Prevalence and clinical impact of Met Y1253D-activating point mutation in radiotherapy-treated squamous cell cancer of the oropharynx

Aberrant signalling through the hepatocyte growth factor/scatter factor receptor Met has been implicated in various aspects of the development of human cancer including the promotion of tumour invasion, angiogenesis and metastasis. Moreover, experimental data indicate that activation of the Met receptor may be involved in cellular resistance towards antineoplastic treatments such as chemotherapy and ionizing radiation. We determined the prevalence and clinical impact of the Met-activating mutation Y1253D in patients with squamous cell cancer of the oropharynx treated by radical radiotherapy. To screen archival tissue for the presence of a low-abundance point mutation, we developed a sensitive screening method using real-time polymerase chain reaction along with peptide nucleic acid-based DNA clamping and melting curve analysis. By this approach, Met Y1253D was detected in tumours of 15 out of 138 patients (10.9%). Both univariate and multivariate survival analysis revealed Met Y1253D to be significantly associated with impaired local tumour control. Our results provide evidence that the Met-activating mutation Y1253D is present in a notable subset of patients with oropharyngeal cancer and indicate that it may interfere with radioresponsiveness of these tumours, supporting the notion of aberrant Met signalling as a potential target for radiosensitization.     

Quantitative [18F]fluorodopa/PET and histology of fetal mesencephalic dopaminergic grafts to the striatum of MPTP-poisoned minipigs

The functional restoration of the dopamine innervation of striatum in MPTP-poisoned G?ttingen minipigs was assessed for 6 months following grafting of fetal pig mesencephalic neurons. Pigs were assigned to a normal control group and a MPTP-poisoned group, members of which received no further treatment, or which received bilateral grafts to the striatum of tissue blocks harvested from E28 fetal pig mesencephalon with and without immunosuppressive treatment after grafting, or with additional co-grafting with immortalized rat neural cells transfected to produce GDNF. In the baseline condition, and again at 3 and 6 months postsurgery, all animals were subjected to quantitative [18F]fluorodopa PET scans and testing for motor impairment. At the end of 6 months, tyrosine hydroxylase (TH)-containing neurons were counted in the grafts by stereological methods. The MPTP poisoning persistently reduced the magnitude of k3(D), the relative activity of DOPA decarboxylase in striatum, by 60%. Grafting restored the rate of [18F]fluorodopa decarboxylation to the normal range, and normalized the scores in motor function. The biochemical and functional recovery was associated with survival of approximately 100,000 TH-positive graft neurons in each hemisphere. Immunosuppression did not impart a greater recovery of [18F]fluorodopa uptake, nor were the number of TH-positive graft neurons or the volumes of the grafts increased in the immunosuppressed group. Contrary to expectation, co-grafting of transfected GDNF-expressing HiB5 cells, a rat-derived neural cell line, tended to impair the survival of the grafts with the lowest values for graft volumes, TH-positive cell numbers, behavioral scores, and relative DOPA decarboxylase activity. From the results we conclude that pig ventral mesencephalic allografts can restore functional dopamine innervation in adult MPTP-lesioned minipigs.     

Nonvisualization of the fetal gallbladder in early pregnancy: comparison with clinical outcome

PURPOSE: To prospectively assess the frequency of a nonvisualized fetal gallbladder in early pregnancy and to determine its prognostic value. MATERIALS AND METHODS: Fetal transvaginal ultrasonography (US) was performed in 29,749 consecutive pregnant women at 14-16 weeks gestation. A nonvisualized fetal gallbladder was defined if the gallbladder could not be depicted during two targeted examinations within 1 week. In such cases, women were offered an amniocentesis for fetal karyotype and hepatic enzyme analysis. Repeat transabdominal fetal US was performed at 22-26 weeks' gestation. If the gallbladder was still not depicted, US was performed postnatally. RESULTS: The gallbladder was not visualized in early pregnancy in 34 fetuses (0.1%; incidence of one in 875 pregnancies). Associated structural malformations were detected in 14 of 34 (41%) fetuses, five of which also had an abnormal karyotype. Pregnancy was terminated in nine of these 14 fetuses. In the remaining five patients who continued pregnancy, the gallbladder was detected later in pregnancy in four. However, only one infant was healthy. Nonvisualization of the gallbladder as an isolated finding was noted in 20 of 34 (59%) fetuses, all of which had a normal outcome. The gallbladder was detected later in pregnancy in 11 of these fetuses and after birth in two neonates, while no gallbladder was detected after delivery in five other neonates. Two patients were lost to follow-up. CONCLUSION: Nonvisualization of the fetal gallbladder in early pregnancy is uncommon but associated in many cases with other fetal anomalies.     

The essential tension of human-machine systems

The initially interchangeable terms ergonomics and human factors have taken on different meanings over the last 50 years. Especially in the area of occupational health hazards, the scope of ergonomics has been narrowed down to the analysis of musculoskeletal stress to determine critical values, which has led to the dose model. In contrast, human factors (sometimes replaced by engineering psychology) have focussed on the optimization of allocating tasks in human-machine systems. An example from the BMW plant in Regensburg shows that in a workplace where the musculoskeletal stress remains below the critical values humans are better than machines, but that situations leading to traumata can nevertheless arise.In conclusion, possibilities provided by virtual reality are discussed regarding the integration of optimal human-machine systems with principles of preventing occupational hazards.     

地塞米松的国外制剂简介

地塞米松（dexamethasone）为肾上腺皮质激素类药物,有影响糖代谢、抗炎、抗过敏、抗毒素等作用,用于感染性和过敏性休克、严重的肾上腺皮质功能减退症,结缔组织病等。现将其国外制剂70、80年代的专利作一简介,这些制剂的专利虽然大多数已过保护期,但比较实用,可供国内药厂研究、开发借鉴。1注射液（i…ectabledexamethasonesolution）制法：磷酸地塞米松注射液加0．1％盐酸半脱氨酸,调节PH值至6．3,用过滤法灭菌。本品在60”C贮存49d仍保持稳定,其半衰期为28．8d。盐酸半脱氨酸、维生素C、焦亚硫酸钠均可用作抗氧剂,用量均为0…     

Cushing's syndrome in childhood and adolescence

Objective: To review the diagnosis, management and outcome of Cushing's syndrome in children and adolescents.
Methods: We conducted a retrospective review of nine cases treated between 1976 and 1996 at the Royal Children's Hospital, Melbourne, Australia.
Results: Six children with Cushing's disease and three with primary adrenal disease were identified. Mean age at diagnosis in the Cushing's disease patients was 11.3 years and in the children with primary adrenal disease 9.5 years. The most common presenting symptoms were weight gain and delayed growth. Two children had the unusual presenting symptoms of an eating disorder and hemihypertrophy, respectively. Laboratory diagnosis of Cushing's syndrome was established by demonstration of elevated urine free cortisol, loss of normal diurnal variation of serum cortisol, and loss of suppressibility of cortisol secretion by low dose dexamethasone. Investigations used to determine the aetiology of hypercortisolism included serum adrenocorticotropic hormone (ACTH) levels, high dose dexamethasone suppression tests, imaging studies, and inferior petrosal sinus sampling. Four patients with Cushing's disease had successful transphenoidal adenomectomies. Two patients with bilateral primary pigmented nodular adrenocortical dysplasia underwent bilateral adrenalectomies. One child with an adrenal adenoma was treated by left adrenalectomy.
Conclusions: Cushing's syndrome in children and adolescents remains a diagnostic challenge. Successful treatment often requires the use of multiple tests to achieve the correct diagnosis, appropriate surgery and a good long-term outcome.     

Induction of cell cycle arrest by the endogenous product of lipid peroxidation, malondialdehyde

We have investigated the effect of the endogenous genotoxin malondialdehyde (MDA) on cell cycle kinetics and the expression and biochemical activity of several cell cycle regulatory proteins. MDA treatment of two human cell lines (RKO and H1299) resulted in a 3- to 6- fold elevation in the levels of the major detectable MDA-DNA adduct, M1G-dR. The increase in M1G-dR was accompanied by irreversible cell cycle arrest, elevation in p53 and p21 protein levels, and inhibition of cyclin E- and cyclin B-associated kinase activities. The decrease in cyclin E- and cyclin B-dependent kinase activities was caused by increased p21 and decreased cdc2 levels, respectively. Comparable levels of p21 induction were observed in RKO (wild-type p53) and H1299 (p53-null) cells. Thus, MDA was able to engage cell cycle checkpoint function in human cell lines when used at concentrations that produce M1G-dR levels of the same magnitude found in human tissues.      

Effect of respiratory virus infections including rhinovirus on clinical status in cystic fibrosis

One hundred and eight patients with cystic fibrosis were investigated over one year to determine whether an association existed between rhinovirus or other respiratory virus infection and clinical status. Forced expiratory volume in one second (FEV1), forced vital capacity (FVC), Shwachman score, Chrispin-Norman chest radiograph score, and percentage weight for height were recorded at the beginning and end of the study; days of intravenous antibiotics were noted. Nasopharyngeal aspirates were taken for viral studies during respiratory exacerbations. Serum was collected at enrollment and 2-6 weeks after each respiratory exacerbation. One hundred and fifty seven exacerbations occurred in 76 patients. Respiratory virus infection was detected in 44 exacerbations and rhinovirus was present in 16% (25/157) of exacerbations. Patients with one or more respiratory virus infections were compared with those who had none. When all respiratory virus infections were considered, patients had a significantly greater deterioration in Shwachman score and received significantly more days of intravenous antibiotics. When rhinovirus was considered separately, patients received significantly more days of intravenous antibiotics, but showed no deterioration in clinical status. However, patients infected with another respiratory virus had a significant decline in FEV1, with trends towards significance for decline in FVC and Shwachman score.