ABO Blood Group and Diabetes Mellitus Influence the Risk for Pancreatic Cancer in a Population from China.

BACKGROUND The mechanism by which diabetes mellitus (DM) impacts the association between ABO blood types and pancreatic cancer is unclear. MATERIAL AND METHODS A retrospective case-control study of 264 patients with pancreatic cancer and 423 age- and sex-matched individuals with nonmalignant diseases was performed to assess whether ABO blood group and DM jointly contribute to pancreatic cancer risk. RESULTS A multivariate analysis with adjustments for risk factors revealed that blood type, chronic pancreatitis, and DM were significantly associated with increased pancreatic cancer risk. The estimated adjusted odds ratios (AORs with 95% confidence intervals [CIs]) were 2.130 (1.409-3.220) for blood type A, 2.383 (1.313-4.325) for blood type AB, 1.518 (1.012-2.276) for DM, and 10.930 (1.202-99.405) for chronic pancreatitis. Blood type A significantly modified the risk for pancreatic cancer in individuals with DM (AOR, 3.506; 95% CI, 1.659-7.409). CONCLUSIONS The risk for pancreatic cancer was associated with ABO blood type, DM, and chronic pancreatitis in a Chinese population. The risk was greatest for individuals with blood type A and DM.

[Endogenous factors in assessing the effectiveness of ferrotherapy for iron-deficiency anemia].

We estimated the role of some endogenous factors influencing the effectiveness of ferrotherapy of iron-deficiency anemia. It was shown to yield good results in case of an initially low hemoglobin level, in the first half of menstrual cycle, in patients with normal Quetelet index or those with AB(IV) and B(III) blood groups at the age below 30 years.

Loss of autophagy in erythroid cells leads to defective removal of mitochondria and severe anemia in vivo.

Timely elimination of damaged mitochondria is essential to protect cells from the potential harm of disordered mitochondrial metabolism and release of proapoptotic proteins. In mammalian red blood cells, the expulsion of the nucleus followed by the removal of other organelles, such as mitochondria, are necessary differentiation steps. Mitochondrial sequestration by autophagosomes, followed by delivery to the lysosomal compartment for degradation (mitophagy), is a major mechanism of mitochondrial turnover. Here we show that mice lacking the essential autophagy gene Atg7 in the hematopoietic system develop severe anemia. Atg7(-/-) erythrocytes accumulate damaged mitochondria with altered membrane potential leading to cell death. We find that mitochondrial loss is initiated in the bone marrow at the Ter119(+)/CD71(High) stage. Proteomic analysis of erythrocyte ghosts suggests that in the absence of autophagy other cellular degradation mechanisms are induced. Importantly, neither the removal of endoplasmic reticulum nor ribosomes is affected by the lack of Atg7. Atg7 deficiency also led to severe lymphopenia as a result of mitochondrial damage followed by apoptosis in mature T lymphocytes. Ex vivo short-lived hematopoietic cells such as monocytes and dendritic cells were not affected by the loss of Atg7. In summary, we show that the selective removal of mitochondria by autophagy, but not other organelles, during erythropoeisis is essential and that this is a necessary developmental step in erythroid cells.

Role of sialic acid in urinary cytoprotective activity of Tamm-Horsfall protein.

OBJECTIVES: Tamm-Horsfall protein (THP) from normal urine has been shown to protect against the cytotoxic effects of toxic urinary cations (TFs) in vivo and in vitro. This study investigated the effect of desialylation on the cytoprotective activity of THP. METHODS: From pooled 24-hour urine specimens from healthy individuals, both TFs and THP were obtained. Sprague-Dawley rats received intravesical NaCl or KCl, and the baseline urodynamic percentage of nonvoiding contractions (NVCs) was recorded. Then, rehydrated TF, TF plus THP, or TF plus THP-desialylated (THP-d) were instilled, followed by KCl, and the urodynamic measurements were repeated. In vitro, human HTB4 bladder cells were incubated overnight with the rehydrated TF, TF plus THP, TF plus THP-d, or assay media alone, and the cytotoxicity levels were determined. RESULTS: Acid hydrolysis resulted in an 88% loss of sialic acid. TFs consistently demonstrated a greater than 50% toxicity for human HTB4 cells compared with cells incubated in media (P <0.01). TF cytotoxic activity was blocked by preincubation with THP but not by preincubation with THP-d. Similarly, rat bladder NVCs increased significantly over baseline when KCl was infused after TF infusion (1.68 NVCs/min; P <0.0001). NVCs were significantly reduced by preincubating TFs with THP (0.42 NVCs/min) but not by preincubating with THP-d (1.55 NVCs/min, P <0.0001). CONCLUSIONS: The cytoprotective function of urinary THP in the bladder can be compromised when a decrease is present in the sialic acid residues on THP. Such a decrease in THP cytoprotective activity may play a critical role in the pathophysiology of interstitial cystitis.

The p domain of norovirus capsid protein forms a subviral particle that binds to histo-blood group antigen receptors.

Norovirus is the most important cause of nonbacterial acute gastroenteritis. We have shown previously that the isolated P domain containing the hinge forms a dimer and binds to histo-blood group antigen (HBGA) receptors with a low affinity (M. Tan, R. S. Hegde, and X. Jiang, J. Virol. 78:6233-6242, 2004). Here, we reported that the P domain of VA387 without the hinge forms a small particle with a significantly increased receptor binding affinity. An end-linked oligopeptide containing one or more cysteines promoted P-particle formation by forming intermolecular disulfide bridges. The binding sensitivity of the P particle to HBGAs was enhanced >700-fold compared to the P dimer, which was comparable to that of virus-like particles. The binding specificity of the P particle was further confirmed by strong binding to the Caco-2 cells, a human colon carcinoma cell line. This binding enhancement was observed in the P particles of both norovirus GI and GII strains. The P particle is estimated to contain 12 P dimers, in which the P2 subdomain builds up the outer layer, while the P1 subdomain forms the internal core. Taken together, our data indicate that the P domain is involved not only in dimerization but also in polymerization of the protein during the capsid assembling. The enhanced receptor binding of the P particle reflects the intrinsic feature of the viral capsid. The easy production of the P particle and its strong binding to HBGAs suggest that the P particle is useful in studying pathogenesis and morphogenesis of norovirus and candidates for antiviral or vaccine development.

Norovirus and histo-blood group antigens: demonstration of a wide spectrum of strain specificities and classification of two major binding groups among multiple binding patterns.

Noroviruses, an important cause of acute gastroenteritis, have been found to recognize human histo-blood group antigens (HBGAs) as receptors. Four strain-specific binding patterns to HBGAs have been described in our previous report. In this study, we have extended the binding patterns to seven based on 14 noroviruses examined. The oligosaccharide-based assays revealed additional epitopes that were not detected by the saliva-based assays. The seven patterns have been classified into two groups according to their interactions with three major epitopes (A/B, H, and Lewis) of human HBGAs: the A/B-binding group and the Lewis-binding group. Strains in the A/B binding group recognize the A and/or B and H antigens, but not the Lewis antigens, while strains in the Lewis-binding group react only to the Lewis and/or H antigens. This classification also resulted in a model of the norovirus/HBGA interaction. Phylogenetic analyses showed that strains with identical or closely related binding patterns tend to be clustered, but strains in both binding group can be found in both genogroups I and II. Our results suggest that noroviruses have a wide spectrum of host range and that human HBGAs play an important role in norovirus evolution. The high polymorphism of the human HBGA system, the involvement of multiple epitopes, and the typical protein/carbohydrate interaction between norovirus VLPs and HBGAs provide an explanation for the virus-ligand binding diversities.

Norwalk virus binds to histo-blood group antigens present on gastroduodenal epithelial cells of secretor individuals.

BACKGROUND & AIMS: Norwalk Virus (NV) is a member of the Caliciviridae family, which causes acute epidemic gastroenteritis in humans of all ages and its cellular receptors have not yet been characterized. Another calicivirus, Rabbit Hemorrhagic Disease Virus, attaches to H type 2 histo-blood group oligosaccharide present on rabbit epithelial cells. Our aim was to test if, by analogy, recombinant NV-like particles (rNV VLPs) use carbohydrates present on human gastroduodenal epithelial cells as ligands. METHODS: Attachment of rNV VLPs was tested on tissue sections of the gastroduodenal junction and on saliva from individuals of known ABO, Lewis, and secretor phenotypes. It was also tested on human Caco-2 cells and on animal cell lines transfected with glycosyltransferases complementary DNA (cDNA). Competition experiments were performed with synthetic oligosaccharides and anticarbohydrate antibodies. Internalization was monitored by confocal microscopy. RESULTS: Attachment of rNV VLPs to surface epithelial cells of the gastroduodenal junction as well as to saliva was detected, yet only from secretor donors. It was abolished by alpha1,2fucosidase treatment, and by competition with the H types 1 and 3 trisaccharides or with anti-H type 1 and anti-H types (3/4) antibodies. Transfection of CHO and TS/A cells with an alpha1,2fucosyltransferase cDNA allowed attachment of VLPs. These transfectants as well as differentiated Caco-2 cells expressing H type 1 structures internalized the bound particles. CONCLUSIONS: rNV VLPs use H type 1 and/or H types (3/4) as ligands on gastroduodenal epithelial cells of secretor individuals.

Molecular diversity in the biosynthesis of GI tract glycoconjugates. A blood-group-related chart of microorganism receptors.

This paper examines the potential of carbohydrate blood-group antigens present on mucosal surfaces in acting as receptors for microorganisms. Mucosal surfaces express significant amounts of carbohydrate blood-group antigens under the control of the Secretor, Lewis and ABO systems. The exact glycoconjugate profile an individual presents to the lumen is complex, and can only be correctly determined by a combination of serology and genotyping. We have isolated and structurally resolved the glycolipids expressed in the small intestine of group O individuals having various common or rare phenotypes. Using this information, we have been able to construct a biosynthetic pathway and propose that the type, size and glycotopes expressed, are controlled to a major extent by blood-group-related glycosyltransferases. Many of these glycotopes are potential receptors for microorganisms; some resemble tumour antigens, while others resemble the lipopolysaccharides of some pathogens. Although the origins of the blood-group glycosyltransferases remain uncertain, it is evident that they significantly diversify the mucosal glycotopes exposed to microbes; and therein may be found a potential explanation for their existence.

The role of blood group antigens in infectious diseases.

The medical literature contains a large number of publications attempting to correlate blood groups with disease. Many of these reports are poorly documented and have limited scientific validity. Only a few agents, such as malaria parasites and parvovirus B19, infect red blood cells (RBCs) and precursors. Most other agents use RBCs as carriers to the target tissue. There is an excess of blood group A individuals among cancer patients compared with normal individuals; malignancy has also been associated with the Lewis antigen. Plasmodium vivax only enters RBCs when the Fy6 Duffy protein is present. Certain Escherichia coli organisms will only attach to epithelial cells carrying P or Dr blood group antigens. The P antigen Is also the receptor for parvovirus B19. Le(b) appears to be the receptor for Helicobacter pylori in gastric tissue. The high frequency blood group antigen AnWJ is the receptor for Haemophilus influenzae. Knowledge of the functions of RBC surface molecules Is expanding and the ability to generate experimental animals devoid of certain molecules will clarify their physiological role.

The classification, recognition and significance of polyagglutination in transfusion medicine.

Polyagglutination, although an uncommon phenomenon in transfusion medicine, is becoming increasingly recognized as a potential pitfall in correct ABO typing and can hinder the rapid allocation of accurately crossmatched blood products. Polyagglutination refers to erythrocytes which demonstrate agglutination with the majority of adult sera upon initial ABO crossmatch testing. Most types of polyagglutination involve alteration of red cell surface antigens through microbial enzymatic activity in patients with sepsis, and subsequent interaction of these newly exposed 'cryptantigens' with naturally occuring IgM antibody which is present in most adult sera. Less common variants include essential inborn variations in red cell development, and have been associated with myelodysplastic syndromes, congenital anemias, and various leukemias; it has been suggested that patients shown to possess these types of polyagglutination may benefit from increased hematologic surveillance. Recognition of polyagglutination in these settings is important to allow successful resolution of ABO typing discrepancies and permit efficient administration of appropriate blood products to these patients, who are often quite ill. The classification and method of laboratory recognition of polyagglutination is reviewed.

Modificaciones del fibrinógeno en la trombosis en la altura / Fibrinogen changes in the high altitude thrombosis

Los estudios de rutina sobre la hemostasis no son los más indicados para anunciar en una fase precoz el establecimiento de una trombosis. Las anormalidades en el mecanismo de la coagulación de la fibrinolisis o de las plaquetas, están lejos de ser parámetros específicos directos que anuncie un riesgo de Trombosis en un paciente determinado. En los resultados de fibrinógeno y la Fibrinólisis, realizados en nuestro medio, se ha considerado a la hipoxia, como componente importante inductor de la Eritrocitosis en ciertas situaciones patológicas y que este factor agravaría el desarrollo de la trombosis en el nativo de la altura, pero estudios anteriores sobre este tema con relación a la función plaquetaria (Caen, J., Drovet, L. Ergueta J., Rodriguez A. 1972-1977) demostraron no ser evidentes. Realizamos un estudio protocolizado reciente, en 50 individuos nativos de la altura, cuyas edades fluctúan entre los 18 y 20 años de edad, en ellos se provocó una hipoxia local (venostasia) durante 10 minutos, con la finalidad de determinar los siguientes parámetros: Fibrinógeno, Fibrinólisis, Hematocrito y Grupos Sanguíneos, este último dato sirvió para relacionar la frecuencia de trombósis y valor de ésta proteína en los del grupo "O". La Fibrinólisis en ambos sexos nos demostró una aceleración en tiempo de 2 horas 15 minutos con relación a los de la costa que es >=3 horas. En el Hematocrito y la Hemoglobina encontramos que las mujeres del grupo sanguíneo "B" muestran una variación significativa en relación a los otros grupos sanguíneos. Los varones del grupo sanguíneo "A" y "O" mostraron también variaciones importantes.

Acción de los cambios hormonales sobre los valores hematimétricos, hemostasia, coagulación y fibrinolisis / Intervention of the hormonal changes in hematimetric hemostatic, coagulation and fibrinolysis values

Determinamos la acción de los cambios hormonales, progesterona y estrogeno sobre la hematopoyesis, hemostasia, coagulacion y fibrinolisis, en mujeres nativas de la altura. Se estudio 50 casos, con se respectiva ficha clinica, antes y despues de ciclo menstrual. Se correlacionaron factores geneticos (Grupos, sanguineos: A, B, O). Los sujetos del grupo O y AB, mostraron disminucion significativa de sus reticulocitos (p<0.001). En cambio, los del grupo A y B, aumentaron el numero de estas celulas (p<0.001). Ademas en el grupo sanguineo O, se observo que hacen uso de las reservas de Fe (Protoporfirina), a diferencia de los otros grupos. Referente a la hemostasia, el estudio cuantitativo y cualitativo (numeracion, agragacion y fragilidad capilar), mostraron una disminucion significativa (p<0.05 - p<0.001). En la coagulacion se observo una disminucion significativa en cuanto a la actividad protrombinica y del tiempo de tromboplastina parcial, (p<0.005 y 0.0001). Esto expliacria los sangrados menstruales prolongados y abundantes. Finalmente, la fibrinolisis tuvo valores superiores a 3 horas, en relacion a os valores normales (12 hrs. 30 min). De este trabajo concluimos, que los factores geneticos influyen en la Eritropoyesis, la Hemostasia, Coagulación y Fribrinolisis, en los sujetos de la altura, lo que nos permitira continuar estos estudios, referentes a la Eritrocitosis de nuestro medio.

Glycosyl phosphatidylinositol-linked blood group antigens and paroxysmal nocturnal hemoglobinuria.

Human erythrocyte cell surface molecules that are attached to the cell membrane by glycosyl-phosphatidylinositol (GPI) anchors include the complement regulatory proteins decay accelerating factor (DAF, CD55) and membrane inhibitor of reactive lysis (MIRL, CD59), as well as the proteins that bear the Cartwright, Dombrock, and JMH blood group antigens. The acquired hematopoietic stem cell disorder paroxysmal nocturnal hemoglobinuria (PNH) results from the absence or marked deficiency in expression of GPI-anchored proteins in affected hematopoietic cells. PNH usually if not always results from a somatic mutation of an X-linked gene called PIG-A; the product of the PIG-A gene is a glycosyl transferase necessary for construction of the GPI anchor. DAF is a ubiquitously expressed protein present in many tissues, including gastrointestinal epithelia, corneal epithelia, and serosa of urinary and reproductive organs. DAF is a 70 kD glycoprotein containing complement regulatory short consensus repeats (SCRs); its gene is located in the regulation of complement activation (RCA) gene cluster on chromosome 1 and is about 40 kb in size. The Cromer blood group antigens, which reside on DAF, include 10 currently defined antigens, of which seven are of high incidence. The molecular basis of the Cr (a-) phenotype has been determined to be a single base pair substitution in DAF SCR4 (G-->C, leading to an ala193 to pro amino acid substitution). The Tc alpha antigen appears to be determined by the amino acid sequence of SCR1, with the Tc (a-b+) phenotype arising from a base pair substitution of G55-->T, leading to an arg18 to leu amino acid substitution. The null phenotype for Cromer antigens occurs when DAF is completely absent; only one example has been completely studied on the molecular level. That individual is homozygous for a point mutation in SCR1 (G314-->A) that creates a stop codon (TGA) in place of one normally encoding trp53 (TGG) and thus prevents further translation of the mRNA. The Dr(a-) phenotype expresses reduced quantities of DAF (approximately 40% of normal levels), as well as a polymorphism of DAF. Lack of the Dr alpha antigen has been proved to result from a single point mutation in SCR3 (C-->T in codon 165) that leads to a single amino acid substitution (ser-->leu). The Cartwright (Yt) antigens reside on acetylcholinesterase (AChE). In erythroid cells, a small exon that encodes the signal for attachment of the GPI anchor is retained in a tissue-specific process.(ABSTRACT TRUNCATED AT 400 WORDS)

The Ernest Witebsky memorial lecture. Red but not dead: not a hapless sac of hemoglobin.

The purpose of this presentation was to demonstrate that the red blood cell is not a hapless sac of hemoglobin and that much research is still needed for better understanding of its complexities. After a brief historical introduction the following subjects are presented: 1). Phosphofructokinase is the rate limiting step in the anaerobic glycolytic pathway. Ribose-5-phosphate, a metabolite of the oxidative pentose phosphate pathway is essential for the generation of phosphoribosylpyrophosphate which in turn is needed for the synthesis of adenosine monophosphate from adenine by the action of adenine phosphoribosyl transferase. 2). There are at least 17 blood group systems with more than 400 epitopes expressed on the red cell membrane. The Rh null and the McLeod phenotypes associated with abnormally shaped red cells and hemolytic anemia are briefly described as is the present understanding of the nature of the Rh complex. 3). The structure of the cytoskeleton and the composition and behavior of the lipid bilayer are presented with some discussion of the MN and Ss sialoglycoproteins and the Leach phenotype. 4). Touched upon is the role of phosphoinositides with some emphasis on recent discoveries relating to the glycophosphoinositide protein anchor. 5). The intricacies of the many faceted transport mechanisms are introduced. Briefly mentioned are the mechanisms activated when regulatory volume adjustments occur in fine tuning red cell volume after exposure respectively to hypotonic or hypertonic stress. Sufficient evidence is presented to convince that a cell doesn't have to have a nucleus to be respected even though it is just a corpuscle.