Membrane rafts in immunoreceptor signaling: new doubts,new proofs?

Immunoreceptors are believed to initiate their signaling by association with membrane rafts rich in src-family kinases and other signaling molecules. Although a recent paper casts doubt over this concept, by exposing drawbacks of a commonly used procedure to disturb rafts by cholesterol extraction, several other recent papers give further support to the concept.     

Functional autoantibodies, a new paradigm in autoimmunity?

The recent detection of stimulatory autoantibodies as a characteristic feature of systemic sclerosis (scleroderma), established the presence of such autoantibodies as a characteristic pathophysiologic finding in a second classical autoimmune disease after autoimmune thyroid disease. This observation raises the possibility of a new paradigm in abnormal autoimmune function, the presence of stimulatory (and suppressive), functional autoantibodies as characteristic features of abnormal autoimmune function. The assumption of such a paradigm opens interesting new research avenues within rheumatology and in other medical specialty areas. Within reproductive medicine, and akin to the concept of hypo- and hyperthyroidism, the possible juxtaposition of polycystic ovarian syndrome (PCOS) and premature ovarian aging (POA), as opposite abnormalities of adrenal function, under control of autoimmune adrenal antibodies, deserves further investigation.     

What's new in the Aire?

Unraveling the mechanisms underlying autoimmune disease remains a difficult challenge. Recent lessons learned from the study of AIRE (autoimmune regulator), the gene responsible for the rare monogenic human syndrome APS-1, highlight the power of genetics to reveal disease pathogenesis. With the discovery of AIRE, central tolerance has re-emerged as a crucial check against autoimmunity. Aire-mediated regulation of diverse self-antigens in the thymus serves as a paradigm for the importance of promiscuous gene expression in the prevention of autoimmune disease. Recent characterization of Aire-targeted antigens continues to bear this out. Here, we review the current progress surrounding the role of Aire in central tolerance from a molecular, genetic and developmental basis.     

A new subdivision,the marginal division,in the neostriatum of the human brain

<正> A new subetemtory was discovered byas at the caudal most edge of the neostriatum(St) and surrounding the rostral berder of the globus pallidus(GP) in the rat btain with neuroanato-my and immunohistochemistry methods.This area was named marginal division(MrD)based on its location.     

Short trunk stature,brachydactyly, and platyspondyly in three sibs: a new form of brachyolmia or a new skeletal dysplasia?

We present a 27-year-old girl with short trunk stature, generalized rectangular platyspondyly and strike precocious calcification of costal cartilage. She had also brachydactyly, small nails, strabismus and delay of menarche. Her 16-year-old sister had also short trunk stature with severe kyphoscoliosis, hearing loss, brachydactyly, platyspondyly and mild precocious calcification of costal cartilages. Their 12-year-old brother had short trunk stature, kyphoscoliosis, brachydactyly, and platyspondyly but did not show precocious calcification of costal cartilage. The patients shared the following features: short trunk stature, brachydactyly, severe rectangular platyspondyly, broad and short femoral necks and hypoplasia of the ileum. In addition, the older sister had strike precocious calcification of costal cartilage while her sister and brother had severe kyphoscoliosis. Although short trunk stature and severe rectangular platyspondyly without significant epiphyseal or metaphyseal changes were in favor of Hobaek type brachyolmia, this diagnosis was not considered, both because, there were no specific radiological findings of this syndrome, such as elongated vertebral bodies extending beyond the pedicles laterally and all of the patients had brachydactyly which was not present in Hobaek type brachyolmia. The parents were healthy and first cousins signifying autosomal recessive inheritance. We considered that the patients could be affected by a new distinct autosomal recessive type brachyolmia or a new skeletal dysplasia.     

Talo-patello-scaphoid osteolysis,synovitis, and short fourth metacarpals in sisters: a new syndrome?

Osteolysis syndromes are characterized by resorption of affected bones with associated swelling and pain. Various forms of multicentric osteolysis syndromes including autosomal dominant and recessive carpal-tarsal osteolysis, Torg, Fran?ois, Whyte-Hemingway, Hajdu-Cheney, Winchester, and other forms have been described. Most present in pre-school years with extensive involvement and destruction of multiple bones. We present a sister-pair, both of whom presented in early teenage, i.e., 13 and 15.5 years, respectively, with bilateral ankle, knee, and later, wrist pain. Radiological examination revealed bilateral osteolysis of tali, scaphoids, and patellae, and short fourth metacarpals in both sisters. Further investigation revealed absence of renal involvement, a normal excretion of amino acids, mucopolysaccharides and oligosaccharides, and presence of chronic synovitis in both sisters. Both parents and a younger brother were without radiographic or clinical evidence of the disease and there was no history of consanguinity. Thus, our sister-pair presented with the same carpal and tarsal bone involvement at a much later age, with evidence of chronic synovitis, along with short fourth metacarpals (brachydactyly type E changes) and without renal disease, suggesting a new syndrome with probable autosomal recessive inheritance.     

Aquaporins—new players in cancer biology

The aquaporins (AQPs) are small, integral-membrane proteins that selectively transport water across cell plasma membranes. A subset of AQPs, the aquaglyceroporins, also transport glycerol. AQPs are strongly expressed in tumor cells of different origins, particularly aggressive tumors. Recent discoveries of AQP involvement in cell migration and proliferation suggest that AQPs play key roles in tumor biology. AQP1 is ubiquitously expressed in tumor vascular endothelium, and AQP1-null mice show defective tumor angiogenesis resulting from impaired endothelial cell migration. AQP-expressing cancer cells show enhanced migration in vitro and greater local tumor invasion, tumor cell extravasation, and metastases in vivo. AQP-dependent cell migration may involve AQP-facilitated water influx into lamellipodia at the front edge of migrating cells. The aquaglyceroporin AQP3, which is found in normal epidermis and becomes upregulated in basal cell carcinoma, facilitates cell proliferation in different cell types. Remarkably, AQP3-null mice are resistant to skin tumorigenesis by a mechanism that may involve reduced tumor cell glycerol metabolism and ATP generation. Together, the data suggest that AQP expression in tumor cells and tumor vessels facilitates tumor growth and spread, suggesting AQP inhibition as a novel antitumor therapy.     

What is new in antithrombotic treatment?

Real progresses have been made during the past years in the comprehension of hemostasis mechanisms, along with rising of new antithrombotic drugs. The later include: 1) direct inhibitors of thrombin such as hirudin, bivalirudin, argatroban, melagatran and ximelagatran; 2) inhibitors of factor Xa such as the synthetic pentasaccharid and DX-9065a; 3) inhibitors of factor IXa; 4) inhibitors of tissue factor-factor VIIa complex such as tissue factor pathway inhibitor (TFPI) or NAPc2 (nematode anticoagulant peptide); 5) drugs enhancing endogenous anticoagulant activity, such as protein C or activated protein C; 6) drugs modulating endogenous fibrinolytic activity. These new drugs are promising a real decrease in mortality and morbidity due to venous thrombo-embolic disease, which is considered as a public health issue. Both physicians and biologists are concerned by these new antithrombotic agents, the former to think about new treatment strategies, the later to monitore, if necessary, the effects of such new drugs. Our review does not include antiplatelet agents which are indicated only in arterial thrombosis.     

What's new in hereditary colorectal cancer?

Precancerous polyposes other than classic familial adenomatous polyposis and the condition hereditary nonpolyposis colorectal cancer, or Lynch syndrome, continue to present major diagnostic challenges for the anatomic pathologist. This editorial highlights the practical significance of novel insights and clinical guidelines in the recent literature, as well as in 4 contributions to this edition of the Archives of Pathology & Laboratory Medicine. The first section will address attenuated familial adenomatous polyposis and a newly recognized type of autosomal-recessive adenomatous polyposis associated with the DNA repair gene MYH. The remainder of the editorial discusses the role of the revised Bethesda guidelines in the diagnosis of hereditary nonpolyposis colorectal cancer and concludes with the recently identified serrated pathway syndrome.     

EMT and MET in carcinoma—clinical observations,regulatory pathways and new models

EMT and MET in carcinoma-clinical observations, regulatory pathways and new models.     

What’s new in ion transports in the cochlea?

Recent advances in the field of the physiology of inner ear fluids permitted the characterization of the molecular mechanisms involved in critical processes such as the absorption of K⁺ through cochlear sensory hair cells (mechanoelectrical transduction) or the secretion of K⁺ by marginal cells of the stria vascularis. In addition, new pathways for ion circulations were evidenced. Mutations of transporters involved in some of these pathways, especially in K⁺ recycling through gap junction systems, and in local pH regulation, are among the most frequent etiologies of genetic deafness in humans.     

DNA immunization--a new chance in vaccine research?

A novel class of vaccines, based on the immunization with "naked" DNA, may hold the promise of protecting against human disease without the disadvantages associated with vaccines presently used, and may help to prevent infections which are not curable today. Direct intramuscular or intradermal inoculation of plasmid DNA encoding sequences of viral proteins results in the synthesis of these proteins, causing humoral and/or cellular immune responses in the recipient. Several advantages are associated with DNA immunization, e.g., cheap to produce, heat stability, amenable to genetic manipulation, mimic viral infection, and no risk of reversion to pathogenicity. Nevertheless, some concerns remain regarding their safety, e.g., the possible integration of plasmid DNA into host chromosomes. In summary, the results concerning the efficiency of DNA vaccination demonstrate clearly that these new vaccines may have a promising future in human immunization.     

What is new in cervical precanceroses cytodiagnostics?

Cytopathology investigation of the uterine cervix transformation zone smear (Pap test) has been accepted during the last 80 years worldwide as a potent tool in lowering the incidence of squamous cell cervical cancer; it can reveal a proportion of adenocarcinomas as well and contributes to the diagnostics of cervicovaginal infections. The technique itself and diagnostic criteria have been internationally unified in the systems Bethesda I (1988) and Bethesda II (2002). Nevertheless, the cytodiagnostics of cervical precanceroses continues to develop vividly in the following fields of interest. In processing the cervical sample:Unified polychrome staining has been accepted as compulsoryProcessing of the sample acquired has split into two branches - conventional preparation - CP and liquid based preparation - LBP. In both types of processing (mainly in LBP) additional tests are employed.In evaluation of the cytology features:Differences of the petrified diagnostic features formulated formerly for CP in the LBP have been described. Differentially-diagnostic pitfalls (look-alikes) are studied. Sensitivity of precanceroses detection in a screening routine with the prevalence of negative findings has been improved with compulsory rescreening of 10-20% random selected negative cases as well as rapid pre- or postscreening of the whole material or involvement of automated pre- or postscreening using image analysis systems.Some cytomorphology findings are followed with additional tests - especially HR HPV detection.Cyto-bioptic correlations are constantly studied.In terms of lowering the incidence of uterine cervix carcinoma: Opportune screening is substituted with nationwide programs aimed at:Involvement of as many women of the target group as possible.Standardized investigation (CP or LBP) in an accredited laboratory with functioning systems of external and internal quality control.Selective additional investigation with non-morphological tests.Appropriate treatment of women with pathology findings.Some newly designed nationwide screening models start with a non-morphological test (HPV) followed by a pap test and colposcopy.Stern control of successful implementation of the achievements listed above is expressed in uterine cervix cancer incidence. Keywords: cervical cytology - Pap test - precanceroses - National programme of cervical cancer screening.