3-O-Laurylglyceryl ascorbate reinforces skin barrier function through not only the reduction of oxidative stress but also the activation of ceramide synthesis.

OBJECTIVE: A higher trans-epidermal water loss (TEWL) occurs in rough skin, in elder skin and also in atopic dermatitis. An impaired skin barrier function is considered to be caused by an incomplete construction of the intercellular lamellar structure due to the quantitative reduction of ceramides. Since these symptoms coexist with oxidative stress, we hypothesized that impairment of the skin barrier function is accelerated by oxidative stress. Thus, the purpose of this study was to clarify the effect of oxidative stress on ceramide synthesis and to characterize whether antioxidants can improve skin barrier function. 3-O-Laurylglyceryl ascorbate (VC-3LG), which is a newly amphipathic derivative of ascorbic acid, was evaluated as a candidate antioxidant. METHODS: We characterized the mRNA expression levels of serine palmitoyltransferase (SPT) in normal human epidermal keratinocytes (NHEKs) treated with H2 O2 using real-time PCR analysis. In order to evaluate the effect of VC-3LG on skin barrier function, we used several assays with reconstructed human epidermis equivalents (RHEEs). RESULTS: Ceramide synthesis was down-regulated in NHEKs by oxidative stress. Treatment with VC-3LG abrogated the down-regulation of SPT mRNA in NHEKs caused by oxidative stress, and stimulated SPT mRNA expression levels. In experiments characterizing the antioxidative properties of VC-3LG, VC-3LG reduced oxidative stress in NHEKs by up-regulating catalase mRNA expression. In addition, VC-3LG stimulated the skin barrier function in RHEEs, which had lower TEWL values compared with untreated RHEEs. Furthermore, VC-3LG increased the quantity of ceramide in RHEEs. CONCLUSION: Taken together, we conclude that VC-3LG reinforces the skin barrier function due to its reduction of oxidative stress and its promotion of ceramide synthesis.

Prevalence and clinical significance of supra- or infraclavicular drainage on preoperative lymphoscintigraphy in women with breast cancer.

OBJECTIVE: Preoperative sentinel lymph node (SLN) mapping by lymphoscintigraphy is helpful to evaluate extra-axillary SLNs over a wider range than the blue dye method. However, the clinical value of extra-axillary SLNs remains uncertain. The goal of this study was to determine the prevalence and clinical significance of supra- or infraclavicular drainage on preoperative lymphoscintigraphy in women with breast cancer. MATERIALS AND METHODS: We retrospectively reviewed the files of 942 consecutive breast cancer women who underwent preoperative lymphoscintigraphy for SLN biopsy at our institution between April 2004 and March 2015. RESULTS: Supra- or infraclavicular drainage was detected in 5/942 women (0.5%) on preoperative lymphoscintigraphy. An axillary hot spot was detected in all five women, and a positive axillary SLN was detected in four women. Breast tumor locations were the upper inner or outer quadrants in four women and the lower outer quadrant in one woman. The median follow-up period was 75 months (mean: 92; range: 26-111 months). Recurrence outside the axilla was found in three (60%) women. The woman with a negative SLN status did not undergo adjuvant chemotherapy, but developed extra-axillary lymph node recurrence 3 years after primary surgery. No patient died of metastatic breast cancer at the last follow-up. CONCLUSIONS: The detection of the supra- or infraclavicular SLNs on lymphoscintigraphy may provide additional staging information to tailor individual treatment regimens with regard to the potential risk of recurrence or metastasis of breast cancer.

Successful treatment of toxoplasmic encephalitis diagnosed early by polymerase chain reaction after allogeneic hematopoietic stem cell transplantation: two case reports and review of the literature.

Toxoplasmic encephalitis represents a rare, but often fatal infection after allogeneic hematopoietic stem cell transplantation. Polymerase chain reaction (PCR)-based preemptive therapy is considered promising for this disease, but is not routinely applied, especially in low seroprevalence countries including Japan. We encountered 2 cases of toxoplasmic encephalitis after transplantation that were successfully treated. The diagnosis of toxoplasmic encephalitis in these cases was confirmed by PCR testing when neurological symptoms were observed. Both patients received pyrimethamine and sulfadiazine treatments within 2 weeks of the development of neurological symptoms, and remained free of recurrence for 32 and 12 months. These results emphasized the importance of the PCR test and immediate treatment after diagnosis for the management of toxoplasmic encephalitis.

Palmdelphin, a novel target of p53 with Ser46 phosphorylation, controls cell death in response to DNA damage.

The tumor suppressor gene p53 regulates apoptosis in response to DNA damage. Promoter selectivity of p53 depends on mainly its phosphorylation. Particularly, the phosphorylation at serine-46 of p53 is indispensable in promoting pro-apoptotic genes that are, however, poorly determined. In the current study, we identified palmdelphin as a pro-apoptotic gene induced by p53 in a phosphorylated serine-46-specific manner. Upregulation of palmdelphin was observed in wild-type p53-transfected cells, but not in serine-46-mutated cells. Expression of palmdelphin was induced by p53 in response to DNA damage. In turn, palmdelphin induced apoptosis. Intriguingly, downregulation of palmdelphin resulted in necroptosis-like cell death via ATP depletion. Upon DNA damage, palmdelphin dominantly accumulated in the nucleus to induce apoptosis. These findings define palmdelphin as a target of serine-46-phosphorylated p53 that controls cell death in response to DNA damage.

Weekly chemotherapy with cisplatin, vincristine, doxorubicin, and etoposide followed by surgery for thymic carcinoma.

OBJECTIVE: We present our experience treating the patients with thymic carcinoma using induction chemotherapy according to weekly chemotherapy with cisplatin, vincristine, doxorubicin, and etoposide (CODE) followed by surgery. PATIENTS AND METHODS: From January 2001 to December 2010, 17 patients were diagnosed as having thymic carcinoma at our hospital. We performed CODE chemotherapy for induction treatment followed by surgical resection in 7 of these patients. RESULTS: Seven patients consisted of 6 men and 1 woman, with an average age of 47.3 years (range 25-67 years). Five patients were clinically staged as Masaoka Stage III, and 2 were Stage IVa. A partial response was identified in 5 patients, and stable disease was observed in 2 patients. No cases of progressive disease were seen. Surgical resection was performed in all the patients: 6 underwent an R0 resection and 1 underwent an R1 resection. The estimated overall survival rates at 5 and 10 years were both 80%, and the relapse-free survival rates at 5 and 10 years were 68.6% and 53.6% respectively. CONCLUSIONS: Induction chemotherapy using the CODE regimen, followed by a complete surgical resection can be performed with a promising survival outcome for patients with thymic carcinoma with borderline resectable lesions.

Post-translational modifications of p53 tumor suppressor: determinants of its functional targets.

Tumor suppressor p53 functions as a "guardian of the genome" to prevent cells from transformation. p53 is constitutively ubiquitinated and degradated in unstressed conditions, thereby suppressing the expression. However, cellular stimuli enable p53 to escape from the negative regulation, and then stably expressed p53 transactivates its target genes to induce cell cycle arrest, DNA repair, or apoptosis. Promoter preference of target genes is determined by modification status of p53. Because p53 has two critical roles in the decision of cell fate, stopping cell cycle to repair damaged DNA or induction of apoptotic cell death in response to DNA damage, elucidation of switching mechanisms on p53 functions is of particular importance. Here we review recent evidence how several post-translational modifications of p53 including methylation, phosphorylation, acetylation, and ubiquitination, affect the functions of p53 in response to cellular stress.

TTK/Mps1 controls nuclear targeting of c-Abl by 14-3-3-coupled phosphorylation in response to oxidative stress.

Upon exposure to genotoxic stress, the c-Abl tyrosine kinase is released from cytoplasmic 14-3-3 proteins and then is targeted to the nucleus. Phosphorylation of Thr735 in c-Abl is critical for binding to 14-3-3; however, kinases responsible for this phosphorylation are unknown. Here, we identify CLK1, CLK4, MST1, MST2 and TTK (also known as Mps1) as novel Thr735 kinases in vitro by expression cloning strategy using phosphospecific antibody. We also demonstrate that ectopic expression of these kinases is capable for phosphorylation of Thr735 in cells. Importantly, upon exposure to oxidative stress, phosphorylation of Thr735 is transiently upregulated, and the status of this phosphorylation remains unchanged in cells silenced for CLK1, CLK4, MST1 or MST2. By contrast, knockdown of TTK attenuates phosphorylation of Thr735, suggesting that TTK is a physiological kinase that phosphorylates Thr735. In concert with these results, we show that, in cells silenced for TTK, c-Abl is accumulated in the nucleus even in unstressed condition and no further targeting into the nucleus occurs after oxidative stress. Moreover, nuclear entrapment of c-Abl by knocking down TTK enhances oxidative stress-induced apoptosis. These findings provide evidence that TTK phosphorylates c-Abl at Thr735 and that this phosphorylation is of importance to the cytoplasmic sequestration of c-Abl.

Larvicidal effects of several chemicals on Strongyloides infective larvae.

The larvicidal effects of 11 anthelmintics, 7 pesticides and 4 disinfectants were evaluated with infective larvae of Strongyloides papillosus (SPL) and Strongyloides venezuelensis (SVZ). The lethal concentrations against SPL and SVZ were found to be similar. Three chemicals (dichlorvos, levamisole and trichlorfon) showed highest larvicidal effects. The 50% lethal concentration (LC(50)) values for the three compounds against SPL larvae were 0.08, 0.24, and 0.59 ppm, respectively.

Frontal lobe dementia with abnormal cholesterol metabolism and heterozygous mutation in sterol 27-hydroxylase gene (CYP27).

Of the primary dementing disorders that cause frontotemporal dementia, the best-known is Pick disease. We report on a 44-year-old woman with progressive frontal lobe dementia and spastic paraplegia. Examination revealed increased serum levels of cholestanol with abnormal cholesterol metabolism and a heterozygous mutation of the sterol 27-hydroxylase gene (CYP27). Biochemical findings were compatible with cerebrotendinous xanthomatosis (CTX); however, the clinical manifestations were very dissimilar. To our knowledge, a symptomatic carrier of this mutation among CTX patients has not been reported. We speculate that the present patient has a previously undescribed neurodegenerative disease related to abnormal cholesterol metabolism with this heterozygous mutation.

Primary subclavian venous thrombosis which developed after sleeping with the arm in an outstretched position: report of a case.

Primary subclavian venous thrombosis is more rare than secondary thrombosis. This type of thrombosis is called "effort thrombosis" or Paget-Schroetter syndrome, and develops after a strenuous effort of the superior limb. A day after a 55-year-old man got drunk and slept in the left lateral position in combination with an abducted and elevated position of the left superior limb, he became aware of swelling and an oppressive feeling in his left superior limb and was admitted 9 days later. Thrombus of the left axillary-subclavian vein was confirmed by venography, and thrombolytic therapy with urokinase was performed immediately. The left arm symptoms improved for the most part. Venography after the therapy revealed thrombolysis at the site of the axillary vein, while the subclavian vein enhanced the collateral vessel pathway. The patient was discharged on the seventh hospital day, and anticoagulant therapy with oral warfarin sodium has since been continued. This is considered to be a rare case of subclavian venous thrombosis caused by sleeping in an abnormal position with the arm outstretched.

Differential sensitivity of Kv1.4, Kv1.2, and their tandem channel to acidic pH: involvement of a histidine residue in high sensitivity to acidic pH.

We studied the effects of acidic pH on the currents through voltage-gated K+ channels, Kv1.2, Kv1.4, and their tandem construct (Kv1.4-Kv1.2). Kv1.4 currents were inhibited considerably under acidic pH in a voltage-independent manner, whereas Kv1.2 currents were less inhibited in an apparently voltage-dependent manner. The apparent voltage-dependent block of Kv1.2 currents was mostly ascribed to the shift of activation voltage, which is probably due to surface charge effects of H+ ions. Mutagenesis analysis identified the histidine residue at 508 (H508) in the S5-H5 linker as a molecular determinant of pH sensitivity of Kv1.4. Currents through the tandem channel showed intermediate characteristics between the two parent channels in both sensitivity and voltage dependence of pH effects. Our results suggest that 1) the H508 plays a critical role in determining pH sensitivity of Kv1.4; and 2) the two parent channels, Kv1.2 and Kv1.4, are involved in determining pH sensitivity and apparent voltage dependence of the tandem channel.

Pancreatitis induced by valproic acid: report of a case.

A 22-year-old woman with intellectual impairment, who had been taking valproic acid continuously for 19 years since being diagnosed with epiloia at the age of 3 years, presented to our hospital following the sudden development of epigastric pain. An abdominal computed tomography scan revealed acute exacerbation of chronic pancreatitis. Conservative treatment was initiated, despite which the pancreatitis became exacerbated, necessitating resection of the pancreatic head and duodenum. Histological examination of the resected specimens revealed a large number of pancreatic calculi in the main pancreatic duct, suggesting chronic pancreatitis with fibrosis at the periphery. The incidence of pancreatitis developing in association with valproic acid is unclear; however, only 40 such cases have been reported in the English literature. Most of the patients previously described presented with acute pancreatitis in the initial stage. However, the clinical course of our patient, with acute exacerbation following a relatively chronic course, was different from those previously described, suggesting the presence of chronic pancreatitis related to valproic acid.

Changes in the inactivation of rat Kv1.4 K(+) channels induced by varying the number of inactivation particles.

N-type inactivation of rat Kv1.4 channels with one, two, or four inactivation balls was investigated using homogeneous populations of channels expressed in Xenopus oocytes. Tandem dimeric and tetrameric constructs of Kv1.4 were made. Channels encoded by tandem cDNAs Kv1. 4-Kv1.4Delta1-145 and Kv1.4-[Kv1.4Delta1-145](3) have two or only one tethered inactivation ball, respectively, whereas Kv1.4 itself encodes channels having four inactivation balls. The time constants for inactivation of macroscopic currents were increased significantly as the number of inactivation balls was decreased, whereas the time constants for recovery from inactivation were not modified. The ratios of the rate constants of inactivation (k(inact)) of Kv1.4-Kv1.4Delta1-145 and Kv1.4-[Kv1.4Delta1-145](3) channels to that of the Kv1.4 channel were 0.65 and 0.4, respectively, whereas the ratios of the rate constant of recovery (k(rec)) of these channels to that of Kv1.4 were almost unity. The rate constants k(inact) for channels having two and four inactivation balls are smaller than those that would be expected if inactivation balls on each channel are independent, suggesting some interaction occurs between inactivation balls. Furthermore, noninactivating current became apparent as the number of inactivation balls on a channel was decreased.

A patient with primary biliary cirrhosis associated with autoimmune hemolytic anemia.

Primary biliary cirrhosis is often associated with autoimmune conditions, such as thyroid disease, sicca complex, and rheumatoid arthritis. However, an association with autoimmune hemolytic anemia has rarely been reported. We present a case of primary biliary cirrhosis associated with warm type autoimmune hemolytic anemia, and we review prior reports.

Psychiatric inpatients and chromosome deletions within 22q11.2.

Velocardiofacial syndrome (VCFS) is a congenital disorder characterised by multiple dysmorphisms, cleft palate, cardiac anomalies, and learning disabilities due to a microdeletion of chromosome 22q11.2. Although VCFS is often associated with psychiatric symptoms, its prevalence among psychiatric patients is unknown. A total of 326 patients admitted in September and October 1997 to a Japanese psychiatric hospital were screened for the clinical features of VCFS. Twelve patients with minor facial dysmorphia were identified; chromosomal analysis with fluorescent in situ hybridisation (FISH) was performed in six patients who, further assessment suggested, were most likely to have VCFS. Chromosome 22q11.2 deletion was identified in a 41 year old woman who had symptoms of schizophrenia but no major dysmorphia, such as cardiovascular anomalies and cleft palate. Her behavioural and neuropsychological profiles were similar to those previously reported in VCFS. She was hemizygous for the FISH probe N25 (GDB locus D22S75) and also for probes N72H9 (D22S181), sc11.1a, C443 (D22S941), sc4.1 (D22S134), sc11.1b, N19B3 (D22S264), N122B5 (D22S934), and N77F7 (D22S939). The size of the deletion was about 3 Mb. Our patient had only some features of VCFS including a square nasal root, hypernasal speech, and hypoparathyroidism. She did, however, have the common larger deletion of type A. This finding suggests that psychiatric symptoms in VCFS can occur without major developmental symptoms such as cardiovascular anomalies and cleft palate. Additional patients with schizophrenia may have subtle features of VCFS which are unrecognised on routine medical examinations.

Similarity and dissimilarity in mode and mechanism of action between YT-146, a selective adenosine receptor A2 agonist, and adenosine in isolated canine hearts.

To elucidate the differences in mode and mechanism of action between YT-146, a highly selective adenosine A2 receptor agonist, and adenosine, we compared their effects on coronary circulation and myocardium and modifications of these effects by glibenclamide, a blocker of ATP-sensitive potassium (K) channels, in three kinds of isolated, blood-perfused canine heart preparations. YT-146 and adenosine were injected i.a. In all preparations both YT-146 and adenosine increased coronary blood flow and in this respect YT-146 was about 5 times as potent as adenosine. The increase in blood flow caused by adenosine was transient, whereas that produced by YT-146 was biphasic; the transient increase was followed by a sustained one. In isolated, blood-perfused sinoatrial (SA) node preparations, YT-146 failed to affect sinus rate, whereas adenosine reduced sinus rate by about 38% at its maximum effect. In isolated, blood-perfused atrioventricular (AV) node preparations, when injected into the artery supplying the AV node, YT-146 exerted no effect on AV conduction time, whereas adenosine prolonged AV conduction time by about 17% at the maximum effect. In isolated, blood-perfused papillary muscle preparations, the force of contraction was affected by neither YT-146 nor adenosine. In the same preparations the effect of YT-146 in increasing coronary blood flow was antagonized by glibenclamide in such a manner that the maximum increase was suppressed, but that of adenosine was not. Reactive hyperemia induced by ischemia for 30 seconds was not affected by glibenclamide. These results suggest that although both YT-146 and adenosine produce an increase in coronary blood flow via adenosine A2 receptors, the opening of ATP- or glibenclamide-sensitive K channels is involved in the action of the former, but scarcely in the action of the latter. The opening of ATP- or glibenclamide-sensitive K-channels is less likely involved in reactive hyperemia.

Vitamin D3 analogue KH1060 combined with TPA synergistically induces mature macrophages in human myeloblastic leukemia ML-1 cells.

A human myeloblastic leukemia cell line, ML-1, was induced to differentiate along the monocytic lineage following exposure to a 1,25-dihydroxyvitamin D3 analogue, 20-epi-22-oxa-24a,26a,27a-tri-homo-1,25-dihydroxyvitam in D3 (KH1060) or 12-O-tetradecanoylphorbol-13-acetate (TPA). The combination of KH1060 and TPA synergistically induced differentiation of ML-1 cells into mature macrophages with multinuclei. Maturation was also observed in other differentiation characteristics such as phagocytic activity, a-naphthyl acetate esterase activity, and expression of surface antigen CD14. Differentiated ML-1 cells showed attenuation of telomerase activity and cessation of proliferating activity based on evaluation of the expression of genes related to cell growth potential. Remarkable synergism was observed in TNF production. Treatment with TPA prior to KH1060 resulted in only slight production of TNF; however, treatment with KH1060 preceding TPA induced a substantial amount of TNF.

[Palliation for a recurrent lung cancer patient with superior vena cava syndrome by arterial infusion of CDDP through the implantable port system--a case report].

A case of lung cancer with superior vena cava syndrome treated with internal thoracic arterial infusion of anti-cancer drugs by the implantable port system was reported with our technique. In this case, blood supply was mainly from internal thoracic artery. A trans-catheterial contrast enhanced helical CT was very helpful to identify the routes of blood supply to the lung cancer.

[Documents related to a medical prescription book in the Date Museum (Date City, Hokkaido)].

This is a report of a prescription book which Munetomo Murayama, a medical doctor attached to the Date Watari Feudal Clan, inherited from his ancestors and handed on to his descendants. It is now preserved in the Date Museum in Date, Hokkaido, Japan, and the records there show that it was donated by a descendant of Dr. Murayama. The prescription book is unique in its detailed descriptions that are different from traditional medicine. It describes specific illnesses and the medications that were used in their treatment. The illnesses described are not serious ailments but illnesses commonly encountered in daily life and commonly available (over-the-counter) drugs recommended for the treatment of stomach ailments, diarrhea ; drugs for external use, also 'tochino' (a non-prescription drug commonly used for all kinds of illnesses in old times in Japan), drugs for tiredness, hemorrhoids, cough relief, aroma therapy, and others. Some of the drugs are also recognized today as being effective and having medicinal effects. They are thought to be agents with medicinal effects and the treatments reported by Dr. Murayama are separate and different from the Shimizu style in which they are applied.

[Primary liposarcoma of the anterior mediastinum--case report and review of literature].

A 76-year-old male with anterior mediastinal tumor was admitted to our hospital. He had undergone mediastinal lipoma surgery 3 years earlier. The tumor was excised surgically. Microscopic sections of the tumor showed liposarcoma composed of myxoid tissue. Further examination of prior specimens taken from this patient proved this case to be a recurrence of liposarcoma. Poorly differentiated tumors, which pathologically tend to be more cellular with less fat per cell component, are likely to have high CT numbers. But CT number is not sufficient to distinguish well-differentiated liposarcoma from benign lipoma.