ATM-dependent DNA damage surveillance in T-cell development and leukemogenesis: the DSB connection

Summary:  The immune system is capable of recognizing and eliminating an enormous array of pathogens due to the extremely diverse antigen receptor repertoire of T and B lymphocytes. However, the development of lymphocytes bearing receptors with unique specificities requires the generation of programmed double strand breaks (DSBs) coupled with bursts of proliferation, rendering lymphocytes susceptible to mutations contributing to oncogenic transformation. Consequently, mechanisms responsible for monitoring global genomic integrity must be activated during lymphocyte development to limit the oncogenic potential of antigen receptor locus recombination. Mutations in ATM (ataxia-telangiectasia mutated), a kinase that coordinates DSB monitoring and the response to DNA damage, result in impaired T-cell development and predispose to T-cell leukemia. Here, we review recent evidence providing insight into the mechanisms by which ATM promotes normal lymphocyte development and protects from neoplastic transformation.     

Substituting human chorionic gonadotropin by gonadotropin-releasing hormone agonist to trigger final follicular maturation, during controlled ovarian hyperstimulation, results in less systemic inflammation.

BACKGROUND: To investigate the degree of systemic inflammation, as reflected by serum C-reactive protein (CRP) levels, associated with controlled ovarian hyperstimulation (COH) with human chorionic gonadotropin (hCG) or gonadotropin-releasing hormone (GnRH) agonist for the induction of final follicular maturation. DESIGN: Prospective, observational study. SETTING: An in vitro fertilization (IVF) unit of an academic medical center. PATIENTS: Twenty-four women undergoing COH and IVF with the flexible GnRH antagonist protocol were prospectively assigned to receive hCG or GnRH agonist for the induction of final follicular maturation. METHODS: Blood was drawn three times during COH for measurement of sex-steroid and CRP levels: the day on which adequate suppression was obtained (Day-0); the day of or prior to administration of hCG (Day-hCG); and (3) the day of ovum pick-up (Day-OPU). Levels were compared among the three time points in the two groups. RESULTS: No between-group differences were observed in terms of patient age, gonadotropin dosage, duration of stimulation or number of oocytes retrieved. Serum CRP levels were significantly higher on Day-OPU than on Day-hCG and Day-0, but the difference was significant only in the hCG group (p<0.03 for both). The percentage change in CRP levels after hCG administration (Day-OPU vs. Day-hCG) (96%) was higher than that after GnRH administration (23%). CONCLUSION: Administration of GnRH agonist in patients undergoing COH for IVF yields a lesser degree of systemic inflammation, as reflected by CRP levels, than hCG.     

Increased occurrence of free immunoglobulin light chains in cerebrospinal fluid and serum in human immunodeficiency virus-1 infection

The presence of free immunoglobulin light chains (FLCs) in the cerebrospinal fluid (CSF) and sera of patients with human immunodeficiency virus-1 (HIV-1) infection, multiple sclerosis (MS), and neurologically healthy control individuals was investigated by paying special attention to ensure that only truly free light chains would be detected. The FLCs were extracted by specifically binding them to Sepharose-coupled anti-FLC monoclonal antibodies, and thereafter they were electrophoresed and immunoblotted with monoclonal antibodies to both light chain (LC) isotypes. A frequent occurrence of kappa and lambda FLCs was found in both CSF and sera of HIV-1 infected patients. In HIV-1 infection and in MS, the frequency of FLCs of the CSF was equal. In healthy controls, only occasional weak FLCs were observed in either CSF or serum. FLC bands of the CSF from patients with HIV-1 infection tended to be more intensive than those of the appropriately diluted sera. Both intrathecal synthesis of FLCs and their transudation from sera through the impaired blood-brain barrier (BBB) may contribute to this. Increasing severity of general HIV-1 infection was accompanied by an increase of FLC intensity in sera. A qualitative demonstration of FLC in the CSF may be meaningful only in the absence of altered BBB function.     

Inhibition by AICA riboside of gluconeogenesis in isolated rat hepatocytes.

5-Amino-4-imidazolecarboxamide (AICA) riboside, the nucleoside corresponding to AICA ribotide (AICAR or ZMP), an intermediate of the de novo pathway of purine biosynthesis, was found to exert a dose-dependent inhibition on gluconeogenesis in isolated rat hepatocytes. Production of glucose from lactate-pyruvate mixtures was half-maximally inhibited by approximately 100 microM and completely suppressed by 500 microM AICA riboside. AICA riboside also inhibited the production of glucose from all other gluconeogenic precursors investigated, i.e., fructose, dihydroxyacetone, and L-proline. Measurements of intermediates of the glycolytic-gluconeogenic pathway showed that AICA riboside provoked elevations of triose phosphates and fructose-1,6-bisphosphate and decreases in fructose-6-phosphate and glucose-6-phosphate. The effects of AICA riboside persisted when the cells were washed 10 min after its addition but were suppressed by 5-iodotubercidin, an inhibitor of adenosine kinase. AICA riboside provoked a dose-dependent buildup of normally undetectable Z nucleotides. After 20 min of incubation with 500 microM AICA riboside, ZMP, ZTP, and ZDP reached 3, 0.3, and 0.1 mumol/g cells, respectively. Concentrations of ATP were not significantly modified by addition of up to 500 microM AICA riboside when the cells were incubated with lactate-pyruvate but decreased with fructose or dihydroxyacetone. The activity of rat liver fructose-1,6-bisphosphatase was inhibited by ZMP with an apparent Ki of 370 microM. It is concluded that AICA riboside exerts a suppressive effect on gluconeogenesis because it provokes an accumulation of ZMP, which inhibits fructose-1,6-bisphosphatase.(ABSTRACT TRUNCATED AT 250 WORDS)     

Acupuncture analgesia and its application in cranio-maxillofacial surgical procedures.

BACKGROUND: The present study investigated the use of acupuncture analgesia in maxillofacial surgery. PATIENTS AND METHODS: Acupuncture analgesia was applied in 120 patients. In 20 of these, surgery was carried out under general anaesthesia in combination with acupuncture analgesia. In 100 patients, acupuncture analgesia was applied in addition to traditional postoperative analgesia. In case of troublesome postoperative pain, it was necessary to carry out additional sessions (1-4) of acupuncture stimulation. RESULTS: When acupuncture analgesia was used, the pulse rate and blood pressure during surgery generally remained stable. In the present study serum cortisol was also measured and showed only minor elevation. DISCUSSION: The present study demonstrated favourable results when the first variant of the brake method of acupoint stimulation was used for 40-50 min with additional manual twirling of the needles. This involved inserting needles into the acupoints and, using slow, rolling manual movements increasing the amplitude step-by-step provoking simultaneous especially strong patient sensations. CONCLUSION: Acupuncture analgesia can be a useful adjunct to conventional anaesthesia in maxillofacial surgery.     

Dreaming during Anesthesia and Anesthetic Depth in Elective Surgery Patients: A Prospective Cohort Study

Background: Dreaming reported after anesthesia remains a poorly understood phenomenon. Dreaming may be related to light anesthesia and represent near-miss awareness. However, few studies have assessed the relation between dreaming and depth of anesthesia, and their results were inconclusive. Therefore, the authors tested the hypothesis that dreaming during anesthesia is associated with light anesthesia, as evidenced by higher Bispectral Index values during maintenance of anesthesia.

Methods: With approval, 300 consenting healthy patients, aged 18-50 yr, presenting for elective surgery requiring relaxant general anesthesia with a broad range of agents were studied. Patients were interviewed on emergence and 2-4 h postoperatively. The Bispectral Index was recorded from induction until the first interview. Dream content and form were also assessed.

Results: Dreaming was reported by 22% of patients on emergence. There was no difference between dreamers and nondreamers in median Bispectral Index values during maintenance (37 [23-55] vs. 38 [20-59]; P = 0.68) or the time at Bispectral Index values greater than 60 (0 [0-7] vs. 0 [0-31] min; P = 0.38). Dreamers tended to be younger and male, to have high home dream recall, to receive propofol maintenance or regional anesthesia, and to open their eyes sooner after surgery. Most dreams were similar to dreams of sleep and were pleasant, and the content was unrelated to surgery.