Amyloid precursor protein binding protein Fe65 is cleaved by caspases during DNA damage-induced apoptosis

Caspases cleave several cellular proteins to execute cell death by apoptosis. The identification of novel substrates of caspases could provide an important clue for elucidation of new apoptosis signaling pathways. In this study, we tested whether an amyloid precursor protein (APP) binding protein Fe65 is proteolytically degraded in neuronal cell death by apoptosis, using a neuron-like cell line, human neuroblastoma SH-SY5Y cells. When treated with DNA damaging agents, etoposide (ETP) and camptothecin (CPT), SH-SY5Y cells underwent apoptosis in a dose-dependent manner. Interestingly, Fe65 (97 kDa) was cleaved to a 65 kDa product during DNA damage-induced apoptosis. Furthermore, the cleavage of Fe65 was accompanied by activation of caspases-9 and -3. The restriction cleavage of Fe65 was completely suppressed by the treatment with a pan-caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp(OMe) fluoromethylketone (z-VAD-fmk). These results reveal the restriction cleavage of Fe65 by caspases during DNA damage-induced apoptosis. Since Fe65 has been shown to suppress APP processing to amyloid β (Aβ) production, our findings may provide a new insight into the molecular mechanism by which DNA damage induces Aβ production and subsequent neuronal cell death in Alzheimer's disease (AD).     

Differences in the bone mineral density in patients with Kanemi Yusho treated before and after the age of 18 years

This study examined patients with Kanemi Yusho. The patients' height, weight, and bone mineral density were measured. The density of the distal end of the radius was measured using dual energy X-ray absorptiometry and the calcaneum was measured with ultrasound. We also measured urine levels of cross-linked N-telopeptides of type I collagen, serum tartrate-resistant acid phosphatase 5b, serum bone-specific alkaline phosphatase, serum Ca, serum P and blood PCB level. The patient group that took PCBs when they were 0 to 18 years old (such patients were 42 to 60 years old at the time of the study) showed no correlation between the bone density of the radius and calcaneum in spite of treatment received when they were over 18 years of age (> 60 years of age at the time of the study). The bone mineral density in Kanemi Yusho was not different from the control group. The levels of only serum bone-specific alkaline phosphatase were correlated with the bone mineral density of the radius and calcaneum in patients treated when they were over 18 years of age (currently over 60 years old). PCBs might have had an effect on bone density and bone metabolism.     

Hyperplastic nodular hepatic lesions following end-to-side portacaval shunting in childhood

We describe a 48-year-old man with nodular intrahepatic lesions accompanied by communication between the inferior vena cava and portal systems as well as absence of intrahepatic portal veins. After infection with malaria in childhood, end-to-side portacaval shunting had been performed to treat upper gastrointestinal bleeding at the age of 15 years. A biopsy specimen obtained under ultrasonographic guidance showed hyperplastic nodules suggestive of focal nodular hyperplasia. The estradiol concentration in the blood was elevated (55 pg/ml). This case suggests that portacaval shunting may be associated with hyperplastic liver nodules through hyperestrogenemia and abnormal hepatic hemodynamics.     

Utility of the Bender Gestalt Test for differentiation of dementia with Lewy bodies from Alzheimer's disease in patients showing mild to moderate dementia

AIMS: We examined the utility of the Bender Gestalt Test (BGT) for the differentiation of dementia with Lewy bodies (DLB) from Alzheimer's disease (AD), comparing BGT scores between DLB and AD patients showing mild to moderate dementia. METHODS: Eighteen DLB patients, 36 AD patients controlled by age, years of education, Clinical Dementia Rating and Mini Mental State Examination scores, and 21 nondemented elderly participants controlled by age and years of education were subjected to the BGT. Their BGT performances were scored according to the Pascal-Suttell method. RESULTS: The DLB group showed significantly higher (that is worse) BGT scores than the other groups. When a cutoff point of 98 was used to differentiate DLB from AD, the patients exceeding 98 were 94% in the DLB group, 17% in the AD group and 0% in the control group. The sensitivity and specificity of this cutoff point were 0.94 and 0.89, respectively. CONCLUSION: The BGT is a useful neuropsychological test to differentiate DLB from AD.     

Usefulness of low- and medium-energy collimators in 123I-MIBG myocardial scintigraphy

The heart-to-mediastinum (H/M) ratio on myocardial scintigraphy with (123)I-metaiodobenzylguanidine (MIBG) is used as a semi-quantitative index. However, the scatter from a photopeak of 529 keV on (123)I is thought to affect the H/M ratio, and collimator selection is important as well. We attempted to determine the usefulness of low- and medium-energy general purpose (LME) collimators by comparing them with low-energy high-resolution (LEHR) and medium-energy low-penetration (MELP) collimators in phantom and clinical studies. In the phantom study, we used a thoracic phantom and plastic bottles filled with (123)I-MIBG solution as upper limbs. Phantom images were acquired with LEHR, LME, and MELP collimators. Regions of interest were placed on the lung, mediastinum, heart, and liver. The average counts in the lung, coefficient of variation (CV%) in the heart, mediastinum, and liver, and H/M ratio were calculated. The H/M ratios obtained with the LEHR collimator and LME collimator were compared in a clinical study. We found that the average count in the lung measured with the LME collimator was reduced to about 30% of that obtained with the LEHR collimator in the phantom study. CV% measured with the LME collimator improved about 10% compared with that determined with the MELP collimator. The H/M ratio measured with the LME collimator was close to that measured with the MELP collimator. In the clinical study, the H/M ratios measured with the LEHR and LME collimators showed a positive relationship (y=2.1x-1.3, x; H/M with LEHR, y; H/M with LME) . LME collimators provided improved contrast and signal-to-noise ratio in evaluation of the H/M ratio on (123)I-MIBG myocardial scintigraphy.     

Bilateral dopaminergic lesions in the ventral tegmental area of rats influence sucrose intake,but not umami and amino acid intake

The role of the dopaminergic cells in the ventral tegmental area (VTA) in response to natural rewards is important in understanding palatability-induced feeding behavior. In this study, we first investigated whether dopaminergic lesions in the VTA would influence the taste preferences of rats for sodium chloride (NaCl), monosodium glutamate (MSG), disodium inosine-5′-monophosphate (IMP), disodium guanine-5′-monophosphate (GMP) and sucrose. Among these taste stimuli, only the preference of sucrose solutions decreased significantly in the VTA lesioned rats, preferences for the other taste stimuli were unaffected. Secondly, we tested whether VTA lesioned rats made slightly deficient in the amino acid lysine (by feeding rats a lysine deficient diet for five days) would detect the deficient amino acid in a choice test. Both the VTA lesioned rats and the control rats chose to consume the lysine solution and there was no difference between these two groups. These results suggest that the dopaminergic neurons in the VTA influence sucrose consumption, but do not alter the consumption of palatable umami compounds and salt. They also do not inhibit the animal's ability to recognize the essential amino acid lysine when the animal is deficient in it. Different central pathways must underlie sucrose preference and preferences for these amino acids and ribonucleotides.     

Clinical practice and research activities for early psychiatric intervention at Japanese leading centres

Aim: To describe clinical practice and research activities for early psychiatric intervention in Japan, a country with a huge number of psychiatric beds and a history of long‐stay, hospital‐based psychiatry. Methods: The characteristics, methods and activities of early intervention studies and implementation at four leading institutions in Japan are described. Results: The Tokyo Youth Club (Tokyo), the Department of Neuropsychiatry of Toyama University Hospital (Toyama), the S endai A t‐risk Mental State and F irst E pisode (SAFE) service (Sendai), and the Il Bosco of Toho University Omori Medical Center (Tokyo) have unique and active psychiatric programmes. Eachcentre has its own clinical research programme and treatment strategies. The Japanese Society for the Prevention of Psychiatric Disorders, founded in 1996, has made a steady contribution to psychiatric care by providing a forum for members to promote best practices for early intervention and by hosting annual meetings to discuss research and treatment. Conclusions: The Japanese psychiatry service is continuing its transition from hospital‐based psychiatry to community‐based psychiatry. Despite these difficult circumstances, the publication of data on the duration of untreated psychosis in Japan along with evidence that early detection determines outcome has encouraged new attempts to promote early psychiatric intervention.     

A patient with of metastatic breast cancer with a well-controlled quality of life using S-1 therapy as first-line chemotherapy

We experienced a case of endocrine therapy-resistant recurrent breast cancer with liver and bone metastases, treated with S-1 as first-line chemotherapy and maintaining a good quality of life. The patient was a 31-year-old premenopausal woman. She was diagnosed with cancer of the left breast(T1(18mm), N0, M(-))and underwent breast-conserving surgery, sentinel lymph node biopsy, and radiation therapy in August 2002. As there was hormone sensitivity, she was treated with LHRH analog for 3 years and tamoxifen for 5 years as adjuvant therapy. After her first childbirth, she had a recurrence of liver and bone metastases. After treatment with endocrine therapy failed, an oral administration of S-1 was initiated as first-line chemotherapy considering her QOL. She received 8 months of S-1 therapy with no severe adverse reactions and maintained a high quality of life. Treatment with S-1 is thought to be useful for first-line chemotherapy if the treatment demonstrates a therapeutic equivalence with taxane on patients' overall survival.     

Megalin/cubilin-mediated uptake of FITC-labeled IgG by OK kidney epithelial cells

In this paper, we characterize the uptake mechanism of fluorescein isothiocyanate-labeled human immunoglobulin G (FITC-hIgG) in opossum kidney (OK) epithelial cells, which have been shown to express megalin and cubilin. Confocal immunofluorescence microscopy showed the punctate expression of the neonatal Fc receptor FcRn in the cytoplasm, but not on the cell surface membrane. Temperature- and energy-dependent uptake of FITC-hIgG was observed at pH 7.4 but not at pH 6.0, indicating that the internalization of FITC-hIgG might not be due to FcRn, which has a binding affinity for IgG under acidic conditions. Under physiological pH conditions, human and bovine serum γ-globulin decreased FITC-hIgG uptake in a concentration-dependent manner. In addition, FITC-hIgG uptake was inhibited by various megalin and/or cubilin ligands including albumin, cytochrome c, transferrin and gentamicin. Endosomal acidification inhibitors (bafilomycin A(1) and chloroquine) significantly decreased the uptake of FITC-hIgG. Clathrin-dependent endocytosis inhibitors (phenylarsine oxide and chlorpromazine) decreased FITC-hIgG uptake. Potassium depletion and hypertonicity, conditions known to inhibit clathrin-dependent endocytosis, also decreased FITC-hIgG uptake. In contrast, caveolin-dependent endocytosis inhibitors (nystatin and methyl-β-cyclodextrin) did not decrease, but rather increased the uptake of FITC-hIgG. These observations suggest that the internalization of FITC-hIgG in OK cells might be, at least in part, due to megalin/cubilin-mediated, clathrin-dependent endocytosis.     

Filtered QRS duration on signal-averaged electrocardiography correlates with ventricular dyssynchrony assessed by tissue Doppler imaging in patients with reduced ventricular ejection fraction

Objectives

The relationships between filtered QRS duration and ventricular dyssynchrony were studied.

Methods

We measured filtered QRS duration on signal-averaged electrocardiography and analyzed tissue Doppler imaging in chronic heart failure patients with ejection fraction less than 50%.

Results

In 64 patients, interventricular and intraventricular dyssynchronies were observed in 25 and 38 patients, respectively. All patients with interventricular dyssynchrony were associated with intraventricular dyssynchrony. Filtered QRS showed 0.82 and 0.78 of the area under the curve (AUC) in the receiver operating characteristic curve (ROC) for the detection of interventricular and intraventricular dyssynchrony, respectively, with 89.7% and 96.2% specificity and 52.0% and 52.6% sensitivity, with cutoff values of 174 and 153 milliseconds. Specificity and sensitivity as well as AUC were lower in the ROC of QRS duration than filtered QRS duration.

Conclusion

Filtered QRS duration provided more reliable information to estimate ventricular dyssynchrony in patients with reduced ventricular ejection fraction than QRS duration did.