Effect of GLP-1 receptor agonist on gastrointestinal tract motility and residue rates as evaluated by capsule endoscopy.

AIM: This study evaluated the effects of a glucagon-like peptide-1 receptor agonist on gastrointestinal (GI) tract motility and residue rates by examining GI transit time and lumen using capsule endoscopy. MATERIAL AND METHODS: GI motility and lumen were assessed by capsule endoscopy before and after liraglutide administration in 14 patients with type 2 diabetes mellitus (T2DM). RESULTS: Gastric transit time in the group with diabetic neuropathy (DN) was 1:12:36±1:04:30h before liraglutide administration and 0:48:40±0:32:52h after administration (nonsignificant difference, P=0.19). Gastric transit time in the non-DN group was 1:01:30±0:52:59h before administration and 2:33:29±1:37:24h after administration (significant increase, P=0.03). Duodenal and small intestine transit time in the DN group was 4:10:34±0:25:54h before and 6:38:42±3:52:42h after administration (not significant, P=0.09) and, in the non-DN group, 3:51:03±0:53:47h before and 6:45:31±2:41:36h after administration (significant increase, P=0.03). The GI residue rate in the DN group was 32.1±24% before administration and 90.0±9.1% after administration (significant increase, P<0.001), and increased in all patients; in the non-DN group, it was 32.1±35.3% before and 78.3±23.9% after administration (significant increase, P<0.001), and also increased in all patients. CONCLUSION: Liraglutide causes delayed gastric emptying and inhibits duodenal and small intestine motility. However, these GI movement-inhibiting effects may be decreased or absent in patients with DN-associated dysautonomia.

Sensitivity of adult T-cell leukaemia lymphoma cells to tumour necrosis factor-related apoptosis-inducing ligand.

Tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) induces apoptosis in many transformed cells, but not in normal cells, and hence TRAIL has recently emerged as a novel anti-cancer agent. Adult T-cell leukaemia lymphoma (ATLL) is a neoplasm of T-lymphocyte origin aetiologically associated with human T-lymphotropic virus type 1 (HTLV-I), and is resistant to standard anti-cancer therapy. We thus characterized the sensitivity of ATLL cells to TRAIL in this study. Although most primary ATLL cells and cell lines expressed TRAIL death receptors on their surface, they showed only restricted sensitivity to TRAIL. Among the 10 ATLL cell lines examined, one was sensitive, but two had insufficient death-receptor expression, two had an unknown resistant mechanism with abrogation of the death signal upstream of caspase-8, and the remaining five showed attenuation of the signal in both extrinsic and intrinsic pathways by X-linked inhibitor of apoptosis and Bcl-2/Bcl-xL respectively. Furthermore, the level of HTLV-I tax expression was significantly correlated to TRAIL resistance. Interestingly, ATLL cells themselves expressed TRAIL on the cell surface. Constitutive production of TRAIL may offer resistance, thus allowing the development of TRAIL-resistant ATLL cells. Consequently, the resistant mechanism in ATLL cells against TRAIL was assigned to multiple factors and was not explained by a definitive single agent.

Significance of HTLV-1 proviral load quantification by real-time PCR as a surrogate marker for HTLV-1-infected cell count.

We developed a real-time (RT) PCR quantitative assay to measure the level of the integrated viral genome of HTLV-1 in host peripheral blood-mononuclear cells (PB-MNC) from healthy carriers and patients with adult T-cell leukemia (ATL). All of the clinical specimens were serologically and molecularly characterized by enzyme-linked immunosorbent assay (ELISA) and Southern blot hybridization (SBH) analyses. The assay system for quantifying the proviral copy level was sensitive, accurate, and reproducible over a wide range of density from 100 to 0.1% with a coefficient of variation (%) of 4.5 to 9.6. The proviral load of the healthy carriers and patients with ATL was 301 +/- 339 copies per 10(4) MNC (3 +/- 3.4%) on average and varied depending on the ATL cell number and the SBH band-status of single or multiple bands. In ATL cases with multiple bands detected by SBH analysis, their ATL cells were shown to harbor multiple copies within one ATL cell, so that the corrected copy number interpolated by the band number in SBH was closely equivalent to the expected ATL cell number in PB, corresponding to the virus-infected cell burden. The proviral load in healthy carriers ranged from 0.1 to 15% of PB-MNC, and, in combination with the fraction (%) of ATL-like flower cells defined by PB smear morphology, enabled carriers to be subgrouped into three categories. This result indicates that the detection of proviral load by(RT) PCR is sufficient and relevant to monitor the infected cell number in the PB and to evaluate the HTLV-1 pathologic status.

Chemotherapy targeting methylthioadenosine phosphorylase (MTAP) deficiency in adult T cell leukemia (ATL).

Methylthioadenosine phosphorylase (MTAP) is an important enzyme used for the salvage of adenine and methionine. Cells lacking this enzyme are expected to be sensitive to purine synthesis inhibitors and/or methionine starvation. We reported previously that the MTAP gene is deleted in adult T cell leukemia (ATL) cells. In the present study, we expanded our series and used a real-time quantitative PCR assay for accurate diagnosis of the deletion and nine of 65 primary ATL samples (13.8%) were MTAP negative. In spite of this low incidence, ATL cells showed significantly higher sensitivity to L-alanosine, an inhibitor of de novo adenosine monophosphate (AMP) synthesis, than normal lymphocytes, suggesting that the MTAP gene is inactivated not only by deletion but also by other mechanisms. Indeed, a real-time quantitative RT-PCR assay disclosed that primary ATL cells had significantly lower MTAP mRNA expression than normal lymphocytes. Since MTAP-negative ATL cell lines also showed much higher sensitivity to L-alanosine than MTAP-positive ATL cell lines, we used these cell lines to investigate whether it is possible to develop selective therapy targeting MTAP deficiency. A substrate of MTAP, methylthioadenosine (MTA) or its substitutes rescued concanavalin A (Con A)-activated normal lymphocyte proliferation from L-alanosine toxicity. All the compounds except 5'-deoxyadenosine, however, also caused the undesirable rescue of MTAP-negative ATL cell lines. 5'-Deoxyadenosine had the desired ability to rescue hematopoietic progenitor cells without rescuing ATL cell lines. These results support the rationale for a chemotherapy regimen of L-alanosine combined with 5'-deoxyadenosine rescue in MTAP-deficient ATL.

Aberrant expression of caspase cascade regulatory genes in adult T-cell leukaemia: survivin is an important determinant for prognosis.

Derangement of either apoptosis or cell division is known to play an important role in tumorigenesis. Fas-mediated apoptosis on normal and leukaemic T cells is finely tuned by inhibitory proteins, such as FAP-1, FLIP and survivin, and defective caspase isoform which can attenuate the function of its intact caspase as a decoy molecule. However, complex involvement of such inhibitors in tumour biology relating to apoptotic pathology remains unclear in the neoplasms. We report the aberrant expression of FAP-1, FLIP and survivin mRNAs on leukaemic T cells from adult T-cell leukaemia (ATL) patients. Among these inhibitors, only survivin was aberrantly expressed in all ATL cases, but not in any normal peripheral blood mononuclear cells (PBMCs). Furthermore, survivin mRNA expression level was characteristic in each subtype of ATL and represented an important determinant for ATL prognosis. However, the apoptotic effector of casp-8, which is essential in Fas-mediated signal transduction, was dominant in defective casp-8 rather than intact casp-8 in ATL cells, suggesting a favourable biological situation for escape from apoptosis. Taken together, ATL cells probably possess many different regulatory mechanisms in order to attenuate Fas-mediated signalling and subsequently expand their populations under escape from apoptosis. Among these inhibitors, survivin is a useful bio-marker to assess tumour biology and may be a potential new target for apoptosis-based selective therapy in neoplasms as the expression is a general feature of neoplasia, but not normal tissues.

Intravascular ultrasound imaging of the pulmonary arteries in primary pulmonary hypertension.

OBJECTIVE: Intravascular ultrasound has the unique ability to provide cross-sectional images of the arterial wall. This study examined intravascular ultrasound (IVUS) images of the proximal pulmonary arteries in primary pulmonary hypertension (PPH). METHODOLOGY: Study 1: Specimens from four patients who had died of PPH (in vitro PPH group) were compared with those of three patients who had died of subarachnoid haemorrhage but had no evidence of cardiopulmonary disease (in vitro control group). Three-centimetre segments of the following levels were examined by IVUS: pulmonary trunk, eight secondary branch arteries of the upper, middle, and lower lobes of both lungs, and the thoracic descending aorta. Study 2: Four patients with PPH (in vivo PPH group) and five patients without pulmonary hypertension and no evidence of cardiopulmonary disease (in vivo control group) were examined. The IVUS images of the apical segmental artery of the right upper lobe and the descending branch of the right pulmonary artery were studied. RESULTS: Echographic examination of formalin-fixed preparations of secondary branch sections of the pulmonary artery failed to show a clear three-layer structure in the in vitro control group (24 preparations), but a distinct three-layer structure and increased vessel wall thickness were observed in the in vitro PPH group (32 preparations). Similar findings were obtained in the in vivo study. The mean echo density of the proximal pulmonary arterial wall correlated well with the mean pulmonary arterial pressure (mPA) in the in vitro PPH, and also correlated with the mPA in the in vivo study (r = 0.960, P < 0.0001). The echo intensity of secondary branch sections of the pulmonary artery was higher in the in vitro PPH group than in the in vitro control group (180.5 +/- 27.0 vs 132.5 +/- 26.7 counts, P < 0.001); similar results were obtained in the in vivo study (144.7 +/- 23.4 vs 85.0 +/- 14.3 counts, P < 0.01). CONCLUSIONS: These results suggest that the histological changes detected in the pulmonary artery walls in the PPH group were responsible for the increased echo intensity.

[Evaluation of the FREEDOM O2, DC Concentrator, a portable oxygen concentrator capable of operating under car battery power].

UNLABELLED: The FREEDOM O2 DC Concentrator, an oxygen concentrator which can be powered by a car battery, was evaluated. The oxygen concentrator was used by a 67 year-old man with sequelae of pulmonary tuberculosis who was receiving long-term oxygen therapy at home (HOT), and whose work required automobile trips over long distances. The equipment used was an adsorption-type oxygen concentrator capable of operating on a DC 12 V power supply, and which can be powered from a residential power outlet (AC 100 V) using a dedicated voltage converter. The trunk-shaped equipment measured 21/584 x 42 cm and weighed 17 kg. The noise level of the equipment was 58.2 +/- 2.5 dB (at 1 meter), and the flow rate can be set to 0.25, 0.50, 0.75, 1.0, 1.5, and 2.0 l/min. RESULTS: 1) The O2 concentration which can be generated by this equipment is 93 +/- 3% (0.25 to 1.5 l/min) or 90 +/- 2.8% (2.0 l/min). 2) Using this equipment, the patient was capable of driving himself in comfort for two hours or longer. Further, it was possible to stay in a hotel during a trip, inhaling oxygen generated by the equipment. Hereafter, this equipment should enable or facilitate long-distance driving, travel and lodging for HOT patients.

[Simultaneous ambulatory electrocardiography and pulse oximetry].

We developed a system for 24-hour ambulatory recording of blood oxygenation (SpO2) and electrocardiography (ECG). Using this system, we studied 10 healthy volunteers and 7 patients with chronic pulmonary diseases. The system incorporated a portable pulse oximeter (SM50) manufactured by Fukuda Denshi KK; the first and second channels were used to record ECG data and the third was used to record SpO2 data. An SpO2 sensor (Dispo-sensor D-25; Nellcor Inc.) was applied to the fourth of fifth finger. The SpO2 data (MicrO2; Siemens AG) were digitized and stored in the ambulatory recording device; the ECG was recorded simultaneously. The data were analyzed with a model DMW-9000H analyzer (Fukuda Denshi KK). A custom-designed program was also used, to remove noise errors. In the healty volunteers, SpO2 was at least 90% for the entire 24 hours. In all the patients, SpO2 fell below 90% at rest during the night or after a 15-minute walk. Transient atrial tachycardia was observed in 3 patients, and during the tachycardia the SpO2 was low. The number of extra ventricular beats divided by the total number of beats increased more in the patients than in the healthy volunteers (1.21 +/- 0.89 vs 0.6 +/- 0.3%, p < 0.05). SpO2 did not change significantly in the patients. In outpatients and in patients receiving home health care, the present system facilitates simultaneous diagnosis of respiratory failure an arrhythmias. In patients with chronic pulmonary diseases desaturation may cause transient atrial tachycardia.

[Long-term effects of a selective alpha 1-adrenergic inhibitor on right and left ventricular masses in patients with chronic pulmonary disease].

We examined the effect of one year of treatment with the selective alpha 1-adrenergic inhibitor doxazosin on right ventricular mass (RV mass), left ventricular mass (LV mass), and arterial blood gases. The subjects were 24 outpatients (18 men and 6 women, mean age 68.3 +/- 9.4 years) with chronic pulmonary disease complicated by hypertension who were clinically stable. One year of drug therapy was associated with significant decreases both in systolic pressure (159 +/- 15.2 vs 125.8 +/- 14.1 mmHg, p < 0.05, n = 24), and in LV mass index (101.0 +/- 13.4 vs 97.6 +/- 11.8 gm-2, p < 0.05), n = 24). We obtained the RV mass index by multiplying the thallium score RV/LV count and the LV mass index obtained by echocardiography. One year of drug therapy was associated with a significant increase in RV mass index (42.9 +/- 31.2 vs 53.6 +/- 30.5 gm-2, p < 0.05, n = 8). Vital capacity decreased (2.18 +/- 1.95 vs 1.95 +/- 0.57 l, p < 0.05, n = 24), but PaO2 improved (77.3 +/- 17.2 vs 82.2 +/- 2.4 mmHg, p < 0.05, n = 24). These data indicate that doxazosin can decrease blood pressure and can depress the left ventricle with no adverse effect on oxygenation in patients with chronic pulmonary disease complicated by hypertension. The worsening of RV hypertrophy may have been caused by a mechanism different from the one that caused LV hypertrophy, and by an increase in the work load on the right ventricles secondary to lung deterioration.

Infrainguinal arterial reconstruction in end-stage renal disease.

A total of 14 infrainguinal revascularizations in 11 patients with end-stage renal disease resulting from diabetes mellitus were reviewed. Indications for surgery comprised gangrene or non-healing ulcerations in eight patients (11 limbs), ischaemic rest pain in two (two limbs) and disabling claudication in one (one limb). No graft failures occurred during the period of observation. There were two immediate postoperative deaths, one amputation, and four persistent non-healing foot ulcers. The remaining four patients showed improvement. Six deaths occurred, including two perioperative deaths. Four patients with non-healing ulcers died within 1 year and 10 months after revascularization, but their deaths were not associated with the foot ulcers. The cumulative patient survival rate was 42% at 1 year. Infrainguinal revascularization in patients with end-stage renal disease caused by diabetes mellitus is feasible when meticulous preoperative assessment and careful perioperative management are employed to minimize operative risk.

Ventricular coupling via the pericardium: normal versus tamponade.

OBJECTIVE: The aim was to examine how regional variations in pericardial pressure affect the mechanical coupling between the ventricles. METHODS: Canine hearts from 14 dogs (14.5-18 kg) were removed and placed in cold cardioplegia solution. Balloons were inserted into the left and right ventricles and the atria. Pericardial pressure over the left ventricle (Pclv) and the right ventricle (Pcrv) was measured with thin balloon catheters. Ventricular and pericardial pressures were measured, and ventricular and pericardial coupling was calculated, under control conditions and with increases in pericardial tension and fluid. RESULTS: At baseline, regional differences in pericardial pressure occurred [Pclv > Pcrv, 4.0(SD 0.9) v 2.9(0.6) mm Hg, p < 0.05]. Ventricular coupling via the pericardium was defined as delta Pclv/delta Pcrv for right ventricular volume increases and delta Pcrv/delta Pclv for left ventricular volume increases. This ratio increased more after increasing right ventricular volume than after increasing left ventricular volume [delta Pclv/delta Pcrv > delta Pcrv/delta Pclv, 1.14(0.33) v 0.51(0.15), p < 0.05]. Increasing the pericardial tension by clamping the pericardium increased pericardial pressures, yet did not alter the regional variations in pressure [Pclv > Pcrv, 8.4(2.2) v 6.4(2.5) mm Hg, p < 0.05] or pericardial coupling [delta Pclv/delta Pcrv > delta Pclv/delta Pcrv, 1.18(0.46) v 0.54(0.16), p < 0.05]. In contrast, creating a mild tamponade increased pericardial pressures, eliminated regional differences in pressure, and altered the coupling between ventricles [delta Pclv/delta Pcrv approximately delta Pclv/delta Pcrv, 0.95(0.11) v 1.05(0.08), p = NS]. These regional differences in pericardial pressure might have a geometrical basis. In four in vivo canine experiments using cine magnetic resonance, the short axis radius of curvature for the right ventricle was greater than for the left ventricle [38.3(4.4) mm v 29.2(3.8) mm, p < 0.05]. CONCLUSIONS: The pericardium partially protects right ventricular filling: regional differences in pericardial pressure normally occurred with lower pericardial pressure over the right ventricle, and left to right ventricular coupling was less. This protection of right ventricular filling was lost with even a small pericardial effusion.

Acute alterations in systolic ventricular interdependence-mechanical dependence of right ventricle on left ventricle following acute alteration of right ventricular free wall.

The purpose of the study was to examine whether systolic ventricular interdependence can be acutely altered by changes in the mechanical properties of the ventricular wall. In eight acute canine studies, we released an aortic constriction during diastole. We measured right ventricular (RV) pressure changes (dPr) caused by sudden changes in left ventricular (LV) pressure (dPl). Measurements were obtained during control, 10 min after right coronary artery occlusion, and then 15 min after injecting glutaraldehyde into the RV free wall. By superimposing the pressure tracings of the beats immediately before and after the aortic release, the instantaneous pressure difference ratio (dPr/dPl) was calculated during systole. Maximal value of the pressure difference ratio decreased from control 0.11 +/- 0.04 to ischemia 0.08 +/- 0.03; (p < 0.05) and increased with glutaraldehyde 0.15 +/- 0.06; (p < 0.05). Thus, acute ischemia in RV free wall decreased the magnitude of systolic ventricular interdependence from LV to RV, while glutaraldehyde, which stiffens the RV free wall, increased the magnitude.

The left ventricle affects the duration of right ventricular ejection.

OBJECTIVE: The aim was to determine if rapid changes in left ventricular pressure can acutely alter right ventricular systolic pressure and thus influence the length of right ventricular ejection. METHODS: The experiments were performed in six open chest anaesthetised dogs, weight 18-25.5 kg. Left and right ventricular pressures and pulmonary blood flow were recorded continuously as left ventricular pressure was abruptly decreased by opening a shunt in systole. From these data, the pressure and flow changes and the duration of right ventricular ejection were determined. RESULTS: Opening the left ventricular shunt caused left ventricular pressure to fall from 94.1(SD 10.5) to 62.6(11.3) mm Hg (p < 0.01), right ventricular pressure to fall from 30.3(4.6) to 27.0(3.6) mm Hg (p < 0.01), and pulmonary flow to fall from 69.5(14.2) to 57.5(13.9) ml.s-1. The duration of right ventricular ejection, determined from pulmonary flow, also decreased from 192.7(22.7) to 157.2(18.7) ms (p < 0.05) and was significantly related to the length of left ventricular systole. Time between end diastole and peak negative dP/dt decreased for both left and right ventricle. Left and right ventricular time intervals were related before (r = 0.99) and after (r = 0.75) opening the shunt. CONCLUSIONS: The duration of right ventricular ejection was decreased by a sudden decrease in left ventricular afterload and was significantly related to the length of left ventricular systole. The duration of right ventricular ejection may be coupled with left ventricular contraction through ventricular interdependence.

Comparative significance in systolic ventricular interaction.

STUDY OBJECTIVE: The aim was to measure the systolic coupling between the ventricles and to determine the relative importance of ventricular interaction in the pressure development of each ventricle. DESIGN: Acute studies were done in dogs to measure the changes in right and left ventricular pressures (dPr, dPl) caused by sudden changes in left ventricular pressure (dPl') with release of an aortic constriction, and sudden changes in right ventricular pressure (dPr') with release of a pulmonary artery constriction, respectively. The instantaneous cross talk gain [dPr/dPl' (Klr) or dPl/dPr' (Krl)] was calculated during the ejection phase. The potential systolic pressure generated by the contralateral ventricle was evaluated as the cross talk gain multiplied by the contralateral systolic developed pressure. EXPERIMENTAL MATERIAL: Studies were done in eight random source dogs (12-18 kg), anaesthetised with sodium pentobarbitone. MEASUREMENTS AND MAIN RESULTS: The maximal Klr was lower than the maximal Krl, at 0.09 (SD 0.05) v 0.25 (0.06), and the mean Klr also was lower than the mean Krl, at 0.04 (0.02) v 0.10 (0.03), p less than 0.05. The potential right ventricular pressures developed by the left ventricle [maximum 10.3(5.6), mean 4.8(2.7) mm Hg] were not significantly different from the potential left ventricular pressures developed by the right ventricle [maximum 8.8(2.7), mean 3.4(0.7) mm Hg]. However, the ratio between the potential transmitted pressure and the measured developed pressure was greater in the right ventricle [maximum 39.0(21.1), mean 17.8(8.9)%] than in the left ventricle [maximum 11.1(7.1)%, p less than 0.05; mean 3.9(1.5)%, p less than 0.01]. This suggests that about 20-40% of the right ventricular systolic pressure may result from the left ventricle and about 4-10% of the left ventricular systolic pressure may result from right ventricle. CONCLUSIONS: Although the pressure coupling was greater in right to left ventricular interaction, right ventricular pressure generation may be more dependent on the left ventricle. Systolic ventricular interaction may be more important for right ventricular systolic function. Further, the parameters of right ventricular systolic function currently used may be considerably affected by the left ventricle.

Utility of venography in shunt surgery on hemodialyzed patients.

Fifty-eight examples of upper extremity venography in 40 patients undergoing or about to undergo hemodialysis and 18 normal subjects were evaluated. In the normal subjects, tools and conditions of venography were investigated. It was considered necessary to maintain 30 degrees flexion of the cubital joint and supination of the antebrachium and use a 35 x 43 cm film to facilitate upper extremity venous system interpretation. In the patient group, standard venography was compared with shunt-delineating venography (called shuntgraphy) as to advantages and drawbacks. Venography proved to be of excellent use in shunt constructive and reconstructive surgeries in that it provided information supplementary to that obtained in shuntgraphy, or even more valuable information.

Side effects and pharmacokinetics of nonionic iodinated contrast medium in hemodialyzed patients.

We conducted contrast CT scanning on 22 dialysis patients using the same method as usually applied to cases with normal renal function and studied the incidences and types of side effects and the pharmacological kinetics of non-ionic iodine contrast medium (Iopamiron 370, 100 ml). During the followup period (five days at most), we found localized urtication as a side effect in only one case (4.5%). Therefore we speculate that non-ionic contrast medium is a safe agent in dialysis patients, as long as it is cautiously used. After contrast medium injection, we conducted dialysis twice, which definitely decreased total blood iodine content. The extraction ratio at first dialysis was particularly high (73% on average). We recognized a statistically positive correlation between this extraction ratio and dialyzer size. Although two cases studied proved the notable acceleration of vicarious excretion in dialysis patients, this acceleration appeared only with high total blood iodine content. This phenomenon was considered mainly due to excretion from the hepatobiliary tract. Vicarious excretion appeared relatively soon after contrast medium injection (within a few hours), but showed a slower decreasing tendency.

[Cardiothoracic ratio and roentgenologic heart size as the indices of body fluid retention in uremics under hemodialysis].

We evaluated the cardiothoracic ratio (CTR) and the roentgenologic heart size (RHS) as the indices of body fluid retention in 31 of uremic patients under hemodialysis. The maximum changes of the roentgenologic thoracic diameter, measured monthly for one year in 31 patients, varied from 10 to 68 mm. The average differences of RHS and CTR between maximum inspiration and forced inspiration in 18 healthy people were 1 mm (RHS) and 2.5% (CTR), respectively, and the change of roentgenologic thoracic diameter was 12 mm. The error of repeated CTR measurements in a period of one year could be estimated more than 2%. In 22 patients the body weight reduction of 1 kg corresponded to a 4 mm decrease of RHS (p less than 0.005) and 1.5% of CTR (p less than 0.05), respectively. In relation to the change of body fluid balance assessed by the change of body weight, RHS showed a higher correlation than CTR. These results could be attributed that RHS was hardly influenced by the respiration, whereas CTR was surprisingly affected. It is concluded that the measurement of RHS is more useful as an index of control of body fluid balance than CTR.