Protein tyrosine phosphatase receptor type Q in cerebrospinal fluid reflects ependymal cell dysfunction and is a potential biomarker for adult chronic hydrocephalus.

BACKGROUND AND PURPOSE: Protein tyrosine phosphatase receptor type Q (PTPRQ) was extracted from the cerebrospinal fluid (CSF) of patients with probable idiopathic normal-pressure hydrocephalus (iNPH) by proteome analysis. We aimed to assess the feasibility of using CSF PTPRQ concentrations for the additional diagnostic criterion of iNPH in Japanese and Finnish populations. METHODS: We compared PTPRQ concentrations among patients with probable iNPH and neurologically healthy individuals (normal control [NC] group), patients with normal-pressure hydrocephalus (NPH) of acquired and congenital/developmental aetiologies, patients with Alzheimer's disease and patients with Parkinson's disease in a Japanese analysis cohort. A corresponding iNPH group and NC group in a Finnish cohort was used for validation. Patients in the Finnish cohort who underwent biopsy were classified into two groups based on amyloid and/or tau deposition. We measured PTPRQ expression levels in autopsied brain specimens of iNPH patients and the NC group. RESULTS: Cerebrospinal fluid PTPRQ concentrations in the patients with NPH of idiopathic, acquired and congenital/developmental aetiologies were significantly higher than those in the NC group and those with Parkinson's disease, but iNPH showed no significant differences when compared with those in the Alzheimer's disease group. For the patients with iNPH, the area under the receiver-operating characteristic curve was 0.860 in the Japanese iNPH and 0.849 in the Finnish iNPH cohorts. Immunostaining and in situ hybridization revealed PTPRQ expression in the ependymal cells and choroid plexus. It is highly possible that the elevated PTPRQ levels in the CSF are related to ependymal dysfunction from ventricular expansion. CONCLUSIONS: Cerebrospinal fluid PTPRQ levels indicated the validity of this assay for auxiliary diagnosis of adult chronic hydrocephalus.

Representation of older patients in clinical trials for drug approval in Japan.

To examine how target patients seen in clinical practice are represented in clinical trials for approved drugs in Japan, we compared the age distribution of older patients enrolled in confirmatory clinical trials for regulatory approval with that of the estimated actual patient population. Drugs for 6 chronic conditions common among older patients (diabetes mellitus, hypertension, rheumatoid arthritis, non-small cell lung cancer, depression and Alzheimer's disease) launched by 2012 in Japan were selected. The disparity in age distribution between patients in trials and patients seen in clinical practice varied depending on the disease, but older patients, especially those aged 75 or older, were generally underrepresented in clinical trials for regulatory approval in Japan. Under-representation of older patients in hypertension trials was particularly marked compared to other conditions, despite the similarity in age distribution of patients seen in clinical practice. One factor causing this disparity may be an upper age limit in clinical trial protocols. More effort is needed to properly characterize the benefits and risks of drugs for older patients. This should include the active enrollment of older patients in clinical trials, the establishment of better assessment tools such as pharmacometric approaches, and the appropriate planning and conducting of post-marketing surveys and studies.

The pleiotrophin-ALK axis is required for tumorigenicity of glioblastoma stem cells.

Increasing evidence suggests that brain tumors arise from the transformation of neural stem/precursor/progenitor cells. Much current research on human brain tumors is focused on the stem-like properties of glioblastoma. Here we show that anaplastic lymphoma kinase (ALK) and its ligand pleiotrophin are required for the self-renewal and tumorigenicity of glioblastoma stem cells (GSCs). Furthermore, we demonstrate that pleiotrophin is transactivated directly by SOX2, a transcription factor essential for the maintenance of both neural stem cells and GSCs. We speculate that the pleiotrophin-ALK axis may be a promising target for the therapy of glioblastoma.

The critical role of cyclin D2 in cell cycle progression and tumorigenicity of glioblastoma stem cells.

Cancer stem cells are believed to be responsible for tumor initiation and development. Much current research on human brain tumors is focused on the stem-like properties of glioblastoma stem cells (GSCs). However, little is known about the molecular mechanisms of cell cycle regulation that discriminate between GSCs and differentiated glioblastoma cells. Here we show that cyclin D2 is the cyclin that is predominantly expressed in GSCs and suppression of its expression by RNA interference causes G1 arrest in vitro and growth retardation of GSCs xenografted into immunocompromised mice in vivo. We also demonstrate that the expression of cyclin D2 is suppressed upon serum-induced differentiation similar to what was observed for the cancer stem cell marker CD133. Taken together, our results demonstrate that cyclin D2 has a critical role in cell cycle progression and the tumorigenicity of GSCs.

Cardiac tamponade due to systemic lupus erythematosus in patient with Prader-Willi syndrome after growth hormone therapy.

We present a 16-year old girl with Prader-Willi syndrome who developed cardiac tamponade as an initial finding of systemic lupus erythematosus. Until one year prior to this episode, she had received growth hormone treatment for nine years. The association among Prader-Willi syndrome, growth hormone treatment and systemic lupus erythematosus is discussed.

Immunomodulatory effects of polysaccharides produced by Lactobacillus delbrueckii ssp. bulgaricus OLL1073R-1.

The extracellular polysaccharides (EPS) produced by lactic acid bacteria (LAB) are associated with the rheology, texture, and mouthfeel of fermented milk products, including yogurt. This study investigated the immunomodulatory effects of EPS purified from the culture supernatant of Lactobacillus delbrueckii ssp. bulgaricus (L. bulgaricus) OLL1073R-1. The crude EPS were prepared from the culture supernatant of L. bulgaricus OLL1073R-1 by standard chromatographic methods, and were fractionated into neutral EPS and acidic EPS (APS). Acidic EPS were further fractionated into high molecular weight APS (H-APS) and low molecular weight APS (L-APS). High molecular weight APS were shown to be phosphopolysaccharides containing D-glucose, D-galactose, and phosphorus. Stimulation of mouse splenocytes by H-APS significantly increased interferon-gamma production, and, moreover, orally administered H-APS augmented natural killer cell activity. Oral administration of yogurt fermented with L. bulgaricus OLL1073R-1 and Streptococcus thermophilus OLS3059 to mice showed a similar level of immunomodulation as H-APS. However, these effects were not detected following administration of yogurt fermented with the starter combination of L. bulgaricus OLL1256 and S. thermophilus OLS3295. We conclude from these findings that yogurt fermented with L. bulgaricus OLL1073R-1, containing immunostimulative EPS, would have an immunomodulatory effect on the human body.

Gastric ciliated metaplasia. A study of 3406 gastrectomy specimens from dwellers of the Atlantic and the Pacific basins.

BACKGROUND: Ciliated cells in gastrectomies from patients dwelling in the Pacific and Atlantic basins have been reported previously. AIM: To compare all the results in an attempt to explain the findings. METHODS: Sections from 3406 gastrectomies were reviewed: 1966 and 1440 from the Atlantic and Pacific basins, respectively. Ciliated cells and intestinal metaplasia (IM) were recorded; IM was classified into focal or extensive IM. The total number of sections/gastrectomy was noted. RESULTS: In the Atlantic basin, 5% of specimens had ciliated metaplasia (CM); it was more frequent in intestinal carcinoma (IC; 9%) than diffuse carcinoma (DC; 3%) or miscellaneous gastric diseases (MGD; 3%). In the Pacific basin, the frequency of specimens with CM was 29%: it was more frequent in IC (43%) than in DC (16%) or MGD (10%). The difference between the frequency of CM in specimens with IC or with DC/MGD in the Atlantic and the Pacific basins was significant (p < or = 0.05). The presence of CM was influenced by age and the extent of IM in both basins, but not by sex or the number of sections investigated. CONCLUSIONS: CM-apparently an independent microscopic marker-was significantly higher in the Pacific than in the Atlantic basin. Environmental carcinogens involved in the evolution of IM and IC seem to be implicated in gastric ciliogenesis. Carcinogens that differ in nature and/or in strength in both basins might activate the latent natural genes encoding ciliated processes in gastric cells in patients subsequently developing gastric carcinoma, more notably of intestinal type.

Extended intestinal metaplasia. A survey of 1392 gastrectomies from dwellers of the Pacific basin.

BACKGROUND: To assess the extent of gastric intestinal metaplasia (IM) in gastrectomy specimens in populations of the Pacific basin having different incidence of gastric carcinoma. MATERIALS AND METHODS: One thousand three hundred and nine-two gastrectomies were investigated: 1088 had a gastric carcinoma and 304 miscellaneous gastric diseases. Twenty-one thousand three hundred and fourteen histological sections were reviewed under low-power (4X). IM was either spotty (SIM) or extended (EIM= encompassing one or more entire low-power fields/section). Widespread IM (WIM) was regarded as EIM if present in > or =5 histological sections. RESULTS AND CONCLUSION: The percent of gastrectomies harboring a carcinoma increased significantly with increasing age more notably in those with diffuse carcinomas (DC) than in those with intestinal carcinomas (IC). The percent of gastrectomies with EIM was significantly higher in specimens with IC than with DC, particularly among elderly patients, and in specimens from countries with a high cancer incidence. The percent of gastrectomies with WIM was higher in specimens having IC than in those having DC. Migration per se did not influence the frequency of specimens with EIM in elderly Japanese patients: Japanese migrants to Hawaii had a similarly high frequency of EIM as those dwelling in Japan. Japanese patients with a gastric carcinoma showed atypical mitoses in areas with EIM far from the tumor, suggesting that cellular mutation(s) play a role in the evolution of EIM towards gastric dysplasia and carcinoma in that ethnic group. The drawback of gastric biopsies in assessing the extent of gastric intestinal metaplasia and, thereby, estimating possible cancer risk in long-term studies has been stressed.

Effect of shear stress on platelet adhesion to expanded polytetrafluoroethylene, a silicone sheet, and an endothelial cell monolayer.

We visualized in real-time platelets adhering to the surface of three representative biomaterials, by using an apparatus consisting of a modified cone and plate rheometer combined with an upright epifluorescence microscope under two shear flows (0.1 and 5.0 dyne/cm2). The materials were expanded polytetrafluoroethylene (ePTFE), silicone sheet, and a monolayer of bovine endothelial cells (ECs) formed on glass, all of which are opaque materials used for artificial blood vessels and medical devices. According to quantitative analysis, the monolayer of ECs formed on glass had better blood compatibility than did either the ePTFE or the silicone sheet under shear flow conditions. Under a shear flow condition of 0.1 dyne/cm2, platelet adhesion was silicone sheet > ePTFE. In contrast, under a shear flow condition of 5.0 dyne/cm2, ePTFE > silicone sheet. These results indicate that the intensity of shear stress could modify the order of hemocompatibility of the materials. Therefore, direct observation of platelet adhesion under shear flow conditions is indispensable for testing and screening biomaterials and for providing a precise quantitative evaluation of platelet adhesion.

Atypical osteosarcomas in Werner Syndrome (adult progeria).

Werner syndrome (WS), adult progeria, is more common in Japan than elsewhere. It predisposes to osteosarcoma (OS) and five other rare tumors. To determine if and how OS is atypical in this genetic disorder, we studied the characteristics of ten Japanese cases with respect to clinical features, pathology, and radiographs, and compared them with a hospital series of 36 skeletal OS with the same atypical age-range, 35 - 57 years. The anatomic sites were also atypical: seven ankle / foot, two radius and one patella compared with only one at the ankle in the hospital series. The osteoblastic cell-type was about equally frequent in both series, but, among others than the three major subtypes, there was only one in WS as compared with 14 (39%) in the hospital series. The types of mutations were sought in five WS cases with OS. One showed no mutation at any of the ten known loci for Japanese, two were of type 4 / 4 and two of type 6 / 6. The mutations 4 and 6 have been found in 66% of alleles of WS cases in Japan. The increased frequency and unusual age and site distributions of OS in WS may be due to increased susceptibility, related to later-life leg ulcers, and weight-bearing on spindly ankles weakened by severe loss of lower limb subcutaneous tissue.

Adrenergic mediation of TNF alpha-stimulated ICAM-1 expression on human brain microvascular endothelial cells.

Adrenergic innervation derived from locus ceruleus has been implicated in regulating BBB permeability and inflammatory responses associated with neurological disorders. This report demonstrates that adrenergic agents attenuate the tumor necrosis factor-alpha (TNF alpha)-induced expression of intercellular adhesion molecule-1 (ICAM-1) on cerebral microvascular endothelial cells (HBMEC) derived from human brains. HBMEC were incubated with isoproterenol (1-10 microM) alone or in the presence of propranolol (10 microM) for 30 min followed by the addition of various concentrations of TNF alpha. ICAM-1 expression on cultured HBMEC was dose-dependently upregulated by TNF alpha. Incubation with isoproterenol significantly reduced levels of ICAM-1 expression indicating the possible involvement of adrenergic agents on ICAM-1 expression. Treatment with propranolol (beta 1/beta 2-adrenergic antagonist) and butoxamine (beta 2-adrenergic antagonist), but not atenolol (beta 1-adrenergic antagonist) reversed this inhibitory effect. Isoproterenol also dose-dependently stimulated cAMP production (assayed by RIA) by HBMEC; propranolol treatment abolished this effect. These data show that the beta 2-adrenergic receptor/cAMP pathway may be partly involved in TNF alpha-stimulated ICAM-1 expression and indicate the possible involvement of adrenergic mediation of capillary function including BBB integrity.

Endothelin receptor antagonist preserves microvascular perfusion and reduces ischemic brain damage following permanent focal ischemia.

Synthesis and release of the potent vasoconstrictor peptide endothelin-1 (ET-1) increases following cerebral ischemia and has previously been shown to mediate the delayed hypoperfusion associated with transient global ischemia. In this study we assessed the impact of ET-1 on perfusion and infarct volume in a focal model of cerebral ischemia by use of the selective ET(A) receptor antagonist Ro 61-1790 (affinity for ET(A) receptor 1000 fold greater than ETB receptor). Control rats subjected to permanent middle cerebral artery occlusion (MCAO) showed extensive reductions in microvascular perfusion 4 h post-MCAO that were significantly attenuated by Ro 61-1790 pretreatment (10 mg/kg, i.v.). Ro 61-1790 concomitantly and significantly reduced the ischemic lesion volume in the same animals. This effect was maintained 24 h post-MCAO providing that the animals received additional i.v. injections of 5 mg/kg Ro 61-1790 at 5 h and 8 h after MCAO. These findings demonstrate that ET(A) receptor antagonism partially preserves tissue perfusion following focal ischemia and that this effect is associated with significant neuroprotection. The results also support the hypothesis that vasoactive mediators, and ET-1 in particular, are important contributors to the pathogenesis of cerebral ischemic injury.

Disappearance of wheezing during epidural lidocaine anesthesia in a patient with bronchial asthma.

BACKGROUND AND OBJECTIVES: Local anesthetics in blood absorbed from the epidural space attenuate bronchial hyperreactivity to chemical stimuli. However, it is not documented whether local anesthetics at clinically relevant concentrations improve active wheezing in patients with bronchial asthma. CASE REPORT: We managed a 60-year-old man with bronchial asthma and active wheezing under continuous epidural anesthesia using plain lidocaine. The wheezing gradually diminished 20 minutes after the epidural injection of 13 mL 2% lidocaine and completely disappeared over 155 minutes during continuous epidural injection of 2% lidocaine (6 mL/h). The plasma concentrations of lidocaine in arterial blood during the epidural anesthesia ranged from 2.5 to 3.9 microg/mL. Wheezing reappeared 55 minutes after termination of the continuous epidural injection of lidocaine. The plasma concentration of lidocaine at this time was 1.9 microg/mL. CONCLUSIONS: At clinically relevant concentrations, lidocaine in the blood absorbed from the epidural space may improve bronchospasm in patients with bronchial asthma.

Real time observation of platelet adhesion to opaque biomaterial surfaces under shear flow conditions.

We developed a new system which enables direct observation of platelet adhesion on opaque biomaterials under shear flow conditions, by combining a thin quartz cone which produces laminar shear flows, with an upright epifluorescence microscope which visualizes stained platelets through the rotating cone. This is the first report on the observation of platelets adhered to opaque biomaterials in real time under shear flow conditions. The direct observation of platelet adhesion to expanded polytetrafluoroethylene (ePTFE) as an opaque biomaterial revealed that the kinetics of platelet adhesion to ePTFE depended greatly on shear stresses, showing that the shear stress of 5.0 dyne/cm2 induced higher adhesiveness of platelets to ePTFE than that of either 0.1 or 15 dyne/cm2. The observation also showed a difference in platelet adhesiveness among ePTFEs with different fibril lengths--0, 3.2, 18, and 35 microm--indicating that ePTFEs with shorter fibril length had lower adhesiveness of platelets under a shear stress of 5.0 dyne/cm2. It is indispensable for analyzing the phenomena of platelet adhesion to opaque biomaterials to observe in real-time rolling, adhesion, and detachment of platelets under shear stresses without disturbing shear flow conditions. The results showed that the mechanical and optical design of the system could serve this purpose.

[Anesthetic management of a morbidly obese patient with intestinal obstruction].

We managed a morbidly obese patient [body weight 150 kg, body height 157 cm (body mass index, 61 kg.m-2)] with intestinal obstruction due to incarcerated postoperative ventral hernia. The trachea was intubated while applying cricoid pressure. The SpO2 decreased rapidly down to 30% during intubation, but increased to 100% after ventilation with oxygen. Potential problems in the anesthetic management of morbidly obese patients for emergency surgery are discussed.

Unusual features of thyroid carcinomas in Japanese patients with Werner syndrome and possible genotype-phenotype relations to cell type and race.

BACKGROUND: Werner syndrome (WS), an autosomal recessive disease characterized by premature aging, has a high frequency of association with six rare neoplasms in Japanese patients, and only four of these neoplasms also occur excessively in whites. Several differ from what is usual in their epidemiology and/or histology. Described in this article are peculiarities in the occurrences of follicular and papillary thyroid carcinomas among Japanese patients and the possible genotype-phenotype relations pertaining to cell types and the absence of excess thyroid carcinoma occurrence in whites with WS. METHODS: Epidemiologic features of 23 histologically diagnosed thyroid carcinomas from a series of 150 cancers in 845 Japanese patients with WS were compared with those of 19,446 tumors in a Japanese national registry of thyroid carcinomas from 1977-1991. Germline mutations had been determined by molecular studies of peripheral blood. RESULTS: The average age of patients with thyroid carcinoma was 39 years for those with WS and 49 years for the registry patients. The female-to-male ratios were 2.3:1 and 6.6:1, respectively. The rates of occurrence of papillary, follicular, and anaplastic carcinomas were 35%, 48%, and 13% for Japanese patients with WS and 78%, 14%, and 2% in the general Japanese population. All four cases of follicular carcinoma had germline mutations of the WS gene in the C-terminal region, and the germline mutation for the only papillary carcinoma was in the N-terminal region. CONCLUSIONS: This study suggests two possible WS genotype-phenotype relations. One concerns thyroid carcinoma histology; the other concerns frequent mutations that occur in the C-terminal region in Japanese patients, but not in white patients, with WS. These may account for the excess thyroid carcinoma occurrence among Japanese.

The cancer problem--carcinogenesis and prevention from the viewpoint of the natural history of cancer.

Cancer is mostly environmental in origin and therefore is theoretically preventable by control of environmental conditions. From the viewpoint of the natural history of cancer, the multi-step nature of neoplasia and the generally long latent period are stressed. The molecular biology of cancer tells us that neoplasia is a disease of the genes, with each tumor having its own series of gene alterations. Numerous carcinogens, mutagens and others, have been identified, and we are now in a good position to promote cancer prevention. The aim is to postpone clinical manifestation of latent cancer to an older age, and has two aspects: one is elimination of carcinogens from the environment and the other is active efforts to improve the lifestyle and develop effective chemopreventive agents. For understanding of prevention, elucidation of molecular mechanisms of interactions between genes and environmental or dietary compounds for each cancer is essential.