Endoscopic duodenitis, gastric metaplasia and Helicobacter pylori.

BACKGROUND AND AIMS: The purpose of this study was to investigate the relationship between gastric metaplasia and Helicobacter pylori in patients with endoscopic duodenitis. METHODS: The subjects were 57 patients with endoscopic duodentitis with or without H. pylori-associated gastritis. Biopsy specimens were obtained from the stomach and duodenal bulb to assess the histological findings and H. pylori infection. Gastric metaplasia was divided into three types: complete, intermediate and incomplete, according to the amount of mucus in the metaplastic cells. In 10 H. pylori-positive patients, endoscopic and histological findings of duodenitis were compared before and after eradication of the bacteria. RESULTS: There was no significant difference in the extent of gastric metaplasia or the appearance and severity of endoscopic duodenitis between H. pylori-positive and -negative groups. The complete type of gastric metaplasia was frequently detected in the H. pylori-negative group, whereas the incomplete type was frequently observed in the H. pylori-positive group. After eradication of H. pylori, the incomplete type changed to the complete type with a decrease of histological inflammation. CONCLUSIONS: The complete type of gastric metaplasia occurred frequently without H. pylori infection, whereas the incomplete type was frequently associated with H. pylori infection.

Distinct characteristics of organic cation transporters, OCT1 and OCT2, in the basolateral membrane of renal tubules.

PURPOSE: This study was performed to determine the detailed mRNA distribution of organic cation transporters, rOCT1 and rOCT2, along the rat nephron and to distinguish the substrate affinities of these transporters. METHODS: The distributions of rOCT1 and rOCT2 mRNA were determined by reverse transcriptase polymerase chain reaction analysis of microdissected nephron segments. Using MDCK cells transfected with rOCT1 or rOCT2 cDNA, the inhibitory effects of various compounds on the uptake of [14C]tetraethylammonium were assessed. RESULTS: rOCT1 mRNA was detected primarily in the superficial and juxtamedullary proximal convoluted tubules, whereas rOCT2 mRNA was detected widely in the superficial and juxtamedullary proximal straight and convoluted tubules, medullary thick ascending limbs, distal convoluted tubule, and cortical collecting duct. The IC50 values for cationic drugs and endogenous cations on [14C]tetraethylammonium uptake across the basolateral membranes in the transfectants indicated that rOCT1 and rOCT2 had similar inhibitor specificity for many compounds but showed moderate differences in the specificity for several compounds, such as 1-methyl-4-phenylpyridinium, dopamine, disopyramide, and chlorpheniramine. CONCLUSIONS: rOCT1 and rOCT2 possess similar but not identical multispecificities for various compounds with distinct distributions along the nephron, indicating that the two transporters share physiologic and pharmacologic roles in the renal handling of cationic compounds.

Endoscopic characteristics of low-grade gastric mucosa-associated lymphoid tissue lymphoma after eradication of Helicobacter pylori.

BACKGROUND AND AIMS: It was recently reported that low-grade gastric lymphoma of mucosa-associated lymphoid tissue (MALT) was regressed by the eradication of Helicobacter pylori. The aim of this study was to confirm the effect of H. pylori eradication on low-grade gastric MALT lymphoma and to investigate the whitish mucosa that appeared with regression of the lesions. METHODS: Forty-seven H. pylori-positive patients with low-grade gastric MALT lymphoma were treated by using triple therapy. Biopsy specimens were histologically graded and B cell clonality was examined by using reverse transcription-polymerase chain reaction before and after eradication treatment. The relationship between the appearance of whitish mucosa and the degree of gastric gland loss was evaluated. RESULTS: Histologic regression was observed 2 months after eradication therapy in 42 of 47 patients. However, B cell monoclonality changed to polyclonality in only 23 patients during the follow-up period. The appearance of whitish mucosa in patients who showed histologic regression became more frequent as the degree of gastric gland loss increased (P< 0.001). CONCLUSIONS: Most low-grade gastric MALT lymphoma histologically regressed after H. pylori eradication. The appearance of whitish mucosa after histologic regression reflected the degree of gastric gland loss. Whitish mucosa is an endoscopic characteristic and may be an endoscopic marker for regression of low-grade gastric MALT lymphoma.

Differential localization of organic cation transporters rOCT1 and rOCT2 in the basolateral membrane of rat kidney proximal tubules.

Organic cation transporters play an important role in the secretion of cationic drugs as well as endogenous cationic metabolites in the renal tubules. Immunoblotting showed the presence of organic cation transporter proteins, rOCT1 and rOCT2, in the rat kidney. By immunofluorescence microscopy, rOCT1 was shown to be concentrated in the proximal tubules in the renal cortex. rOCT2, on the other hand, was rich in the proximal tubules in the outer stripe of the outer medulla. Confocal microscopy revealed that both rOCT1 and rOCT2 were localized to the basolateral membranes of these tubule cells. These findings directly show that rOCT1 and rOCT2 are basolateral membrane proteins and are differentially distributed along the proximal tubules.

Hormonal regulation of organic cation transporter OCT2 expression in rat kidney.

Rat (r) OCT2 was identified as the second member of the organic cation transporter (OCT) family, and is predominantly expressed in the kidney. We reported previously that rOCT2 was responsible for the gender differences in renal basolateral membrane organic cation transport activity. As renal rOCT2 expression in males is much higher than that in females, we hypothesized that rOCT2 expression may be under the control of sex hormones. Treatment of male and female rats with testosterone significantly increased the expression levels of rOCT2 mRNA and protein in the kidney, whereas estradiol treatment moderately decreased the expression levels of rOCT2. There was no regulation of renal rOCT1 mRNA expression by testosterone or estradiol. Treatment of male and female rats with testosterone significantly stimulated the tetraethylammonium (TEA) accumulation by renal slices, whereas estradiol treatment caused a decrease in the TEA accumulation by slices from male but not female rats. The present findings suggested that testosterone up-regulates renal rOCT2 expression and estradiol moderately down-regulates rOCT2.

Mucosal change of the stomach with low-grade mucosa-associated lymphoid tissue lymphoma after eradication of Helicobacter pylori: follow-up study of 48 cases.

Low-grade mucosa-associated lymphoid tissue (MALT) lymphoma of the stomach has been demonstrated to be closely linked to Helicobacter pylori (H. pylori) and to be frequently remissioned after the cure of H. pylori infection. Several previous studies have focused on proliferating lymphocytes but little is known about gastric epithelial change and the duration of the remission after the cure of H. pylori infection. We performed a long-term follow-up investigation on the effects of anti-H. pylori treatment on MALT lymphoma and chronic gastritis at the histologic and molecular levels. Forty-eight patients with low-grade gastric MALT lymphoma and 28 chronic gastritis patients in whom H. pylori infection was eradicated were studied. After eradication, 43 MALT lymphoma patients showed complete histologic remission and continuous remission was observed during follow-up for up to 43 months (mean, 17.8 months). As for epithelial changes after eradication, "emptiness of lamina propria" was more pronounced in the mucosa with MALT lymphoma than that with chronic gastritis, and its severity in MALT lymphoma cases significantly decreased during the observation period whereas the glandular area increased. Cystic change of the fundic gland also occurred more frequently in MALT lymphoma cases than chronic gastritis cases. B-cell clonality before eradication analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR) was detected in almost all MALT lymphoma cases (43 cases), but rare in chronic gastritis cases (6 cases). After eradication, in spite of histologic regression, 21 MALT lymphoma patients had a persistent monoclonal population during the follow-up period. B-cell monoclonality preceding the malignant transformation was noted in 4 cases. These observations indicate that 1) complete histologic remission of low-grade gastric MALT lymphomas seems stable even if a monoclonal B cell population is detectable in some cases, 2) there may be a stage of disease where monoclonal B cells are present but there is no histologic evidence of MALT lymphoma, and 3) regenerative change of the damaged glands may occur in histologic regressed MALT lymphoma cases.

Gender differences in expression of organic cation transporter OCT2 in rat kidney.

The organic cation transporter (OCT) mediates translocation of various cationic molecules including drugs, toxins and endogenous substances. We examined gender differences in the expression of rat (r) OCT2 in the kidney. Slices and basolateral membrane vesicles of male rat kidney showed a higher transport activity for tetraethylammonium than those of female rat kidney. The expression levels of rOCT2 mRNA and protein in the kidney of males were much higher than those in females. There was no gender difference in mRNA expression of rOCT1 and rOCT3. These findings suggest that rOCT2 is responsible for the gender differences in renal basolateral membrane organic cation transport activity.

Optimization of antitumor effect of liposomally encapsulated doxorubicin based on simulations by pharmacokinetic/pharmacodynamic modeling.

It has been reported that long circulating liposomes enhanced the antitumor effect of doxorubicin (DOX) by increasing delivery of DOX to tumor tissues. However, there is no quantitative information on the relationship between the antitumor effect and liposomal characteristics governing the release rate of entrapped drugs, although the importance of drug release-rate control from liposomes has been pointed out. Here, we developed a physiological model for free and liposomal DOX to calculate the time course of free DOX in the extracellular space and linked this with a cell kill kinetic model to quantify the antitumor effect of DOX. Simulations were performed to clarify the relationship between antitumor effect and pharmacokinetic or physicochemical parameters of liposomes, as well as pharmacological or physiological parameters of tumor tissues. The importance of long circulation time of liposomes was confirmed. The optimum rate of drug release from long circulating liposomes was found at the release rate constant of around 0.06 h(-1). This optimum value was not dependent on the tumor proliferation time, sensitivity of tumor cells to DOX, or the tumor blood flow-rate. This simulation indicated that the optimization of the delivery to tumor tissue by long circulating liposomes could be possible by changing the release rate of DOX for the maximum antitumor effect.

Molecular mechanisms of organic cation transport in OCT2-expressing Xenopus oocytes.

The molecular mechanisms of organic cation transport by rat OCT2 was examined in the Xenopus oocyte expression system. When extracellular Na+ ions were replaced with K+ ions, uptake of tetraethylammonium (TEA) by OCT2-expressing oocytes was decreased, suggesting that TEA uptake by OCT2 is dependent on membrane potential. Kinetic analysis revealed that the decreased TEA uptake by ion substitution was caused at least in part by decreased substrate affinity. Acidification of extracellular buffer resulted in decreased uptake of TEA, whereas TEA efflux from OCT1- and OCT2-expressing oocytes was not stimulated by inward proton gradient, in consistent with basolateral organic cation transport in the kidney. Inhibition of TEA uptake by various organic cations revealed that apparent substrate spectrum of OCT2 was similar with that of OCT1. However, the affinity of procainamide to OCT1 was higher than that to OCT2. Uptake of 1-methyl-4-phenylpyridinium was stimulated by OCT2 as well as OCT1, but uptake of levofloxacin, a zwitterion, was not stimulated by both OCTs. These results suggest that OCT2 is a multispecific organic cation transporter with the characteristics comparable to those of the basolateral organic cation transporter in the kidney.

Functional characteristics and membrane localization of rat multispecific organic cation transporters, OCT1 and OCT2, mediating tubular secretion of cationic drugs.

We have isolated a kidney-specific organic cation transporter, rat OCT2, which is distinct from rat OCT1 (Okuda M, Saito H, Urakami Y, Takano M and Inui K (1996) Biochem Biophys Res Commun 224:500-507). In our study, the functional characteristics and membrane localization of OCT1 and OCT2 were investigated by uptake studies using MDCK cells transfected with rat OCT1 or OCT2 cDNA (MDCK-OCT1 or MDCK-OCT2) and immunological studies. Tetraethylammonium (TEA) uptake by both MDCK-OCT1 and MDCK-OCT2 cells was markedly elevated when TEA was added to the basolateral medium, but not to the apical medium. Efflux of TEA from MDCK-OCT1 and MDCK-OCT2 cells was not changed by extracellular pH from 5.4 to 8.4, whereas TEA uptake by both transfectants was decreased by acidification of extracellular medium. Apparent Km values for TEA uptake by MDCK-OCT1 and MDCK-OCT2 cells were 38 and 45 microM, respectively. Although various hydrophilic organic cations such as 1-methyl-4-phenylpyridinium, cimetidine, quinidine, nicotine, N1-methylnicotinamide and guanidine markedly inhibited TEA uptake by both MDCK-OCT1 and MDCK-OCT2 cells, there were no significant differences in the apparent inhibition constants (Ki) against these organic cations between both transfectants. Furthermore, immunological studies using a polyclonal antibody against OCT1 revealed that OCT1 was expressed in the basolateral membranes but not in the brush-border membranes of the rat kidney. These results suggested that both OCT1 and OCT2 are basolateral-type organic cation transporters with broad substrate specificities, mediating tubular secretion of cationic drugs.

Gastric metaplasia and Helicobacter pylori.

OBJECTIVES: We investigated the relationships between gastric metaplasia occurring during the healing and scarring stages of duodenal ulcers and Helicobacter pylori by examining the course of gastric metaplasia in H. pylori-eradicated and non-eradicated patients. METHODS: One hundred and six H. pylori-positive patients with active duodenal ulcers were assigned to either a non-eradication group or an eradication group. The non-eradication group received lansoprazole for 6 wk, followed by an H2-receptor antagonist. The eradication group also received amoxicillin and metronidazole for 1 wk, in addition to lansoprazole, after initial endoscopic examination. In both groups, biopsy specimens were obtained from the ulcer margin in the active stage and from the center of the scar in the scarring stage. Specimens were examined microscopically as well as by rapid urease test to assess the extent of gastric metaplasia and to detect the presence of H. pylori. RESULTS: The extent of gastric metaplasia increased as the ulcers healed. The extent of gastric metaplasia was of a lesser degree in the non-eradication group than in the eradication group at the time of healing, and this tendency became increasingly apparent in the course of follow-up, resulting in reduced defense mechanisms against acidity to promote the recurrence of ulcers. In the eradication group, among those in whom eradication was successful, gastric metaplasia presented a well-developed appearance with abundant intracellular mucus and remained in this condition for a prolonged period, resulting in adequate defense mechanisms against acidity to prevent the recurrence of ulcers. CONCLUSION: By the eradication of H. pylori, gastric metaplasia becomes well-developed and remains so for a prolonged period. Thus, the eradication of H. pylori appears to play a role in the prevention of ulcer recurrences by developing adequate defenses against acidity.

[The course of gastric type epithelium in duodenal ulcer and duodenitis; role on the eradication of Helicobacter pylori].

The course of gastric type epithelium during the healing process and beyond the scarring stage of duodenal ulcer was studied in patients with and without Helicobacter pylori (H. pylori) eradication. Materials were consist of 110 patients with active H. pylori ulcers, 27 patients with H. pylori positive ulcer scars and 6 patients with active H. pylori positive duodenitis. The results obtained were as follows. 1) In the non-eradication group, the degree of gastric type epithelium increased as the ulcers healed, but gastric type epithelium remained immature compared with the eradication group. 2) In the non-eradication group, the degree of gastric type epithelium decreased subsequently with or without recurrence of the duodenal ulcer. Under H. pylori positive condition, the degree of gastric type epithelium appeared to be reduced because of invasion by H. pylori. When this condition continued, ulcers probably recurred because of diminished defences against acid in damaged areas of gastric type epithelium. 3) In the successful eradication group, gastric type epithelium became well developed and mature state (grade 4), and remained in this condition for long period because it was not invaded by H. pylori. The appearance of mature state of gastric type epithelium appears to play a role in the prevention of ulcer recurrences by maintaining an adequate defence mechanisms against acid. 4) In the unsuccessful eradication group, the degree of gastric type epithelium remained lower mature state than that of successful eradication group. 5) In cases of H. pylori positive ulcer scar, the degree of gastric type epithelium reached also well developed and mature state when H. pylori was successfully eradicated, and maintained in this condition for a prolonged period. Ulcer recurrence was not observed. 6) In case of H. pylori positive duodenitis, the degree of gastric type epithelium reached mature state after successful eradication, and endoscopic findings of inflammation was improved.

cDNA cloning and functional expression of a novel rat kidney organic cation transporter, OCT2.

A cDNA encoding a novel organic cation transporter, designated as OCT2 was isolated from the rat kidney. The rat OCT2 cDNA (2,205 bp) had an open reading frame encoding for a 593-amino acid protein (calculated molecular mass of 66 kDa) which shows 67% identity with the rat OCT1. Northern hybridization and reverse transcription-PCR analyses revealed that the rat OCT2 mRNA transcript was expressed predominantly in the kidney, at higher level in the medulla than in the cortex, but this transcript was not detected in the brain, heart, lung, liver, small intestine or spleen. When expressed in Xenopus oocytes, rat OCT2 stimulated the uptake of tetraethylammonium, and the uptake was markedly inhibited by the presence of cimetidine, procainamide and quinidine. These findings suggest that OCT2 is responsible for the transport of cationic drugs in the kidney.

Frontal midline theta rhythm: differentiating the physiological theta rhythm from the abnormal discharge.

The theta rhythm that appears in the frontal midline was studied morphologically and clinically in EEGs performed on 788 patients and 161 normal subjects in their late teens or older. This theta rhythm was classified into 2 types. The Type 1 theta rhythm appeared in short bursts maximally in the Fz lead and spread mainly to the anterior region. It had a high frequency, low voltage and regular waveform. The Type 2 theta rhythm appeared in long runs maximally in the Fz lead and spread mainly to the posterior areas. It had a relatively low frequency, high voltage and irregular waveform. Type 1 was observed in a younger age group (mean age: 20.3 years) that was comprised of healthy subjects and one mentally retarded patient. In no case was the Type 1 theta rhythm accompanied by a paroxysmal EEG abnormality. We therefore believe that Type 1 is a physiological EEG activity (Fm theta). On the other hand, Type 2 was observed in a relatively older age group (mean age: 30.7 years) comprised of patients diagnosed as having epilepsy or intractable headaches. Five of 9 cases showed epileptic EEG abnormalities. We therefore believe that Type 2 might have clinical significance in diagnosis of epilepsy and other cerebral dysfunctions. The EEG pattern that we call the frontal mid-line theta rhythm may be either a physiological theta rhythm or an abnormal discharge. It is possible to determine whether the theta rhythm is the former or the latter, and we believe this differentiation to be clinically important.

Midline theta rhythm revisited.

The midline theta rhythm consists of runs of theta waves occurring in the midline, especially in the central and parietal vertex regions. Few reports regarding this uncommon EEG finding have been published. It has been given various names, e.g. theta discharges in the middle-line, theta spindles, etc. Out of the 4,236 patients who were administered EEG examinations during an investigation period of 9 months, the midline theta rhythm, with a frequency in the range of 4-7 Hz, voltage over 50 microV, duration over 3 seconds, and most prominent in the central and parietal vertex areas, was recorded in 35 (0.83%). The age distribution of these patients peaked in two groups, adults aged 21-40 years and elderly patients aged 61-77 years. The waveform of the theta rhythm observed in adults 40 years old and under was often sinusoidal and regular. In this group, the most common clinical disorder was epilepsy. Often, the appearance of the theta rhythm observed in elderly patients was triangular and irregular, and sometimes sharp. In this group, the common clinical symptoms were headaches and dizziness, characterized by diagnoses of organic brain diseases such as cerebrovascular disorders. This study re-examines the clinical significance of the midline theta rhythm, taking into consideration studies that have been published in the past.

[Mu rhythm: clinical assessment of the atypical type].

Of 5,218 patients who received EEG examination at our laboratory during a 9-month period in 1989, 241 showed the 7-13 Hz arch-shaped activity originating from over the Rolandic area known as mu rhythm. These subjects were divided into two groups as follows: Group 1, 171 subjects showing typical mu rhythm, i.e., recorded during wakefulness and not affected by visual stimulation but blocked voluntary movements or tactile stimuli; and, Group 2, 70 subjects showing atypical mu rhythm, i.e., accentuated or activated by drowsiness, photic stimuli, or hyperventilation. No difference between the two groups was found with regard to frequency, amplitude or origin of the mu rhythm. Age distribution for Group 1 showed a peak between the ages of 6 and 15 (67.5%), while that for Group 2 peaked between the ages of 11 and 15 (35.7%) considering high incidence in older age range. There was no significant difference between the two groups in regard to gender. Although both groups showed a high incidence of epilepsy, Group 2 showed higher incidence of intractable epilepsy (p less than 0.05), as well as of severe intracranial trauma and of organic brain disease. On EEG recorded among epileptic patients, paroxysmal discharge was more frequent in Group 2 (p less than 0.01), although no other difference between the two groups was observed. Atypical mu rhythm may indicate more severe epilepsy, and careful observation of patients with atypical mu rhythm is recommended.

The Rolandic mu rhythm: a clinical study of the atypical group.

We studied 241 patients whose electroencephalograms (EEGs) showed 7-13 Hz arch shaped wave patterns (mu rhythm) that are known to appear in the Rolandic area. The patients were then classified into two groups depending on the conditions of appearance of the mu rhythm. Group I (typical group) consisted of 171 cases. In this group, the presence of the wave patterns was not affected by the opening of the eyes, and it was blocked by spontaneous movements, or when sensorimotor stimulation was applied. The characteristic symptoms for this group were observed in patients diagnosed as having well-controlled epilepsy, psychiatric disorders, collagen diseases, etc. In Group I, the peak lay between the ages 6 through 15. Group II (atypical group) consisted of 70 cases. In contrast to Group I, the presence of the wave patterns in this group was reinforced by drowsiness, photic stimulation and hyperventilation. The characteristic symptoms for this group were observed in patients diagnosed as having intractable epilepsy or organic brain disorders. In Group II the peak lay between ages 11 through 15. However, in Group II the cases were almost equally distributed among the various age groups. Paroxysmal abnormal EEG patterns were found to be jointly present with more frequency in the Group II sample of epileptic patients than the Group I sample. Therefore, when the mu rhythm associated with conditions indicating Group II type patients is observed, care must be exercised in the observation of further progression of the illness, and in searching for the possibility of organic brain disorders.

Peroral cholangiopancreatoscopy (PCPS) and peroral direct cholangioscopy (PDCS).

Peroral cholangiopancreatoscopy (PCPS) using a mother and babyscope was attempted in 30 cases and the duct systems were successfully inspected in 25 cases. This procedure should be useful in cases with biliary and pancreatic diseases if the bending system and biopsy channel of the babyscope can be improved. Peroral direct cholangioscopy (PDCS) using four kinds of forward-viewing small-caliber fiberscopes was successfully employed in 14 of 22 cases. These instruments have a biopsy channel as well as an air-supplying and an aspiration channel, so that a stone can be removed with a basket catheter under visual control. PDCS should become valuable therapeutically in bile duct diseases if the fiberscope can be improved.