Publications by authors named "Masayuki Kimura"

156 Publications

Comparison of acute inhalation toxicity of sulfuric acid by the inhalation and intratracheal instillation methods.

J Toxicol Pathol 2021 Jul 24;34(3):269-273. Epub 2021 Apr 24.

Biological Research Laboratories, Nissan Chemical Corporation, 1470 Shiraoka, Shiraoka-shi, Saitama 349-0294, Japan.

Recently, intratracheal instillation has been focused on as a simple, low-cost alternative to the inhalation method. In this study, intratracheal instillation of sulfuric acid, a typical acidic compound, was performed to compare the acute toxicity of acidic compounds that could cause damage to the respiratory system between intratracheal instillation and inhalation. Sulfuric acid was administered to male rats at doses of 0.7, 2, 7, 20, and 60 mg/kg by dividing the total dose into four doses. General condition and body weight were examined up to 14 days after administration, and macropathological and histopathological examinations were performed. The half-lethal dose was then estimated. All animals administered 20 and 60 mg/kg sulfuric acid and one animal administered 2 mg/kg sulfuric acid died within 4 h after administration. No abnormalities were observed in other animals. At 20 and 60 mg/kg, multiple red foci or diffuse red areas were macroscopically observed in the lungs. In these lesions, histopathologically, clefts between the mucosal epithelium and basement membrane and necrosis of the alveolar epithelium were observed. Deaths in these groups may have resulted from lung injury. No notable changes were observed in other animals. Therefore, the half-lethal dose of sulfuric acid by intratracheal instillation was estimated as 7-20 mg/kg. The acute toxicity by intratracheal instillation was evaluated with two-fold sensitivity since the exposure at the half-lethal sulfuric acid concentration in inhalation studies was calculated as 43.2 mg/kg.
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http://dx.doi.org/10.1293/tox.2020-0086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8280304PMC
July 2021

A case report of RccHan: WIST rat with multiple neoplastic and non-neoplastic proliferative lesions.

J Toxicol Pathol 2021 Jul 30;34(3):251-259. Epub 2021 Apr 30.

Toxicology and Environmental Science Department, Biological Research Laboratories, Nissan Chemical Corporation, 1470 Shiraoka, Shiraoka-shi, Saitama 349-0294, Japan.

It is extremely rare to have multiple spontaneous proliferative lesions in young adult rats. Here, we report the occurrence of different proliferative lesions in multiple tissues of a 7-week-old female rat in a 1-week repeated toxicity study. Grossly, multiple white patches and nodules in the bilateral kidneys, femoral and subcutaneous masses, and a nodule in the liver were observed. Renal lesions were diagnosed as renal mesenchymal tumors. One of the femoral subcutaneous masses was diagnosed as an adenolipoma consisting of mammary epithelial cells and mature adipocytes. The other femoral and abdominal subcutaneous masses were diagnosed as lipomas consisting of mature adipocytes. The liver nodule was diagnosed as non-regenerative hepatocellular hyperplasia, which was characterized by the proliferation of slightly hypertrophic hepatocytes. In the cauda equina, the growth of enlarged Schwann cells around the axon was observed, and this lesion was diagnosed as a neuroma.
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http://dx.doi.org/10.1293/tox.2021-0004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8280308PMC
July 2021

[A Case of Unresectable Colorectal Cancer with Complete Remission after Palliative Surgery Due to Continued Pharmacotherapy].

Gan To Kagaku Ryoho 2021 Mar;48(3):413-415

Dept. of Surgery, Numazu City Hospital.

A 50s-year-old man was admitted to our hospital because of abdominal pain and vomitting. CT showed a thickened wall of the sigmoid colon, marked enlargement of the oral side, and a 30 mm tumor on the left lateral section of the liver. We diagnosed colonic obstruction due to sigmoid colon cancer with liver metastasis. We failed to place a colonic stent for decompression, so we performed a colostomy using the cecum. An exploratory laparoscopy was performed instead of curative surgery due to peritoneal disseminations, followed by chemotherapy and molecular targeted therapy. Although primary lesion, liver metastatic lesion and disseminated lesions were reduced by pharmacotherapy the patient developed a grade 2 skin disorder around the colostomy. Therefore, it was determined that molecular targeted therapy could not be continued. The resection of the primary lesion and closure of the colostomy were performed to continue pharmacotherapy. Pharmacotherapy was resumed after operation. The patient is currently getting complete remission, undergoing maintenance therapy with no skin disorders. In this case, surgery was performed as part of the multidisciplinary treatment. It suggested that palliative surgery might be an effective option in multidisciplinary treatment.
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March 2021

[A Case of Rapidly Growing Breast Spindle Cell Carcinoma].

Gan To Kagaku Ryoho 2020 Dec;47(13):2341-2342

Dept. of Frontier Surgery, Graduate School of Medicine, Chiba University.

We report a case of rapidly growing breast spindle cell carcinoma. The case was a 69-year-old female. Her chief complaint was right breast pain. She was being followed after surgery for left breast cancer but was seen because of right breast pain. In the right mammary gland CD area, a 27×27 mm large unclear mass lesion was observed, which had not been seen half a year prior. Right mastectomy and axillary dissection were performed following a preoperative diagnosis of pT2N1M0, pStage ⅡB ductal carcinoma. Currently, 2 years and 2 months have passed since the operation, and recurrence has not been observed. Case reports of rapidly growing breast spindle cell carcinoma are occasionally found, but no literature specifically defines acute growth. Here, we defined rapid growth using the tumor doubling time(DT)proposed by Gerstenberg et al. Of all the reported cases of breast spindle cell carcinoma, the DT was fewer than 90 days in most cases. Breast spindle cell carcinoma demonstrates rapid grown compared to normal breast cancer.
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December 2020

[A Case of Rectal Cancer with Collet-Sicard Syndrome].

Gan To Kagaku Ryoho 2020 Dec;47(13):2225-2226

Dept. of Surgery, Numazu City Hospital.

The case was a woman in her 50s. Total pelvic resection was performed for advanced rectal cancer(cT4b[vagina]N3M0, cStage Ⅲc), after neoadjuvant chemoradiation therapy. Five months after the operation, she was unable to stand due to severe back pain. Spinal MRI revealed multiple bone metastases and lumbar fractures. In addition, dysphagia and dysarthria rapidly progressed almost simultaneously with back pain. Initially, brain metastasis was suspected, but head MRI revealed Collet-Sicard syndrome due to skull base metastasis. Irradiation to the skull base and high cervical spine, thoracolumbar spine was started. After irradiation, her back pain and cranial nerve symptoms improved. She was discharged and received palliative treatment. About a month after discharge, she was hospitalized for recurrent dysphagia and died on day 5 of hospitalization. Collet-Sicard syndrome is caused by damage to the cranial nerves Ⅸ to Ⅻ and is often caused by a tumor. Trauma, vasculitis, and internal carotid artery dissection have been reported as other causes. Symptoms such as hoarseness, dysarthria, tongue atrophy, dysphagia, and headache have been reported. Collet-Sicard syndrome due to bone metastasis of colorectal cancer were very rare, and we found only one other report. We report our case with some literature considerations.
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December 2020

[A Case of Effective Peritoneo-Venous Shunt for Refractory Malignant Ascites in a Gastric Cancer Patient with Peritoneal Dissemination].

Gan To Kagaku Ryoho 2020 Dec;47(13):2059-2061

Dept. of Surgery, Numazu City Hospital.

This paper reports a case of refractory ascites in a patient with gastric cancer. A peritoneo-venous shunt(PVS)was inserted in the patient, which contributed to extending the duration of home-based care as well as improving the patient's quality of life. The patient was a female in her 70s. She was diagnosed with gastric cancer and underwent total gastrectomy. Five years and 7 months after the surgery, she was diagnosed with peritoneal recurrence. Ascites temporarily decreased following chemotherapy, but gradually worsened thereafter. Since the patient required frequent puncture drainage for the ascites, cell-free concentrated ascites reinfusion therapy(CART)was performed. However, on the day prior to the scheduled second course of CART, marked abdominal distension was observed. Therefore, a PVS was inserted. No PVS-associated complications were observed. Following the insertion of the PVS, the patient's abdominal circumference and body weight markedly improved. Best supportive care(BSC)was provided to the patient as she became weak after undergoing several courses of chemotherapy on an outpatient basis. On the other hand, the PVS was working properly. The patient was able to continue her daily life activities at home. She died from the cancer after 164 days of the PVS insertion.
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December 2020

[A Case of Intussusception Due to Ileal Malignant Lymphoma of AYA Generation].

Gan To Kagaku Ryoho 2021 Jan;48(1):142-144

Dept. of Surgery, Numazu City Hospital.

The case is a 17-year-old man. He had complained of right lower abdominal pain for a week. He had no symptoms such as fever, weight loss, or night sweats. He was diagnosed with intussusception by abdominal contrast-enhanced CT and was hospitalized. The day after hospitalization, lower gastrointestinal endoscopy was performed, and a tumor 25 mm in size was found in the invagination of the ileum. Intussusception was recovered by intestinal scope insufflation, and the tumor was found to be a type 1 tumor located approximately 5 cm proximal to the Bauhin's valve. On day 17 of hospitalization, he had intussusception again at the time of surgery, and performed laparoscopic reduction before performing laparoscopy-assisted partial resection of the small intestine and appendectomy. The postoperative course was good and he was discharged on POD12(on day 29 of hospitalization). Histopathological diagnosis was diffuse large B-cell lymphoma(DLBCL), and chemotherapy was to be administered at the referral hospital. In intussusception of the adolescents and young adults(AYA)generation, such as this case outside of childhood, it is necessary to treat the patient with consideration for the presence of neoplastic lesions such as malignant lymphoma. We report our case with some literature considerations.
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January 2021

Sequential histological changes in the liver of medaka exposed to methylazoxymethaol acetate.

J Toxicol Pathol 2020 Oct 25;33(4):219-226. Epub 2020 Jul 25.

Veterinary Clinical Pathology, Faculty of Veterinary Medicine, Okayama University of Science, 1-3 Ikoinooka, Imabari, Ehime 794-8555, Japan.

We performed a medaka bioassay for the carcinogenicity of methylazoxymethaol acetate (MAM-Ac) to examine the sequential histological changes in the liver from 3 days after exposure until tumor development. The medaka were exposed to MAM-Ac at a concentration of 2 ppm for 24 hours, and were necropsied at 3, 7, 10, 14, 21, 28, 35, 42, 49, 60, and 91 days after exposure. MAM-Ac induced four cases of hepatocellular adenoma and one case of hepatocellular carcinoma in 8 fish after 60 or 91 days of exposure. Histological changes in the liver until tumor development were divided into three phases. In the cytotoxic phase (1-10 days), MAM-Ac-exposed hepatocytes showed vacuolar degeneration and underwent necrosis and apoptosis, resulting in multiple foci of hepatocyte loss. In the repopulation phase (14-35 days), the areas of hepatocyte loss were filled with hepatic cysts and the remaining hepatocytes were surrounded by hepatic stellate-like cells (or spindle cells) and gradually disappeared. In the proliferation phase (42-91 days), the original hepatic parenchyma was regenerated and progressively replaced by regenerative hyperplastic nodules and/or liver neoplasms. The medaka retained a strong hepatocyte regenerative ability in response to liver injury. It is considered that this ability promotes the proliferation of initiated hepatocytes in multistep carcinogenesis and influences the development of liver tumor over a short period in medaka.
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http://dx.doi.org/10.1293/tox.2020-0033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677625PMC
October 2020

The effects of β-naphthoflavone on rat placental development.

J Toxicol Pathol 2019 Oct 20;32(4):275-282. Epub 2019 Aug 20.

Veterinary Clinical Pathology, Faculty of Veterinary Medicine Okayama University of Science, 1-3 Ikoinooka, Imabari, Ehime 794-8555, Japan.

The morphological effects of β-naphthoflavone (β-NF) on placental development in pregnant rats were examined. β-NF, administered to pregnant rats intraperitoneally at 15 mg/kg bw from gestation day (GD) 9 to GD 14, had no effect on maternal body weight gain, mortality, or clinical sign. In the β-NF-exposed rats, intrauterine growth retardation (IUGR) rates increased on GDs 17 and 21, although there was no effect on fetal mortality rate, fetal or placental weight, or external fetal abnormality. Histopathologically, β-NF induced apoptosis and inhibition of cell proliferation of the trophoblastic septa in the labyrinth zone, resulting in its poor development. In the basal zone, β-NF induced spongiotrophoblast apoptosis and delayed glycogen islet regression, resulting in their cystic degeneration. β-NF-induced CYP1A1 expression was detected in the endothelial cells of the fetal capillaries in the labyrinth zone and in the endothelial cells of the spiral arteries in the metrial gland, but not in any trophoblasts. This indicates that CYP1A1 is inducible in the endothelial cells of the fetal capillaries in the labyrinth zone, and that these cells have an important role in metabolizing CYP1A1 inducers crossing the placental barrier.
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http://dx.doi.org/10.1293/tox.2019-0047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6831496PMC
October 2019

Pterobreathers in a model for a layered crystal with realistic potentials: Exact moving breathers in a moving frame.

Phys Rev E 2019 Aug;100(2-1):022206

Department of Electrical Engineering, Kyoto University Katsura, Nishikyo-ku, Kyoto 615-8510, Japan.

In this article we perform a thorough analysis of breathers in a one-dimensional model for a layered silicate for which there exists fossil and experimental evidence of moving excitations along the close-packed lines of the K^{+} layers. Some of these excitations are likely breathers with a small energy of about 0.2 eV as the numerically obtained breathers described in the present model. Moving breathers as exact solutions of the dynamical equations are obtained at the price of being generically associated with a plane wave, a wing, with finite amplitude, although this amplitude can be very small. We call them pterobreathers. For some frequencies the wings disappear and the solutions become exact moving breathers with no wings, showing the phenomenon of supertransmission of energy. We perform a theoretical analysis of pterobreathers in systems with substrate potential and show that they are characterized by a single frequency in the moving frame plus the frequency of the wings. We have also studied high-energy stationary breathers which transform into single and double kinks and stable multibreathers with very strong localization.
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http://dx.doi.org/10.1103/PhysRevE.100.022206DOI Listing
August 2019

[A Case of Colon Metastasis from Invasive Lobular Carcinoma of the Breast].

Gan To Kagaku Ryoho 2018 Dec;45(13):2473-2475

Dept. of Surgery, Numazu City Hospital.

The patient was a 48-year-old woman. She consulted our hospital with a chief complaint of vomiting. Colonoscopy showed stenosis and edematous mucosa, and biopsy was performed. Histological examination demonstrated the lesion to be colonic metastasis of breast cancer, invasive lobular carcinoma. Although colorectal metastasis of breast cancer has a poor prognosis and chemotherapy is considered as the main treatment modality, hormone therapy is also a treatment option depending on the condition.
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December 2018

[A Case of HER2 Positive Locally Advanced Breast Cancer Successfully Treated with a Combination Therapy of Eribulin, Trastuzumab and Pertuzumab].

Gan To Kagaku Ryoho 2018 Dec;45(13):2470-2472

Dept. of Surgery, Numazu City Hospital.

The patient was an 82-year-oldwoman. She consultedour hospital with a chief complaint of left breast mass. MRI showed enhancedtumor with skin andextensive pectoral muscle invasion, so it was unresectable. Immunohistopathological analysis revealeda HER2-positive lesion. We administerederibulin, trastuzumab andpertuzumab, after which the tumor became resectable. Histological examination revealedremarkable response. Combination therapy of eribulin, trastuzumab andpertuzumab was well toleratedandconsid eredto be effective.
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December 2018

[Pulmonary Metastasis Resection Twice after Curative Resection of Esophageal Cancer-A Long-Term Survival Case].

Gan To Kagaku Ryoho 2018 Dec;45(13):2456-2457

Dept. of Surgery, Numazu City Hospital.

The prognosis of patients with esophageal cancer recurrence is poor, and surgical treatment is rarely performed. Here, we report on a patient with long-term survival who underwent pulmonary metastasis resection twice after curative resection of esophageal cancer. A 62-year-old male underwent curative resection of esophageal cancer after preoperative chemoradiotherapy. The histopathological diagnosis was poorly differentiated squamous cell carcinoma(pT2N1M0, fStage Ⅱ). Five months after the operation, right lung metastasis(right-S2)was detected. Accordingly, pulmonary metastasis resection was performed. Fourteen months after the initial operation, left lung metastases(left-S3/S6)were detected. The patient underwent resection again for the pulmonary metastases. The patient died of pneumonia without recurrence 8 years 3 months after the initial operation. In selected cases, surgical resection seems effective for treating distant esophageal cancer metastasis, suggesting that surgery should be an option in cases of accumulation of numerous distant metastases in esophageal cancer.
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December 2018

[Long-Term Survival of a Rectal Cancer Patient with Virchow Lymph Node Metastasis, Liver Metastasis, and Para-Aortic Lymph Node Metastasis].

Gan To Kagaku Ryoho 2018 Dec;45(13):1875-1876

Dept. of Surgery, Numazu City Hospital.

A 67-year-old female was diagnosed with Stage Ⅳ rectal cancer with paraaortic lymph node metastasis. The patient underwent Hartmann's operation with D3 lymph node and paraaortic lymph node dissection. Postoperative chemotherapy with FOLFIRI was then administered for 1 year. However, liver metastasis developed, for which partial hepatectomy was performed. Postoperative chemotherapy with S-1(20 courses)was then administered. Three years and 11 months following the first operation, lymph node metastases developed and resection of lymph nodes(No. 12p, No. 16b1int)was performed. Postoperative chemotherapy with capecitabine(Cape)(8 courses)was then administered. Five years and 7 months following the first operation, Virchow lymph node metastasis developed. Despite chemotherapy with Cape and bevacizumab (Bmab), Virchow lymph node swelling recurred, and resection was performed. Nine years and 4 months following the first operation, lymph node metastases developed, and resection of lymph nodes(Virchow, No. 16b1int)was performed. Postoperative chemotherapy with S-1(8 courses)was then administered. At present, 11 years and 4 months after the first operation, the patient, whose chemotherapy has been discontinued, is alive without recurrence.
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December 2018

[A Case of Gallbladder Jejunal Anastomosis and Duodenal Jejunal Anastomosis to Maintain QOL for an Elderly Patient with Pancreatic Cancer].

Gan To Kagaku Ryoho 2018 Dec;45(13):1818-1820

Dept. of Surgery, Numazu City Hospital.

An 87-year-oldwoman was admittedto our hospital with abdominal pain andfever. Computedtomography showeda 25 mm tumor mass in the pancreatic headandshowedd ilatation of the pancreatic duct andcommon bile duct. She was diagnosed with obstructive cholangitis due to pancreatic head cancer. An endoscopic naso-biliary drainage(EUS)tube was inserted, and an endoscopic ultrasound(ENBD)examination was performed. At this time, duodenal perforation occurred, and an emergency operation was performed. During the laparotomy, perforation was found in the anterior wall of the duodenum. The contamination in the abdominal cavity and the degree of tissue damage in the duodenum were mild. Gall bladder jejunal andd uodenal jejunal anastomoses were performedfor biliary bypass andto close the perforation andbypass the gastrointestinal tract, respectively. She hadno postoperative complications andwas discharged 13 days postoperatively. Oral intake was possible after discharge, andthe patient returnedhome without complications. She died 5 months postoperatively. In this case, we performedbile duct andgastrointestinal bypass surgery prophylactically. Although this surgery will not be effective for all patients, we thought that it wouldbe useful for predicting the patient's future condition and for increasing the procedural options, even in case of emergency surgery.
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December 2018

Spironolactone in Combination with α-glycosyl Isoquercitrin Prevents Steatosis-related Early Hepatocarcinogenesis in Rats through the Observed NADPH Oxidase Modulation.

Toxicol Pathol 2018 07 29;46(5):530-539. Epub 2018 May 29.

1 Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, Fuchu-shi, Tokyo, Japan.

Administration of the diuretic, spironolactone (SR), can inhibit chronic liver diseases. We determined the effects of SR alone or in combination with the antioxidant α-glycosyl isoquercitrin (AGIQ) on hyperlipidemia- and steatosis-related precancerous lesions in high-fat diet (HFD)-fed rats subjected to a two-stage hepatocarcinogenesis model. Rats were fed with control basal diet or HFD, which was administered with SR alone or in combination with an antioxidant AGIQ in drinking water. An HFD increased body weight, intra-abdominal fat (adipose) tissue weight, and plasma lipids, which were reduced by coadministration of SR and AGIQ. SR and AGIQ coadministration also reduced hepatic steatosis and preneoplastic glutathione S-transferase placental form-positive foci, in association with decrease in NADPH oxidase (NOX) subunit p22phox-positive cells and an increase in active-caspase-3-positive cells in the foci. Hepatic gene expression analysis revealed that the coadministration of SR and AGIQ altered mRNA levels of lipogenic enzymes ( Scd1 and Fasn), antioxidant-related enzymes ( Catalase), NOX component ( P67phox), and anti-inflammatory transcriptional factor ( Pparg). Our results indicated that SR in combination with AGIQ had the potential of suppressing hyperlipidemia- and steatosis-related early hepatocarcinogenesis through the reduced expression of NOX subunits.
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http://dx.doi.org/10.1177/0192623318778508DOI Listing
July 2018

[A Comparison of the Treatment Methods for Obstructive Colorectal Cancer].

Gan To Kagaku Ryoho 2017 Nov;44(12):1203-1204

Dept. of Surgery, Numazu City Hospital.

Purpose: Emergency surgery for obstructive colorectal cancer is considered to be associated with a high degree of risk, and surgery may after decompression is considered to be safer. In cases of obstructive colorectal cancer, decompression can be achieved with surgery, an ileus tube, or a stent, depending on the disease condition. We herein compare the treatment methods for obstructive colorectal cancer.

Methods: Forty-two patients with obstructive colorectal cancer underwent emergency treatment between January 2012 and December 2016.

Results: Among the patients with obstructive colorectal cancer, 18 receiveda stent, 10 receiveda nasal ileus tube, 6 receiveda transanal ileus tube, 5 underwent stoma construction, and 3 underwent emergency surgery without decompression. The stent group showed the highest laparoscopic operation rate. There was no significant difference in the overall survival of the treatment groups. One patient in the stent group developed duplicated cancer.

Conclusion: Stent placement can be considered to be a viable option in the emergency treatment for obstructive colorectal cancer because laparoscopic surgery anda preoperative examination can be performed.
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November 2017

Short Leukocyte Telomere Length Precedes Clinical Expression of Atherosclerosis: The Blood-and-Muscle Model.

Circ Res 2018 02 14;122(4):616-623. Epub 2017 Dec 14.

From the INSERM UMRS 1116 (A.B., S.T., C.L.), Department of Geriatric Medicine, CHRU de Nancy (A.B., S.G.), Department of Vascular Surgery, CHRU de Nancy (N.S., S.M.), Department of Urology, CHRU de Nancy (J.H., P.E.), Department of Nephrology, CHRU de Nancy (L.F., M.K.), and Department of Cardiology, CHRU de Nancy (N.S.), Université de Lorraine, Nancy, France; Center of Human Development and Aging, Rutgers, The State University of New Jersey, New Jersey Medical School, Newark (M.K., A.A.); Department of Internal Medicine, North Hospital, APHM, and UMR-S1076 (P.M.R.) and Department of Plastic Surgery, Conception Hospital, APHM and UMR-S1076 (B.B.), Aix-Marseille University, France; Department of Vascular Surgery (M.B.) and Department of Orthopedic Surgery (X.F.), North Hospital, APHM, Marseille, France; Laboratory for Experimental Surgery and Surgical Research "NS Christeas", National and Kapodistrian University of Athens, Greece (I.P.T., I.P.D., P.K., A.T., M.K., A.G., G.S.); European University of Cyprus, School of Sciences, Engomi (I.P.T.); First Department of Adult Cardiac Surgery, Onassis Cardiac Surgery Center, Athens, Greece (K.P., G.S.); Department of Surgery, Hippokration Hospital and Medical School of Athens, National and Kapodistrian University of Athens, Greece (E.M.); Department of Surgery, Iaso General Hospital, Athens, Greece (M.V.-G.); Hebrew University-Hadassah School of Public Health and Community Medicine, Jerusalem, Israel (J.D.K.); and Groningen Institute for Evolutionary Life Sciences, University of Groningen, The Netherlands (S.V.).

Rationale: Short telomere length (TL) in leukocytes is associated with atherosclerotic cardiovascular disease (ASCVD). It is unknown whether this relationship stems from having inherently short leukocyte TL (LTL) at birth or a faster LTL attrition thereafter. LTL represents TL in the highly proliferative hematopoietic system, whereas TL in skeletal muscle represents a minimally replicative tissue.

Objective: We measured LTL and muscle TL (MTL) in the same individuals with a view to obtain comparative metrics for lifelong LTL attrition and learn about the temporal association of LTL with ASCVD.

Methods And Results: Our Discovery Cohort comprised 259 individuals aged 63±14 years (mean±SD), undergoing surgery with (n=131) or without (n=128) clinical manifestation of ASCVD. In all subjects, MTL adjusted for muscle biopsy site (MTL) was longer than LTL and the LTL-MTL gap similarly widened with age in ASCVD patients and controls. Age- and sex-adjusted LTL (=0.005), but not MTL (=0.90), was shorter in patients with ASCVD than controls. The TL gap between leukocytes and muscle (LTL-MTL) was wider (=0.0003), and the TL ratio between leukocytes and muscle (LTL/MTL) was smaller (=0.0001) in ASCVD than in controls. Findings were replicated in a cohort comprising 143 individuals.

Conclusions: This first study to apply the blood-and-muscle TL model shows more pronounced LTL attrition in ASCVD patients than controls. The difference in LTL attrition was not associated with age during adulthood suggesting that increased attrition in early life is more likely to be a major explanation of the shorter LTL in ASCVD patients.

Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02176941.
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http://dx.doi.org/10.1161/CIRCRESAHA.117.311751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5821479PMC
February 2018

Effect of dibutyltin on placental and fetal toxicity in rat.

J Toxicol Sci 2017 ;42(6):741-753

Courses of Veterinary Laboratory Medicine, School of Veterinary Medicine, Faculty of Agriculture, Tottori University.

In order to elucidate the effect of chorioallantoic and yolk sac placenta on the embryonic/fetal toxicity in dibutyltin dichloride (DBTCl)-exposed rats, we examined the histopathological changes and the tissue distribution of dibutyltin in the placentas and embryos. DBTCl was orally administered to the groups at doses of 0 mg/kg during gestation days (GD)s 7-9 (control group) and 20 mg/kg during GDs 7-9 (GD7-9 treated group), and GDs 10-12 (GD10-12 treated group). The total fetal mortality was increased, and malformations characterized by craniofacial dysmorphism were detected in the GD7-9 treated group. The embryonic/fetal weight and placental weight showed a decrease in both DBTCl-treated groups. Histologically, some embryos on GD 9.5 in the GD7-9 treated group underwent apoptosis without any changes of yolk sac. In the laser ablation-inductively coupled plasma-mass spectrometry analysis (LA-ICP-MS), tin was detected in the embryo, allantois, yolk sac, ectoplacental cone and decidual mass surrounding the conceptus on GD 9.5 in the GD7-9 treated group. Thus, it is considered that the embryo in this period is specifically sensitive to DBTCl-induced apoptosis, compared with other parts. The chorioallantoic placentas in both DBTCl-treated groups showed the developmental delay and hypoplasia in the fetal parts of placenta, resulting from apoptosis and mitotic inhibition. Thus, it was speculated that the DBTCl-induced malformations and fetal resorption resulted from the apoptosis in the embryo caused by the direct effect of DBTCl. The DBTCl-induced lesions in the chorioallantoic placenta were a non-specific transient developmental retardation in the fetal parts of placenta, leading to intrauterine growth retardation.
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http://dx.doi.org/10.2131/jts.42.741DOI Listing
March 2018

Leukocyte telomere length, T cell composition and DNA methylation age.

Aging (Albany NY) 2017 09;9(9):1983-1995

Center of Development and Aging, New Jersey Medical School, Rutgers State University of New Jersey, Newark, NJ 07103, USA.

Both leukocyte telomere length (LTL) and DNA methylation age are strongly associated with chronological age. One measure of DNA methylation age─ the extrinsic epigenetic age acceleration (EEAA)─ is highly predictive of all-cause mortality. We examined the relation between LTL and EEAA. LTL was measured by Southern blots and leukocyte DNA methylation was determined using Illumina Infinium HumanMethylation450 BeadChip in participants in the Women's Health Initiative (WHI; n=804), the Framingham Heart Study (FHS; n=909) and the Bogalusa Heart study (BHS; n=826). EEAA was computed using 71 DNA methylation sites, further weighted by proportions of naïve CD8 T cells, memory CD8 T cells, and plasmablasts. Shorter LTL was associated with increased EEAA in participants from the WHI (=-0.16, =3.1x10). This finding was replicated in the FHS (=-0.09, =6.5x10) and the BHS (=-0.07, =3.8x 10). LTL was also inversely related to proportions of memory CD8 T cells (=4.04x10) and positively related to proportions of naive CD8 T cells (=3.57x10). These findings suggest that for a given age, an individual whose blood contains comparatively more memory CD8 T cells and less naive CD8 T cells would display a relatively shorter LTL and an older DNA methylation age, which jointly explain the striking ability of EEAA to predict mortality.
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http://dx.doi.org/10.18632/aging.101293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5636670PMC
September 2017

Telomere length dynamics in early life: the blood-and-muscle model.

FASEB J 2018 01 29;32(1):529-534. Epub 2017 Aug 29.

Center of Human Development and Aging, Rutgers New Jersey Medical School, The State University of New Jersey, Newark, New Jersey, USA; and

Telomere length (TL) trajectories in somatic tissues during human growth and development are poorly understood. We examined a blood-and-muscle model during early life, focusing on TL trajectories in leukocytes, representing the highly proliferative hematopoietic system, and skeletal muscle, a minimally proliferative tissue. Leukocyte TL (LTL) and skeletal muscle TL (MTL) were measured in 28 fetuses and 73 children. LTL and MTL were highly variable across individuals (sd: fetal LTL = 0.72 kb, MTL = 0.72 kb; children LTL = 0.81 kb, MTL = 0.82 kb) but were highly correlated within individuals (fetuses, = 0.76, < 0.0001; children, = 0.87, < 0.0001). LTL was shorter than MTL in fetuses (10.63 11.01 kb; = 0.0004) and children (8.46 9.40 kb; <0.0001). The LTL-MTL gap was smaller in fetuses than children. TL in children was inversely correlated with body mass index (BMI) (LTL: -0.047 ± 0.016 kb/BMI, < 0.005; MTL: -0.037 ± 0.017 kb/BMI, = 0.03). We conclude that variations in TL across adults and differences in TL between somatic tissues are largely established in early life. Because TL plays a significant role in aging-related diseases, insight into the factors that fashion TL in somatic tissues during early development should contribute to an understanding of the relationship of TL with these disease and longevity in humans.-Sabharwal, S., Verhulst, S., Guirguis, G., Kark, J. D., Labat, C., Roche, N. E., Martimucci, K., Patel, K., Heller, D. S., Kimura, M., Chuang, D., Chuang, A., Benetos, A., Aviv, A. Telomere length dynamics in early life: the blood-and-muscle model.
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http://dx.doi.org/10.1096/fj.201700630RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5731134PMC
January 2018

Correlation of Leukocyte Telomere Length Measurement Methods in Patients with Dyskeratosis Congenita and in Their Unaffected Relatives.

Int J Mol Sci 2017 Aug 13;18(8). Epub 2017 Aug 13.

Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.

Several methods have been employed to measure telomere length (TL) in human studies. It has been difficult to directly compare the results from these studies because of differences in the laboratory techniques and output parameters. We compared TL measurements (TLMs) by the three most commonly used methods, quantitative polymerase chain reaction (qPCR), flow cytometry with fluorescence in situ hybridization (flow FISH) and Southern blot, in a cohort of patients with the telomere biology disorder dyskeratosis congenita (DC) and in their unaffected relatives (controls). We observed a strong correlation between the Southern blot average TL and the flow FISH total lymphocyte TL in both the DC patients and their unaffected relatives (² of 0.68 and 0.73, respectively). The correlation between the qPCR average TL and that of the Southern blot method was modest (² of 0.54 in DC patients and of 0.43 in unaffected relatives). Similar results were noted when comparing the qPCR average TL and the flow FISH total lymphocyte TL (² of 0.49 in DC patients and of 0.42 in unaffected relatives). In conclusion, the strengths of the correlations between the three widely used TL assays (qPCR, flow FISH, and Southern blot) were significantly different. Careful consideration is warranted when selecting the method of TL measurement for research and for clinical studies.
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http://dx.doi.org/10.3390/ijms18081765DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5578154PMC
August 2017

Short Telomeres, but Not Telomere Attrition Rates, Are Associated With Carotid Atherosclerosis.

Hypertension 2017 08 19;70(2):420-425. Epub 2017 Jun 19.

From the INSERM UMRS 1116 (S.T., C.L., P.R., A.B.), Department of Geriatric Medicine, CHRU de Nancy (C.L., A.B.), and Inserm, Centre d'Investigations Cliniques-Plurithématique 14-33, CHRU Nancy (P.R.), Université de Lorraine, Nancy, France; Cardiology Center, Ghardaia, Algeria (M.T.); and Center of Human Development and Aging, Rutgers, The State University of New Jersey, New Jersey Medical School, Newark (M.K., A.A.).

Short telomeres are associated with atherosclerosis. However, the temporal relationship between atherosclerosis and telomere length is unclear. The objective of this work was to examine the temporal formation and progression of carotid atherosclerotic plaques in relation to telomere dynamics. In a longitudinal study, comprising 154 French men and women (aged 31-76 years at baseline), carotid plaques were quantified by echography, and telomere length on leucocytes was measured by Southern blots at baseline and follow-up examinations. Telomere attrition rates during the 9.5-year follow-up period were not different in individuals with plaques at both baseline and follow-up examinations (23.3±2.0 base pairs/y) than in individuals who developed plaques during the follow-up period (26.5±2.0 base pairs/y) and those without plaques at either baseline or follow-up examination (22.5±2.3 base pairs/y; =0.79). At baseline, telomere length was associated with presence of carotid plaques (=0.02) and with the number of regions with plaques (=0.005). An interaction (=0.03) between age and the presence of plaques was observed, such that the association between plaques and telomere length was more pronounced at a younger age. In conclusion, carotid atherosclerosis is not associated with increased telomere attrition during a 9.5-year follow-up period. Short telomere length is more strongly associated with early-onset than late-onset carotid atherosclerosis. Our results support the thesis that heightened telomere attrition during adult life might not explain the short telomeres observed in subjects with atherosclerotic disease. Rather, short telomeres antecedes the clinical manifestation of the disease.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.117.09354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5903283PMC
August 2017

Endometrial adenocarcinoma with choriocarcinomatous differentiation in the uterus of a goat.

J Vet Med Sci 2017 Jun 19;79(6):1091-1095. Epub 2017 May 19.

Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509, Japan.

An 11-year-old female goat had invasive and metastatic endometrial adenocarcinoma in the uterus. There was a notable proliferation of endometrial epithelial cells in a tubular growth pattern, with a desmoplastic response. The endometrial epithelial tumor cells metastasized to the kidney, liver and lung. In contrast to the primary and metastatic tumor cells, pleomorphic tumor cells with a choriocarcinoma-like growth pattern infiltrated the mesometrium. Cell proliferation activity was high in both types of tumor cells. Both types of tumor cells expressed cytokeratins AE1/AE3, 7 and CAM5.2; choriocarcinomatous cells also had positive immunoreactions to human chorionic gonadotropin, human placental alkaline phosphatase and α-inhibin. The present case was diagnosed as endometrial adenocarcinoma with choriocarcinomatous differentiation.
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http://dx.doi.org/10.1292/jvms.17-0015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5487789PMC
June 2017

Telomeres and the natural lifespan limit in humans.

Aging (Albany NY) 2017 04;9(4):1130-1142

Center of Human Development and Aging, Rutgers, The State University of New Jersey, New Jersey Medical School, Newark, NJ 07103, USA.

An ongoing debate in demography has focused on whether the human lifespan has a maximal natural limit. Taking a mechanistic perspective, and knowing that short telomeres are associated with diminished longevity, we examined whether telomere length dynamics during adult life could set a maximal natural lifespan limit. We define leukocyte telomere length of 5 kb as the 'telomeric brink', which denotes a high risk of imminent death. We show that a subset of adults may reach the telomeric brink within the current life expectancy and more so for a 100-year life expectancy. Thus, secular trends in life expectancy should confront a biological limit due to crossing the telomeric brink.
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http://dx.doi.org/10.18632/aging.101216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5425118PMC
April 2017

Association Between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases: A Mendelian Randomization Study.

JAMA Oncol 2017 May;3(5):636-651

Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire.

Importance: The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation.

Objective: To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases.

Data Sources: Genomewide association studies (GWAS) published up to January 15, 2015.

Study Selection: GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available.

Data Extraction And Synthesis: Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population.

Main Outcomes And Measures: Odds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation.

Results: Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [95% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [95% CI, 0.49-0.81]), celiac disease (OR, 0.42 [95% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [95% CI, 0.05-0.15]).

Conclusions And Relevance: It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.
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http://dx.doi.org/10.1001/jamaoncol.2016.5945DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5638008PMC
May 2017

Shorter telomere length in Europeans than in Africans due to polygenetic adaptation.

Hum Mol Genet 2016 06 2;25(11):2324-2330. Epub 2016 Mar 2.

The Center of Human Development and Aging, New Jersey Medical School, Rutgers, Newark, NJ 07103, USA,

Leukocyte telomere length (LTL), which reflects telomere length in other somatic tissues, is a complex genetic trait. Eleven SNPs have been shown in genome-wide association studies to be associated with LTL at a genome-wide level of significance within cohorts of European ancestry. It has been observed that LTL is longer in African Americans than in Europeans. The underlying reason for this difference is unknown. Here we show that LTL is significantly longer in sub-Saharan Africans than in both Europeans and African Americans. Based on the 11 LTL-associated alleles and genetic data in phase 3 of the 1000 Genomes Project, we show that the shifts in allele frequency within Europe and between Europe and Africa do not fit the pattern expected by neutral genetic drift. Our findings suggest that differences in LTL within Europeans and between Europeans and Africans is influenced by polygenic adaptation and that differences in LTL between Europeans and Africans might explain, in part, ethnic differences in risks for human diseases that have been linked to LTL.
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http://dx.doi.org/10.1093/hmg/ddw070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5081046PMC
June 2016

Canine mammary minute oncocytomas with neuroendocrine differentiation associated with multifocal acinar cell oncocytic metaplasia.

J Vet Diagn Invest 2016 Nov 3;28(6):722-728. Epub 2016 Oct 3.

Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, Tokyo, Japan (Nagahara, Kimura, Itahashi, Kawashima, Murayama, Yoshida, Shibutani)Laboratory of Veterinary Pathology, School of Veterinary Medicine, Azabu University, Kanagawa, Japan (Sugahara)

Two solitary and minute tumors of 1 and 1.5 mm diameter were identified by microscopy in the left fourth mammary gland of a 13-year-old female Labrador Retriever dog, in addition to multiple mammary gland tumors. The former tumors were well circumscribed and were composed of small-to-large polyhedral neoplastic oncocytes with finely granular eosinophilic cytoplasm, and were arranged in solid nests separated by fine fibrovascular septa. Scattered lumina of variable sizes containing eosinophilic secretory material were evident. Cellular atypia was minimal, and no mitotic figures were visible. One tumor had several oncocytic cellular foci revealing cellular transition, with perivascular pseudorosettes consisting of columnar epithelial cells surrounding the fine vasculature. Scattered foci of mammary acinar cell hyperplasia showing oncocytic metaplasia were also observed. Immunohistochemically, the cytoplasm of neoplastic cells of the 2 microtumors showed diffuse immunoreactivity to anti-cytokeratin antibody AE1/AE3, and finely granular immunoreactivity for 60-kDa heat shock protein, mitochondrial membrane ATP synthase complex V beta subunit, and chromogranin A. One tumor also had oncocytic cellular foci forming perivascular pseudorosettes showing cellular membrane immunoreactivity for neural cell adhesion molecule. The tumors were negative for smooth muscle actin, neuron-specific enolase, vimentin, desmin, S100, and synaptophysin. Ultrastructural observation confirmed the abundant mitochondria in the cytoplasm of both neoplastic and hyperplastic cells, the former cells also having neuroendocrine granule-like electron-dense bodies. From these results, our case was diagnosed with mammary oncocytomas accompanied by neuroendocrine differentiation. Scattered foci of mammary oncocytosis might be related to the multicentric occurrence of these oncocytomas.
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http://dx.doi.org/10.1177/1040638716664381DOI Listing
November 2016

Aberrant cell cycle regulation in rat liver cells induced by post-initiation treatment with hepatocarcinogens/hepatocarcinogenic tumor promoters.

Exp Toxicol Pathol 2016 Aug 9;68(7):399-408. Epub 2016 Jul 9.

Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509, Japan. Electronic address:

The present study aimed to determine the onset time of hepatocarcinogen/hepatocarcinogenic tumor promoter-specific cell proliferation, apoptosis and aberrant cell cycle regulation after post-initiation treatment. Six-week-old rats were treated with the genotoxic hepatocarcinogen, carbadox (CRB), the marginally hepatocarcinogenic leucomalachite green (LMG), the tumor promoter, β-naphthoflavone (BNF) or the non-carcinogenic hepatotoxicant, acetaminophen, for 2, 4 or 6 weeks during the post-initiation phase using a medium-term liver bioassay. Cell proliferation activity, expression of G2 to M phase- and spindle checkpoint-related molecules, and apoptosis were immunohistochemically analyzed at week 2 and 4, and tumor promotion activity was assessed at week 6. At week 2, hepatocarcinogen/tumor promoter-specific aberrant cell cycle regulation was not observed. At week 4, BNF and LMG increased cell proliferation together with hepatotoxicity, while CRB did not. Additionally, BNF and CRB reduced the number of cells expressing phosphorylated-histone H3 in both ubiquitin D (UBD)(+) cells and Ki-67(+) proliferating cells, suggesting development of spindle checkpoint dysfunction, regardless of cell proliferation activity. At week 6, examined hepatocarcinogens/tumor promoters increased preneoplastic hepatic foci expressing glutathione S-transferase placental form. These results suggest that some hepatocarcinogens/tumor promoters increase their toxicity after post-initiation treatment, causing regenerative cell proliferation. In contrast, some genotoxic hepatocarcinogens may disrupt the spindle checkpoint without facilitating cell proliferation at the early stage of tumor promotion. This suggests that facilitation of cell proliferation and disruption of spindle checkpoint function are induced by different mechanisms during hepatocarcinogenesis. Four weeks of post-initiation treatment may be sufficient to induce hepatocarcinogen/tumor promoter-specific cellular responses.
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http://dx.doi.org/10.1016/j.etp.2016.06.002DOI Listing
August 2016
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