing prevalence of NIDDM with the onset and establishment of affluence, which does not fit with conventional models of multifactorial genetic disease. But in this article a new model of genetic disease based on the concept of redundancy is explored. The idea is that mutant genes interact synergistically in highly redundant systems to degrade performance and increase the risk of disease. The mutational load is in turn determined by the pre-conceptual environment. This model can explain a rapidly changing prevalence of NIDDM.     

Could statins exert a protective effect on epistaxis of systemic origin?

Epistaxis, that is a relatively frequent occurrence of hemorrhage from the nose, is reported in up to 60% of the population with peak incidences in subjects under the age of ten ("essential" epistaxis, usually linked to an altered vasomotor regulation) and, with even greater entity, over the age of 60. The cause of nosebleeds can generally be divided into two categories, local and systemic factors, although it should be remembered that a significant number of nosebleeds occur with no obvious cause. Actually, according to the common observation the epistaxis prone subject is an elderly with hypertension associated to some degree of vascular alteration. The statins essentially exert a competitive inhibition of 3-hydroxy-3 methyl glutaryl coenzyme A (HMG-CoA) reductase that results in cholesterol synthesis inhibition. In the last years, however, there has been a growing evidence that these drugs exert a number of vascular actions that are independent of lipid lowering and result in a vasoprotective effect. Due to their favourable influence on the vascular wall, and the consequent possible modulatory effect on blood pressure, a possible utility of statins in preventing many cases of nosebleed is hypothesized, to our knowledge for the first time.