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PubMed1988

Comparison of bone reactions to coated tricalcium phosphate and pure titanium dental implants in the canine iliac crest.

Titanium and TCP-coated implants were compared after insertion in the canine iliac crest. Observation time was 14 wk. Evaluation included pull-out tests, energy dispersive X-ray analysis, and histologic examination of in situ, undemineralized implants. The TCP-coated implants were more firmly attached to bone than were the titanium implants. The calcium/phosphorus ratios around the titanium implants were higher than around the TCP-coated implants. Both types of implants were closely surrounded by bone after a 14-wk implantation.

Animals↗
PubMed1995

Prevention of the excitatory actions of bradykinin by inhibition of PGI2 formation in nodose neurones of the guinea-pig.

1. Intracellular recordings were made from neurones in intact guinea-pig nodose ganglia in vitro and from acutely isolated adult guinea-pig and rabbit nodose neurons to study a bradykinin (BK)-mediated block of a slow spike after-hyperpolarization (AHPslow) that is prominent in 30-40% of these neurones. 2. BK (100 nM) reversibly blocked the AHPslow, resulting in an ablation of the spike accommodative properties of these neurones. The B1 BK receptor agonist [des-Arg9]-BK did not mimic or prevent the actions of BK. In contrast, the B2 BK receptor antagonist D-Arg-[Hyp3,Thi5,D-Tic7,Oic8]-BK (HOE 140) prevented BK-induced block of the AHPslow and the effect of BK on spike frequency adaptation. 3. The BK block of the AHPslow in acutely dissociated neurones was prevented by indomethacin, indicating that this BK effect was dependent upon a cyclo-oxygenase metabolite intrinsic to these neurones. 4. One to twenty femtomoles of the prostanoids PGE2, PGD2, 9 alpha, 11 beta-PGF2 (a metabolite of PGD2), PGF2 alpha, TxB2 and PGI2 were released spontaneously from a nodose ganglion in 15 min. BK (100 nM) selectively increased PGI2 release 2.8-fold without affecting the release of the other prostanoids. Treatment with 10 microM tranylcypromine (TCP), a putative PGI2 synthase inhibitor, completely prevented the BK-induced release of PGI2. 5. In the presence of 10 microM TCP, BK no longer produced significant effects on the AHPslow. In contrast, 10 microM TCP did not prevent PGI2 from blocking the AHPslow. 6. These results suggest that vagal afferents that exhibit AHPslow also possess the B2 type of BK receptor. Activation of these BK receptors results in the production of PGI2, which in turn controls spike frequency adaptation by affecting the amplitude of the AHPslow.

Animals↗
PubMed2005

Investigating the effect of clonogen resensitization on the tumor response to fractionated external radiotherapy.

In this work we further develop the modeling of tumor dynamics by proposing a mechanism of tumor resensitization that is based on the process of reoxygenation. Reoxygenation is modeled using the concept of nonstationary diffusion of oxygen. This leads to the derivation of an explicit expression for the radiosensitivity parameter that predicts a radiosensitivity that increases with time. To account for the resensitization mechanism, the time-dependent expression for the radiosensitivity is then incorporated within a tumor control probability (TCP) model that already includes tumor cell repopulation and repair. We fit a set of experimental animal TCP curves corresponding to several different fractionation regimes using both the modified (with resensitization) and unmodified (without resensitization) versions of the TCP model. In comparison to the unmodified model, the modified model produces statistically superior fits, and is able to describe an "inverse" dose-fractionation behavior present in the data.

Animals↗
PubMed1998

Improvements in prostate radiotherapy from the customization of beam directions.

A methodology for optimizing the beam directions in radiotherapy treatment planning has been developed and tested on a cohort of twelve prostate patients. An optimization algorithm employing a an objective cost function was used, based on beam's-eye-view volumetrics but also employing a simple dose model and biological considerations for organs-at-risk (OARs). The cost function embodies information about the volume of OARs in a single field and their position relative to the planning target volume (PTV). The proximity of the PTV to the surface of the patient is also included. Within the algorithm "importance factor" were used to model the clinical importance of different organs-at-risk so that all organs-at-risk were included in a single objective score. "Gantry-angle-windows" were introduced to restrict the available beam directions. The methodology was applied to twelve prostate patients to determine the optimum beam directions for three-field direction plans. Orientation-optimized and standard treatment plans were compared via measures of tumor control probability (TCP) and normal tissue complication probability (NTCP). Standard plans had fixed beam directions whereas orientation-optimized plans contained beam directions chosen by the algorithm. The beam-weights of both the orientation-optimized and standard plans were optimized using a dose-based simulated annealing algorithm to allow the improvements by optimizing the beam directions to be studied in isolation. The results of the comparison show that optimization of the beam directions yielded better plans, in terms of TCP and NTCP, than the standard plans. When the dose to the isocenter was scaled to produce a rectal NTCP of 1%, the average TCP of the orientation-optimized plans was (5.7 +/- 1.4)% greater than that for the standard plans. In conclusion, the customization of beam directions in the treatment planning of prostate patients using and objective cost function and allowed gantry-angle-windows produces superior three-field direction plans compared to standard treatment plans.

Algorithms↗
PubMed1997

Monitoring of an Alkaline 2,4,6-Trichlorophenol-Degrading Enrichment Culture by DNA Fingerprinting Methods and Isolation of the Responsible Organism, Haloalkaliphilic Nocardioides sp. Strain M6.

A site situated near Alkali Lake (Oregon) and highly contaminated by chloroaromatic compounds was chosen for isolation of alkaliphilic chlorophenol-degrading bacteria. Prolonged cultivation of an enrichment culture followed by successive transfers resulted in a strong increase in the 2,4,6-trichlorophenol (2,4,6-TCP) degradation rate. Repetitive extragenic palindromic PCR and amplified ribosomal DNA restriction analysis were applied to distinguish members of the enrichment culture and monitor them during the enrichment procedure. Comparison of the fingerprints of the isolates obtained from the enrichment culture and its total DNA fingerprint indicated the presence of an unidentified bacterium in the enrichment culture, assisting in its isolation. The 2,4,6-TCP-degrading isolate, M6, was tentatively identified as a Nocardioides sp. strain based on its partial 16S RNA sequence and fatty acid profile. Strain M6 was capable of utilizing up to 1.6 g of 2,4,6-TCP per liter as a sole carbon and energy source and could also grow on 2,4-dichlorophenol and 2,4,5-trichlorophenol. A high-cell-density suspension of this strain degraded a wide range of chlorinated phenols from di- to pentachlorophenol while showing a clear preference for phenols containing chlorine substituents in positions 2 plus 4. Based on its optimal pH (9.0 to 9.4) and sodium ion concentration (0.2 to 0.4 M) for growth, Nocardioides sp. strain M6 is a slightly halophilic alkaliphile.

Journal Article↗
PubMed1970

Growth Inhibition of Mycobacterium tuberculosis After Single-Pulsed Exposures to Streptomycin, Ethambutol, and Rifampin.

It was reported earlier that the degree of growth inhibition of tubercle bacilli after single-pulsed isoniazid exposures is a function of the time-concentration product (TCP) of exposure rather than of either time or concentration alone (TCP = hr exposure x mug of drug/ml). In the present investigation, these time and concentration studies have been extended to streptomycin (SM), ethambutol (EMB), and rifampin (RMP). Mycobacterium tuberculosis H37Ra was grown in Sautons liquid medium at 37 C with aeration. Rapidly growing cells were harvested and resuspended at 0.5 to 0.6 mg (dry wt)/ml in fresh medium; incubation was continued in the presence of various concentrations of the appropriate drug. At time intervals, samples were diluted 1:200 into drug-free medium for turbidimetric growth assay. Minimal inhibitory concentrations of EMB, SM, and RMP were approximately 0.2, 0.02, and 0.002 mug/ml, respectively. When cells were pulsed with 0.0125 to 0.0625 mug of RMP per ml at time intervals of up to 9.5 hr, the degree of subsequent growth inhibition appeared to be a function of TCP. A similar relationship was observed when SM was tested over a range of 0.125 to 1.0 mug/ml and various time intervals of up to 8 hr. In contrast, inhibition of tubercle bacilli after EMB exposures was dependent primarily on exposure time and was affected only slightly by concentration. At any particular exposure time between 3 and 16 hr, 1.25 to 7.5 mug of EMB per ml produced similar levels of inhibition, but marked inhibition did not occur unless the exposure time exceeded 10 hr. Relationships of these latter findings to the mode of action of EMB and the potential clinical significance of the RMP, SM, and EMB data are discussed.

Journal Article↗
PubMed1996

Alterations in Vibrio cholerae motility phenotypes correlate with changes in virulence factor expression.

Motility is thought to contribute to the virulence of Vibrio cholerae, but the role it plays in pathogenesis is not completely understood. To investigate the influence of motility on virulence gene expression and intestinal colonization, we have isolated mutants with altered swarming abilities in soft agar medium. Both spontaneous hyperswarmer (exhibiting faster swarm rates) and spontaneous or transposon-induced nonmotile mutants of strain 0395 were obtained. Surprisingly, we found that two of three classes of hyperswarmer mutants were defective in autoagglutination, a phenotype associated with expression of toxin-coregulated pili (TCP), an essential ToxR-regulated colonization factor of V. cholerae. In contrast, nonmotile mutants exhibited autoagglutination under growth conditions that normally repress this phenotype. Further characterization of mutant strains revealed differences in the expression of other virulence determinants. Class I hyperswarmer mutants were defective in production of TCP, cholera toxin, and a cell-associated hemolysin but showed increased levels of protease and fucose-sensitive hemagglutinin. All nonmotile mutants examined, including those with insertions in a sequence homologous to motB, exhibited increased expression of TCP pilin, cholera toxin, and cell-associated hemolysin but dramatically decreased levels of fucose-sensitive hemagglutinin and HEp-2 adhesins. In general, nonmotile mutants displayed few or no defects in intestinal colonization, while class I hypermotile mutants were highly defective in colonization. These results suggest that the motility phenotype of V. cholerae is tightly coupled to the expression of multiple ToxR-regulated and non-ToxR-regulated virulence determinants.

Agglutination↗
PubMed1996

Relative significance of mannose-sensitive hemagglutinin and toxin-coregulated pili in colonization of infant mice by Vibrio cholerae El Tor.

A previously described in-frame deletion in mshA--the gene encoding the structural subunit of the mannose-sensitive hemagglutinin pilus--has been introduced into the chromosome of three El Tor O1 strains of Vibrio cholerae. None of the deltamshA mutants showed significant attenuation or loss of colonization potential in the infant mouse cholera model. A second mutation, created by insertion of a kanamycin resistance cartridge into deltamshA, also failed to affect in vivo behavior. In contrast, strains carrying mutations in tcpA (encoding the monomer of the toxin-coregulated pilus [TCP]) were markedly attenuated and showed dramatically impaired colonization. This result was in line with those of previous studies. Protection tests performed with antibodies to TCP and to MshA showed that only the former were able to confer immunity against El Tor O1 challenge in this model. Studies with mutants constructed from two O139 strains similarly suggest that TCP but not mannose-sensitive hemagglutinin pili are critical for colonization by strains of this serogroup.

Animals↗
PubMed2000

The virulence regulatory protein ToxR mediates enhanced bile resistance in Vibrio cholerae and other pathogenic Vibrio species.

The transmembrane regulatory protein ToxR is required for expression of virulence factors in the human diarrheal pathogen Vibrio cholerae, including cholera toxin (CT) and the toxin coregulated pilus (TCP). ToxR is necessary for transcription of the gene encoding a second regulatory protein, ToxT, which is the direct transcriptional activator of CT and TCP genes. However, ToxR, independent of ToxT, directly activates and represses transcription of the outer membrane porins OmpU and OmpT, respectively. The genes encoding TCP and CT (and including ToxT) lie on horizontally acquired genetic elements, while the toxR, ompU, and ompT genes are apparently in the ancestral Vibrio chromosome. The contribution of ToxR-dependent modulation of outer membrane porins to cholera pathogenesis has remained unknown. We demonstrate that ToxR mediates enhanced bile resistance in a ToxT-independent manner. In both classical and El Tor biotypes of V. cholerae, a toxR mutant strain has a reduced minimum bactericidal concentration (MBC) of bile, the bile component deoxycholate (DC), and the anionic detergent sodium dodecyl sulfate (SDS) compared to both wild-type and toxT mutant strains. Classical and El Tor toxR mutant strains also exhibit reduced growth rates at subinhibitory concentrations of DC and SDS. Growth of either V. cholerae biotype in subinhibitory concentrations of bile or DC induces increased ToxR-dependent production of a major 38-kDa outer membrane protein, which was confirmed to be OmpU by Western blot. Measurement of transcription of a ompUp-lacZ fusion in both biotypes reveals stimulation (about two- to threefold) of ToxR-dependent ompU transcription by the presence of bile or DC, suggesting that ToxR may respond to the presence of bile. The toxR mutant strains of three additional human intestinal pathogenic Vibrio species, V. mimicus, V. fluvialis, and V. parahaemolyticus, display lower MBCs of bile, DC, and SDS and have altered outer membrane protein profiles compared to the parental wild-type strains. Our results demonstrate a conserved role for ToxR in the modulation of outer membrane proteins and bile resistance of pathogenic Vibrio species and suggest that these ToxR-dependent outer membrane proteins may mediate enhanced resistance to bile. We speculate that ToxR-mediated bile resistance was an early step in the evolution of V. cholerae as an intestinal pathogen.

Adhesins, Bacterial↗
PubMed2001

Immune response genes modulate serologic responses to Vibrio cholerae TcpA pilin peptides.

Cholera is an enteric disease caused by Vibrio cholerae. Toxin-coregulated pilus (TCP), a type 4 pilus expressed by V. cholerae, is a cholera virulence factor that is required for host colonization. The TCP polymer is composed of subunits of TcpA pilin. Antibodies directed against TcpA are protective in animal models of cholera. While natural or recombinant forms of TcpA are difficult to purify to homogeneity, it is anticipated that synthesized TcpA peptides might serve as immunogens in a subunit vaccine. We wanted to assess the potential for effects of the immune response (Ir) gene that could complicate a peptide-based vaccine. Using a panel of mice congenic at the H-2 locus we tested the immunogenicity of TcpA peptide sequences (peptides 4 to 6) found in the carboxyl termini of both the classical (Cl) and El Tor (ET) biotypes of TCP. Cl peptides have been shown to be immunogenic in CD-1 mice. Our data clearly establish that there are effects of the Ir gene associated with both biotypes of TcpA. These effects are dynamic and dependent on the biotype of TcpA and the haplotypes of the host. In addition to the effects of the classic class II Ir gene, class I (D, L) or nonclassical class I (Qa-2) may also affect immune responses to TcpA peptides. To overcome the effects of the class II Ir gene, multiple TcpA peptides similar to peptides 4, 5, and 6 could be used in a subunit vaccine formulation. Identification of the most protective B-cell epitopes of TcpA within a particular peptide and conjugation to a universal carrier may be the most effective method to eliminate the effects of the class II and class I Ir genes.

Amino Acid Sequence↗
PubMed2003

The global regulator ArcA modulates expression of virulence factors in Vibrio cholerae.

A Vibrio cholerae arcA mutant was constructed and used to examine the role of the global anaerobiosis response regulator ArcA in the expression of virulence factors in this important human pathogen. In V. cholerae, expression of the major virulence factors cholera toxin (CT) and toxin-coregulated pilus (TCP) is regulated by the transcriptional activator ToxT. toxT expression, in turn, is controlled by the transmembrane DNA binding proteins ToxR and TcpP. In the V. cholerae arcA mutant, although ToxR and TcpP were unaffected, Northern blot and reverse transcription-PCR analyses indicated that the expression of toxT was significantly decreased with concomitant reduction in the expression of CT and TCP. CT and TCP expression was completely restored in the V. cholerae arcA mutant strain by expressing a cloned toxT gene in the mutant. These results suggest that ArcA functions as a positive regulator of toxT expression under both aerobic and anaerobic conditions, although as expected, the effect was more pronounced during anaerobic growth. This was reflected in a reduction of virulence of the V. cholerae arcA mutant strain in the infant mouse cholera model.

Animals↗
PubMed1997

Outer membrane translocation arrest of the TcpA pilin subunit in rfb mutants of Vibrio cholerae O1 strain 569B.

The toxin-coregulated pilus (TCP) of Vibrio cholerae is a type 4-related fimbrial adhesin and a useful model for the study of type 4 pilus biogenesis and related bacterial macromolecular transport pathways. Transposon mutagenesis of the putative perosamine biosynthesis genes in the rfb operon of V. cholerae 569B eliminates lipopolysaccharide (LPS) O-antigen biosynthesis but also leads to a specific defect in TCP export. Localization of TcpA is made difficult by the hydrophobic nature of this bundle-forming pilin, which floats anomalously in sucrose density gradients, but the processed form of TcpA can be found in membrane and periplasmic fractions prepared from these strains. While TcpA cannot be detected by surface immunogold labelling in transmission electron microscope preparations, EDTA pretreatment facilitates immunofluorescent antibody labelling of whole cells, and ultrathin cryosectioning techniques confirm membrane and periplasmic accumulation of TcpA. Salt and detergent extraction, protease accessibility, and chemical cross-linking experiments suggest that although TcpA has not been assembled on the cell surface, subunit interactions are otherwise identical to those within TCP. In addition, TcpA-mediated fucose-resistant hemagglutination of murine erythrocytes is preserved in whole-cell lysates, suggesting that TcpA has obtained its mature conformation. These data localize a stage of type 4 pilin translocation to the outer membrane, at which stage export failure leads to the accumulation of pilin subunits in a configuration similar to that within the mature fiber. Possible candidates for the outer membrane defect are discussed.

Animals↗
PubMed1998

Chemotactic adaptation is altered by changes in the carboxy-terminal sequence conserved among the major methyl-accepting chemoreceptors.

In Escherichia coli and Salmonella typhimurium, methylation and demethylation of receptors are responsible for chemotactic adaptation and are catalyzed by the methyltransferase CheR and the methylesterase CheB, respectively. Among the chemoreceptors of these species, Tsr, Tar, and Tcp have a well-conserved carboxy-terminal motif (NWET/SF) that is absent in Trg and Tap. When they are expressed as sole chemoreceptors, Tsr, Tar, and Tcp support good adaptation, but Trg and Tap are poorly methylated and supported only weak adaptation. It was recently discovered that CheR binds to the NWETF sequence of Tsr in vitro. To examine the physiological significance of this binding, we characterized mutant receptors in which this pentapeptide sequence was altered. C-terminally-mutated Tar and Tcp expressed in a receptorless E. coli strain mediated responses to aspartate and citrate, respectively, but their adaptation abilities were severely impaired. Their expression levels and attractant-sensing abilities were similar to those of the wild-type receptors, but the methylation levels of the mutant receptors increased only slightly upon addition of attractants. When CheR was overproduced, both the adaptation and methylation profiles of the mutant Tar receptor became comparable to those of wild-type Tar. Furthermore, overproduction of CheR also enhanced adaptive methylation of wild-type Trg, which lacks the NWETF sequence, in the absence of any other chemoreceptor. These results suggest that the pentapeptide sequence facilitates effective adaptation and methylation by recruiting CheR.

Adaptation, Physiological↗
PubMed2005

Virulence and the environment: a novel role for Vibrio cholerae toxin-coregulated pili in biofilm formation on chitin.

The toxin-coregulated pilus (TCP) of Vibrio cholerae is required for intestinal colonization and cholera toxin acquisition. Here we report that TCP mediates bacterial interactions required for biofilm differentiation on chitinaceous surfaces. We also show that undifferentiated TCP- biofilms have reduced ecological fitness and, thus, that chitin colonization may represent an ecological setting outside the host in which selection for a host colonization factor may take place.

Bacterial Toxins↗
PubMed2004

Bone formation in transplants of human bone marrow stromal cells and hydroxyapatite-tricalcium phosphate: prediction with quantitative CT in mice.

PURPOSE: To determine whether quantitative computed tomography (CT) can be used to estimate the extent of new bone formation in hydroxyapatite-tricalcium phosphate (HA-TCP)-based transplants. MATERIALS AND METHODS: Bone-forming transplants were generated by attaching cultured human bone marrow stromal cells to aliquots of HA-TCP particles and were placed in subcutaneous pockets in immunocompromised mice. After 8 weeks, the transplants were individually imaged; each scan included a phantom. Overall bone mineral density (BMD) of each transplant was obtained. Hematoxylin-eosin-stained sections of the same transplants were then examined histologically, which is the reference standard for assessing bone formation. The extent of bone in each transplant was scored on a semiquantitative scale ranging from 0 to 4 by three independent blinded observers; the bone score for each transplant was calculated by averaging the three observer scores. BMD was compared with the histologically determined bone score for each transplant. Statistical evaluations included (a) calculation of empiric receiver operating characteristic curves to determine optimum BMD thresholds and (b) determination of the relationship between BMD and bone score, including derivation of Pearson correlation coefficients. RESULTS: One hundred twenty transplants were evaluated. Average BMD of 600 mg/cm3 K2HPO4 or more was noted in transplants with appreciable bone formation (bone score > or = 3), while average BMD of less than 600 mg/cm3 K2HPO4 was seen in transplants with poor bone formation (bone score < 3) (P <.001). Among transplants with appreciable bone formation, the BMD was proportional to the extent of mineralized matrix present in the new bone. CONCLUSION: Use of quantitative CT offers a practical approach for the noninvasive determination of new bone formation in mineralizing bone marrow stromal cells and HA-TCP transplants.

Animals↗
PubMed1998

Hypertensive response to chronic NO synthase inhibition is different in Sprague-Dawley rats from two suppliers.

Experiments were conducted to determine whether Sprague-Dawley rats from different suppliers have the same hypertensive response to chronic inhibition of nitric oxide synthase. Rats (240-260 g) obtained from either Harlan or Charles River Laboratories were maintained in metabolic cages for baseline (week 0) measurements before receiving Nomega-nitro-L-arginine methyl ester (L-NAME) in the drinking water for 2 wk at 5 or 65 mg . kg-1 . day-1. Baseline values for tail cuff pressure (TCP) were significantly higher in Harlan rats (131 +/- 2 mmHg) compared with Charles River rats (108 +/- 3 mmHg, P < 0.001). At 65 mg . kg-1 . day-1, L-NAME produced a significantly larger increase in TCP in Harlan versus Charles River rats (41 +/- 4 vs. 29 +/- 4%, respectively, P < 0.01). Food and water intake and sodium and water excretion were not different between groups. Urinary excretion of nitrate and nitrite (UNOxV) was significantly reduced in all rats given L-NAME. UNOxV was decreased by 69 +/- 12 and 62 +/- 7% in Harlan and Charles River rats, respectively. The lower dose of L-NAME increased TCP and decreased UNOxV in both Harlan and Charles River rats; these effects were more pronounced in the Harlan rats. These results suggest that NO plays a more significant role in the maintenance of arterial pressure in Sprague-Dawley rats from Harlan compared with Charles River Laboratories. Such findings may also provide insight as to why some of the mechanisms associated with chronic L-NAME treatment are not consistent between laboratories.

Animals↗
PubMed1997

Effects of chest wall counterpressures on lung mechanics under high levels of CPAP in humans.

We assessed the respective effects of thoracic (TCP) and abdominal/lower limb (ACP) counterpressures on end-expiratory volume (EEV) and respiratory muscle activity in humans breathing at 40 cmH2O of continuous positive airway pressure (CPAP). Expiratory activity was evaluated on the basis of the inspiratory drop in gastric pressure (DeltaPga) from its maximal end-expiratory level, whereas inspiratory activity was evaluated on the basis of the transdiaphragmatic pressure-time product (PTPdi). CPAP induced hyperventilation (+320%) and only a 28% increase in EEV because of a high level of expiratory activity (DeltaPga = 24 +/- 5 cmH2O), contrasting with a reduction in PTPdi from 17 +/- 2 to 9 +/- 7 cmH2O . s-1 . cycle-1 during 0 and 40 cmH2O of CPAP, respectively. When ACP, TCP, or both were added, hyperventilation decreased and PTPdi increased (19 +/- 5, 21 +/- 5, and 35 +/- 7 cmH2O . s-1 . cycle-1, respectively), whereas DeltaPga decreased (19 +/- 6, 9 +/- 4, and 2 +/- 2 cmH2O, respectively). We concluded that during high-level CPAP, TCP and ACP limit lung hyperinflation and expiratory muscle activity and restore diaphragmatic activity.

Adult↗
PubMed2001

SPINK1/PSTI mutations are associated with tropical pancreatitis in Bangladesh. A preliminary report.

BACKGROUND/AIMS: Tropical pancreatitis (TP) refers to a severe type of idiopathic chronic pancreatitis that develops in children in tropical regions of Africa and southern Asia. Phenotypically TP is subdivided into fibrocalculous pancreatic diabetes (FCPD) and tropical calcific pancreatitis without diabetes mellitus (TCP). Recently an association was identified between idiopathic pancreatitis in the USA and Europe and mutations in the serine protease inhibitor, Kazal type 1 (SPINK1) gene (previously termed pancreatic secretory trypsin inhibitor, PSTI). Our aim was to determine if either form of TP has a genetic basis. METHODS: We studied 8 well-characterized patients from Bangladesh with FCPD, 4 with TCP and 4 controls without pancreatic disease. The entire SPINK1 gene was sequenced in these patients. RESULTS: We detected two disease-associated SPINK1 mutations (N34S/IVS1 - 37T > C and IVS3 + 2T > C) in 6 of 8 patients from Bangladesh with FCPD but not in 4 patients with TCP (p < 0.03) or 4 controls (p < 0.03). CONCLUSIONS: We conclude that SPINK1 mutations are associated with FCPD in Bangladesh. Since SPINK1 mutations in Europeans and North Americans are associated with idiopathic chronic pancreatitis that is phenotypically different from FCPD, we further conclude that mutated SPINK1 markedly increases the risk of developing a variety of pancreatic diseases possibly through a chronic elevation of active trypsin within the pancreas.

Adult↗