Evaluation of immunotoxic and immunodisruptive effects of inorganic arsenite on human monocytes/macrophages

A trivalent inorganic arsenic, arsenite, has been causing chronic inflammation in humans through the consumption of contaminated well water. The total peripheral blood arsenic concentrations of chronic arsenic-exposed patients, who had inflammatory-like immune responses, are less than 1 microM, thus, nM concentrations may be very important regarding the chronic inflammatory effects by arsenite. However, there are few reports about the biological effects of low concentrations of arsenite in mammalian cells, especially in normal immune effector cells. In this study, we examined whether arsenite has any biological and/or toxicological effects on the differentiation of human peripheral blood monocytes into macrophages using the colony-stimulating factor (CSF) in vitro compared with that of other metallic compounds, and found that arsenite sensitively inhibited the CSF-induced in vitro maturation of monocytes into macrophages at nM levels, and it also induced small, nonadhesive and CD14-positive abnormal macrophage generation from monocytes with granulocyte-macrophage CSF (GM-CSF) at 50-500 nM without cell death. The addition of other metallic compounds, including chromium, selenium, mercury, cadmium, nickel, copper, zinc, cobalt, manganese and other human pentavalent arsenic metabolites, such as inorganic arsenate, monomethylarsonic acid and dimethylarsinic acid, could not induce the same abnormal cell generation from monocytes with CSFs at any concentration and any additional time schedules; they showed only simple cytolethality in monocytes and macrophages at n-mM levels accompanied by cell death. This work may have implications in the arsenic-induced chronic inflammation in humans.     

Change in the post-discharge destinations from a senile dementia therapy ward in Japan: the second report

Background: The new long‐term care insurance (LTCI) system, known as Kaigo‐Hoken, was implemented in April 2000. We previously reported a change in the type of destination after discharge from a senile dementia therapy ward (named the Midori ward) following implementation of the LTCI system at Fukuoka Prefectural Onga Hospital during the period from 1 April 1999 to 31 March 2001 in Psychogeriatrics (2003; 3 : 104–108). We subsequently investigated the type of destination after discharge from the Midori ward at Fukuoka Prefectural Onga Hospital during the period from 1 April 2001 to 31 March 2002. Methods: We used data from a total of 320 discharged inpatients with dementia who fulfilled the criteria according to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM‐IV) for dementia of the Alzheimer's type, vascular dementia and other types of dementia. We compared the period from 1 April 1999 to 31 March 2000 before the LTCI implementation and the periods from 1 April 2000 to 31 March 2001 and 1 April 2001 to 31 March 2002 after the LTCI implementation. The type of destination after discharge and the place of origin of the inpatients before admission were classified into one of the following groups: (i) nursing home or geriatric care facility group; (ii) hospitalization group; (iii) home group; and (iv) death group. Results: No significant change was evident when the subjects’ post‐discharge destinations were compared or when the subjects’ pre‐admission residences and post‐discharge destinations were compared. These results were similar to our previous report which appeared in Psychogeriatrics (2003; 3 : 104–108). Conclusion: While the LTCI system has become more widely used, it is still necessary to analyze each case and provide the care that encourages people with dementia in senile dementia therapy wards to return to their homes under the LTCI system.     

Destination after discharge from a senile dementia therapy ward before and after the implementation of long-term care insurance in Japan

Background: In Japan a new long‐term care insurance (LTCI) system, the so‐called ‘Kaigo‐Hoken’, was started in April 2000. The present study analyzes the change in the type of destination after discharge from a senile dementia therapy ward before and after the implementation of LTCI at Fukuoka Prefectural Onga Hospital, Japan. Methods: The present study examines data from 199 inpatients discharged from the Fukuoka Prefectural Onga Hospital that had been diagnosed with dementia and met the DSM IV criteria for Alzheimer's type, vascular dementia or other type of dementia. For the purposes of comparison two periods were defined, ‘the first period’ was defined as the period from 1 April 1999 to 31 March 2000, before LTCI was implemented, while ‘the second period’ was defined as the period from 1 April 2000 to 31 March 2001, after LTCI had started. Subject data was analyzed on the basis of where the subject had resided pre‐admission and their destination after discharge using the following classifications: nursing home or geriatric care facility, hospitalization, home and death. Results: While the certification rate of inpatients regarding long‐term care increased slightly in the second period, no significant change was observed based on where the subject had resided pre‐admission and their destination after discharge between the first and second periods. Conclusions: While LTCI is essential for Japan, it is necessary that people with dementia in senile dementia therapy wards are encouraged to return to their homes under the care and support of LTCI.     

Blue rubber bleb nevus syndrome: Report of a patient with hemangiomas of the vaginal portion of the cervix appearing during pregnancy

Blue rubber bleb nevus syndrome (BRBNS) is a rare disorder showing venous malformations in the skin and gastrointestinal tract, and other internal organs. We encountered a patient with BRBNS in whom hemangiomas of the uterine cervix appeared during pregnancy. This was apparently the first reported occurrence. To avoid unexpected bleeding from hemangiomas, patients with BRBNS should be examined repeatedly for hemangiomas of the birth canal, and special care should be taken in deciding the mode of delivery.     

Involvement of peripheral mechanism in the verapamil-induced potentiation of morphine analgesia in mice

Morphine's analgesic actions are thought to be mediated through both the central and peripheral nervous systems. L-type calcium channel blockers have been reported to potentiate the analgesic effects of morphine, but the locus of this interaction is not known. In this experiment, we examined the site of verapamil-induced potentiation of morphine analgesia in mice using the quaternary opioid receptor antagonist naloxone-methiodide (NLX-M). Subcutaneous injections of morphine increased locomotor activity and serum corticosterone level, which are mediated by the central nervous system. These central effects were not antagonized by 0.1 mg/kg of NLX-M, whereas this dose of NLX-M partially antagonized the analgesic effect of morphine. Treatment with verapamil potentiated morphine analgesia in a dose-dependent manner. The verapamil-induced potentiation of morphine analgesia was abolished by pretreatment with NLX-M (0.1 and 1 mg/kg). These findings suggest that peripheral mechanisms partially contribute to morphine analgesia and mediate the potentiation of morphine analgesia by verapamil.     

Arachidonate-enriched triglyceride oil does not promote tumor development in a rat medium-term multi-organ carcinogenesis model

The modifying potential on tumor development of arachidonate-enriched triglyceride oil (ARA-oil) containing approximately 40% arachidonic acid was investigated in a medium-term multi-organ carcinogenesis bioassay using male and female F344 rats. The animals were sequentially given five carcinogens with different target sites in the first 4 weeks, and then administered ARA-oil for 24 weeks at dietary levels of 0% (control), 1.25%, 2.5% or 5.0%. No statistically significant differences in incidences and multiplicities of hyperplastic and neoplastic lesions were showed in the large intestine in either sex. In the liver, kidney, and lung in both sexes, and the mammary gland and uterus in females, tumor promoting potential was not evident with ARA-oil treatment. ARA-oil did not affect the quantitative data for glutathione S-transferase placental form positive foci of the liver. Increased induction of hyperplastic or neoplastic lesions in the urinary bladder and thyroid in ARA-oil-treated groups was without dose dependence. In addition, a second experiment with ARA-oil only administration for 8-week revealed no effects on cellular proliferation in the urinary bladder or thyroid in either sex. These results indicate that ARA-oil has no tumor promoting potential in any organs or tissues initiated with the five carcinogens applied in the present study.     

Role of pharmacokinetic effects in the potentiation of morphine analgesia by L-type calcium channel blockers in mice

The present study was designed to investigate the pharmacokinetic interaction of morphine with three classes of L-type calcium channel blockers (CCB) and its relationship to morphine-induced mechanical antinociception in mice. The CCB classes were benzothiazepine (diltiazem), dihydropyridine (nimodipine), and phenylalkylamine (verapamil). Each of the three classes of L-type CCB (diltiazem, 40 and 80 mg/kg; nimodipine, 40 mg/kg; verapamil, 40 mg/kg), when administered prior to morphine (4 mg/kg, s.c.), potentiated the analgesic effect of morphine and markedly increased the level of morphine in serum. Pretreatment with diltiazem (40 and 80 mg/kg) and verapamil (40 mg/kg) also increased morphine level in the brain. However, these drugs produced less increase in morphine level in the brain than they produced in serum (i.e., they decreased the brain-to-serum ratio of morphine). Pretreatment with nimodipine (40 mg/kg) did not affect the morphine level in the brain and also decreased the brain-to-serum ratio of morphine. When morphine (3.2-100 mg/kg, s.c.) was injected alone, the brain-to-serum ratio of morphine was constant, regardless of the morphine dose. These results suggest that increases in morphine concentration in peripheral blood may be, at least in part, involved in the ability of L-type CCBs to potentiate the analgesic effect of morphine.     

Utility of Smart Arc CDR for intensity-modulated radiation therapy for prostate cancer

Volumetric-modulated arc therapy (VMAT) is a widespread intensity-modulated radiation therapy (IMRT) method, however, VMAT requires adaptation of the radiation treatment planning system (RTPS) and linear accelerator (linac); these upgrades are quite expensive. The Smart Arc of Pinnacle³ (Philips), which is the software used in VMAT calculations, can select constant dose rate (CDR) mode. This approach has a low initial cost because the linac upgrade is not required. The objective of this study was to clarify the utility of CDR mode for prostate IMRT. Pinnacle³ and Clinac 21EX linac (Varian, 10 MV X-rays) were used for planning. The plans were created for 28 patients using a fixed multi-field IMRT (f-IMRT), VMAT and CDR techniques. The dose distribution results were classified into three groups: optimal, suboptimal and reject. For the f-IMRT, VMAT and CDR results, 25, 26 and 21 patients were classified as ‘optimal’, respectively. Our results show a significant reduction in the achievement rate of ‘optimal’ for a CDR when the bladder volume is <100 cm³. The total numbers of monitoring units (MUs) (average ± 1σ) were 469 ± 53, 357 ± 35 and 365 ± 33; the average optimization times were ∼50 min, 2 h and 2 h 40 min, and the irradiation times were ∼280 s, 60 s and 110 s, respectively. CDR can reduce the total MUs and irradiation time compared with f-IMRT, and CDR has a lower initial cost compared with VMAT. Thus, for institutions that do not currently perform VMAT, CDR is a useful option. Additionally, in the context of patient identification, bladder volume may be useful.     

Pharmacodynamic evaluation of biapenem in peritoneal fluid using population pharmacokinetic modelling and Monte Carlo simulation

This study evaluated the pharmacodynamics of biapenem in peritoneal fluid (PF). Biapenem (300 or 600mg) was administered via a 0.5-h infusion to 19 patients before abdominal surgery. Venous blood and PF samples were obtained after 0.5, 1, 2, 3, 4, 5 and 6h. Drug concentration data (108 plasma samples and 105 PF samples) were analysed using population pharmacokinetic modelling. A three-compartment model fits the data, with creatinine clearance (CL(Cr)) as the most significant covariate: CL (L/h)=0.036xCL(Cr)+4.88, V1 (L)=6.95, Q2 (L/h)=2.05, V2 (L)=3.47, Q3 (L/h)=13.7 and V3 (L)=5.91, where CL is the clearance, Q2 and Q3 are the intercompartmental clearances, and V1, V2 and V3 are the volumes of distribution of the central, peripheral and peritoneal compartments, respectively. A Monte Carlo simulation using the pharmacokinetic model showed the probabilities of attaining the bactericidal exposure target (30% of the time above the minimum inhibitory concentration (T>MIC)) in PF were greater than or equal to those in plasma. In the cases of CL(Cr)=90 and 60mL/min, the site-specific pharmacodynamic-derived breakpoints (the highest MIC values at which the probabilities of target attainment in PF were >/=90%) were 2mug/mL for 300mg every 12h, 4mug/mL for biapenem 300mg every 8h (q8h) and 8mug/mL for 600mg q8h. Thus, these results should support the clinical use of biapenem as a treatment for intra-abdominal infections and facilitate the design of the dosing regimen.