Lack of interaction between bropirimine and 5-fluorouracil on human dihydropyrimidine dehydrogenase

1. Bropirimine (2-amino-5-bromo-6-phenyl-4-pyrimidinone) is a member of a class of antineoplastic agents that are administered concomitantly or sequentially with anticancer 5-fluorouracil (5-FU) prodrugs in clinical patients. Interactions between bropirimine and 5-fluorouracil (5-FU) were investigated on dihydropyrimidine dehydrogenase (DPD) activity, the rate-limiting enzyme of 5-FU metabolism, in human liver cytosol. Apparent DPD activity was determined by measuring the recovery of [¹⁴C]5-FU by HPLC.

2. The apparent activity of 5-FU metabolism (2.1 - 100 μm) showed a linear relationship in the Eadie-Hofstee plot in the pooled cytosol, suggesting that a single enzyme is responsible for apparent 5-FU metabolism. K_m and V_max were estimated to be 23 μm and 0.32 nmol min^?1 mg^?1 protein, respectively. Apparent DPD activity for 5-FU (25 μm) in the cytosol from 12 individual donors ranged from 0.017 to 0.39 (0.16 ± 0.12) nmol min^?1 mg^?1 protein, indicating a large intersubject variance.

3. The suicidal inactivators of the DPD enzyme, (E)-5-(2-bromovinyl)uracil and 5- bromouracil (6.3 - 50 μm), illustrated concentration-dependent inhibition on DPD activity. Isocytosine (6.3 - 100 μm), used as a negative control, did not affect DPD activity. Bropirimine (6.3 - 100 μm) also did not show any inhibition of DPD activity. Therefore, bropirimine is unlikely to cause increases in 5-FU levels in clinical patients after coadministration of bropirimine with 5-FU prodrugs.     

Angiotensin-converting enzyme inhibitor therapy affects myocardial fatty acid metabolism after acute myocardial infarction

BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitor therapy has an early mortality benefit in unselected patients with acute myocardial infarction (AMI). However, the effects of ACE inhibition on myocardial fatty acid metabolism in this patient population have not been studied. We tested the hypothesis that ACE inhibitor therapy improves myocardial fatty acid metabolism and decreases mortality rate in patients after AMI. METHODS: Forty-two patients after first anterior AMI and primary angioplasty were randomly assigned to titrated oral enalapril (n = 24) or placebo therapy (n = 18). Iodine 123-labeled 15-(p-iodophenyl)-3-(R,S)-methylpentadecanoic acid (BMIPP) single photon emission computed tomography imaging was performed an average of 4.8 days after AMI and 1 month after AMI. BMIPP abnormalities were quantified as a severity index by a polar map. RESULTS: There were no significant changes in baseline characteristics, cardiac function, and angiographic findings between patients in the enalapril group and patients in the placebo group. However, BMIPP severity index from acute phase to chronic phase was significantly decreased in the enalapril-treated group (118+/-48 to 82+/-36, P<.05), but not in the placebo group (123+/-65 to 115+/-58, P not significant). CONCLUSION: ACE inhibition therapy improved myocardial fatty acid metabolism and regional left ventricular function in patients after anterior AMI. BMIPP single photon emission computed tomography findings imply that this better outcome may be attributable to an improvement of cellular function with ACE inhibitors.     

Clinicians’ perspectives on support for children with a parent who is diagnosed with breast cancer

Background

There are few data on clinicians’ perspectives regarding support for children who have a parent who has been diagnosed with breast cancer. The purpose of this study was to survey the attitudes of physicians and nurses regarding the care of children who had a parent diagnosed with breast cancer.

Methods

A survey was mailed to 898 physicians and 135 nurses who were members of the Japanese Breast Cancer Society in 2009. They were asked to answer questions about their attitudes toward and current practice regarding care for children who had a parent with breast cancer.

Results

A total of 340 surveys (284 physicians and 56 nurses) were used in this analysis. The mean age of the respondents was 47.2 years, and their mean number of years of practice was 21.7 years. While 69.1 % of them reported that they felt it important for people in their roles to provide support for children, 84.4 % felt they could not provide sufficient support. The results also suggested that female gender in practitioners and nurses as opposed to doctor status seemed to be associated with preference for intervention, current practice of intervention, and recognition of difficulty to support.

Conclusions

Physicians and nurses express a variety of opinions with regard to support for children with a parent who has breast cancer. It is important to cooperate with other specialists including physicians, nurses, and psychologists and allocate roles appropriately among them to improve outcomes for these children.     

Bortezomib therapy‐related lung disease in Japanese patients with multiple myeloma: Incidence,mortality and clinical characterization

Because of the potentially high mortality rate (6.5%) associated with bortezomib‐induced lung disease (BILD) in Japanese patients with relapsed or refractory multiple myeloma, we evaluated the incidence, mortality and clinical features of BILD in a Japanese population. This study was conducted under the Risk Minimization Action Plan (RMAP), which was collaboratively developed by the pharmaceutical industry and public health authority. The RMAP consisted of an intensive dissemination of risk information and a recommended countermeasure to health‐care professionals. All patients treated with bortezomib were consecutively registered in the study within 1 year and monitored for emerging BILD. Of the 1010 patients registered, 45 (4.5%) developed BILD, 5 (0.50%) of whom had fatal cases. The median time to BILD onset from the first bortezomib dose was 14.5 days, and most of the patients responded well to corticosteroid therapy. A retrospective review by the Lung Injury Medical Expert Panel revealed that the types with capillary leak syndrome and hypoxia without infiltrative shadows were uniquely and frequently observed in patients with BILD compared with those with conditions associated with other molecular‐targeted anticancer drugs. The incidence rate of BILD in Japan remains high compared with that reported in other countries, but the incidence and mortality rates are lower than expected before the introduction of bortezomib in Japan. This study describes the radiographic pattern and clinical characterization of BILD in the Japanese population. The RMAP seemed clinically effective in minimizing the BILD risk among our Japanese population.     

Defect of hepatocyte growth factor activator inhibitor type 1/serine protease inhibitor, Kunitz type 1 (Hai-1/Spint1) leads to ichthyosis-like condition and abnormal hair development in mice

Hepatocyte growth factor activator inhibitor type 1 (HAI-1)/serine protease inhibitor, Kunitz type 1 (SPINT1) is a membrane-bound, serine proteinase inhibitor initially identified as an inhibitor of hepatocyte growth factor activator. It also inhibits matriptase and prostasin, both of which are membrane-bound serine proteinases that have critical roles in epidermal differentiation and function. In this study, skin and hair phenotypes of mice lacking the Hai-1/Spint1 gene were characterized. Previously, we reported that the homozygous deletion of Hai-1/Spint1 in mice resulted in embryonic lethality attributable to impaired placental development. To test the role of Hai-1/Spint1 in mice, the placental function of Hai-1/Spint1-mutant mice was rescued. Injection of Hai-1/Spint1^+/+ blastocysts with Hai-1/Spint1^−/− embryonic stem cells successfully generated high-chimeric Hai-1/Spint1^−/− embryos (B6Hai-1^−/−High) with normal placentas. These embryos were delivered without apparent developmental abnormalities, confirming that embryonic lethality of Hai-1/Spint1^−/− mice was caused by placental dysfunction. However, newborn B6Hai-1^−/−High mice showed growth retardation and died by 16 days. These mice developed scaly skin because of hyperkeratinization, reminiscent of ichthyosis, and abnormal hair shafts that showed loss of regular cuticular septation. The interfollicular epidermis showed acanthosis with enhanced Akt phosphorylation. Immunoblot analysis revealed altered proteolytic processing of profilaggrin in Hai-1/Spint1-deleted skin with impaired generation of filaggrin monomers. These findings indicate that Hai-1/Spint1 has critical roles in the regulated keratinization of the epidermis and hair development.     

Monitoring the autonomic nervous activity as the objective evaluation of music therapy for severely and multiply disabled children

Severely and multiply disabled children (SMDC) are frequently affected in more than one area of development, resulting in multiple disabilities. The aim of the study was to evaluate the efficacy of music therapy in SMDC using monitoring changes in the autonomic nervous system, by the frequency domain analysis of heart rate variability. We studied six patients with SMDC (3 patients with cerebral palsy, 1 patient with posttraumatic syndrome after head injury, 1 patient with herpes encephalitis sequelae, and 1 patient with Lennox-Gastaut syndrome characterized by frequent seizures, developmental delay and psychological and behavioral problems), aged 18-26 (mean 22.5 ± 3.5). By frequency domain method using electrocardiography, we measured the high frequency (HF; with a frequency ranging from 0.15 to 0.4 Hz), which represents parasympathetic activity, the low frequency/high frequency ratio, which represents sympathetic activity between the sympathetic and parasympathetic activities, and heart rate. A music therapist performed therapy to all patients through the piano playing for 50 min. We monitored each study participant for 150 min before therapy, 50 min during therapy, and 10 min after therapy. Interestingly, four of 6 patients showed significantly lower HF components during music therapy than before therapy, suggesting that these four patients might react to music therapy through the suppression of parasympathetic nervous activities. Thus, music therapy can suppress parasympathetic nervous activities in some patients with SMDC. The monitoring changes in the autonomic nervous activities could be a powerful tool for the objective evaluation of music therapy in patients with SMDC.     

The relation between carotid plaque echogenicity and oxidative stress marker 8-iso-prostaglandin F2α

Echolucent plaques are associated with high risk of ischemic cerebrovascular events. Oxidative stress has been implicated in the process of atherosclerotic plaque development from initiation to progression. We assessed the relation between carotid plaque echogenicity and urinary 8-iso-prostaglandin F2α, as an index of oxidative stress. This cross-sectional study was conducted prospectively on 290 consecutive outpatients. Each patient was evaluated for carotid plaque echogenicity using the gray-scale median at the maximal thickness plaque and urinary 8-iso-prostaglandin F2α using enzyme linked immunosorbent assay. By Pearson correlation analysis, we found significant negative linear relation between gray-scale median values and the urinary 8-iso-prostaglandin F2α levels (r = -0.133, p = 0.023). This correlation remained significant after adjustment for atherosclerotic risk factors, thickness of the maximal plaque and medication use (β = -0.137, p = 0.031). We herein show that higher levels of urinary 8-iso-prostaglandin F2α is associated with lower plaque echogenicity.     

The effects of gonadal steroid manipulation on the expression of Kiss1 mRNA in rat arcuate nucleus during postnatal development

Kisspeptins, encoded by Kiss1 gene, play pivotal roles in the regulation of reproduction. Recently, several studies reported a sex difference in Kiss1 expression in the arcuate nucleus (ARC) during the neonatal period. In this study, we investigated the effect of gonadal steroid manipulation on the sex difference in Kiss1 expression in ARC of rats. At neonatal and prepubertal stages, females had a greater number of Kiss1 neurons than the males. Gonadectomy at those stages resulted in significant increases in the Kiss1 neuron number and the sex differences disappeared. We also confirmed the expression of estrogen receptor ?? in kisspeptin neurons in neonates. Altogether, our results indicate that ARC Kiss1 expression is negatively regulated by gonadal steroids from early postnatal stages, and that the sex difference in ARC Kiss1 expression is attributed to the difference in circulating gonadal steroid levels. We also found that neonatal estrogenization inhibits Kiss1 expression and impairs negative feedback system.     

Balance of older trekkers: data on alpine accidents and performance as assessed using a video game machine

The number of alpine accidents involving older trekkers has increased markedly in developed countries in recent years. More than 76.8% of the trekkers involved in alpine accidents in Japan were older than 40 years, with some experiencing a stroke or myocardial infarction while trekking at altitude. In the present study, we surveyed social trends in trekkers by interview at a popular mountain site, Mt Tanigawa (1963 m in altitude). The total number of trekkers interviewed was 511, and more than 60% of these were older than 40 years. Of trekkers older than 60 years, 42% complained of conditions such as hypertension or diabetes. In 2 volunteer groups (10 younger subjects and 10 older subjects), physical condition was assessed before and after trekking. Significant body weight loss induced by dehydration was observed more often in older subjects than in younger subjects (P < .05). Balance, as measured using the Nintendo WiiFit (Nintendo, Kyoto, Japan), worsened in the older group (P < .05). Local police records for 2009 showed that the total number of alpine accidents was 65. Injuries provoked by stumbling, slipping, and falling accounted for 51% of these, and 82% of casualties were older than 40 years, with 35% being older than 60 years. In conclusion, many older people involved in nonchallenging middle-altitude trekking have problems with regard to overall health and balance. Alpine accidents caused by myocardial infarction, stroke, or hypoglycemia tend to be more common in this population. Alpine rescue teams should be well prepared for this, and older trekkers should be made aware of their increased risk of injury in alpine settings.