Whole-body diffusion-weighted MRI and (18)F-FDG PET/CT can discriminate between different lymphoma subtypes.

AIM: To determine whether combined 2-[(18)F]-fluoro-2-deoxy-d-glucose ((18)F-FDG) positron-emission tomography (PET)/computed tomography (CT) and diffusion-weighted imaging (DWI) can be used for characterisation of different lymphoma subtypes, i.e., indolent versus aggressive lymphoma, and also to assess the prognostic value of different quantitative parameters of whole-body (WB) DWI and (18)F-FDG PET/CT. MATERIALS AND METHODS: Pre-therapeutic WB magnetic resonance imaging (MRI) including DWI and (18)F-FDG PET/CT were performed in lymphoma patients. Different quantitative DWI and (18)F-FDG PET/CT parameters were evaluated for characterisation of different lymphoma subtypes. These parameters were also correlated, both separately and in combination, against overall survival (OS) and progression-free survival (PFS). A lesion-by-lesion analysis was performed for correlation analysis between maximum standardised uptake value (SUVmax), mean standardised uptake value (SUVmean) and mean apparent diffusion coefficient (ADC). RESULTS: Fifty patients were included in the study and divided into three groups: Hodgkin's lymphoma (HL), n=12; aggressive non-Hodgkin's lymphoma (NHL), n=29 (including 20 patients with diffuse large B-cell lymphoma, DLBCL); and indolent NHL, n=9. Indolent NHL showed significantly lower mean ADC values than the other two lymphoma groups (p=0.013). Aggressive NHL had a higher SUVmax than HL. The OS analysis of all patients showed a relationship (p=0.006) between increased mean ADC and longer OS. A model with both SUVmean and mean ADC, strengthened the possibility to predict PFS; however, a separate analysis of the DLBCL patients showed that none of the quantitative parameters could predict OS or PFS. CONCLUSION: ADC can discriminate between indolent and aggressive NHL. This finding can be useful in assessing possible transformation from indolent to aggressive NHL. ADC, ADC/SUV, and SUV cannot predict OS/PFS independent of lymphoma subtype.

Ethical reflections on clinical trials with human tissue engineered products.

Ex-vivo tissue engineering is an emerging medical technology. Its aim is to regenerate tissues and organs and to restore them to full physiological activity. Some clinical trials with human tissue engineered products (HTEPs) have been conducted and others will follow. These trials not only have to confirm the therapeutic value of the HTEP, they also have to provide insight in its regenerative activity, its safety and long-term effects. The development of these trials is aggravated by the complexity of the tissue engineering process and product. This paper investigates how this complexity influences the ethical conduct of clinical trials with HTEPs. We focus on the value and validity of the trial, the risk-benefit ratio and the protection of the trial participant. We argue that trials with HTEPs need a robust methodology. The risk-benefit ratio of a new HTEP must be determined and compared with available efficacious therapies. This requires the identification and minimisation of risks associated with tissue engineering. Finally a process as complex as tissue engineering presents serious challenges for the informed consent process, and for the protection of the trial participant during and after the trial.

Paramagnetic hyperfine splitting in the Eu Mössbauer spectra of CaF(2):Eu.

(151)Eu Mössbauer spectra in zero magnetic field of highly dilute (0.1 mol%) Eu(2+) ions in CaF(2) showed an almost temperature-independent asymmetrically split pattern, arising from the paramagnetic hyperfine interaction AS. I in a cubic crystal field with slow electron spin relaxation; in a small external magnetic field B of 0.2 T such that gµ(B)B>A an almost symmetrical pattern was observed. Both the spectra with and without external field are well described using the spin Hamiltonian and previous electron paramagnetic resonance data. A more concentrated (2 mol% Eu(2+)) sample exhibited a strongly broadened symmetrical resonance line due to an increased Eu-Eu spin relaxation rate; in an external magnetic field of 0.2 T the Mössbauer spectra exhibited further broadening and additional magnetic structures due to the reduced relaxation rate. When a large field of 6 T was applied such that gµ(B)B is much larger than the crystal field splitting, a fully resolved hyperfine pattern was observed at 2.5 K, with an effective field at the Eu nuclei of -33.7 T; at higher temperatures superimposed patterns originating from excited electronic states were observed in the spectra. The present results on the highly dilute CaF(2) : 0.1%Eu(2+) sample deliver a straightforward explanation for previous observations of a seemingly large dependence of the Eu(2+) isomer shift on europium concentration.

Indomethacin inhibits duodenal mucosal bicarbonate secretion and endogenous prostaglandin E2 output in human subjects.

Nonsteroidal anti-inflammatory drugs are a frequent cause of gastric and duodenal mucosal injury. We examined the effect of indomethacin on duodenal mucosal bicarbonate secretion and prostaglandin output in healthy subjects. Subjects received either 50 mg of indomethacin or placebo orally 13 hours and 1 hour before study. A 4-cm segment of proximal (the duodenal bulb) or distal (10 to 14 cm beyond the pylorus) duodenum was isolated and perfused with 154 mM NaCl containing a nonabsorbable marker. In the proximal duodenum indomethacin reduced both basal and acid-stimulated bicarbonate secretion by approximately 65% (p less than 0.01); in the distal duodenum indomethacin decreased basal and acid-stimulated bicarbonate output by approximately 45% (p less than 0.01). Oral indomethacin inhibited basal and acid-stimulated duodenal prostaglandin E2 output in both the proximal and distal duodenum. We conclude that, by decreasing duodenal mucosal bicarbonate production and prostaglandin output in humans, oral indomethacin, in two doses of 50 mg each, impairs an important duodenal defense mechanism.

Impaired proximal duodenal mucosal bicarbonate secretion in patients with duodenal ulcer.

The defensive factors that prevent the human duodenal mucosa from acidic and peptic damage have not been fully evaluated. To determine whether duodenal mucosal bicarbonate production was altered in patients with inactive duodenal ulcer, we measured basal and acid-stimulated bicarbonate output from the duodenal bulb and the distal duodenum in healthy subjects and patients with inactive duodenal ulcer. As compared with 16 normal subjects, the 12 patients had significantly less mean (+/- SE) basal proximal duodenal mucosal bicarbonate secretion (185 +/- 13 vs. 107 +/- 18 mumol per centimeter per hour; P less than 0.001). Moreover, in response to a physiologic amount of hydrochloric acid (2 mmol per five minutes) instilled directly into the duodenal bulb, peak proximal duodenal bicarbonate output in the patients was 41 percent of the normal response (263 +/- 65 vs. 642 +/- 77 mumol per centimeter per hour; P less than 0.01). There was little overlap between groups. In contrast, bicarbonate outputs in the distal duodenum were similar in the two groups. We conclude that most patients with duodenal ulcer disease have decreased proximal duodenal mucosal bicarbonate production at rest, in response to hydrochloric acid, and in relation to peak gastric acid secretion. Impaired proximal duodenal mucosal bicarbonate secretion may be an important factor in the development and natural history of duodenal ulcer.

Human duodenal mucosal bicarbonate secretion. Evidence for basal secretion and stimulation by hydrochloric acid and a synthetic prostaglandin E1 analogue.

The factors responsible for prevention of duodenal mucosal injury are not known. This series of experiments was performed to determine whether the human duodenum secretes bicarbonate that could prevent mucosal damage. To isolate a 4-cm segment of proximal (i.e., the duodenal bulb) or distal duodenum free of contamination from either gastric or pancreaticobiliary secretion, or both, methods were developed using occlusive balloons. The test segment was perfused with NaCl (2 ml/min, 37 degrees C) containing [14C]PEG as a nonabsorbable marker, and bicarbonate output was quantitated. Mean (+/- SE) basal proximal duodenal bicarbonate output was 143 +/- 17 mumol/cm X h. A 5-min infusion of 25, 50, and 100 mM HCl directly into the isolated proximal duodenal test segment increased bicarbonate output to 167 +/- 29, 199 +/- 19, and 278 +/- 49 mumol/cm X h, respectively, during the hour after acidification. Distal duodenal acidification (25, 50, and 100 mM) also increased bicarbonate output from the isolated proximal duodenal test segment. A synthetic prostaglandin E1 analogue, misoprostol (1.67-13.3 micrograms/min), infused directly into proximal or distal test segments significantly stimulated bicarbonate outbreak; peak responses were 644 +/- 35 mumol/cm X h and 171 +/- 20 mumol/cm X h (p less than 0.001), respectively. Thus, in humans, the proximal and distal duodenal mucosa secretes bicarbonate at rest; direct acidification of the proximal duodenum stimulates bicarbonate output; acidification of the distal duodenum beyond the isolated test segment also increased proximal duodenal bicarbonate output; and a synthetic prostaglandin E1 analogue stimulated both proximal and distal bicarbonate output; however, distal duodenal bicarbonate output was significantly less, indicating a proximal-to-distal gradient in bicarbonate secretion.

The effect of sodium bicarbonate versus aluminum-magnesium hydroxide on postprandial gastric acid in duodenal ulcer patients.

When ingested 1 hour after a meal, conventional liquid antacids have a buffering effect of approximately 2 hours, while in the fasting state their effect is brief, lasting less than 1 hour. We tested the hypothesis that equal doses of antacid, one water soluble (sodium bicarbonate) and the other water insoluble (aluminum hydroxide plus magnesium hydroxide, MaaloxR), would have similar durations of postprandial buffering if the water soluble antacid regenerates the particulate protein buffer of the meal that leaves the stomach more slowly than liquids. Tests were conducted in random order on three separate days in 10 patients with duodenal ulcer. The effects of 30 ml of 2.39 M sodium bicarbonate (6.17 g, about 1 teaspoonful), the aluminum-magnesium antacid, each equivalent to 71.7 mmol of in vitro buffer, and water as a control on pH, hydrogen ion activity, and titratable acidity were compared. Thirty milliliters of each was swallowed 1 and 3 hours after ingestion of a standard solid plus liquid. Compared to the water control each dose of sodium bicarbonate significantly increased intragastric pH and decreased hydrogen ion activity and titratable acidity for only 1 hour. Each dose of the aluminum-magnesium antacid significantly buffered intragastric contents for 2 hours. These findings indicate that sodium bicarbonate transiently buffers postprandial intragastric contents. Therefore, sodium bicarbonate fails to reconstitute the protein buffer of the meal effectively, and the observations suggest that it leaves the stomach rapidly with the liquid phase of the meal. However, the water insoluble, aluminum-magnesium antacid has a longer duration of buffering, probably because it leaves the stomach more slowly, largely with the solid portion of the meal.

Screening for eye irritancy using cultured HeLa cells.

To investigate whether toxicity tests on HeLa cells were predictive of eye irritancy, 18 compounds of known eye irritancy and in vitro cytotoxicity were tested on HeLa cells in the MIT-24 system. The results correlated well with eye irritancy as determined by the Draize test in rabbits for 16 of the test substances, but failed to detect the high eye irritancy of 1-heptanol and allyl alcohol, both of which were cytotoxic in other cellular systems.

Effects of acute experimental esophagitis on mechanical properties of the lower esophageal sphincter.

The mechanical properties of the cat lower esophageal sphincter (LES) circular muscle were studied in untreated animals and in cats that had biopsy-proven esophagitis induced by 30-min perfusions of 0.1 N HCl 5 cm above the LES on four consecutive days. The location of the in vivo LES was identified by the pull-through method with a pressure measuring probe. Consecutive rings were cut from the LES and esophagus and tested in vitro. Force-length curves were obtained in standard Tyrode solution, in Tyrode solution with 140 mM KCl, and in Ca-free Tyrode solution with 5 mM ethylenediaminetetra-acetic acid to determine basal, total, and passive forces, respectively. The active force was measured as the difference between the total and passive forces, whereas the basal-active force was measured as the difference between the basal and passive forces. In the untreated animals, LES rings exhibited the steepest basal force-length curve and the highest active and total forces under maximal KCl stimulation. The passive force of the LES rings was equal to that of the esophageal body rings. Basal in vitro forces were significantly reduced in all acid-perfused animals, whereas the passive forces were not affected. Active and basal-active forces were also significantly reduced. The maximum active force developed by LES rings was reduced, whereas esophageal rings, four rings proximal to the ring corresponding to the high pressure point, were not affected. The reduction in LES active force was related to the intensity of histologic damage, whereas basal-active forces were uniformly reduced. This study shows that in vitro mechanical properties of the LES are affected by induction of esophagitis and suggests that the ability to develop tonus in the basal state is reduced by acid perfusion, even in animals in which the ability to develop active contraction in response to maximal KCl stimulation is preserved. The response to KCl is reduced only by more extensive histologic damage.