Cardioprotective Action of Perindopril versus Candesartan in Renovascular Hypertensive Rats

We investigated the effects of an angiotensin-converting enzyme inhibitor and an angiotensin II type 1 receptor blocker on cardiac hypertrophy in rats with renovascular hypertension. Renovascular hypertensive (Goldblatt) rats were surgically prepared from Wistar rats. Four weeks later, the rats showed a significant increase in blood pressure. At high doses, both the perindopril (1 mg/kg/day) and the candesartan (2 mg/kg/day) decreased the systolic pressure in these rats to the level of control Wistar rats. At low doses (perindopril 0.1 mg/kg/day and candesartan 0.1 mg/kg/day), these drugs lowered blood pressure to 85% of that in hypertensive rats. Echocardiographic and morphological studies revealed severe cardiac hypertrophy and fibrosis in untreated Goldblatt rats. High-dose treatment with both drugs suppressed the progression of hypertrophy and fibrosis. Also, low-dose perindopril prevented cardiac hypertrophy and fibrosis. In contrast, at the same levels of blood-pressure reduction, low-dose candesartan did not prevent cardiac fibrosis nor the upregulation of cardiac collagen types I and III mRNA observed in untreated Goldblatt rats. Atrial natriuretic peptide mRNA was up-regulated in untreated Goldblatt rats. These changes were significantly decreased by both doses of perindopril or the high dose of candesartan. Serum levels of angiotensin II and aldosterone were significantly higher in untreated Goldblatt rats. Both doses of perindopril inhibited activation of the renin-angiotensin system, whereas candesartan had weaker effects. In particular, serum aldosterone was 347 ± 20 pg/ml in low-dose perindopril versus 1796 ± 324 pg/ml in low-dose candesartan. These results suggest that there were no differences between the cardioprotective actions of perindopril and candesartan at high dosages. On the other hand, low-dose treatment with perindopril was more effective in preventing cardiac fibrosis than was low-dose treatment with candesartan, despite similar changes in blood pressure. It is possible that changes in aldosterone secretion are related to this difference.     

Familial Creutzfeldt-Jakob Disease with a codon 200 mutation presenting as thalamic syndrome: diagnosis by single photon emission computed tomography using (99m)Tc-ethyl cysteinate dimer

The clinical features of familial Creutzfeldt-Jakob disease with a codon 200 point mutation [fCJD (E200K)] are similar to those of sporadic CJD (sCJD). MRI diffusion-weighted imaging (MRI-DWI) has been reported to be useful for the early diagnosis of CJD. We describe a Japanese fCJD (E200K) case in which thalamic symptoms were the initial manifestations. On admission, electroencephalography (ECG) showed no periodic synchronous discharge (PSD), and MRI showed no abnormalities. However, single photon emission computed tomography (SPECT) using (99m)Tc-ethyl cysteinate dimer ((99m)Tc-ECD) revealed hypoperfusion in the right thalamus. We conclude that the thalamic form of CJD tends to show no high-intensity area (HIA) by MRI-DWI, and that SPECT may be more useful for visualizing the affected area responsible for the thalamic symptoms at an early stage.     

Autonomic responses to orthostatic stress in head-up tilt testing: Relationship to test-induced prolonged asystole

Background: Prolonged asystole is sometimes an extreme manifestation of neurally mediated syncope. Hypothesis: To investigate the mechanism of head-up tilt testing-induced prolonged (life-threatening) cardiac asystole, we measured temporal changes in frequency domain heart rate variability indices in 25 patients with syncope of undetermined etiology. Methods: Head-up tilt testing (80°) was performed in 25 patients for up to 40 min or until asystole or syncope occurred. Three patients (Group 1; 37 ±13 years, 1 man, 2 women) had an episode of prolonged cardiac asystole (≥ 10 s) during testing, necessitating cardiopulmonary resuscitation. Syncope, but no asystole, was induced in 10 patients (Group 2; 48 ± 31 years, 6 men, 4 women), and 12 patients (Group 3; 55 ± 20 years, 5 men, 7 women) failed to show asystole or syncope during testing. Power spectra of low (0.04–0.15 Hz) and high (0.15–0.40 Hz) frequency, and total (0.01–1.00 Hz) frequency spectra were measured in consecutive 2 min segments throughout the test. Results: Maximally changed values in heart rate, systolic blood pressure, and heart rate variability indices during testing were compared among the three groups (maximally changed values did not include the values during tilt-induced symptoms). High frequency spectra in Groups 2 and 3, but not in Group 1, decreased during the test. High frequency spectra, low frequency spectra, and total spectra in Group 1 were significantly higher than those in Groups 2 and 3 during testing. In Group 1 patients, findings at test-induced asystole were consistent with exaggerated sympathetic and concurrent persistent parasympathetic activity. Conclusion: Unusual autonomic responses to orthostatic stress can cause prolonged asystole, and this autonomic nerve dysregulation may relate to asystolic episodes associated with cardiovascular collapse.     

Immunological and molecular analysis of B lymphocytes in low-grade MALT lymphoma of the stomach. Are there any useful markers for predicting outcome after Helicobacter pylori eradication?

Background: Background: Although Helicobacter pylori eradication is effective in treating low-grade gastric mucosa-associated lymphoid tissue (MALT) lymphoma, the condition in some patients deteriorates even after the eradication. Therefore, it is important to predict the disease outcome before starting H. pylori eradication. We investigated the usefulness of flow cytometry, quantifying CD19- and CD20-positive B lymphocytes in MALT lymphoma tissue, for predicting the disease outcome after H. pylori eradication. Methods: Tissue specimens from 14 patients with H. pylori-positive low-grade gastric MALT lymphoma were examined by histology, Southern blotting, and flow cytometry before therapy. Serum levels of soluble interleukin (IL)-2 receptor were also measured. The relationship between the data and the prognosis after H. pylori eradication was analyzed. Results: Remission occurred in 10 of the 14 patients. The condition in the 4 remaining patients deteriorated even after H. pylori eradication. The percentages of CD19- and CD20-positive cells in MALT lymphoma tissue from the patients in remission were both significantly lower than those in the tissue from patients not in remission. Indeed, 4 of the 5 patients in whom both CD19- and CD20-positive cells accounted for more than 50% of the total number of lymphocytes had gastrectomy, whereas all patients in whom both CD19- and CD20-positive cells accounted for less than 50% of the total number of lymphocytes achieved remission. Although immunoglobulin gene rearrangement was present in all patients operated on, there were also 6 patients whose MALT lymphoma was ameliorated in spite of the presence of gene rearrangement. The serum level of soluble IL-2 receptor was in the normal range in all patients tested. Conclusions: Analysis of mature B-cell markers in MALT lymphoma tissue is more useful than the examination of immunoglobulin gene rearrangement or serum levels of soluble IL-2 receptor in predicting the outcome of low-grade gastric MALT lymphoma after H. pylori eradication. Received: January 5, 2001 / Accepted: November 2, 2001     

Functional analysis of JAK3 mutations in transient myeloproliferative disorder and acute megakaryoblastic leukaemia accompanying Down syndrome

JAK3 mutations have been reported in transient myeloproliferative disorder (TMD) as well as in acute megakaryoblastic leukaemia of Down syndrome (DS-AMKL). However, functional consequences of the JAK3 mutations in TMD patients remain undetermined. To further understand how JAK3 mutations are involved in the development and/or progression of leukaemia in Down syndrome, additional TMD patients and the DS-AMKL cell line MGS were screened for JAK3 mutations, and we examined whether each JAK3 mutation is an activating mutation. JAK3 mutations were not detected in 10 TMD samples that had not previously been studied. Together with our previous report we detected JAK3 mutations in one in 11 TMD patients. Furthermore, this study showed for the first time that a TMD patient-derived JAK3 mutation (JAK3(I87T)), as well as two novel JAK3 mutations (JAK3(Q501H) and JAK3(R657Q)) identified in an MGS cell line, were activating mutations. Treatment of MGS cells and Ba/F3 cells expressing the JAK3 mutants with JAK3 inhibitors significantly decreased their growth and viability. These results suggest that the JAK3 activating mutation is an early event during leukaemogenesis in Down syndrome, and they provide proof-of-principle evidence that JAK3 inhibitors would have therapeutic effects on TMD and DS-AMKL patients carrying activating JAK3 mutations.     

Monte Carlo simulation of the acquisition conditions for 177Lu molecular imaging of hepatic tumors

Annals of Nuclear Medicine - To examine the impact of acquisition time on Lutetium-177 (177Lu) single-photon emission computed tomography (SPECT) images using Monte Carlo simulation. A gamma camera...