Type I hyperlipoproteinemia caused by lipoprotein lipase defect in lipid-interface recognition was relieved by administration of medium-chain triglyceride.

We have previously reported lipoprotein lipase with a defect of lipid-interface recognition in a patient with type I hyperlipoproteinemia. In this patient, lipoprotein lipase from post-heparin plasma (PHP) hydrolyzed monomeric substrate tributyrin, but scarcely hydrolyzed triolein emulsified with Triton X-100 and that in very-low-density lipoproteins ([VLDL] d < 1.006 g/mL), and did not bind to VLDL. The triglyceride (TG) level of this patient did not decrease to less than 1,000 mg/dL with a low-fat diet (1,400 kcal containing 10 g fat/d). When the patient took 30 g medium-chain TG (MCT) in addition to the 1,400-kcal diet, her serum TG level decreased to 250 mg/dL and her clinical signs improved. The low clearance rate of serum TG with heparin injection improved after intake of MCT. Caproic acid levels were maintained at 1.4% and 2.6% in chylomicrons and VLDL after MCT intake, respectively. The patient's lipoprotein lipase hydrolyzed triolein emulsified with 2% tricaprin at the same rate as that of control lipoprotein lipase. The patient's lipoprotein lipase-catalyzed hydrolyzing rate of triolein in chylomicrons obtained after MCT administration was also enhanced up to 70% of that of control lipoprotein lipase. These findings suggest that hypertriglyceridemia caused by lipoprotein lipase with a defect in lipid-interface recognition could be relieved with the administration of medium-chain TG, and that one of the mechanisms of this effect might be a modification of TG-rich lipoproteins by MCT.     

Elevated urinary levels of vitamin D-binding protein in the inhabitants of a cadmium polluted area, Jinzu River basin, Japan

Environmental cadmium (Cd) pollution and its effects on human health are still important issues. The most severe and representative manifestation of chronic Cd intoxication is Itai-itai disease, which is a syndrome that includes renal tubular dysfunction, osteomalacia, and generalized pain due to multiple bone fractures. The whole mechanism of how renal dysfunction relates to the development of bone lesions is unresolved. Vitamin D-binding protein (DBP) binds, transports and activates vitamin D, which plays a major role in calcium homeostasis and bone turnover. In this study, we measured urinary DBP levels and investigated their relationship to the markers of renal tubular dysfunction in the inhabitants of a Cd-polluted Jinzu River basin in Toyama Prefecture, Japan (Cd group). We also investigated age-matched subjects from an area known to have lower levels of Cd pollution (reference group). Urinary DBP was measured by a fluorometric enzyme-linked immunosorbent assay (ELISA), which was established in our laboratory. Significantly higher levels of urinary DBP were observed in the Cd group compared to the reference group. We observed significant positive correlations between urinary levels of DBP and renal tubular dysfunction markers in both groups. In the Cd group, urinary levels of DBP had a negative correlation with serum phosphate value. These results indicate that excretion of urinary DBP is increased after long-term Cd exposure and that the loss of DBP in urine may be linked to renal tubular dysfunction and possibly bone lesions in the inhabitants of Cd-polluted areas.     

Phase 1 Study of Monotherapy with KHK2866, an Anti-Heparin-Binding Epidermal Growth Factor-Like Growth Factor Monoclonal Antibody,in Patients with Advanced Cancer

Background

KHK2866 is a recombinant, humanized, non-fucosylated, monoclonal antibody directed at heparin-binding epidermal growth factor-like growth factor (HB-EGF).

Objective

To determine the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, potential immunogenicity, and preliminary clinical efficacy of KHK2866 monotherapy in patients with advanced and refractory cancer in a first-in-human, phase 1 study.

Materials and Methods

Using a standard 3?+?3 dose-escalation design, 20 patients received KHK2866 (0.3, 1, and 3 mg/kg) intravenously once weekly. Two additional patients received 0.1 mg/kg in a cohort which was subsequently added following protocol amendment.

Results

The first three patients enrolled experienced grade 2 hypersensitivity (acute infusion reactions) after the first dose of KHK2866. After prophylactic treatment with an H1-blocker and corticosteroids in subsequently recruited patients, two grade 2 hypersensitivity reactions were observed in the remaining 19 patients. Grade 2/3 neurotoxicity appeared to be dose-limiting at 3 mg/kg in the original dose-escalation cohorts (n?=?2), at 1 mg/kg in the MTD dose expansion cohort (n?=?1), and at 0.1 mg/kg (n?=?1). Neurotoxicity was manifested as complex partial seizure activity, aphasia, and confusion after first-dose administration. Pharmacokinetic exposure to KHK2866 increased proportionally to dose. Mean elimination half-life was 71.9–118 h over the dose range from 0.3 to 3 mg/kg. All KHK2866 doses decreased serum free HB-EGF levels, generally below the lower limit of quantification.

Conclusions

The study was terminated because of neuropsychiatric toxicity. The only predictive factor for neuropsychiatric toxicity was administration of KHK2866. These effects were reversible, but were not predictable. Their etiology is not presently understood. [Study registered at ClinicalTrials.gov #NCT0179291]

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Carbon tetrachloride affects inflammation-related biochemical networks in the mouse liver as identified by a customized cDNA microarray system

Objectives  

We have attempted to upgrade and validate an in-house cDNA microarray system developed by our group for the evaluation of chemical toxicity.     

Paternal childcare at 6 months and risk of maternal psychological distress at 1 year after delivery: The Japan Environment and Children’s Study (JECS)

BackgroundPaternal childcare is reported to benefit maternal mental health, but specific childcare behaviors have not been comprehensively determined. This study sought to identify paternal childcare behaviors associated with maternal mental health by adjusting for other covariates associated with maternal mental health and examining childcare behaviors.MethodsThis study investigated whether seven types of paternal childcare behaviors at 6 months after delivery were associated with maternal psychological distress at 1 year after delivery, which was assessed using the Kessler Psychological Distress Scale (K6). After exclusions from a dataset of 103,062 pregnancies obtained in the Japan Environment and Children’s Study, we evaluated data from 75,607 mothers.ResultsMore than 70% of fathers were always or sometimes involved in “playing at home,” “playing outdoors,” “changing diapers,” and “bathing,” 60%–70% in “helping with feeding” and “dressing,” and 45.9% in “putting the child to bed.” All paternal childcare behaviors showed some beneficial association with less maternal psychological distress, both moderate (K6 score 5–12) and severe (K6 score ≥ 13) distress. Playing at home was the most beneficial association identified (adjusted odds ratio [aOR] 0.66, 95% confidence interval [CI] 0.56–0.76 for moderate psychological distress; aOR 0.36, 95% CI 0.28–0.48 for severe psychological distress).ConclusionsThese seven types of paternal childcare behaviors may help lessen maternal psychological distress. Emphasis should be given to building education systems and working environments that promote paternal childcare.     

Abnormalities in the fatty acid composition of the postmortem entorhinal cortex of patients with schizophrenia,bipolar disorder,and major depressive disorder

Previous studies of postmortem orbitofrontal cortex have shown abnormalities in levels of n−3 polyunsaturated fatty acids (PUFAs), especially docosahexaenoic acid (DHA), in individuals with schizophrenia, bipolar disorder, and major depressive disorder (MDD). We have previously measured PUFA levels in the postmortem hippocampus from patients with schizophrenia or bipolar disorder and control subjects; however, we found no significant differences between the groups except for small changes in n−6 PUFAs. Furthermore, our study of the postmortem amygdala showed no significant differences in major PUFAs in individuals with schizophrenia, bipolar disorder, or MDD in comparison with controls. In the present study, we investigated whether there were any changes in PUFAs in the entorhinal cortexes of patients with schizophrenia (n=15), bipolar disorder (n=15), or MDD (n=15) compared with unaffected controls (n=15) matched for characteristics including age and sex. In contrast to previous studies of the orbitofrontal cortex and hippocampus, we found no significant differences in major PUFAs. However, we found a 34.3% decrease in docosapentaenoic acid (DPA) (22:5n−3) in patients with MDD and an 8.7% decrease in docosatetraenoic acid (22:4n−6) in those with schizophrenia, compared with controls. Changes in PUFAs in patients with these psychiatric disorders may be specific to certain brain regions.     

Response of lipoprotein lipase to calorie intake in streptozotocin-induced diabetic rats.

The mechanism regulating lipoprotein lipase (LPL) expression in adipose tissue was examined in rats in the conditions of different calorie intakes with and without streptozotocin-induced (STZ-) diabetes. The LPL activity released from adipose tissue was greater with the higher calorie intake (20 g of normal chow diet per day) than with the lower calorie intake (13 g of normal chow diet per day), and was greater in normal rats than in STZ-diabetic rats. The LPL activity was proportional to the serum insulin level in all conditions. Dot-blot analysis showed that the amount of LPL mRNA in adipose tissue was increased by the higher calorie diet and that the increase was less in the diabetic state. Expression of mRNA was also nearly parallel with the serum insulin level. LPL activity released from the heart was not affected by either the calorie intake or the diabetic state. These results suggest that the mechanisms of LPL expression in adipose tissue and the heart are different, and that LPL expression in adipose tissue was closely dependent on the insulin level.     

How do universities confront and manage environmental problems?]

Occupational medicine is concerned with the recognition and prevention of diseases related to the work environment. The special tools, namely, epidemiology, toxicology, and public health and clinical expertise, are joined by another specialty, environmental medicine. The Environmental Science Center (ESC) of the University of Tokyo was established in April 1975 for the purpose of treating chemically-hazardous wastes deriving from the university. The ESC houses various sections including research, education, operations, management, and also a waste-collection and-treatment division. In this review, the author intends to summarize the activity of the ESC, and then review the approaches we have applied in order to deal with the environmental problems we have faced.