Central nervous system leukemia in children with acute nonlymphoblastic leukemia

Factors contributing to the development of central nervous system (CNS) leukemia, and the impact of leukemic involvement of this site on subsequent remission length, were determined in 184 children with acute nonlymphoblastic leukemia who had been treated in two successive clinical trials. Preventive CNS therapy in both studies consisted of intrathecal methotrexate (12 mg/m2) given monthly during the first six months of therapy and then every three months until all treatment was stopped. Children with CNS leukemia at diagnosis or relapse were given intrathecal chemotherapy weekly for four weeks and then monthly throughout the remainder of the treatment course. Those continuing in complete remission received 2,400 rad cranial irradiation plus five doses of intrathecal methotrexate before cessation of therapy. The 38 children (20.7%) with CNS leukemia at diagnosis were more likely to have an initial leukocyte count greater than or equal to 25 X 10(9)/L (P = .01) and age less than 2 years (P = .03). The presence of CNS leukemia at diagnosis did not adversely affect the remission induction rate (P = .13) or the length of complete remissions (P = .73). CNS relapse ended initial remissions in 11 patients only and did not preclude subsequent long-term survival, as four of these children are off therapy and in second complete remission for 33+ to 78+ months. Three features at diagnosis were predictive of CNS relapse: monocytic or myelomonocytic leukemia (P = .002); age less than 2 years (P = .0001); and leukocyte count greater than or equal to 25 X 10(9)/L (P = .012). By stepwise Cox regression analysis, each factor was found to have independent predictive value. Despite the apparent effectiveness of intrathecal methotrexate as preventive CNS treatment, our findings indicate that more effective prophylaxis is needed for patients with features predisposing to CNS relapse.     

PIP5K2A-dependent regulation of excitatory amino acid transporter EAAT3

Introduction

According to previous observations, the gene encoding the phosphatidylinositol-4-phosphate 5-kinase II alpha (PIP5K2A) is associated with schizophrenia. Specifically, the mutation ^N251SPIP5K2A has been discovered in schizophrenic patients but not in healthy individuals. A defect of the excitatory amino acid transporter EAAT3 has similarly been implicated in the development of schizophrenia. The present study thus explored whether PIP5K2A is involved in the regulation of EAAT3 activity.

Materials and methods

EAAT3 was expressed in Xenopus oocytes either without or with PIP5K2A, and EAAT3 transporter activity was estimated from the glutamate (2-mM)-induced current (I_glu) in dual electrode voltage clamp experiments. EAAT3 protein abundance in the cell membrane was estimated by Western blotting and confocal microscopy.

Results

In EAAT3-expressing oocytes, I_glu was enhanced by coexpression of wild type PIP5K2A. Coexpression of the schizophrenia-associated mutant ^N251SPIP5K2A significantly decreased I_glu in oocytes expressing EAAT3 with or without additional expression of wild type PIP5K2A. Thus, ^N251SPIP5K2A exerts a dominant inhibitory effect.

Discussion

Membrane abundance of EAAT3 was increased by wild type PIP5K2A and decreased by ^N251SPIP5K2A in both EAAT3-expressing oocytes and human embryonic kidney cells. The present observations disclose a novel mechanism of EAAT3 regulation, which may contribute to the deranged regulation of excitability in schizophrenic patients.     

铀矿接尘人员矽肺发生的特点

目的 了解铀矿接尘人员矽肺发生的规律与特点。方法 利用单因素分析法对核工业矿山与地质系统间、纯铀矿与混铀矿接尘人员间,矽肺患者的发病工龄、发病年龄、病程及死亡年龄进行分析。结果 随着时间的推移,铀矿接尘人员的发病工龄、发病年龄、病程及死亡年龄均延长。地质系统的矽肺Ⅰ期患者的发病工龄、发病年龄分别为(10.15±5.95)年、(40.60±9.86)岁,短于矿山系统的患者[(14.23±8.12)年、(41.38±10.98)岁];地质系统的矽肺Ⅰ期患者的病程(P50)及死亡年龄分别为14.29年及(53.69±10.04)岁,长于矿山系统的患者[12.52年及(51.45±10.85)岁]。纯铀矿的矽肺Ⅰ期患者的发病工龄为(11.78±8.06)年,发病年龄为(38.04±9.89)岁,短于混铀矿的患者[(12.74±6.29)年、(41.40±10.67)岁];纯铀矿的矽肺Ⅰ期患者的病程(P50)为14.59年,死亡年龄为(53.93±10.60)岁,均长于混铀矿的患者[13.20年、(51.82±10.20)岁]。结论地质系统与矿山系统、纯铀矿及混铀矿接尘者矽肺发生情况的差别可能与所接触粉尘的理化性质及各自的工作环境有关。     

Missense polymorphisms in three oxidative‐stress enzymes (GSTP1, SOD2, and GPX1) and dyskinesias in Russian psychiatric inpatients from Siberia

Neuronal degeneration due to oxidative stress (OS) has been proposed as a mechanism for tardive dyskinesia (TD) pathogenesis. Cellular defense mechanisms against OS may involve detoxification enzymes (e.g., glutathione peroxidase‐1, GPX1; superoxide dismutase‐2, SOD2 [also commonly known as MnSOD]; and glutathione S‐transferase P1, GSTP1). Several pharmacogenetic studies have examined TD and OS in different ethnic groups, but not in Russians. Here we report the association between orofaciolingual (TDof) and limb‐truncal dyskinesias (TDlt) and polymorphisms of GSTP1 (Ile105Val), MnSOD (Ala‐9Val), and GPX1 (Pro197Leu) genes in 146 Russian inpatients from Siberia. We applied AIMS instrument to rate dyskinesias. Two‐part model analyses, logistic and multivariate parametric regressions were applied to assess the effects of different variables (e.g., genotype, age, gender, and medication use). Our analyses do not suggest that Pro197Leu (GPX1) is associated with TD. However, our analyses suggest that the 105Val‐allele of Ile105Val (GSTP1) may be associated with a lower risk and a severity of TDof and TDlt and that Ile105Val pharmacogenetics may be different in Slavonic Caucasians from that in American Caucasians. Furthermore, we find evidence for an association between Ala‐9Val (MnSOD) and TDof, but not TDlt. Subject to further replication, our findings extend the available knowledge on the pharmacogenetics of TD and oxidative stress. Copyright © 2009 John Wiley & Sons, Ltd.     

DIURNAL EFFECTS OF FLUOXETINE AND NALOXONE ON THE HUMAN HYPOTHALAMIC-PITUITARY-ADRENAL AXIS

1. Central serotonergic pathways are hypothesized to be involved in the stimulation of hypothalamic adrenocorticotropic hormone (ACTH) secretagogue release by both circadian- and stress-induced mechanisms. We aimed to investigate this hypothesis by measuring the effect of the highly specific serotonin re-uptake inhibitor fluoxetine (FX) on ACTH and Cortisol release in the morning and in the afternoon in humans, both by itself and in combination with the opioid antagonist naloxone (Nal). Naloxone causes ACTH release in humans by removing an endogenous inhibitory opioid tone on central noradrenergic pathways stimulatory to hypothalamic corticotropin-releasing hormone (CRH) secretion. Serotonergic agents may act directly or indirectly through these central noradrenergic pathways and, if so, would be expected to be additive to or synergistic with Nal in causing ACTH and Cortisol release. 2. Oral FX (40 mg) was given at approximately 07.00 or 11.00 h, either alone or with intravenous Nal 3 h later, to normal human volunteers. Plasma ACTH and Cortisol levels were measured for 5 h after FX dosing. 3. Fluoxetine produced a small but non-significant increase in Nal-stiimilated ACTH and Cortisol release in both morning and afternoon studies. Naloxone alone did not cause different ACTH and Cortisol responses in the morning and afternoon. 4. These results suggest that serotonergic pathways are not major regulators of the hypothalamic-pituitary-adrenal axis in humans or that FX has counteracting acute inhibitory effects on the axis, such as inhibition of hypothalamic arginine vasopressin secretion, which has been demonstrated in chronic animal studies.     

Body mass index development during the first 6 months of life in infants born to human immunodeficiency virus-seropositive mothers

The development of body mass index (BMI) was measured during the first 6 months of life in three groups of infants [human immunodeficiency virus (HIV) -uninfected, n = 92; later symptomatic HIV-infected, n = 18; early symptomatic HIV-infected, n = 9] born to HIV-positive mothers and compared with a reference group (n = 65) born to healthy mothers. A trend towards lower values in the two groups of HIV-infected infants was already evident at birth. Among the four groups, HIV-uninfected infants showed the highest BMI values while the early-infected infants showed the lowest BMI values at all measurements. The later-infected group had a value close to the reference at 1 month, and then increased at slower rates than the uninfected and the reference groups. Infants born to HIV-positive mothers may have higher energy and nutrient requirements after birth, either to sustain an increased BMI development (when uninfected) or to meet catabolic mechanisms (when infected).     

Gingival granulomatosis with polyangiitis (Wegener's granulomatosis) as a primary manifestation of the disease

Granulomatosis with polyangiitis (GPA) is a potentially lethal disease characterized by systemic necrotizing vasculitis, which affects small‐ and medium‐sized blood vessels and is often associated with serum cytoplasmic antineutrophil cytoplasmic antibody. The upper and lower respiratory tract and kidney are the most involved sites, but oral lesions can be identified in 6–13% of the cases, whereas in only 2% of the cases, oral manifestations represent the first signal of the disease usually as gingival swellings or unspecific ulcerations. Without treatment, the mainstay of which is the combination of immunosuppressants and systemic corticosteroids, GPA may run a fatal course. In this report we describe an original case of GPA affecting a 75‐year‐old female patient referred to our service due to a gingival swelling with 3‐month duration. Although the patient was correctly diagnosed and promptly treated, she died 3 months after the initial diagnosis.