Plasma long-chain polyunsaturated fatty acids and neurodevelopment through the first 12 months of life in phenylketonuria

The aims of the study were to examine the relationship between long-chain polyunsaturated fatty acid (LCPUFA) status at diagnosis of phenylketonuria (PKU) and neurodevelopment through the first 12 months of life, and to assess whether any difference exists between infants breastfed and bottlefed in the first days of life on the basis of LCPUFA status. Twenty infants with PKU were prospectively examined through the first year of life. Plasma fatty acids were measured in infants at diagnosis. Plasma phenylalanine levels were determined monthly. Main outcome measures were the Bayley Mental Developmental Index (MDI) and Psychomotor Developmental Index (PDI) at 5 and 12 months of age, and the visual function at 12 months, evaluated by P100 wave latencies with visual evoked potentials. A higher PDI score was associated with higher plasma arachidonic acid at diagnosis (adjusted correlation coefficient of PDI at 5 months, r=0.38, p=0.05). P100 wave latency at 15 minutes of arc (15') was associated with the early plasma arachidonic acid (adjusted r=-0.56, p=0.02) and phenylalanine levels at 12 months (adjusted r=0.22, p=0.05). No association was found between MDI score and any essential fatty acids. Breastfed infants exhibited higher plasma arachidonic acid (mean difference, delta, =3.4%; 95% confidence interval [CI]=1.2-5.6%) and shorter P100 wave latency at 15' (delta=-21 ms, 95%CI=-30 to -12) than bottlefed infants. Within the population of this study, a weak positive association has been found between plasma LCPUFAs at diagnosis (higher in breastfed infants) and neurodevelopmental indices through the first year of life.     

Goseki classification in adenocarcinoma of the cardia

BACKGROUND: To assess an additional prognostic value of Goseki histological classification to TNM staging system in adenocarcinoma of the cardia. METHODS: Sixty-one patients curatively resected for advanced (T2, T3 and T4) cardia cancer at the I Division of General Surgery, University of Verona were classified in four different grades according to Goseki. Survival curves were estimated with Kaplan-Meier method and compared by the log-rank test. Multivariate analysis was performed by Cox regression model. c2 test was used to compare Goseki to Lauren classification and grading. After discharge from hospital all patients were followed with a mean follow-up of 39.5 months. RESULTS: Lauren classification and grading were significantly related to tubular differentiation (p<0.01). Kaplan-Meier estimates of survival showed a better 5-year outcome for tumors with good tubular differentiation (19%), even though the difference with poor tubular differentiated tumors was not statistically significant (p'0.06). Diffuse type carcinomas and tumors with poor cytological differentiation showed a worse prognosis at univariate analysis (p<0.01). Multivariate analysis showed no additional prognostic significance of any of the histological classification analyzed. Only T (p<0.02; RR 2.2; IC 1.2-4) and N (p<0.01; RR 5; IC 2.4-11) were independent prognostic factors. CONCLUSIONS: In adenocarcinoma of the cardia, Goseki classification did not add any information to Lauren classification and to TNM staging system.     

A randomised controlled trial of intravenous immunoglobulin in IgM paraprotein associated demyelinating neuropathy

This multicentre randomised double blind crossover trial tested the short term efficacy of intravenous immunoglobulin (IVIg) 2.0 g/kg given over 24 or 48 hours in patients with paraproteinaemic demyelinating neuropathy (PDN). Twenty-two patients were randomised and completed the trial. After 2 weeks, the overall disability grade decreased during both IVIg treatment and placebo but neither change was significant nor was the mean difference between the treatment effects. After 4 weeks the overall disability decreased by a mean of 0.55 [0.67] grades during the IVIg period (p = 0.001) while it was substantially unmodified during the placebo period. The mean difference between the treatment effects was significant (p = 0.05). Overall during the IVIg period 10 patients improved and 11 were stable and one got worse. During the placebo period 4 patients improved, 4 deteriorated and 14 were stable. Many secondary outcome measures, including Rankin scale, time to walk 10 metres, grip strength, sensory symptoms score were significantly better during IVIg treatment. Two serious adverse events occurred during the trial, both during placebo treatment. In conclusion the trial showed some short-term benefit of IVIg in about half of the patients confirming previous observation. Received: 6 August 2001, Received in revised form: 6 March 2002, Accepted: 12 March 2002 RID="*" ID="*"The other members of the INCAT group are Jacques Aubry PhD, Institut de Biologie, INSERM Unit 463, 9 Quai Moncousu, 44 035 Nantes, France; Nicole Baumann MD, InSERM Unit 495, Salpetriere Hospital, 75 651 Paris, Cedex 13 France; Robert Hadden PhD, Michael Lunn, MD, Department of Neuroimmunology, Guy's, King's and St. Thomas' School of Medicine, Guy's Hospital, London SE1 9 UL, UK; Martin Knapp Phd, Personal Social Services Research Unit, London School of Economics and Political Science, Houghton Street, London WC2A 1AE, UK; Jean-Marc Léger MD, Pierre Bouche MD, Service d'Eplorations Functionelles de la Salpetriere, 47 Boulevard de l'Hospital, 75 651 Paris, Cedex 13, France; Radim Mazanec CSc, Charles University, 2^nd Medical School, University Hospital, V uvalu 84, Prague 5, Czech Republic; Nicoletta Meucci MD, Institute of Clinical Neurology, University of Milan, Ospedale Maggior-Policlinico, via Sforza, 20 122 Milan, Italy; Frans van der Meché PhD, Department of Neurology, Erasmus Medical Center Rotterdam, dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands; and Klaus Toyka PhD, Universitat Würzburg, Josef-Schneider Strasse 2, 97 080 Würzburg, Germany Correspondence to Giancarlo Comi, MD     

Effects of dark rearing on phosphorylation of neurotrophin Trk receptors

Total lack of visual experience (dark rearing, DR) is known to affect development of mammalian visual cortex (VC) and to prolong the critical period of visual cortical plasticity. Neurotrophins (NTs) have been proposed to play a relevant role in activity dependent processes important for the final shaping of cortical visual connections. Neurotrophin supply or antagonism of endogenous NT action profoundly affect visual cortical development and plasticity; in particular, exogenous supply of NTs counteracts DR effects on VC development. However, the effects of DR on NT expression are still debated and mounting evidence reports a mismatch between BDNF mRNA and protein expression in DR animals. To gain insight into the effects of DR on expression of nerve growth factor (NGF) and the functional state of NT signalling pathways, we assessed the phosphorylation state of Trk receptors in light-reared animals (LR), in dark-reared animals (DR), in DR animals briefly exposed to light and in DR animals with exogenous supply of NTs [NGF, brain-derived neurotrophic factor (BDNF) and NT-4] in the VC. We report that DR increases the expression of NGF but reduces the phosphorylation of TrkA and TrkB receptors with respect to LR; normal phosphorylation is rapidly rescued by a brief exposure to light. Exogenous supply of NGF, BDNF or NT4 in DR animals also rescues the phosphorylation of their receptors.     

Che-1 affects cell growth by interfering with the recruitment of HDAC1 by Rb

DNA tumor virus oncoproteins bind and inactivate Rb by interfering with the Rb/HDAC1 interaction. Che-1 is a recently identified human Rb binding protein that inhibits the Rb growth suppressing function. Here we show that Che-1 contacts the Rb pocket region and competes with HDAC1 for Rb binding site, removing HDAC1 from the Rb/E2F complex in vitro and from the E2F target promoters in vivo. Che-1 overexpression activates DNA synthesis in quiescent NIH-3T3 cells through HDAC1 displacement. Consistently, Che-1-specific RNA interference affects E2F activity and cell proliferation in human fibroblasts but not in the pocket protein-defective 293 cells. These findings indicate the existence of a pathway of Rb regulation supporting Che-1 as the cellular counterpart of DNA tumor virus oncoproteins.     

Residual symptoms in depression: an emerging therapeutic target

Residual symptoms, despite successful response to therapy, appear to be the rule in unipolar depression. Most of the residual symptoms occur in the prodromal phase of illness. Residual symptoms are associated with biological correlates, mainly involving the hypothalamic-pituitary-adrenal (HPA) axis and the sleep architecture. They are powerful predictors of relapse. These findings have led to the hypothesis that residual symptoms upon recovery may progress to become prodromal symptoms of relapse. A sequential strategy (encompassing pharmacotherapy in the acute phase of illness and cognitive behavioral therapy in its residual phase) has been developed and was found to be effective in decreasing relapse rate in controlled studies. A largely untested assumption in unipolar depression is that pharmacological strategies that are effective in the short term are the most suitable for postacute and residual phases or maintenance. The literature on subclinical symptomatology calls for specific, stage-oriented, therapeutic approaches. The efficacy of antidepressant drugs may be assessed not only on differential remission rates, but also on differential amount of residual symptomatology after response.     

Acute hemorrhage secondary to gastric ulcer. Results of emergency endoscopic treatment in 775 cases

The aim of this study was to investigate the effects of endoscopic injection therapy on the clinical outcome of patients with gastric ulcer bleeding. Seven hundred and seventy-five patients with gastric ulcer bleeding were observed over a 10-year period (January 1990 to May 2000) in the First Division of General Surgery of the University of Verona. The prognostic and therapeutic implications of endoscopic treatment of acute severe gastrointestinal bleeding were analyzed on the basis of medical history and clinical and endoscopic findings. The ulcers were classified according to Forrest's classification of bleeding activity. Endoscopic therapy was performed in 500 patients with active bleeding. Haemostasis was initially obtained in all patients except one. Rebleeding occurred in 13%. All these patients were treated endoscopically at the first attempt. Multivariate analysis revealed that recent surgery, ulcer site and Forrest classification independently influenced the recurrence rate. The mortality of the entire cohort studied was 8.1%. Only 31 patients (4%) underwent surgical treatment with a higher mortality compared to unoperated patients (19.3% vs 7.7%). Endoscopic treatment is a safe procedure with a low mortality and cost, and, if successful, substantially reduces the need for emergency surgery.     

Inv(16) acute myeloid leukemia cells show an increased sensitivity to cytosine arabinoside in vitro

Abstract: Karyotype represents the major independent prognostic factor for response and remission duration in acute leukemia. In particular, it has been reported that acute myeloid leukemia (AML) patients with inv(16) abnormality show a better prognosis, especially in case of treatment with high-dose Ara-C (HD Ara-C) containing regimens. In this study we aimed at testing whether leukemic cells from patients showing the inv(16) were more sensitive to Ara-C in vitro, compared to AML blasts from patients with normal karyotype or chromosomal abnormalities other than t(15;17) or t(8;21). We analyzed blast cells from 30 patients who were diagnosed and treated in our institution. The IC₅₀ of Ara-C, as tested by the XTT colorimetric assay, was significantly lower in cases with inv(16) (18.5±15.88 μmol/l vs. 38±14.6 μmol/l, in cases with other abnormalities, p = 0.01). This result was confirmed by a higher incorporation of [³H]-Ara-C into DNA (p = 0.02 and p = 0.001 compared to samples with normal and abnormal karyotype, respectively). All the same, Ara-C induced apoptosis was significantly increased in cells from patients with inv(16). Our data suggest a possible interaction between the molecular background of inv(16) and a modification of intracellular metabolism of Ara-C, and could thus provide a rationale for HD-Ara-C-based schedules for patients with inv(16) AML.