Recent studies have revealed an inverse association between height and cardiovascular disease. However, the background mechanism of this association has not yet been clarified. Height has also been reported to be positively associated with cancer. Therefore, well-known cardiovascular risk factors, such as increased oxidative stress and chronic inflammation, are not the best explanations for this inverse association because these risk factors are also related to cancer. However, impaired blood flow is the main pathological problem in cardiovascular disease, while glowing feeding vessels (angiogenesis) are the main characteristic of cancer pathologies. Therefore, endothelial maintenance activity, especially for the productivity of hematopoietic stem cells such as CD34-positive cells, could be associated with the height of an individual because this cell contributes not only to the progression of atherosclerosis but also to the development of angiogenesis. In addition, recent studies have also revealed a close connection between bone marrow activity and endothelial maintenance; bone marrow-derived hematopoietic stem cells contribute towards endothelial maintenance. Since the absolute volume of bone marrow is positively associated with height, height could influence endothelial maintenance activity. Based on these hypotheses, we performed several studies. The aim of this review is not only to discuss the association between height and bone marrow activity, but also to describe the potential mechanism underlying endothelial maintenance. In addition, this review also aims to explain some of the reasons that implicate hypertension as a major risk factor for stroke among the Japanese population. The review also aims to clarify the anthropological reasons behind the high risk of atherosclerosis progression in Japanese individuals with acquired genetic characteristics.
Aged ; Atherosclerosis/physiopathology* ; Body Height/physiology* ; Bone Marrow/physiology* ; Disease Progression ; Endothelium/physiology* ; Humans ; Hypertension/physiopathology* ; Japan/epidemiology* ; Male ; Middle Aged ; Risk Factors ; Stroke/physiopathology*

BACKGROUND AND PURPOSE: Migraine patients are particularly prone to the complication of medication-overuse headache (MOH). Although it has been shown that A allele carriers for the tumor necrosis factor (TNF)-beta gene G252A polymorphism are at high risk of the development of migraine without aura, the relationship between the TNF-beta gene G252A polymorphism and MOH is unknown. We investigated whether the TNF-beta gene G252A polymorphism is involved in the aggravation of migraine by overuse of medications. METHODS: Forty-seven migraine patients (6 males and 41 females; age 36.4+/-10.3 years, mean+/-SD) and 22 MOH patients (1 male and 21 females; age 39.6+/-9.9 years) who had migraine were included in this study. The genotype for the TNF-beta gene G252A polymorphism was determined by polymerase-chain-reaction restriction-fragment-length polymorphism analysis. RESULTS: The distribution of TNF-beta gene G252A genotype frequency differed significantly between migraine and MOH patients (p=0.013). The G/G genotype was carried by 23% of the migraine patients but it was absent in MOH patients. CONCLUSIONS: G/G genotype carriers appear to be less susceptible to the aggravation of migraine by overuse of medications. The G252A TNF-beta gene polymorphism may be one of the factors contributing to the complications of MOH in patients with migraine.
Alleles ; Genotype ; Headache ; Humans ; Lymphotoxin-alpha ; Male ; Migraine Disorders ; Migraine without Aura ; Tumor Necrosis Factor-alpha

Objective:Delayed gastric emptying (DGE) after pylorus-preserving pancreatoduodenectomy (PpPD) is a persistent and frustrating complication. To preserve pylorus ring with denervation and devascularization may be a risk factor of DGE after pancreaticoduodenectomy. We conducted this study to confirm the hypothesis that pylorus-resecting pancreatoduodenectomy (PrPD) reduces the incidence of DGE compared to PpPD. Moreover, long-term outcomes of PrPD and the adverse effect of postsurgical DGE on long-term outcomes have not been reported. Therefore, in addition, this study focused on long-term outcomes during 24 months after surgery between PrPD versus PpPD. Methods: Between October 2005 and March 2009, at Wakayama Medical University Hospital (WMUH), 130 patients with pancreatic or periampullary lesions were randomized to preservation of the pylorus ring (PpPD) or to resection of the pylorus ring (PrPD). In PpPD, the proximal duodenum was divided 3-4cm distal to the pylorus ring. In PrPD, the stomach was divided just adjacent the pylorus ring and the nearly total stomach more than 95% was preserved. Shortterm and long-term outcomes were evaluated between PpPD and PrPD. Primary endpoint is the incidence of DGE. DGE was defined according to a consensus definition and clinical grading about postoperative DGE proposed by the international study group of pancreatic surgery (ISGPS). This RCT was registered at Clinical Trials.Gov NCT00639314. Results: Of 130 patients who were enrolled in this study, 64 patients were randomized to PpPD and 66 to PrPD. The overall incidence of DGE in this RCT was 10.8% (14 of 130 patients); the overall incidence of DGE was significantly lower in PrPD (4.5%) than PpPD (17.2%) (P =0 .0244). DGE was classified into three categories proposed by the International Study Group of Pancreatic Surgery. The proposed clinical grading classified 11 cases of DGE in PpPD into grades A (n=6), B (n=5), and C (n=0), and one case in PrPD into each of the three grades. In long-term outcomes, weight loss > grade 2 (Common Terminology Criteria for Adverse Events, Ver. 4.0) at 24 months after surgery improved significantly in PrPD (16.2%) compared with PpPD (42.2%) (P = 0.011). Nutritional status and late postoperative complications were similar between PpPD and PrPD. The incidence of weight loss greater than Grade 2 at 24 months after surgery was 63.6% in patients with DGE group and 25.3% in patients without DGE group (P = 0.010). Tmax (the time to peak 13CO2 content in 13C-acetate breath test) at 24 months after surgery in patients with DGE was significantly delayed compared with those without DGE (27.9 ± 22.7min vs.16.5 ± 10.1min, P=0.023). Serum albumin at 24 months after surgery was higher in patients without DGE than those with DGE (3.7±0.6 g/dl vs. 4.1±0.4 g/dl, P=0.013). Conclusion: This study clarified that PrPD can lead to a significant reduction in the incidence of DGE compared with PpPD. Moreover, PrPD offers similar longterm outcomes with PpPD. DGE may be associated with weight loss and poor nutritional status in long-term outcomes.

Objective:Delayed gastric emptying (DGE) after pylorus-preservingpancreatoduodenectomy (PpPD) is a persistent and frustrating complication. Topreserve pylorus ring with denervation and devascularization may be a risk factorof DGE after pancreaticoduodenectomy. We conducted this study to confirm thehypothesis that pylorus-resecting pancreatoduodenectomy (PrPD) reduces theincidence of DGE compared to PpPD. Moreover, long-term outcomes of PrPDand the adverse effect of postsurgical DGE on long-term outcomes have not beenreported. Therefore, in addition, this study focused on long-term outcomes during24 months after surgery between PrPD versus PpPD.Methods: Between October 2005 and March 2009, at Wakayama MedicalUniversity Hospital (WMUH), 130 patients with pancreatic or periampullarylesions were randomized to preservation of the pylorus ring (PpPD) or to resectionof the pylorus ring (PrPD). In PpPD, the proximal duodenum was divided 3-4cmdistal to the pylorus ring. In PrPD, the stomach was divided just adjacent thepylorus ring and the nearly total stomach more than 95% was preserved. Shorttermand long-term outcomes were evaluated between PpPD and PrPD. Primaryendpoint is the incidence of DGE. DGE was defined according to a consensusdefinition and clinical grading about postoperative DGE proposed by theinternational study group of pancreatic surgery (ISGPS). This RCT was registeredat Clinical Trials.Gov NCT00639314.Results: Of 130 patients who were enrolled in this study, 64 patients wererandomized to PpPD and 66 to PrPD. The overall incidence of DGE in this RCTwas 10.8% (14 of 130 patients); the overall incidence of DGE was significantlylower in PrPD (4.5%) than PpPD (17.2%) (P =0 .0244). DGE was classified intothree categories proposed by the International Study Group of Pancreatic Surgery.The proposed clinical grading classified 11 cases of DGE in PpPD into grades A(n=6), B (n=5), and C (n=0), and one case in PrPD into each of the three grades.In long-term outcomes, weight loss > grade 2 (Common Terminology Criteriafor Adverse Events, Ver. 4.0) at 24 months after surgery improved significantlyin PrPD (16.2%) compared with PpPD (42.2%) (P = 0.011). Nutritional statusand late postoperative complications were similar between PpPD and PrPD. Theincidence of weight loss greater than Grade 2 at 24 months after surgery was63.6% in patients with DGE group and 25.3% in patients without DGE group (P= 0.010). Tmax (the time to peak 13CO2 content in 13C-acetate breath test) at24 months after surgery in patients with DGE was significantly delayed comparedwith those without DGE (27.9 ± 22.7min vs.16.5 ± 10.1min, P=0.023). Serumalbumin at 24 months after surgery was higher in patients without DGE than thosewith DGE (3.7±0.6 g/dl vs. 4.1±0.4 g/dl, P=0.013).Conclusion: This study clarified that PrPD can lead to a significant reduction inthe incidence of DGE compared with PpPD. Moreover, PrPD offers similar longtermoutcomes with PpPD. DGE may be associated with weight loss and poornutritional status in long-term outcomes.

The objective of this study is to investigate the effect of the ultrasound-microbubble technique in nuclear factor kappa B (NF-κB) decoy oligodeoxynucleotide (ODN) transfection in the gingival tissue in mice. The 6-FAM-labeled scrambled decoy ODN with microbubbles was applied to the periodontal tissue in 8-week-old male C57BL/6J mice by ultrasound radiation at low (LUM-Sc) and high (HUM-Sc) intensities to optimize the transfection condition of the ultrasound-microbubble method. Histological inspections were performed two hours after transfection to compare the expression with that in the sham-operated group without ultrasound radiation (A-Sc). Then, an NF-κB decoy was transfected into the periodontal tissue using the high-intensity ultrasound-microbubble (HUM-NF) technique to examine the anti-inflammatory effects of the decoy ODN. Western blot analysis was performed to investigate the expression of interleukin(IL)-1β, IL-6 and intercellular adhesion molecule-1 (ICAM-1) in the gingival tissues in the HUM-Sc, the HUM-NF and control groups. The fluorescence microscopy results showed that the fluorescent intensity in the periodontal tissues in the LUM-Sc and HUM-Sc groups was significantly higher than that in the A-Sc and the control groups. The fluorescent intensity in the HUM-Sc group, especially in the gingival connective tissue, was the highest of all groups. Western blot analysis indicated that the protein expression levels of IL-1β, IL-6 and ICAM-1 in the HUM-NF group were significantly lower than those in the HUM-Sc and the control groups. These findings suggest that the high-intensity ultrasound-microbubble technique is an effective tool for decoy transfection into the periodontal tissue.

OBJECTIVESEpidemiological studies have suggested that exposure to environmental and occupational electromagnetic fields (EMFs) contribute to the induction of brain tumors, leukemia, and other neoplasms. The aim of this study was to investigate the genotoxic effects of exposure to 50-Hz EMFs. and of co-exposure to cisplatin, a mutagen and carcinogen, and 50-Hz EMFs, using an in vivo newborn rat astrocyte micronucleus assay.

METHODSThree day-old male Sprague-Dawley rats were co-exposed to 50-Hz EMFs and 1.25 or 2.5 mg/kg of cisplatin. Brain cells were dissociated into single cells and cultured for 96 hours, then stained with acridine orange and an antibody against glial fibrillary acidic protein. The frequency of micronucleated astrocytes was counted with a fluorescent microscope.

RESULTSThe frequency of micronuclei was not increased in rat astrocytes exposed to EMFs alone. However, the frequencies of micronuclei in co-exposure to 2.5 mg/kg cisplatin and EMFs (7.5- and 10-mT) were significantly increased, compared with those in exposure to 2.5 mg/kg cisplatin alone (sham-exposure, 0-mT EMFs) for 72 hours (p<0.01).

CONCLUSIONExposure to EMFs alone did not have a genotoxic effect but co-exposure to EMFs increased the genotoxic activity induced by cisplatin. Our findings suggest that EMFs enhance the genotoxic effects of cisplatin.

OBJECTIVESAn increase in incidence of the illegal use of tablets containing 3,4-methylenedioxymethamphetamine hydrochloride (MDMA) has recently become a widespread social problem. MDMA ingested orally reacts with nitrite in the stomach and is synthesized intoN-nitroso-3,4-methylenedioxymethamphetamine (N-MDMA). The aim of this study is to investigate the genotoxic effects of MDMA and N-MDMA on the basis of the results of an in vitro micronucleus (MN) test and an in vitro chromosomal aberration (CA) test using a Chinese hamster lung fibroblast cell line (CHL/IU).

METHODSTablets containing MDMA obtained from the Regional Bureau of the Ministry of Health, Labor and Welfare were purified, and N-MDMA was synthesized from MDMA in our laboratory. To evaluate the effects of MDMA and N-MDMA, the MN test established by our laboratory and the CA test in accordance with the guidelines for toxicity studies of drugs recommended by the Ministry of Health, Labor and Welfare were performed.

RESULTSIn the MN test, no increased frequency of MNs was not found for MDMA. On the other hand, an apparently increased frequency of MNs was observed for N-MDMA. In the CA test, no CA was found for MDMA, but CA was observed for N-MDMA apparently.

CONCLUSIONN-MDMA genotoxicity was observed in the MN and CA tests. However, no MDMA genotoxicity was observed.

OBJECTIVESIt is important to assess the risk of static magnetic fields (SMFs) on human health, because epidemiological studies have indicated that SMFs play a role in the development of diseases such as leukemia and brain tumor. In our environment, we have numerous chances to be exposed to not only SMFs but also many chemicals containing mutagens. The aim of this study is to investigate the effect of SMFs on the induction of micronuclei induced by some mutagens.

METHODSBALB/c mice were exposed to 4.7 tesla (T) SMF for 24 hr immediately after the injection of carboquone (alkylating agent), colcemid (spindle poison), mitomycin C (cross-linking agent), vincristine (spindle poison), sodium fluoride (a byproduct of aluminum plants under strong SMF) or 1-ethyl-1-nitrosourea (brain tumor-, gliomas- and thymic lymphoma-inducing chemical).

RESULTSThe frequency of micronuclei induced by six mutagens increased after co-exposure to SMF.

CONCLUSIONSAn additive/synergistic effect of SMF and chemicals was observed from the results of increased frequency of micronuclei induced by mutagens in mouse bone marrow erythrocytes.

OBJECTIVESKetamine hydrochloride (KT) is a secondary amine that has been safely used as an injectable anesthetic and analgesic to avoid the production of nitroso compounds in the stomach. However, ketamine in the tablet form has recently become an abused, recreational drug. The aim of this study was to investigate the genotoxic effects of N-nitrosoketamine (NKT) and KT on the basis of an in vitro micronucleus (MN) test using a Chinese hamster lung fibroblast cell line (CHL/IU).

METHODSNKT was synthesized from KT in our laboratory. In the MN tests, CHL/IU cells were continuously treated with either NKT or KT for 24, 48, or 72 hours without the S9 mix. The cells were also treated with NKT or KT with or without the S9 mix for 6 hours, followed by a recovery period of 18, 42, or 66 hours (short-term treatment). The results were considered to be statistically significant when the p-values of both Fisher's exact test and the trend test were less than 0.05.

RESULTSAfter the short-term treatment with either NKT or KT with and without the S9 mix, the frequency of micronuclei significantly increased. However, the frequency of micronuclei did not significantly increase after the continuous treatment with either NKT or KT. Both NKT and KT were determined to be genotoxic in the short-term treatment with or without the S9 mix, but they were determined to be nongenotoxic in continuous treatment.

CONCLUSIONOur findings suggest that NKT has a stronger genotoxic effect than KT.