Dosimetric and image quality comparison of two digital mammography units with different target/filter combinations: Mo/Mo, Mo/Rh, W/Rh, W/Ag.

PURPOSE: Our aim was to allocate a digital mammography unit to the screening programme on the basis of the ALARA (as low as reasonably achievable) radiation protection principle. MATERIALS AND METHODS: Two Hologic Selenia mammography units were studied: one with a molybdenum anode and the other with a tungsten anode. After optimisation of the image production chain, we evaluated doses in a phantom under standard conditions. In this phase, we exposed a polymethyl-methacrylate (PMMA) phantom to the two mammography units and recorded the exposure parameters used by them. The phantom was subsequently replaced by a dedicated Radcal ionisation chamber on which preliminary dose assessments were conducted. Image quality of the two systems was compared by exposing a phantom containing geometrical inserts and setting the exposure parameters used for the dose assessments on each mammography unit. Dosimetric assessments of exposure data were recorded from the mammographic examinations of approximately 400 women (1,600 exposures). RESULTS AND CONCLUSIONS: The unit with the tungsten anode achieved a lower patient dose. As a result, the Selenia-W device was allocated to the breast screening programme.

Chronic activation of the D2 autoreceptor inhibits both glutamate and dopamine synapse formation and alters the intrinsic properties of mesencephalic dopamine neurons in vitro.

Dysfunctional dopamine (DA)-mediated signaling is implicated in several diseases including Parkinson's disease, schizophrenia and attention deficit and hyperactivity disorder. Chronic treatment with DA receptor agonists or antagonists is often used in pharmacotherapy, but the consequences of these treatments on DA neuron function are unclear. It was recently demonstrated that chronic D2 autoreceptor (D2R) activation in DA neurons decreases DA release and inhibits synapse formation. Given that DA neurons can establish synapses that release glutamate in addition to DA, we evaluated the synapse specificity of the functional and structural plasticity induced by chronic D2R activation. We show that chronic activation of the D2R with quinpirole in vitro caused a parallel decrease in the number of dopaminergic and glutamatergic axon terminals. The capacity of DA neurons to synthesize DA was not altered, as indicated by the lack of change in protein kinase A-mediated Ser(40) phosphorylation of tyrosine hydroxylase. However, the spontaneous firing rate of DA neurons was decreased and was associated with altered intrinsic properties as revealed by a prolonged latency to first spike after release from hyperpolarization. Moreover, D2R function was decreased after its chronic activation. Our results demonstrate that chronic activation of the D2R induces a complex neuronal reorganization involving the inhibition of both DA and glutamate synapse formation and an alteration in electrical activity, but not in DA synthesis. A better understanding of D2R-induced morphological and functional long-term plasticity may lead to improved pharmacotherapy of DA-related neurological and psychiatric disorders.

From biological gastroenterology to fundamental neurosciences: how studies in gastric emptying have led to the discovery of a new mechanism of neuronal functioning.

Gastric emptying undergoes complex regulation by the nervous system, which organizes in particular the inhibition of duodenum motility after a rise in intra-gastric pressure: the gastro-duodenal inhibitory reflex. It was first shown in mammals that this reflex could be organized by a sympathetic ganglion, the coeliac plexus. The excitation of gastric mechanosensitive fibres leads in this ganglion to the release of a neurotransmitter, which in turn activates ganglionic neurones leading to inhibition of the duodenum contractions. It rapidly became apparent that this reflex presented striking properties since it was organized in the absence of action potentials along the nerve fibres. Then it was shown that the neurotransmitter released in the coeliac plexus was gaseous: nitric oxide (NO). The nature of the mechanism conducting, without action potentials, the excitation along the nerve fibres was recently determined. This mechanism necessitates the integrity of particular areas of the neuronal membrane (the lipid rafts) and the activation in cascade of the following second messenger sequence: ceramide, calcium, NO and guanosine cyclic monophosphate (c-GMP). These results show how studies in biological gastroenterology have led to the rethinking of one of the central dogmas in neuroscience according to which excitation is only conducted along the nerves by the action potential.

Chronic activation of the D2 dopamine autoreceptor inhibits synaptogenesis in mesencephalic dopaminergic neurons in vitro.

Chronic blockade or activation of dopamine receptors is critical for the pharmacological treatment of diseases like schizophrenia, Parkinson's or attention deficit and hyperactivity disorder. However, the long-term impact of such treatments on dopamine neurons is unclear. Chronic blockade of the dopamine D2 receptor in vivo triggers an increase in the axonal arborization of dopamine neurons [European Journal of Neuroscience, 2002, 16, 787-794]. However, the specific involvement of presynaptic (autoreceptors) vs. postsynaptic D2 receptors as well as the molecular mechanisms involved have not been determined. Here, we examined the role of D2 autoreceptors in regulating the ability of mouse dopamine neurons to establish axon terminals. Chronic activation of this receptor with quinpirole, a specific agonist, decreased the number of axon terminals established by isolated dopamine neurons. This effect was accompanied by a decrease in dopamine release and was mediated through inhibition of protein kinase A. The decrease in axon terminal number induced by D2 receptor activation was also occluded when the mammalian Target of Rapamycin pathway of mRNA translation was blocked. Our results suggest that chronic activation of the D2 autoreceptor inhibits synaptogenesis by mesencephalic dopamine neurons through translational regulation of the synthesis of proteins required for synapse formation. This study provides a better understanding of the impact of long-term pharmacological interventions acting through the D2 receptor.

Modulation by C2 ceramide of the nicotinic transmission within the coeliac ganglion in the rabbit.

We have investigated the modulation by ceramide of the nicotinic activation of the prevertebral sympathetic neurons. Our study was performed in vitro in rabbit isolated coeliac ganglion, using intracellular recording techniques. We have used C(2) ceramide, a permeant analog of ceramide. The effects of C(2) ceramide were first assessed when nicotinic activation was elicited without modulatory mechanisms (fast excitatory postsynaptic potentials triggered by stimulation of the thoracic splanchnic nerves with a single pulse). In all the neurons tested, C(2) ceramide triggered an increase in the amplitude of the fast excitatory postsynaptic potentials demonstrating a direct facilitatory effect on the nicotinic activation. We then investigated the effects of C(2) ceramide on modulatory mechanisms of this activation. These mechanisms occur when a train of pulses of supramaximum intensity is applied on the splanchnic nerves. During the train, a gradual depression of fast nicotinic activation occurred: the pulses failed to systematically elicit action potentials. We have previously demonstrated that this regulatory phenomenon is partly modulated by nitric oxide which exerts a dual effect: facilitation or inhibition of the nicotinic activation. In all the neurons tested, C(2) ceramide decreased the number of action potentials fired during a train of pulses, demonstrating an indirect inhibitory effect on the nicotinic activation. The use of 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (nitric oxide scavenger) suppressed the inhibitory effect of C(2) ceramide, demonstrating that this effect is mediated through the nitric oxide pathway. C(2) dihydro-ceramide, an inactive analog of ceramide, was without effect on the nicotinic activation of the ganglionic neurons. These results demonstrate that ceramide exerts a complex modulation of the nicotinic activation of the prevertebral neurons: direct facilitation and indirect inhibition involving the nitric oxide pathway. In fact, C(2) ceramide plays a key gating role in the dual effect of the nitric oxide pathway by activating the inhibitory effect. The existence of this gating mechanism involving ceramide and nitric oxide opens new perspectives in terms of our understanding of the modulation of synaptic transmission within the prevertebral ganglia. Our study demonstrates that sphingolipids are involved in complex modulations of the synaptic activation within the prevertebral ganglia, and thus contribute to their integrative properties.

Evidence for a recessive inheritance of Turcot's syndrome caused by compound heterozygous mutations within the PMS2 gene.

Turcot's syndrome is a genetic disease characterized by the concurrence of primary brain tumors and colon cancers and/or multiple colorectal adenomas. We report a Turcot family with no parental consanguinity, in which two affected sisters, with no history of tumors in their parents, died of a brain tumor and of a colorectal tumor, respectively, at a very early age. The proband had a severe microsatellite instability (MIN) phenotype in both tumor and normal colon mucosa, and mutations in the TGFbeta-RII and APC genes in the colorectal tumor. We identified two germline mutations within the PMS2 gene: a G deletion (1221delG) in exon 11 and a four-base-pair deletion (2361delCTTC) in exon 14, both of which were inherited from the patient's unaffected parents. These results represent the first evidence that two germline frameshift mutations in PMS2, an MMR gene which is only rarely involved in HNPCC, are not pathogenic per se, but become so when occurring together in a compound heterozygote. The compound heterozygosity for two mutations in the PMS2 gene has implications for the role of protein PMS2 in the mismatch repair mechanism, as well as for the presymptomatic molecular diagnosis of at-risk family members. Furthermore, our data support and enlarge the notion that high DNA instability in normal tissues might trigger the development of cancer in this syndrome.

Coeliac disease and unfavourable outcome of pregnancy.

BACKGROUND: Up to 50% of women with untreated coeliac disease experience miscarriage or an unfavourable outcome of pregnancy. In most cases, after 6-12 months of a gluten free diet, no excess of unfavourable outcome of pregnancy is observed. The prevalence of undiagnosed coeliac disease among pregnant women is not known. AIM: To determine the prevalence of untreated coeliac disease among women attending the obstetrics-gynaecological department. METHODS: Endomysial antibodies, which are specific and sensitive for coeliac disease, were evaluated in all women attending the obstetrics-gynaecology department of a large city hospital over a 90 day period. RESULTS: Of 845 pregnant women screened, 12 were identified as having coeliac disease. Three had previously been diagnosed but were not following a gluten free diet. The remaining nine underwent a small intestinal biopsy, which confirmed the diagnosis. The outcome of pregnancy was unfavourable in seven of these 12 women. Six healthy babies were born with no problems after the women had been on a gluten free diet for one year. CONCLUSIONS: Overall, 1 in 70 women was affected by coeliac disease, either not diagnosed (nine cases) or not treated (three cases). Their history of miscarriages, anaemia, low birth weight babies, and unfavourable outcome of pregnancy suggests that testing for coeliac disease should be included in the battery of tests prescribed for pregnant women. Coeliac disease is considerably more common than most of the diseases for which pregnant women are routinely screened. Unfavourable events associated with coeliac disease may be prevented by a gluten free diet.

Reference intervals of CD3, CD4, CD8, CD4/CD8, and absolute CD4 values in Asian and Non-Asian populations.

A study to determine reference intervals in normal Asian and non-Asian populations for CD3 (T cells), CD4 (T helper/inducer cells), CD8 (T suppressor/cytotoxic cells), and for the CD4/CD8 ratio and absolute CD4 lymphocyte count was performed. Coulter Clone/Cytostat reagents were used. The samples were lysed using the Coulter Q-Prep and analyzed on the Coulter Profile II flow cytometer. The Asian population appeared to have a lower mean percentage of CD3 and CD4 cells, a lower CD4/CD8 ratio, and lower absolute CD4 lymphocytes. These findings indicate that race should be a consideration in determining reference intervals for immunophenotyping for CD3, CD4, and CD8.

Fluconazole treatment of children with severe fungal infections not treatable with conventional agents.

Fluconazole was evaluated prospectively in 173 children aged between 4 months and 16 years in whom conventional antifungal therapy was ineffective or contraindicated. Children entered the study on an individual compassionate request basis for treatment of confirmed or presumed fungal infection or for prophylaxis of fungal infections. Sixty-two children had cancer, 40 had undergone transplantation, 14 had AIDS and 52 had other conditions. The mean fluconazole dosage was 3.4 mg/kg/day (range 0.16-11.1 mg/kg/day) and the mean duration of therapy was 36 days (range 1-340 days). Efficacy was evaluated in 63 children with confirmed fungal infection as documented by the presence of a fungal pathogen at baseline; clinical cure or improvement was achieved in 83% (52/63), pathogen eradication in 73% (43/59). All 173 children were assessed for safety. Related or possibly related adverse events occurred in 6% (11/173) of patients; seven children were withdrawn from therapy because of adverse events. Results of this study demonstrate that the clinical efficacy and safety profile of fluconazole in the treatment of fungal infections in children are favorable, results being similar to those obtained in adults.

Fluconazole treatment of neonates and infants with severe fungal infections not treatable with conventional agents.

Fluconazole was evaluated prospectively in 40 neonates and infants between the ages of 2 days and 3 months in whom conventional antifungal therapy was ineffective or contraindicated. The patients received therapy on an individual compassionate request basis for microbiologically documented or presumed fungal infection. The mean fluconazole dosage was 5.3 mg/kg/day (range 1-16 mg/kg/day) and the mean duration of therapy was 26 days (range 2-80 days). Efficacy was evaluated in neonates with proven fungal infection as documented by the presence of a pathogen at baseline. A positive clinical response was achieved in 97% (31/32) of the clinically evaluable patients; eradication of the fungal organism was achieved in 97% (30/31) of evaluable patients. Adverse events occurred in two patients (5%); therapy was not discontinued in either patient. These favorable safety and efficacy data are similar to results obtained with fluconazole in older children and adults.