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PubMed1996

Assessment of gastric acidity in intensive care patients: intermittent pH registration cannot replace continuous pH monitoring.

OBJECTIVE: To test the accuracy of colour-scaled indicator papers to measure pH values and to study the correlation between this method of measuring gastric juice pH once daily and 24-h continuous intragastric pH monitoring in intensive care patients. DESIGN: The accuracy of indicator papers was tested in the laboratory using colourless solutions and aspirated gastric juice and was then verified with a laboratory pH meter. Continuous intragastric pH monitoring was performed in mechanically ventilated ICU patients. Percentages of time with a pH value <3.0 and median pH values by 24-h continuous intragastric pH monitoring were compared to pH values measured once daily with indicator paper. SETTING: A mixed ICU. PATIENTS: A total of 150 measurements were taken by continuous pH monitoring in 91 mechanically ventilated ICU patients. MEASUREMENTS AND RESULTS: The correlation between the pH measured with the indicator paper and subsequently verified with a laboratory pH meter in colourless solutions was 0.96 [regression coefficient (RC) 0.98, 95% confidence interval (CI) 0.91-1.05]. Measured in gastric juice it was 0.95 (RC 0.95, 95% CI 0.88-1.01). The correlation between median pH values, determined with 24-h continuous intragastric pH monitoring, and values measured with indicator papers was 0.39 (RC 0.43, 95% CI 0.26-0.59). The mean difference in pH, as determined by the analysis of Bland and Altman], was 0.9 with a SD of 4.7. The correlation between the percentage of time with pH < 3.0, as obtained with continuous registration, and median gastric pH values (also obtained with continuous registration) was -0.94 (RC-0.06, 95% CI-0.06- -0.05); the correlation between the time and gastric pH values (measured with indicator paper) was-0.40 (RC-0.02, 95% CI-0.03- -0.02). CONCLUSION: The colour-scaled indicator paper is an accurate method of measuring pH values, but there is a poor correlation between gastric pH values measured once daily and a total measurement derived from 24-h continuous intragastric pH monitoring. Changes in intragastric pH values cannot be accurately studied when measuring acidity once daily. The influence of various treatment regimens on intragastric acidity in relation to the development of gastric colonization and nosocomial pneumonia should be investigated either with continuous intragastric monitoring or with frequent measurements in aspirated gastric juice.

Adult↗
PubMed2002

Effects of pH and pH fluctuations on microbial fermentation and nutrient flow from a dual-flow continuous culture system.

Eight dual-flow continuous culture fermenters (1400 ml) were used in two consecutive periods to study the effects of pH and pH fluctuations on microbial fermentation and nutrient flow. Fermenters were maintained at 39 degrees C, with solid and liquid dilution rates of 5 and 10%/h, respectively, and fed continuously a 60% alfalfa hay and 40% concentrate diet (18.9% crude protein, 36.6% neutral detergent fiber, 17.6% acid detergent fiber). Treatments were high pH (constant at 6.4); low pH (constant at 5.7); cycles of 4 h at pH 6.4 and 4 h at pH 5.7; and pH constant at 6.4, except for two 30-min drops per day to pH 5.7, followed by a 3-h slow recovery to pH 6.4. The low pH (constant at 5.7) produced lower apparent dry matter, neutral detergent fiber and acid detergent fiber digestion, lower total and branch-chained volatile fatty acid concentrations, and lower acetate and higher propionate proportions than high pH (constant at 6.4). There were no differences in these estimates between constant high pH and the two treatments that alternated high pH and low pH. The constant low pH reduced protein degradation and increased nonammonia N and dietary N flow compared with constant high pH. The pH treatments had no effect on bacterial N flow or efficiency of microbial protein synthesis. Flow of essential amino acids was highest for constant low pH and lowest for constant high pH. Results indicate that constant low pH reduced fiber and protein digestion and increased the flow of total and some individual amino acids. However, the effects of transitory decreases of pH were either small or insignificant with the conditions tested in this study.

Amino Acids↗
PubMed2006

The acid tolerance response of Bacillus cereus ATCC14579 is dependent on culture pH, growth rate and intracellular pH.

The food pathogen Bacillus cereus is likely to encounter acidic environments (i) in food when organic acids are added for preservation purposes, and (ii) during the stomachal transit of aliments. In order to characterise the acid stress response of B. cereus ATCC14579, cells were grown in chemostat at different pH values (pH(o) from 9.0 to 5.5) and different growth rates (micro from 0.1 to 0.8 h(-1)), and were submitted to acid shock at pH 4.0. Cells grown at low pH(o) were adapted to acid media and induced a significant acid tolerance response (ATR). The ATR induced was modulated by both pH(o) and micro, and the micro effect was more marked at pH(o) 5.5. Intracellular pH (pH(i)) was affected by both pH(o) and micro. At a pH(o) above 6, the pH(i) decreased with the decrease of pH(o) and the increase of micro. At pH(o) 5.5, pH(i) was higher compared to pH(o) 6.0, suggesting that mechanisms of pH(i) homeostasis were induced. The acid survival of B. cereus required protein neo-synthesis and the capacity of cells to maintain their pH(i) and DeltapH (pH(i) - pH(o)). Haemolysin BL and non-haemolytic enterotoxin production were both influenced by pH(o) and micro.

Acids↗
PubMed1999

Dynamic regulation of gastric surface pH by luminal pH.

In vivo confocal imaging of the mucosal surface of rat stomach was used to measure pH noninvasively under the mucus gel layer while simultaneously imaging mucus gel thickness and tissue architecture. When tissue was superfused at pH 3, the 25 microm adjacent to the epithelial surface was relatively alkaline (pH 4.1 +/- 0.1), and surface alkalinity was enhanced by topical dimethyl prostaglandin E2 (pH 4.8 +/- 0.2). Luminal pH was changed from pH 3 to pH 5 to mimic the fasted-to-fed transition in intragastric pH in rats. Under pH 5 superfusion, surface pH was relatively acidic (pH 4.2 +/- 0.2). This surface acidity was enhanced by pentagastrin (pH 3.5 +/- 0.2) and eliminated by omeprazole, implicating parietal cell H,K-ATPase as the dominant regulator of surface pH under pH 5 superfusion. With either pH 5 or pH 3 superfusion (a) gastric pit lumens had the most divergent pH from luminal superfusates; (b) qualitatively similar results were observed with and without superfusion flow; (c) local mucus gel thickness was a poor predictor of surface pH values; and (d) no channels carrying primary gastric gland fluid through the mucus were observed. The model of gastric defense that includes an alkaline mucus gel and viscous fingering of secreted acid through the mucus may be appropriate at the intragastric pH of the fasted, but not fed, animal.

Animals↗
PubMed2004

Global transcription profiles and intracellular pH regulation measured in Bacillus licheniformis upon external pH upshifts.

For optimization of propagation conditions for an industrially used Bacillus licheniformis, this study examines the effect of transferring cells at the early-stationary growth phase (pH 5.3) to fresh growth medium at pH 5.0-8.0. Intracellular pH (pH(i)) was measured on a single-cell level, using fluorescence ratio imaging microscopy after staining with 5(6)-carboxyfluorescein diacetate succinimidyl ester. Transcription profiles were determined using a genome DNA microarray. The optimum extracellular pH (pH(ex)) value for growth of B. licheniformis was found to be pH 7.0, resulting in the shortest lag phase, highest maximum specific growth rate and maximum biomass formation. An average pH gradient (Delta pH = pH(i) - pH(ex)) of approx. 1.0 was found in B. licheniformis 15 min after transfer to pH(ex) 5.0-8.0. Up-regulation of genes involved in sucrose uptake at pH 7.0 could be related to the optimum growth observed. Transcription profiles indicated that the organism was experiencing phosphate starvation upon transfer to pH 7.0 and pH 8.0. Mechanisms involved in pH(i) regulation appeared to include changes in fatty acid synthesis to yield a more rigid cell membrane structure at low pH(ex) values and conversion of pyruvate to acetoin instead of acetate for neutralization of low pH(ex) values.

Adaptation, Physiological↗
PubMed2002

[Diagnosis of human brucellosis. Role of pH in the seroagglutination test and influence of pH on the agglutinating activity of IgM, IgG and IgA antibodies].

OBJECTIVE: To evaluate the role of pH in the seroagglutination test (SAT)and Rose Bengal (RB) test, and to determine the influence of pH on the agglutinating activity of IgM, IgG and IgA antibodies. MATERIALS AND METHODS: The SAT was performed at pH 7.2 or pH 5.0 in standard microtiter-type polystyrene plates using Ring Test antigen or the Brucella suspension (BRUCAPT) provided in the Brucellacapt kits. Specific antibodies against native hapten were determined by radial immunodiffusion. Additionally, IgG, IgA and IgM fractions were separated from 8 sera by absorption chromatography and their agglutinating capacity was studied at pH 7.2 and 5.0. RESULTS: We studied 72 sera from patients with clinical brucellosis taken at the time of hospitalization, 16 from persons in contact with infected animals, and 16 from healthy donors. SAT results at pH 5.0 correlated with those obtained with the Rose Bengal test. Four Rose Bengal-positive sera were found to be SAT-negative at pH 7.2 and SAT-positive at pH 5.0. SAT performed at pH 5.0 with BRUCAPT antigen yielded higher titers than tests performed at pH 7.2 or 5.0 with Ring Test antigen (p < 0.001), with highest titers in IDR-positive sera. Among the 8 IgG fractions, all but one agglutinated at pH 7.2, and in 4, IgG titers showed significant increases at pH 5.0. Three IgA fractions were SAT-negative at pH 7.2 and SAT-positive at pH 5.0; the other 5 agglutinated at both pH conditions and were DTT-sensitive. All IgA fractions but one were positive by Rose Bengal. Agglutinating activity of the IgM fraction was not affected by pH. CONCLUSION: The SAT performed with the buffer and antigen suspension included in the Brucellacapt kit (pH 5.0) is highly useful for detecting agglutinating and non-agglutinating antibodies at pH 7.2.

Agglutination Tests↗
PubMed1981

Potassium ion is required for the generation of pH-dependent membrane potential and delta pH by the marine bacterium Vibrio alginolyticus.

The electrochemical potential gradient of protons in the marine bacterium Vibrio alginolyticus was measured as a function of external pH. In K+-containing cells, the membrane potential (delta psi) and delta pH vary with external pH as reported in other bacteria. On the other hand, K+-depleted cells show little pH dependence in the magnitude of delta psi from pH 6.0 to 8.5. The cytoplasmic pH in these cells varies depending on external pH, resulting in the generation of a small delta pH at acidic pH. Addition of K+ to K+-depleted cells leads to partial dissipation of delta psi and concomitant generation of delta pH. Strikingly, this effect of K+ is dependent on external pH. Collapse of delta psi and generation of delta pH by the addition of K+ decrease with increasing external pH. Thus, the delta psi and delta pH obtained after addition of K+ are essentially the same as those determined in K+-containing cells, and cytoplasmic pH becomes less dependent on external pH. The results suggest that the variation of delta psi and delta pH with external pH is controlled by K+ transport.

Cell Membrane↗
PubMed2005

Structure of the split PH domain and distinct lipid-binding properties of the PH-PDZ supramodule of alpha-syntrophin.

Pleckstrin homology (PH) domains play diverse roles in cytoskeletal dynamics and signal transduction. Split PH domains represent a unique subclass of PH domains that have been implicated in interactions with complementary partial PH domains 'hidden' in many proteins. Whether partial PH domains exist as independent structural units alone and whether two halves of a split PH domain can fold together to form an intact PH domain are not known. Here, we solved the structure of the PH(N)-PDZ-PH(C) tandem of alpha-syntrophin. The split PH domain of alpha-syntrophin adopts a canonical PH domain fold. The isolated partial PH domains of alpha-syntrophin, although completely unfolded, remain soluble in solution. Mixing of the two isolated domains induces de novo folding and yields a stable PH domain. Our results demonstrate that two complementary partial PH domains are capable of binding to each other to form an intact PH domain. We further showed that the PH(N)-PDZ-PH(C) tandem forms a functionally distinct supramodule, in which the split PH domain and the PDZ domain function synergistically in binding to inositol phospholipids.

Animals↗
PubMed1992

Glutamate transport into synaptic vesicles. Roles of membrane potential, pH gradient, and intravesicular pH.

Glutamate, the major excitatory neurotransmitter in the mammalian central nervous system, is transported into bovine synaptic vesicles in a manner that is ATP dependent and requires a vesicular electrochemical proton gradient. We studied the electrical and chemical elements of this driving force and evaluated the effects of chloride on transport. Increasing concentrations of Cl- were found to increase the steady-state ATP-dependent vesicular pH gradient (delta pH) and were found to concomitantly decrease the vesicular membrane potential (delta psi). Low millimolar chloride concentrations, which cause 3-6-fold stimulation of vesicular glutamate uptake, caused small but measurable increases in delta pH and decreases in delta psi, when compared to control vesicles in the absence of chloride. Nigericin in potassium buffers was used to alter the relative proportions of delta pH and delta psi. Compared to controls, at all chloride concentrations tested, nigericin virtually abolished delta pH and increased the vesicle interior positive delta psi. Concomitantly, nigericin increased ATP-dependent glutamate uptake in 0-1 mM chloride but decreased glutamate uptake in 4 mM (45%), 20 mM (80%), and 140 mM (75%) Cl- (where delta pH in the absence of nigericin was large). These findings suggest that either delta psi, delta pH, or a combination can drive glutamate uptake, but to different degrees. In the presence of 4 mM Cl-, where uptake is optimal, both delta psi and delta pH contribute to the driving force for uptake. When the extravesicular pH was increased from 7.4 to 8.0, more Cl- was required to stimulate vesicular glutamate uptake. In the absence of Cl-, as extravesicular pH was lowered to 6.8, uptake was over 3-fold greater than it was at pH 7.4. As extravesicular pH was reduced from 8.0 toward 6.8, less Cl- was required for maximal stimulation. Decreasing the extravesicular pH from 8.0 to 6.8 in the absence of Cl- significantly increased glutamate uptake activity, even though proton-pumping ATPase activity actually decreased about 45% under identical conditions. In the absence of chloride, nigericin increased glutamate uptake at all the pH values tested except pH 8.0. Glutamate uptake at pH 6.8 in the presence of nigericin was over 6-fold greater than uptake at pH 7.4 in the absence of nigericin. We conclude from these experiments that optimal ATP-dependent glutamate uptake requires a large delta psi and a small delta pH.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenosine Triphosphate↗
PubMed1992

Modulation of nicotinic acetylcholine receptor channel by pH: a difference in pH sensitivity of Torpedo and mouse receptors expressed in Xenopus oocytes.

1. In this study, effects of pH on the ion channel function of nicotinic acetylcholine receptor (nAChR) from Torpedo californica electroplax and mouse muscle BC3H-1 cells were investigated using Xenopus laevis oocytes injected with in vitro synthesized RNA transcripts. The acetylcholine (ACh)-induced whole-cell peak current responses and slow desensitization rates were measured by voltage-clamp. 2. The ACh-induced peak currents of Torpedo nAChRs were reversibly diminished when extracellular pH was reduced from 7.4 to 5.0 and increased at pH greater than 7.4. This pH dependence had an apparent pKa of 7.0. In contrast, the peak current of mouse muscle nAChRs were reversibly decreased at both acidic and alkaline pH's. This bell-shaped pH profile with a maximum at pH 7.4 had two apparent pKa values of 5.6 and 9.2. 3. The peak current responses of four mouse-Torpedo nAChR hybrids consisting of three Torpedo subunits and one mouse nAChR subunit displayed similar pH profiles at acidic pH, with a pKa of 6.0 to 6.5, which lay between the pKa 5.6 for mouse and the pKa 7.0 for Torpedo nAChRs. Two of these combinations, alpha M beta T gamma T delta T and alpha T beta T gamma M delta T, also had an alkaline pH dependence of the current response similar to that of mouse receptor, with a pKa of 9.3 to 9.5. 4. The slow desensitization rate of Torpedo nAChRs increased at both acidic and alkaline pH's, with two pKa values of 6.5 and 9.5, whereas that of mouse muscle receptors remained unchanged from pH 6.5 to pH 9.0 and increased at pH less than 6.0, with a pKa of 4.7. 5. Substitution of each subunit of Torpedo nAChR with a mouse counterpart resulted in a pH dependence pattern (pKa 6.0 to 6.4 and pKa 9.1 to 9.3) similar to that of Torpedo nAChR except the substitution with mouse beta subunit (pKa 4.8 and pKa 8.9), which appears to carry the characteristic acidic group determining the pH dependence of mouse nAChR desensitization. 6. The apparent pKa values obtained from the pH dependence studies of nAChR channel activation and desensitization suggest the involvement of different amino acid residues in determining channel functions of Torpedo and mouse nAChRs. The groups with pKa 7.0 and 6.5 on Torpedo nAChR can be tentatively identified as His residues, whereas those with pKa 5.6 and 4.7 on mouse receptor as Glu or Asp residues. The alkaline pKa of 8.9 to 9.5 may be Cys, Tyr, or Lys.

Allosteric Regulation↗
PubMed2000

Reflux and pH: 'alkaline' components are not neutralized by gastric pH variations.

The ability of the 'alkaline' components of reflux to cause harm in vivo is still open to debate, although these components have been shown in vitro to be capable of damaging the mucosa. The precipitation of bile acids and lysolecithin that occurs at low pH values is the main reason for questioning in vivo mucosal damage. This study was undertaken to determine the composition of gastric aspirates at different original pH values and the degree of solubility of the alkaline components when pH modifications are artificially induced. The samples for chemical analysis were collected from indwelling nasogastric tubes after surgical procedures that did not involve the upper gastrointestinal tract. Bile acid and lysolecithin concentrations were assessed by means of dedicated methods. Thirty-five samples were available for bile acid evaluation and 27 for lysolecithin evaluation. Bile acid and lysolecithin assessments were repeated after pH adjustment at 2, 3.5, 5.5 and 7. For easier assessment of the results, three ranges of the original pH were selected (pH < 2, 2 < or = pH < 5, pH > or = 5). For each pH range, results were pooled together and compared with those in the other pH ranges. Bile acid concentrations were 113+/-48, 339+/-90 and 900+/-303 (mean +/- s.e.m. micromol/L), respectively, in the three groups selected on account of the different original pH values. Differences were significant (p < 0.001). Both taurine- and glycine-conjugated bile acids were represented even at pH < 2. No major differences were observed in bile acid concentration with the artificially induced pH variations. Lysolecithin concentrations were 5.99+/-3.27, 30.80+/-8.43 and 108.37+/-22.17 (mean +/- SEM microg/ml), respectively, in the three groups selected on account of the different original pH ranges. Differences were significant (p < 0.001). No significant differences in lysolecithin concentration were detected with the artificially induced pH variations. In conclusion, both bile acids and lysolecithin are naturally represented in the gastric environment even at very low pH values, although their concentrations decrease on lowering of the naturally occurring pH. Given the concentration variability of bile acids and lysolecithin, further studies are needed to assess the minimal concentration capable of mucosal damage in vivo.

Bile Acids and Salts↗
PubMed1985

Effect of External pH on the Internal pH of Chlorella saccharophila.

The overall internal pH of the acid-tolerant green alga, Chlorella saccharophila, was determined in the light and in the dark by the distribution of 5,5-dimethyl-2-[(14)C]oxazolidine-2,4-dione ([(14)C]DMO) or [(14)C]benzoic acid ([(14)C]BA) between the cells and the surrounding medium. [(14)C]DMO was used at external pH of 5.0 to 7.5 while [(14)C]BA was used in the range pH 3.0 to pH 5.5. Neither compound was metabolized by the algal cells and intracellular binding was minimal. The internal pH of the algae obtained with the two compounds at external pH values of 5.0 and 5.5 were in good agreement. The internal pH of C. saccharophila remained relatively constant at pH 7.3 over the external pH range of pH 5.0 to 7.5. Below pH 5.0, however, there was a gradual decrease in the internal pH to 6.4 at an external pH of 3.0. The maintenance of a constant internal pH requires energy and the downward drift of internal pH with a drop in external pH may be a mechanism to conserve energy and allow growth at acid pH.

Journal Article↗
PubMed2001

Effect of 'pH' on the rate of asparagine deamidation in polymeric formulations: 'pH'-rate profile.

The rate of Asn deamidation of a model hexapeptide (L-Val-L-Tyr-L-Pro-L-Asn-Gly-L-Ala) was measured as a function of effective pH ('pH') in glassy and rubbery polymeric solids containing poly(vinyl pyrrolidone) (PVP) and in solution controls at 70 degrees C. The reaction exhibited pseudo-first-order kinetics in all samples over a wide 'pH' range (0.5 < 'pH' < 12); the formation of similar products suggests that the reaction mechanism is unaffected by matrix type. Rates of deamidation were comparable for the polymeric and solution samples in the acidic range ('pH' < 4). Solution-state rates were faster than those in polymeric solids at neutral 'pH' (6 < 'pH' < 8), increasing to a > 10,000-fold difference in the basic range ('pH' > 8). Specific base catalysis was observed in solution and in the polymeric solids under neutral conditions (6 < 'pH' < 8). In solution, the reaction exhibited general base catalysis for 'pH' > 8, whereas the reaction was 'pH'-independent in the polymeric solids in this range. The 'pH'-rate profile and supporting buffer catalysis data are consistent with a change in the rate-determining step in the basic range from 'pH'-dependent attack of the deprotonated backbone amide nitrogen on the Asn side chain in solution to 'pH'-independent ammonia expulsion in the polymeric solids. The results suggest that polymer matrix incorporation not only affects the magnitude of the deamidation rate constant but also the 'pH' dependency of the reaction and the rate-determining step in the basic 'pH' range.

Amides↗
PubMed1999

The pH partition theory predicts the accumulation and toxicity of doxorubicin in normal and low-pH-adapted cells.

The accumulation and toxicity of the weak base doxorubicin has been investigated as a function of extracellular pH, intracellular pH and the cellular pH gradient in cells previously cultured under normal (pH 7.4) and low-pH (6.8) conditions. Low-pH-adapted cells exhibit transmembrane pH gradients which substantially differ from normal cells at the same extracellular pH. No relationship was obtained between intracellular pH and the uptake or toxicity of doxorubicin in the two cell types. In contrast, doxorubicin accumulation and toxicity increased with increasing extracellular pH in both normal and low-pH-adapted cells. However, at the same extracellular pH, drug cytotoxicity was more pronounced in normal than in low-pH-adapted cells. The difference in doxorubicin accumulation and cytotoxicity at the same extracellular pH was found to be dependent on the difference in the transmembrane pH gradient of the two cell types. As the cellular pH gradient differs between tumour and normal tissue, this observation suggests a basis for enhancing cellular drug uptake in either tissue type.

Animals↗
PubMedDate not supplied

Hsp27 protects the cytoskeleton and nucleus from the effects of 42 degrees C at pH 6.7 in CHO cells adapted to growth at pH 6.7.

CHO cells are normally sensitized to hyperthermia by acidic pH. However, CHO cells adapted to growth in pH 6.7 medium become less sensitive to heat killing at the reduced pH. The adapted cells maintain their ability to develop thermotolerance at pH 6.7 and their steady state intracellular pH is elevated. Furthermore, the small molecular weight stress chaperone, hsp27, is elevated in unheated cells maintained at pH 6.7. This report documents that the cytoskeletal and nuclear components of the low pH adapted CHO cells are resistant to 42 degrees C-induced collapse and protein accretion, respectively. Hyperthermia induced a perinuclear collapse of the microtubular cytoskeleton and an increase in the amount of insoluble protein associated with the nuclei and nuclear matrix fractions in the control cells heated at pH 7.3 or heated after acute acidification to pH 6.7. Protection from these effects was observed in the low pH adapted cells heated at pH 6.7. Hsp70 does not appear to play a dominant role in the response of the adapted cells to 42 degrees C. The induction of hsp70 during heating is abrogated by pH 6.7 in cells cultured at either pH 7.3 or pH 6.7. The resistance of the microtubular cytoskeleton to perinuclear collapse and the absence of protein aggregation in the nucleus during 42 degrees C may be due to the elevated levels of hsp27 both before heating and during the heat treatment. In summary, the phenotype of CHO cells adapted to growth at low pH includes resistance of the cytoskeleton to 42 degrees C-induced perinuclear collapse and resistance to 42 degrees C-induced aggregation of nuclear proteins, in addition to the reduction in heat cytotoxicity, upregulation of intracellular pH and upregulation of hsp27.

Adaptation, Physiological↗
PubMed2003

The occurrence of Philadelphia chromosome (Ph) negative leukemia after hematopoietic stem cell transplantation for Ph positive chronic myeloid leukemia: implications for disease monitoring and treatment.

Chronic myeloid leukemia (CML) is a clonal neoplastic disorder, characterized by t(9;22)(q34;q11) that results in the formation of the Philadelphia chromosome (Ph) and the BCR/ABL fusion gene. Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for CML. Much of its therapeutic efficacy is attributed to a graft-versus-leukemia (GVL) effect exerted by donor-derived lymphoid cells against the Ph positive (Ph+) clone. Post-HSCT monitoring by cytogenetic and molecular detection of the Ph+ clone is necessary, so that pre-emptive immunologic or pharmacologic treatment may be administered at an early stage of relapse. However, under rare circumstances a second Ph negative (Ph-) leukemia may evolve post-HSCT. The pathogenetic possibilities included leukemia arising from donor-derived hematopoietic stem cells (HSCs), or transformation of residual recipient-derived Ph- HSCs that have survived the conditioning chemotherapy and radiotherapy. Recipient-derived Ph- leukemia may be related to genetic alterations that precede the onset of CML, or myelotoxic effects of the HSCT conditioning regimen. The diagnosis of Ph- relapses requires detailed investigations by conventional karyotyping, fluorescence in-situ hybridization (FISH), and molecular analysis; as well as chimerism studies that help to document the donor or recipient origin of the leukemia. Although uncommonly reported in the past, Ph- relapses may in fact be more frequent if leukemic relapses post-HSCT are more thoroughly evaluated with these investigations. The recognition of Ph- relapses are important in several ways. Ph- relapses cannot be identified by monitoring investigations targeting the Ph+ clone, so that the early detection of Ph- leukemia is usually not possible. Furthermore, Ph- relapses will not respond to therapeutic strategies effective against the Ph+ CML clone.

Hematopoietic Stem Cell Transplantation↗
PubMed1992

Effect of Elicitation and Changes in Extracellular pH on the Cytoplasmic and Vacuolar pH of Suspension-Cultured Soybean Cells.

We have employed both (31)P nuclear magnetic resonance spectroscopy and two intracellular fluorescent pH indicator dyes to monitor the pH of the vacuole and cytoplasm of suspension-cultured soybean cells (Glycine max Merr cv Kent). For the (31)P nuclear magnetic resonance studies, a flow cell was constructed that allowed perfusion of the cells in oxygenated growth medium throughout the experiment. When the perfusion medium was transiently adjusted to a pH higher than that of the ambient growth medium, a rapid elevation of vacuolar pH was observed followed by a slow (approximately 30 minute) return to near resting pH. In contrast, the concurrent pH changes in the cytoplasm were usually fourfold smaller. These data indicate that extracellular pH changes are rapidly communicated to the vacuole in soybean cells without significantly perturbing cytoplasmic pH. When elicitors were dissolved in a medium of altered pH and introduced into the cell suspension, the pH of the vacuole, as above, quickly reflected the pH of the added elicitor solution. In contrast, when the pH of either a polygalacturonic acid or Verticillium dahliae elicitor preparation was adjusted to the same pH as the ambient medium, no significant change in either vacuolar or cytoplasmic pH was observed during the 35 minute experiment. These results were confirmed in experiments with pH-sensitive fluorescent dyes. We conclude that suspension-cultured soybean cells do not respond to elicitation by significantly changing the pH of their vacuolar or cytoplasmic compartments.

Journal Article↗
PubMed1992

[Clinical and molecular biological study of Ph positive acute leukemia: comparison with blast crisis of chronic myelogenous leukemia and Ph negative acute lymphoblastic leukemia].

Eight cases of Philadelphia positive acute leukemia (Ph+AL) were compared with 13 cases of Ph+ chronic myelogenous leukemia in blast crisis (BC) and 10 cases of Ph negative acute lymphoblastic leukemia (Ph-ALL) based on the clinical and molecular biological findings. Distinguishing clinical features were a high leukocyte count (median; 147.9 x 10(3)/microliters) for Ph+AL, and a high incidence of tumor formation and basophilia for BC. A cytogenetic study demonstrated the disappearance or marked reduction of Ph+ metaphases in Ph+AL in remission, while Ph+ cells persisted in BC. The major bcr gene was not rearranged in 4 Ph+AL cases, whereas it was found rearranged in 4 other cases of Ph+ AL and 6 cases of BC. Reverse transcriptase polymerase chain reaction technique demonstrated the presence of minor bcr/abl mRNA in the former three cases, and major bcr/abl mRNA in the latter 4 cases. Remission rates were 63% for Ph+AL, 38% for BC, and 100% for Ph-ALL, and the 50% survival were 12, 5 and 29 months, respectively. It was concluded that Ph+AL can be differentiated from BC by a marked reduction of Ph+ cells at remission, and that the prognosis of Ph+AL is better than BC, but worse than Ph-ALL.

Adolescent↗