Synaptotagmins 1 and 7 in vesicle release from rods of mouse retina.

Synaptotagmins are the primary Ca2+ sensors for synaptic exocytosis. Previous work suggested synaptotagmin-1 (Syt1) mediates evoked vesicle release from cone photoreceptor cells in the vertebrate retina whereas release from rods may involve another sensor in addition to Syt1. We found immunohistochemical evidence for syntaptotagmin-7 (Syt7) in mouse rod terminals and so performed electroretinograms (ERG) and single-cell recordings using mice in which Syt1 and/or Syt7 were conditionally removed from rods and/or cones. Synaptic release was measured in mouse rods by recording presynaptic anion currents activated during glutamate re-uptake and from exocytotic membrane capacitance changes. Deleting Syt1 from rods reduced glutamate release evoked by short depolarizing steps but not long steps whereas deleting Syt7 from rods reduced release evoked by long but not short steps. Deleting both sensors completely abolished depolarization-evoked release from rods. Effects of various intracellular Ca2+ buffers showed that Syt1-mediated release from rods involves vesicles close to ribbon-associated Ca2+ channels whereas Syt7-mediated release evoked by longer steps involves more distant release sites. Spontaneous release from rods was unaffected by eliminating Syt7. While whole animal knockout of Syt7 slightly reduced ERG b-waves and oscillatory potentials, selective elimination of Syt7 from rods had no effect on ERGs. Furthermore, eliminating Syt1 from rods and cones abolished ERG b-waves and additional elimination of Syt7 had no further effect. These results show that while Syt7 contributes to slow non-ribbon release from rods, Syt1 is the principal sensor shaping rod and cone inputs to bipolar cells in response to light flashes.

Interaction of Np(v) with borate in alkaline, dilute-to-concentrated, NaCl and MgCl2 solutions.

The interaction of Np(v) with borate was investigated in 0.1-5.0 M NaCl and 0.25-4.5 M MgCl2 solutions with 7.2 ≤ pHm ≤ 10.0 (pHm = -log[H+]) and 0.004 M ≤ [B]tot ≤ 0.16 M. Experiments were performed under an Ar-atmosphere at T = (22 ± 2) °C using a combination of under- and oversaturation solubility experiments, NIR spectroscopy, and extensive solid phase characterization. A bathochromic shift (≈5 nm) in the Np(v) band at λ = 980 nm indicates the formation of weak Np(v)-borate complexes under mildly alkaline pHm-conditions. The identification of an isosbestic point supports the formation of a single Np(v)-borate species in dilute MgCl2 systems, whereas a more complex aqueous speciation (eventually involving the formation of several Np(v)-borate species) is observed in concentrated MgCl2 solutions. The solubility of freshly prepared NpO2OH(am) remained largely unaltered in NaCl and MgCl2 solutions with [B]tot = 0.04 M within the timeframe of this study (t ≤ 300 days). At [B]tot = 0.16 M, a kinetically hindered but very significant drop in the solubility of Np(v) (3-4 log10-units, compared to borate-free systems) was observed in NaCl and dilute MgCl2 solutions with pHm ≤ 9. The drop in the solubility was accompanied by a clear change in the colour of the solid phase (from green to white-greyish). XRD and TEM analyses showed that the amorphous NpO2OH(am) "starting material" transformed into crystalline solid phases with similar XRD patterns in NaCl and MgCl2 systems. XPS, SEM-EDS and EXAFS further indicated that borate and Na/Mg participate stoichiometrically in the formation of such solid phases. Additional undersaturation solubility experiments using the newly formed Na-Np(v)-borate(cr) and Mg-Np(v)-borate(cr) compounds further confirmed the low solubility ([Np(v)]aq ≈ 10-6-10-7 M) of such solid phases in mildly alkaline pHm-conditions. The formation of these solid phases represents a previously unreported retention mechanism for the highly mobile Np(v) under boundary conditions (pHm, [B]tot, ionic strength) of relevance to certain repository concepts for nuclear waste disposal.

Proteolytic and proteomic changes in milk at quarter level following infusion with Escherichia coli lipopolysaccharide.

Mastitis is a major disease in dairy cattle, which causes significant economic losses due to decreased milk production, veterinary costs, and discarded milk. Escherichia coli is one of the most prevalent species of gram-negative bacteria that induce clinical mastitis. The objective of the present study was to characterize the proteolytic and proteomic changes in milk in response to infusion with lipopolysaccharide (LPS) at quarter level in a model mastitis system. One quarter of each of 2 cows was infused with 0.1 or 5 µg of LPS. The somatic cell count of the infused quarters reached a peak 6 h after infusion to a greater extent in the cow infused with 5 µg of LPS and changes in plasmin activity in milk differed between the 2 animals. Urea-polyacrylamide gel electrophoretograms of milk samples of the cow infused with 5 µg of LPS obtained at different time points after infusion and incubated for up to 7 d showed almost full hydrolysis of ß- and α(s1)-casein during incubation of milk samples due to indigenous proteolytic activity. Two-dimensional gel electrophoretograms of milk at 0, 6, or 12 h after infusion with LPS showed hydrolysis of α(s)-casein and ß-casein as well as the appearance of lower molecular weight products. Eleven fragments from proteolysis of the caseins were identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and, in addition, proteolysis patterns of casein by the indigenous bovine milk proteases plasmin and cathepsin D were studied in model studies using 2-dimensional gel electrophoretograms. Twelve hours after infusion, lower abundance markers of inflammation were identified, including serotransferrin, fibrinogen ß chain, protein S100 A12, and the antimicrobial polypeptide cathelicidin.

Characterization of surgical aerosols by the compact single-particle mass spectrometer LAMPAS 3.

A new method is presented using an optical particle counter and the compact mobile laser mass spectrometer LAMPAS 3 for in situ analysis of single particles generated by electrosurgical dissection of biological tissues. The instrumental performance is demonstrated for analysing aerosol particles formed during rapid thermal evaporation of porcine liver and porcine kidney tissues. Particle number concentrations of up to 5,000 particles per cubic centimetre were detected during surgical dissection. Chemical analysis of tissue particles was performed by bipolar time-of-flight mass spectrometry. The application of an online mass spectrometric particle analysis for surgical aerosols is reported here for the first time.

Proteomic and peptidomic study of proteolysis in quarter milk after infusion with lipoteichoic acid from Staphylococcus aureus.

Mastitic milk is associated with increased bovine protease activity, such as that from plasmin and somatic cell enzymes, which cause proteolysis of the caseins and may reduce cheese yield and quality. The aim of this work was to characterize the peptide profile resulting from proteolysis in a model mastitis system and to identify the proteases responsible. One quarter of each of 2 cows (A and B) was infused with lipoteichoic acid from Staphylococcus aureus. The somatic cell counts of the infused quarters reached a peak 6h after infusion, whereas plasmin activity of those quarters also increased, reaching a peak after 48 and 12h for cow A and B, respectively. Urea-polyacrylamide gel electrophoretograms of milk samples of cow A and B obtained at different time points after infusion and incubated for up to 7 d showed almost full hydrolysis of ß- and α(S1)-casein during incubation of milk samples at peak somatic cell counts, with that of ß-casein being faster than that of α(S1)-casein. Two-dimensional gel electrophoretograms of milk 6h after infusion with the toxin confirmed hydrolysis of ß- and α(S1)-casein and the appearance of lower-molecular-weight products. Peptides were subsequently separated by reversed-phase HPLC and handmade nanoscale C(18) columns, and identified by matrix-assisted laser desorption/ionization time-of-flight tandem mass spectrometry. Twenty different peptides were identified and shown to originate from α(s1)- and ß-casein. Plasmin, cathepsin B and D, elastase, and amino- and carboxypeptidases were suggested as possible responsible proteases based on the peptide cleavage sites. The presumptive activity of amino- and carboxypeptidases is surprising and may indicate the activity of cathepsin H, which has not been reported in milk previously.

Pathogen reduction technology (Mirasol) treated single-donor platelets resuspended in a mixture of autologous plasma and PAS.

BACKGROUND AND OBJECTIVES: Mirasol pathogen reduction technology (PRT) for platelet concentrates uses riboflavin and ultraviolet light. Previously, we described increased metabolism and activation for PRT platelets stored in 100% plasma. To improve platelet quality, we resuspended platelets in a mixture of plasma and platelet additive solution (PAS). MATERIALS AND METHODS: Single-donor platelets were resuspended in plasma and split into an untreated control and a PRT-treated single product. One hundred and fifty millilitre PAS (SSP+) was added to both. Over 7 days, we assayed pH, glucose consumption-, lactate production rate and CD62p with and without TRAP. RESULTS: On day 5, PRT units showed a significantly lower pH (7.087 +/- 0.105 vs. 7.288 +/- 0.200) accompanied by a higher lactate production (0.104 +/- 0014 vs. 0.063 +/- 0.017 mmol/10(12)/h) and glucose consumption rate (0.039 +/- 0005 vs. 0.028 +/- 0.009 mmol/10(12) platelets/h). CD62p expression was higher in treated units (44.5 +/- 13.0 vs. 16.5 +/- 7.6%). CONCLUSION: In comparison to PRT platelets resuspended in 100% plasma, a mixture of plasma and PAS improves pH and platelet metabolism but not platelet activation. Prolonged shelf-life for up to 7 days may be possible

Development of a bibliographical search matrix exemplified by a computer-assisted literature search on the evidence of condyle position analysis.

Apart from monographs, textbook publications and publications on websites, scientific studies have also been published concerning the method of condyle position analysis. Determination of the current research status, which can serve as basis for further scientific publications, would therefore be helpful. Accessing the texts published on this subject in scientific journals is comparatively difficult, since a keyworded search term by which the subject area can be narrowed down directly is not available in the dline" database. The development of a computer-assisted bibliographical search matrix, which facilitates clear identification of relevant publications in scientific journals through "Medline", is described in this paper as an example. This search matrix can be used in corresponding web services and can also be imported into research software and saved for future computer-assisted searches. The currently available scientific studies on condyle position analysis have been found and structured with regard to contents on the basis of the search matrix and with the aid of other research sources. The matrix describing the structure of the contents serves as a logical classification on the basis of which the publications have been classified. In addition to the classification by subject, the evidence levels were determined for the scientific studies - on the basis of their concept - and thus the external evidence on condyle position analysis as a procedure was developed.

Condylar position analysis with a new electronic condylar position measuring instrument E-CPM: influence of different examiners and a working bite on reproducibility.

PURPOSE: Condylar position analysis facilitates a quantitative comparison of the condylar position with and without a bite record, different records and changed influencing factors. Handling by the examiner when positioning the model is a significant factor with regard to the accuracy of the examination. Measurement accuracy could be improved when positioning the models by using special working bites, hence the objective of the experiments described in this study consisted in examining the extent to which the measuring results are influenced by different examiners and by using working bites. MATERIALS AND METHODS: In the first trial, one examiner performed ten measurements without and with an interposed working bite for five model pairs in each case. In the second trial, nine examiners (three specialized dentists, three dental assistants, three students) performed ten measurements in each case without and with an interposed working bite. The three-dimensional position was read digitally with the E-CPM (Gamma Dental, Klosterneuburg/Vienna, Austria), recorded by means of spreadsheet software (Microsoft Excel) and diagnostic software (CMDfact, CMD3D module, dentaConcept, Hamburg), and evaluated with graphing software (Sigma Plot, Systat Software, USA). RESULTS: In the first trial, it was shown that the reproducibility of mounting was improved markedly (p <0.01) by using bite records in the form of working bites. In the second trial, it was shown that the mean error increased significantly (p <0.01) when several examiners performed the measurements compared with the results of one examiner alone. No significantly different results occurred (p < 0.01) in the comparison of the different groups of examiners with different educational and training backgrounds. This applied for the mounting methods without and with working bite. On the other hand, the reproducibility of mounting improved distinctly (p<0.01) in every group of examiners when working bites were used. CONCLUSIONS: Reproducibility of condylar position analysis was improved significantly by mounting the models with special working bites. This applied for operators of different professional background (dentists, dental assistants and dental students), while there were no significant differences between results of the three groups.

Diffusion-weighted MRI in the diagnosis of cholesteatomas.

OBJECTIVE: The diagnosis of a cholesteatoma can be difficult in cases with an intact tympanic membrane. The aim of our study was to examine whether diffusion-weighted MRI can confirm the diagnosis of a cholesteatoma. STUDY DESIGN: A preoperative diffusion-weighted MRI (echo-planar imaging) scan of the temporal bone was performed in 31 patients with clinically suspected cholesteatoma. The diagnosis was confirmed by pathohistological examination in 18 cases, while the majority of the remaining patients showed chronic otitis media without cholesteatoma. RESULTS: In 3 out of 18 patients with histologically confirmed cholesteatoma, diffusion-weighted imaging produced a hyperintense signal. Another 4 of the 18 cases had a questionable positive result. No increased signal was observed in 11 of these 18 patients. Of 12 patients without a cholesteatoma, 2 showed a positive signal while a questionable hyperintense signal was observed in 5 patients. CONCLUSIONS: According to our present findings, diffusion-weighted MRI (echo-planar imaging) can--with a low sensitivity and specificity--be helpful in individual cases in provisionally diagnosing a cholesteatoma in association with standard MRI and high-resolution CT, even though the lack of a hyperintense signal in diffusion-weighted MRI does not exclude a cholesteatoma.

Translocations t(11;18)(q21;q21) and t(14;18)(q32;q21) are the main chromosomal abnormalities involving MLT/MALT1 in MALT lymphomas.

The recently discovered MLT/MALT1 gene is fused with the API2 gene in the t(11;18)(q21;q21), which characterizes about one-third of MALT lymphomas. In order to screen for variant translocations and amplifications of MLT/MALT1, we have developed a novel, undirected two-color interphase fluorescence in situ hybridization (FISH) assay with two PAC clones flanking MLT/MALT1. This assay was applied to 108 marginal zone B-cell lymphomas (MZBCLs), including 72 extranodal MALT lymphomas, 17 nodal, and 19 splenic MZBCL. In 19 MALT lymphomas (26%), but in none of the nodal or splenic MZBCL, separated hybridization signals of the MLT/MALT1 flanking probes, were found. Further FISH analyses showed that 12 of these 19 cases displayed the classical t(11;18) and the remaining seven cases revealed the novel t(14;18)(q32;q21), involving the MLT/MALT1 and IGH genes. The frequency at which these translocations occurred varied significantly with the primary location of disease. The t(11;18) was mainly detected in gastrointestinal MALT lymphomas, whereas the t(14;18) occurred in MALT lymphomas of the parotid gland and the conjunctiva. Amplification of MLT/MALT1 was not observed in any of the lymphomas analyzed. We conclude that the translocations t(11;18)(q21;q21) and t(14;18)(q21;q32) represent the main structural aberrations involving MLT/MALT1 in MALT lymphomas, whereas true amplifications of MLT/MALT1 occur rarely in MZBCL.

Studies on the prevalence of Riemerella anatipestifer in the upper respiratory tract of clinically healthy ducklings and characterization of untypable strains.

A total of 44 bacterial strains obtained from 49 clinically healthy ducklings of different ages originating from four different farms were identified as members of the species Riemerella anatipestifer (RA) using conventional biochemical test methods. Numerical analysis of the whole-cell fatty acid patterns of these isolates resulted in two different clusters, one of which showed a similar pattern to that of the type strain of RA. Strains having a different fatty acid methyl esters (FAME)-profile (cluster II) were designated R. anatipestifer-like (RA-like). Sequencing of 16S rRNA genes of RA-like field isolates revealed 99% identity to RA. The significance of these observations are discussed. The present findings document for the first time that RA seems to represent a normal part of the pharyngeal flora of healthy Pekin ducks.

Chromosomal gains and losses are uncommon in hairy cell leukemia: a study based on comparative genomic hybridization and interphase fluorescence in situ hybridization.

In contrast to other subtypes of lymphoproliferative malignancies, the genetic mechanisms underlying the pathogenesis of hairy cell leukemia (HCL) are unknown. We studied densely infiltrated splenic tissue of 14 cases of HCL for the presence of chromosomal gains and losses by comparative genomic hybridization (CGH). Chromosomal imbalances were detected in only four of the 14 cases. Chromosomal gains involved the regions 5q13-q31 (two cases) and 1p32-p36.2 (one case). A loss of the region 11q14-q22 was found in one additional patient. The imbalances affecting the regions 5q and 11q were confirmed by interphase fluorescence in situ hybridization (FISH) using PAC clone 144G9 (5q31) and YAC clones 755B11 (11q22.3-q23.1) and 801E11 (11q22.3-q23.1 spanning the ATM gene) and occurred in 61% to 75% of analyzed nuclei. The latter DNA probes and probes hybridizing to chromosomal regions, which are frequently deleted in other subtypes of non-Hodgkin lymphomas (NHL), namely 9p21/ P16(INK4A), 13q14/D13S25, and 17p13/P53 were subsequently applied to all 14 cases of HCL, but no additional abnormalities were found. We conclude that overrepresentation of chromosome 5 represents a recurrent aberration in HCL and that the commonly overrepresented region resides in 5q13-q31. Chromosomal imbalances including deletions of the tumor suppressor gene loci 9p21/P16(INK4A), 13q14/D13S25, and 17p13/P53 rarely occur in HCL in contrast to some other subtypes of B-cell NHL. The pathogenetic role of 11q/ATM alterations in HCL remains to be determined.

Competitive exclusion of Salmonella enteritidis by Salmonella gallinarum in poultry.

Salmonella Enteritidis emerged as a major egg-associated pathogen in the late 20th century. Epidemiologic data from England, Wales, and the United States indicate that S. Enteritidis filled the ecologic niche vacated by eradication of S. Gallinarum from poultry, leading to an epidemic increase in human infections. We tested this hypothesis by retrospective analysis of epidemiologic surveys in Germany and demonstrated that the number of human S. Enteritidis cases is inversely related to the prevalence of S. Gallinarum in poultry. Mathematical models combining epidemiology with population biology suggest that S. Gallinarum competitively excluded S. Enteritidis from poultry flocks early in the 20th century.

Detection of t(11;18)(q21;q21) by interphase fluorescence in situ hybridization using API2 and MLT specific probes.

The translocation of chromosome 11, long arm, region 2, band 1, to chromosome 18, long arm, region 2, band 1 (t(11;18)(q21;q21)) represents a recurrent chromosomal abnormality in extranodal marginal zone B-cell lymphoma (MZBCL) of mucosa-associated lymphoid tissue (MALT) type and leads to a fusion of the apoptosis inhibitor-2 (API2) gene on chromosome 11 and the MALT lymphoma-associated translocation (MLT) gene on chromosome 18. A 2-color fluorescence in situ hybridization (FISH) assay, which can be used for the detection of t(11;18) in interphase nuclei and metaphase chromosomes on fresh and archival tumor tissue, was developed. The P1 artificial chromosome (PAC) clone located immediately telomeric to the MLT gene and the PAC clone spanning the API2 gene were differentially labeled and used to visualize the derivative chromosome 11 resulting from t(11;18), as evident by the overlapping or juxtaposed red and green fluorescent signals. The assay was applied to interphase nuclei of 20 cases with nonmalignant conditions and 122 B-cell non-Hodgkin's lymphomas (NHLs). The latter group comprised 20 cases of nodal follicle center cell lymphoma and diffuse large B-cell NHL, 10 cases of gastric diffuse large B-cell lymphoma, 10 cases of hairy cell leukemia, and 82 cases of MZBCL (41 extranodal from various locations, 19 nodal, and 22 splenic MZBCL) including 35 cases with an abnormal karyotype, 2 of which revealed t(11;18). By interphase FISH, t(11;18) was detected in 8 gastrointestinal low-grade MALT-type lymphomas including the 2 cytogenetically t(11;18)(+) cases. In the 8 t(11;18)(+) cases, the FISH results were confirmed by reverse transcriptase-polymerase chain reaction (RT-PCR) using API2 and MLT specific primers. Our results indicate that t(11;18)(q21;q21) specifically characterizes a subgroup of low-grade MZBCL of the MALT-type and that the FISH assay described here is a highly specific and rapid test for the detection of this translocation.

Analysis of the P53, RB/D13S25, and P16 tumor suppressor genes in marginal zone B-cell lymphoma: An interphase fluorescence in situ hybridization study.

The genetic mechanisms underlying the genesis, disease progression, and high-grade transformation of marginal zone B-cell lymphoma (MZBCL) are poorly understood. We analyzed 33 cases of histologically and immunophenotypically well-characterized MZBCL (12 extranodal, 11 nodal, and 10 splenic MZBCL; 27 at primary diagnosis and six during the course of disease) by dual-color interphase fluorescence in situ hybridization (FISH) for deletions of tumor suppressor genes. We investigated loci known to play a role in the genesis or disease progression of other subtypes of lymphoid malignancies, namely the P53 gene (17p13), the retinoblastoma gene (RB, 13q14), the D13S25 locus (13q14), and the P16(INK4A) gene (9p21). Heterozygous deletions of P53 were detected in three out of the 33 cases, including two splenic and one extranodal MZBCL. One of these patients was analyzed at primary diagnosis and two during the course of disease. Heterozygous deletions of the RB gene (nodal MZBCL) and D13S25 (splenic MZBCL) were found in one case each. P16 deletions were not detected in any of our cases. We conclude that deletions of the analyzed tumor suppressor genes are relatively rare in MZBCL, which contrasts with the findings in some other subtypes of NHL.

Polysomy 13 with concomitant deletion of 13q13-14 involving the retinoblastoma gene and the D13S25 locus in a case of acute myeloid leukemia.

We herein describe a case of acute myeloblastic leukemia (AML), FAB subtype M4, with an unfavorable clinical course and a complex karyotype, including 4-9 copies of chromosome 13. Polysomy 13 was a result of clonal evolution. Fluorescence in situ hybridization (FISH) revealed a cytogenetically unrecognizable deletion within 13q13-14 that included the retinoblastoma gene (RB) and the D13S25 locus in all but one copy of chromosome 13. The only chromosome 13 that did not show a deletion affecting the q13-14 region was translocated to chromosome 7, resulting in a dic(7;13)(q21;p11). In this case, the coexistence of polysomy and a partial deletion within the same chromosome point toward a possible formation of a fusion product with oncogenic potential and its consecutive amplification as a critical alteration in this case.

Quinupristin/dalfopristin-resistant enterococci of the satA (vatD) and satG (vatE) genotypes from different ecological origins in Germany.

The semisynthetic streptogramin combination quinupristin/dalfopristin (Synercid) is a promising alternative for treatment of infections due to multiply resistant gram-positive bacteria including vancomycin-resistant Enterococcus faecium. Resistance is mediated by acetyltransferases SatA (VatD) or SatG (VatE). Recent papers have indicated a possible link between the use of the streptogramin virginiamycin S/M as a feed additive in commercial animal husbandry and a selection of quinupristin/dalfopristin-resistant E. faecium (QDRE). We screened manure samples from two different turkey farms and from six different pig farms (using virginiamycin), samples from a sewage water treatment plant, 24 broiler carcasses, 10 pork samples, and 200 stool samples of nonhospitalized humans for QDRE. Our strain culture collection of hospital E. faecium isolates from the last 2 years was also reviewed for QDRE. All manure and sewage samples were positive for QDRE, as well as 11 from broiler carcasses (46%), 1 from pork (10%), and 28 from human stool specimens (14%). Thirty-six hospital isolates of E. faecium exhibited resistance to quinupristin/dalfopristin. In 141 QDRE of different origin satA (vatD) and satG (vatE) genes were detected (seven isolates from humans with an unknown resistance mechanism). Streptogramin resistance determinants were tansferable in filtermating experiments for 5 of 10 satA (vatD) and 9 of 22 satG (vatE) isolates. Different EcoRI patterns of satG (vatE) plasmids and corresponding hybridizations of the satG (vatE) gene indicated nonhomologous resistance plasmids in isolates of different origin. The results of this study indicate a common gene pool for streptogramin resistance in E. faecium of different ecological origin. A selection of QDRE using the streptogramin virginiamycin S/M as a feed additive and a spread of the resistance via the food chain to humans is probable.

Genetic abnormalities in marginal zone B-cell lymphoma.

Marginal zone B-cell lymphoma (MZBCL) including extranodal mucosa-associated lymphoid tissue (MALT)-type lymphoma, nodal, and splenic MZBCL represents a distinct subtype of B-non-Hodgkin's lymphoma. Recently, important progress in the elucidation of the genetic mechanisms underlying the pathogenesis and disease progression of these lymphomas has been made. The API2 gene, an inhibitor of apoptosis, and the novel MLT gene have been found to be altered by the t(11;18)(q21;21), which represents the most frequent structural chromosomal abnormality in extranodal low-grade MALT lymphoma. Another gene involved in the regulation of apoptosis, the BCL10 gene, has been cloned from a MALT lymphoma cytogenetically characterized by the t(1;14)(p22;q32). Along the same lines, inactivating mutations of the proapoptotic FAS gene have been detected in a relatively high proportion of extranodal MZBCLs. Considering these data and the fact that at least some MALT lymphomas show low levels of apoptosis and seem to escape from FAS-mediated apoptosis one may speculate that abrogation of apoptosis constitutes a central pathogenetic mechanism in the development of these lymphomas. The pathogenetic role of trisomy 3, the most frequent numerical chromosomal change of MZBCL, is not known. The minimal overrepresented region has been delineated to 3q21-23 and 3q25-29 using comparative genomic hybridization. The BCL6 proto-oncogene, located on 3q27, which is rearranged in some MZBCL and a high proportion of large cell B-cell lymphomas with extranodal localization, represents one of the candidate genes residing in these critical regions.