Angiotensin II type 1a receptor mediates doxorubicin-induced cardiomyopathy.

Although the serious cardiotoxicity of doxorubicin (DOX), a useful chemotherapeutic agent, limits the use of this agent, the mechanism of DOX-induced cardiomyopathy remains unclear. Since accumulating evidence suggests that activation of the renin-angiotensin system is involved in the development of various types of cardiovascular remodeling, we examined the role of angiotensin II (Ang II) in DOX-induced cardiotoxicity using Ang II type 1a receptor (AT1) knockout (KO) mice. To examine the role of AT1 in the acute effects of DOX, we injected a single 20 mg/kg dose of DOX into AT1KO mice, wild type (WT) mice and WT mice treated with an AT1 antagonist, RNH-6270; to examine the role of AT1 in the chronic effects of DOX, we injected mice of the same groups with 1 mg/kg DOX once a week for 12 weeks. Echocardiography revealed that cardiac function was significantly impaired in WT mice, but not in AT1KO mice or WT mice administered RNH-6270, by both acute and chronic DOX treatment. Histological analysis showed that DOX induced myofibrillar loss and increased the number of apoptotic cells in WT mice, but not in AT1KO mice or WT mice administered RNH-6270. Expression of the ANP gene was downregulated by DOX treatment in WT mice, and this alteration was attenuated in AT1KO mice and in RNH-6270-treated mice. We conclude that the AT1-mediated Ang II signaling pathway plays an important role in DOX-induced cardiac impairment, suggesting that an AT1 antagonist can be used to prevent DOX-induced cardiomyopathy.     

Effect of multiple dosing of ketoconazole on pharmacokinetics of midazolam, a cytochrome P-450 3A substrate in beagle dogs.

To evaluate effects of multiple dosing of ketoconazole (KTZ) on hepatic CYP3A, the pharmacokinetics of intravenous midazolam (MDZ, 0.5 mg/kg) before and during multiple dosing of KTZ were investigated in beagle dogs. KTZ tablets were given orally to dogs (n = 4) for 30 days (200 mg b.i.d.). With coadministration of KTZ, t(1/2beta) of MDZ were significantly increased both on day 1 (2-fold) and on day 30 (3-fold). Total body clearance (CL(tot)) of MDZ declined gradually during the first 5 days after the start of KTZ treatment, and thereafter CL(tot) appeared to reach a plateau phase (one-fourth), depending on plasma KTZ concentrations. The effects of KTZ on the biotransformation of MDZ were also investigated using dog liver microsomes (n = 5). The K(i) values of KTZ for MDZ 1'-hydroxylation and 4-hydroxylation were 0.0237 and 0.111 microM, respectively, indicating that KTZ extensively inhibits hepatic CYP3A activity in dogs. CL(tot) values estimated from in vitro K(i) values corrected by unbound fraction of KTZ and unbound concentrations of the drug in plasma were consistent with in vivo CL(tot) of MDZ. The results in this study suggest that KTZ treatment is necessary until plasma concentrations of the drug reach a steady state to evaluate the effect of multiple dosing of the drug on hepatic CYP3A in vivo. In addition, it is suggested that K(i) values corrected by unbound fraction of KTZ and unbound concentrations of the drug in plasma enable precise in vitro-in vivo scaling.     

Effects of combined treatment with 40 degrees C hyperthermia and bleomycin on the accumulation of heat shock protein in murine L cells.

Our research group has reported the enhanced cytotoxicity of combined treatment with bleomycin (BLM) and low hyperthermia at 40 degrees C, using murine L cells, and suggested that post-heating could inhibit BLM-induced sublethal damage repair. For further understanding of the involved mechanisms, we subsequently investigated the kinetics of the cellular accumulations of inducible 72-kDa heat shock protein (hsp72) after 40 degrees C hyperthermia and/or BLM treatment using the same cell line. Western blot analysis showed significantly enhanced accumulation of hsp72 after a low hyperthermia at 40 degrees C for 40, 105 or 180 min, and no significant enhancement of it after exposure to 10 microg/ml BLM at 37 degrees C for either 40 or 105 min. When the cells were heated in the presence of BLM, the accumulations of hsp72 were markedly suppressed, with the maxima of hsp72 accumulation decreasing to 38% and 63% of those induced by hyperthermia alone for 40 or 105 min, respectively. On the other hand, sequential treatment with hyperthermia either before or after BLM treatment did not show significant alteration of the heat-induced accumulations of hsp72. It was demonstrated that BLM was necessary during heating to effectively suppress the heat-induced accumulation of hsp72. This study indicates that the suppression of heat-induced accumulation of hsp72 by BLM may partially contribute to enhance cytotoxicity of the simultaneous treatment of 40 degrees C hyperthermia and BLM.     

Dopamine D2 receptor SPECT imaging: Basicin vivo characteristics and clinical applications of123I-IBZM in humans

The purposes of this study are to evaluate the utility of kit formulation, the basicin vivo characteristics, and clinical usefulness of dopamine D₂ receptor imaging with¹²³I-(S)-(-)-3-iodo-2-hydroxy-6-methoxy-N-[(1-ethyl-2-pyrrodinyl)methyl]-benzamide (¹²³I-IBZM). We studied 22 normal controls, 3 early symptomatic Huntington’s disease patients, and 1 patient with visual hallucination on and off neuroleptics.¹²³I-IBZM could be conveniently prepared with a high degree of purity from a kit, but with relatively low radiochemical yield. We demonstrated¹²³I-IBZM receptor binding equilibrium by performing serial SPECT scanning in a normal volunteer. The basal ganglia/frontal cortex (BG/FC) ratios plateaued after the specific binding reached equilibrium approximately 60 minutes after injection. The BG/FC ratio declined significantly with age. The ratios for the Huntington’s disease patients were significantly lower than those for normal controls. The images of the patient off neuroleptic therapy showed dramatically increased BG activity compared with those obtained while on therapy. The BG/FC ratio provides an estimate of B_max/K_d and hence the receptor density. It appears important to perform SPECT early in the equilibrium phase and at a fixed time after injection to obtain significantly high signal to noise ratios.¹²³I-IBZM is an ideal tracer for SPECT including a rotating gamma camera type which can provide estimates of the receptor density objectively by calculating the BG/FC ratio, and is a promising agent for the investigation of dopamine D₂ receptors in clinical conditions.     

Comparison of 1-day, 2-day,and 3-day administration of antimicrobial prophylaxis in radical prostatectomy

An adequate protocol for antimicrobial prophylaxis (AMP) in radical prostatectomy has not been established. We retrospectively compared the incidence and severity of infectious complications after radical prostatectomy with three different protocols for AMP. The study cohort consisted of 67 patients with prostate cancer who underwent radical prostatectomy at Hakodate Goryoukaku Hospital between January 2003 and December 2005. As a prophylactic antimicrobial agent, one of the cephalosporins or penicillins was administered intravenously to all patients. The analyzed protocols were for: (1) a 3-day group: administration of AMP until the second postoperative day (POD 2), (2) a 2-day group: administration of AMP until POD 1, and (3) a 1-day group: administration of AMP only on the operative day. The incidence and severity of infectious complications were retrospectively investigated. Three patients in the 3-day group (9.4%), 2 patients in the 2-day group (12.5%), and 2 patients in the 1-day group (10.5%) developed some infectious complications. The incidence of infectious complications was not significantly different among the three groups. No patients developed severe infectious complications such as sepsis. We conclude that single-day AMP is sufficient in patients with radical prostatectomy.     

Passive enhancement of the somatosensory P100 and N140 in an active attention task using deviant alone condition.

OBJECTIVE: We investigated the changes in the somatosensory P100 and N140 during passive (reading) versus active tasks (counting, button pressing) and oddball (target=20%, standard=80%) versus deviant alone conditions (standards were omitted). METHODS: Nine healthy subjects performed the 3 tasks (reading, counting and button pressing) under two conditions. Standard and target electrical stimuli were presented in a random order to the index or middle fingers of the left hand at a constant 800 ms interstimulus interval in the oddball conditions. In the deviant alone conditions, only target stimuli were presented with the same timing as in the oddball conditions. RESULTS: The N140 amplitude increased for the deviant alone stimuli compared with the oddball standard and target stimuli regardless of whether the task was passive or active, indicating passive shifts of attention related to temporal infrequency. The P100 amplitude also increased for the deviant alone stimuli compared with the oddball standard and target stimuli in both passive and active tasks, but the enhancement seemed to be even smaller than that of the N140 amplitude. CONCLUSIONS: The somatosensory N140 passively increased even if subjects tried to attend actively to the stimulus source when the deviant alone condition was used. This change in N140 amplitude may be related to a strong orienting effect against a 'silent' background. SIGNIFICANCE: The present study provided evidence that the N140 is an indicator of passive attention against a silent background when the deviant alone condition or long interstimulus interval was used.     

Absolute quantification of regional cerebral glucose utilization in mice by 18F-FDG small animal PET scanning and 2-14C-DG autoradiography.

The purpose of this study was to evaluate the feasibility of absolute quantification of regional cerebral glucose utilization (rCMR(glc)) in mice by use of (18)F-FDG and a small animal PET scanner. rCMR(glc) determined with (18)F-FDG PET was compared with values determined simultaneously by the autoradiographic 2-(14)C-DG method. In addition, we compared the rCMR(glc) values under isoflurane, ketamine and xylazine anesthesia, and awake states. METHODS: Immediately after injection of (18)F-FDG and 2-(14)C-DG into mice, timed arterial samples were drawn over 45 min to determine the time courses of (18)F-FDG and 2-(14)C-DG. Animals were euthanized at 45 min and their brain was imaged with the PET scanner. The brains were then processed for 2-(14)C-DG autoradiography. Regions of interest were manually placed over cortical regions on corresponding coronal (18)F-FDG PET and 2-(14)C-DG autoradiographic images. rCMR(glc) values were calculated for both tracers by the autoradiographic 2-(14)C-DG method with modifications for the different rate and lumped constants for the 2 tracers. RESULTS: Average rCMR(glc) values in cerebral cortex with (18)F-FDG PET under normoglycemic conditions (isoflurane and awake) were generally lower (by 8.3%) but strongly correlated with those of 2-(14)C-DG (r(2) = 0.95). On the other hand, under hyperglycemic conditions (ketamine/xylazine) average cortical rCMR(glc) values with (18)F-FDG PET were higher (by 17.3%) than those with 2-(14)C-DG. Values for rCMR(glc) and uptake (percentage injected dose per gram [%ID/g]) with (18)F-FDG PET were significantly lower under both isoflurane and ketamine/xylazine anesthesia than in the awake mice. However, the reductions of rCMR(glc) were markedly greater under isoflurane (by 57%) than under ketamine and xylazine (by 19%), whereas more marked reductions of %ID/g were observed with ketamine/xylazine (by 54%) than with isoflurane (by 37%). These reverse differences between isoflurane and ketamine/xylazine may be due to competitive effect of (18)F-FDG and glucose uptake to the brain under hyperglycemia. CONCLUSION: We were able to obtain accurate absolute quantification of rCMR(glc) with mouse (18)F-FDG PET imaging as confirmed by concurrent use of the autoradiographic 2-(14)C-DG method. Underestimation of rCMR(glc) by (18)F-FDG in normoglycemic conditions may be due to partial-volume effects. Computation of rCMR(glc) from (18)F-FDG data in hyperglycemic animals may require, however, alternative rate and lumped constants for (18)F-FDG.     

Intraoperative radiotherapy for oncological and function-preserving surgery in patients with advanced lower rectal cancer

Backgrounds Pelvic autonomic nerve preservation (PANP) with lateral lymph node dissection (LLND) has been introduced in rectal cancer surgery in Japan; however, its indication has not been standardized yet. Materials and methods Forty-four patients with advanced lower rectal cancer were randomized to either the standard treatment group (control group) or the intraoperative radiotherapy (IORT) group. All patients underwent potentially curative resection of the rectum with total mesorectal excision. The control group underwent bilateral LLND and limited PANP. The IORT group underwent bilateral LLND, complete PANP, and IORT. Patients allocated to the IORT group received IORT to the bilateral preserved pelvic nerve plexuses. Patients’ clinicopathologic parameters, postoperative complications, voiding function, and prognosis were compared between the two groups. Results Among 44 patients enrolled, three patients were excluded from the analysis, resulting in 19 patients in the IORT group and 22 patients in the control group. Patients’ demographic and pathological parameters and postoperative complications were well balanced between the two groups. Oncological outcomes including overall and disease-free survival were also similar. Local recurrence was observed in one patient in each group. Among the 34 patients not complicated with intrapelvic abscess, the mean duration of urinary catheter indwelling was 8 days in the IORT group and 13 days in the control group (p = 0.055). In the long term, medication for urination was necessitated in four patients in the control group, whereas in none in the IORT group (p = 0.059). Discussions Oncological outcomes in the IORT group are equal to those in the control group, and voiding functions in the IORT group are superior to those in the control group. These results suggest that IORT may be useful to expand the indication of complete PANP with LLND for advanced lower rectal cancer.     

The benefits of standardizing the operative procedure for the assistant in laparoscopy-assisted gastrectomy for gastric cancer

Background and aim  Laparoscopy-assisted distal gastrectomy (LADG) has not yet been widely adopted for the treatment of gastric cancers because of the perceived complexity of the procedure. In addition to the proficiency of the operator, other factors could potentially be optimized to improve postoperative outcomes. The aim of this study was to evaluate a standardized operative procedure for assistants performing LADG. Materials and methods  Of 114 patients, 64 initially underwent conventional LADG (CLDG) and then 50 underwent standardized procedure (SLDG) in which the role of assistant in LADG was completely established. Parameters compared for the SLDG and CLDG groups were operation time, estimated blood loss, intra- or postoperative complications, preservation of the vagus nerve, and the number of pathologically examined lymph nodes. Results  The operation time for the SLDG procedure (mean ± SE, 229 ± 6 min) was shorter than for the CLDG procedure (261 ± 8 min; P < 0.002), and the estimated blood loss for SLDG (57 ± 7 ml) was less than for CLDG (108 ± 17 ml, P < 0.004). The celiac branch of the vagus nerve was preserved in 73% of SLDG patients compared with 52% of CLDG patients (P < 0.03). More lymph nodes were pathologically examined in SLDG patients (38.3 ± 1.5) than in CLDG patients (32.5 ± 1.8, P = 0.02). Conclusions  Standardization of the LADG procedure for assistants enabled a shorter operation time, reduced blood loss, a higher rate of vagus nerve preservation, and more accurate lymph node dissection.