Reliability and validity of the Japanese version of the Dysexecutive Questionnaire (DEX) in Alzheimer's disease: validation of a behavioral rating scale to assess dysexecutive symptoms in Japanese patients with Alzheimer's disease

BACKGROUND: Both executive cognitive dysfunction and behavioral problems contribute to dysexecutive symptoms in daily life. The aim of the present study was to develop a behavior rating scale for assessing dysexecutive symptoms in Japanese patients with AD. METHOD: The Dysexecutive Questionnaire (DEX), devised by Burgess et al. (1998), was used to evaluate 122 Japanese patients with AD. The factor structure, internal consistency, test-retest reliability, and construct validity of the Japanese version of the DEX were then examined. RESULTS: The Japanese version of the DEX demonstrated a good internal reliability and a good test-retest reliability. Factor analysis revealed three factors that were named 'apathy', 'hyperactivity' and 'planning and monitoring process of the purposive action'. The 'apathy' factor of the DEX was significantly correlated with the 'apathy' score of the Neuropsychiatric Inventory (NPI), while 'planning and monitoring process' factor of the DEX was significantly correlated with the total score of the Frontal Assessment Battery (FAB) and the 'hyperactivity' factor of the DEX was significantly correlated with the 'aggression', 'euphoria' and 'disinhibition' scores of the NPI. CONCLUSIONS: The Japanese DEX is a reliable and valid instrument for assessing executive dysfunction conveniently in real life situations of AD patients. While two factors, 'apathy' and 'hyperactivity', were associated with emotional and behavioral changes, the 'planning and monitoring process' was associated with the cognitive executive function in the patients with AD. These findings suggest that both a neuropsychiatric syndrome and cognitive function contribute to the dysexecutive symptoms experienced by AD patients in daily life.     

Frequency and clinical characteristics of early-onset dementia in consecutive patients in a memory clinic

AIMS: To investigate the frequency, rate of causes of dementia, and clinical characteristics of early-onset dementia in consecutive patients of a memory clinic. METHODS: A total of 668 consecutive demented patients were involved in this study. We examined the distribution of patients' diagnosis, differences in sex, education, dementia severity and cognitive function at the first visit, and the duration from onset to consultation. We also examined the changes in the proportion of subjects during the research period. RESULTS: There were 185 early-onset patients, 28% of all demented patients. No significant differences were observed between the early-onset and late-onset dementia groups in Clinical Dementia Rating and Mini-Mental State Examination score at the first consultation, but the duration from onset to consultation was significantly longer in the early-onset group. In the early-onset group, the rates of patients with Alzheimer's disease and dementia with Lewy bodies were relatively low and the rate of patients with frontotemporal lobar degeneration was relatively high. There were no significant differences in the proportion between either demented subjects and nondemented subjects or early-onset dementia patients and late-onset dementia patients during the research period. CONCLUSION: We conclude that early-onset dementia is not rare and its clinical characteristics and causes are different from late-onset dementia.     

Novel intronic CYP21A2 mutation in a Japanese patient with classic salt-wasting steroid 21-hydroxylase deficiency

Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency (21-OHD) is an autosomal recessive disorder caused by the defective CYP21A2 gene that leads to various degrees of impaired secretion of both cortisol and aldosterone. In the present study, we analyzed the CYP21A2 gene in a Japanese male patient with 21-OHD and functionally characterized the mutant CYP21A2 gene. The patient presented with hypoglycemia and a salt-losing crisis during the neonatal period, and was diagnosed as having the salt-wasting form of 21-OHD based on the clinical and laboratory findings. Analysis of the CYP21A2 gene revealed that the patient is homozygous for a novel C to A conversion at −9 position of intron 9 (IVS9-9C>A) and that his parents are heterozygous for the IVS9-9C>A mutation. Transient expression of the IVS9-9C>A mutant CYP21A2 gene in COS-1 cells demonstrated that the mutation creates an aberrant splice acceptor site at −7 position of intron 9 and totally inactivates the authentic splice acceptor site of intron 9, which results in complete deficiency of 21-hydroxylase activity and loss of immunoreactive 21-hydroxylase protein. Clinical presentations of the patient as the severe salt-wasting form of 21-OHD are in good agreement with these results of the expression study. In conclusion, the patient is a homozygote for the novel intronic IVS9-9C>A mutation, which affects messenger RNA splicing and totally inactivates 21-hydroxylase to give rise to clinically manifest classic salt-wasting 21-OHD.     

Changes in plasma von Willebrand factor-cleaving protease (ADAMTS13) levels in patients with unstable angina

INTRODUCTION: Increased plasma levels of von Willebrand factor (VWF) have been reported in acute myocardial infarction (AMI). Recently, we showed reduced activity of a VWF-cleaving protease (ADAMTS13) in AMI patients. However, there is no information as to whether ADAMTS13 affects the pathogenesis of unstable angina (UA). Thus, the purpose of this study was to examine changes in plasma VWF and ADAMTS13 levels in UA patients. MATERIALS AND METHODS: Plasma VWF and ADAMTS13 levels (mU/ml) were measured in 45 patients with UA, 55 with stable exertional angina (SEA) and 47 with chest pain syndrome (CPS) at the time of coronary angiography. Levels were also measured in 15 UA patients after 6 months of follow-up. RESULTS: VWF antigen levels (mU/ml) increased significantly in UA patients compared with SEA or CPS (2129.3+/-739.5, 1571.8+/-494.2 and 1569.5+/-487.0, respectively; P<0.0001 in UA vs. SEA or CPS). ADAMTS13 antigen levels (mU/ml) were significantly lower in UA patients than SEA or CPS (737.3+/-149.5, 875.3+/-229.0 and 867.7+/-195.5, respectively; P<0.01 in UA vs. SEA or CPS). Furthermore, there was a significant inverse correlation between VWF and ADAMTS13 antigen levels (r=-0.302, P=0.0002). The antigen levels at 6 months of follow-up were not different compared to the acute phase in the 15 UA patients that had repeated blood sampling. CONCLUSIONS: These findings suggest that there is prolonged thrombogenicity in UA patients represented as an imbalance between VWF and ADAMTS13 activity.     

EGFR inhibition in EGFR-mutant lung cancer cells perturbs innate immune signaling pathways in the tumor microenvironment

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) elicit potent cell cycle arrest in EGFR-mutant non–small-cell lung cancer (NSCLC) cells. However, little is known about the mechanisms through which these drugs alter the tumor phenotype that contributes to the immune escape of EGFR-mutant cells. Using EGFR-mutant NSCLC cell lines and tissue samples from patients, we investigated the changes in immune checkpoints expressed in tumor cells following EGFR inhibition. Subsequently, we also analyzed the role of soluble factors from the dying tumor cells in the activation of immune signaling pathways involved in therapy resistance. Upon EGFR-TKI treatment, we found that EGFR-mutant cells upregulated the expression of innate immune checkpoint CD24 in vitro. We then analyzed biopsy samples from six patients who developed resistance to a first-generation EGFR-TKI without the acquired T790M mutation. Immunohistochemistry revealed that levels of tumor CD24 expression were increased upon treatment compared with those from pre-treatment samples. Monocyte-derived macrophages facilitated antibody-dependent cellular phagocytosis when EGFR-TKI-treated EGFR-mutant cells were incubated with anti-CD24 antibodies in vitro, suggesting that CD24 may be a therapeutical target for EGFR-mutant lung cancer. Moreover, EGFR inhibition accelerated the release of cell-free DNA (cfDNA) from dying tumor cells, which activated the type I interferon signaling pathways in human THP-1 monocytes in a stimulator of interferon genes-dependent manner. Our study indicates that EGFR inhibition in EGFR-mutant NSCLC cells fosters a tumor microenvironment associated with immune escape. Thus, CD24 targeted therapy and cfDNA monitoring may contribute to improved treatment outcomes in patients with EGFR-mutant NSCLC.     

Transient heating of expressed breast milk up to 65°C inactivates HIV‐1 in milk: A simple,rapid, and cost‐effective method to prevent postnatal transmission

The postnatal transmission of human immunodeficiency virus (HIV) from mothers to children occurs through breastfeeding. Although heat treatment of expressed breast milk is a promising approach to make breastfeeding safer, it is still not popular, mainly because the recommended procedures are difficult to follow, or time‐consuming, or because mothers do not know which temperature is sufficient to inactivate HIV without destroying the nutritional elements of milk. To overcome these drawbacks, a simple and rapid method of heat treatment that a mother could perform with regular household materials applying her day‐to‐day art of cooking was examined. This structured experiment has demonstrated that both cell‐free and cell‐associated HIV type 1 (HIV‐1) in expressed breast milk could be inactivated once the temperature of milk reached 65°C. Furthermore, a heating method as simple as heating the milk in a pan over a stove to 65°C inhibited HIV‐1 transmission retaining milk's nutritional key elements, for example, total protein, IgG, IgA, and vitamin B₁₂. This study has highlighted a simple, handy, and cost‐effective method of heat treatment of expressed breast milk that mothers infected with HIV could apply easily and with more confidence. J. Med. Virol. 85:187–193, 2013. © 2012 Wiley Periodicals, Inc.     

Value of Laparoscopic Appendectomy in Perforated Appendicitis

Background The purpose of this clinical study was to evaluate the efficacy of laparoscopic appendectomy in patients with perforated appendicitis. Methods This study involved a total of 73 consecutive patients who had undergone appendectomy for perforated appendicitis between January 1999 and December 2004. While 39 patients underwent open appendectomy (OA) during the first 3 years, the remaining 34 patients underwent laparoscopic appendectomy (LA) during the last 3 years. Results There was no case of LA converted to OA. No significant difference was found in the operating time between the two groups. Laparoscopic appendectomy was associated with less analgesic use, earlier oral intake restart (LA, 2.6 days; OA, 5.1 days), shorter median hospital stay (LA, 11.7 days; OA, 25.8 days), and lower rate of wound infections (LA, 8.8%; OA, 43.6%). Conclusions These results suggest that LA for perforated appendicitis is a safe procedure that may prove to have significant clinical advantages over conventional surgery.