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Chronic stress induces dendritic atrophy in the inferior colliculus (IC, auditory mesencephalon) and impairs auditory avoidance conditioning. The aim of this study was to determine in Golgi preparations and in cued fear conditioning whether stress affects other auditory components, like the thalamic medial geniculate nucleus (MG) or the posterior thalamic nucleus (PO), in Sprague-Dawley rats. Chronic restraint stress produced a significant dendritic atrophy in the MG (stress: 407+/-55 microm; control: 808+/-120 microm; p<0.01) but did not affect auditory fear conditioning. The last result was in apparent contrast with the fact that stress impairs both the acquisition of auditory avoidance conditioned responses and the dendritic structure in two major nuclei of the auditory system. In order to analyze this disagreement, we investigated whether the stress-related freezing to tone occurring in the fear conditioning protocol corresponded to a conditioned or an unconditioned fear response, using changes in tone instead of light throughout conditioning trials. Chronic stress significantly enhanced visual fear conditioning in stressed animals compared to controls (stress: 58.9+/-8.42%, control: 23.31+/-8.01%; p<0.05), but this fear enhancement was related to unconditioned fear. Conversely, chronic stress did not affect the morphology of the PO (subserving both auditory and somatosensory information) or the corresponding auditory and somatosensory unconditioned responses (acoustic startle response and escape behavior). Our results suggest that the auditory conditioned stimulus can be processed in part independently of the IC and MG in the stressed animals, and sent to the amygdala via the PO inducing unconditioned fear. Comparable alterations could be produced in major depression.

The coordination chemistry of three new quinoline pendant arm derivatives of [9]aneN(3) (L(1), L(2)) and [9]aneN(2)S (L(3)) toward Cu(II), Zn(II), Cd(II), Hg(II), and Pb(II) has been investigated both in solution and in the solid state. The protonation constants for L(1)-L(3) and stability constants with the aforementioned metal ions have been determined potentiometrically in 0.10 M NMe(4)Cl MeCN/H(2)O (1:1 v/v) solution at 298.1 +/- 0.1 K; the measured values show that Cu(II) has the highest affinity for all three ligands, followed by Zn(II), Hg(II), Pb(II), and Cd(II). For each metal ion considered, 1:1 complexes with L(1)-L(3) have also been isolated in the solid state and [Cu(L(1))](BF(4))(2) (1), [Zn(L(1))](BF(4))(2) (2), [Cd(L(1))](ClO(4))(2) (3), [Hg(L(1))](NO(3))(2) (4), [Pb(L(1))](ClO(4))(2) x MeCN (5), [Zn(2)Cl(2)(L(2))(2)](BF(4))(2) x 1/2 MeNO(2) x H(2)O (6), [Cu(L(3))](ClO(4))(2) (7), [Zn(L(3))(NO(3))]NO(3) (8), [Cd(L(3))(NO(3))(0.82)Cl(0.18)]NO(3) (9), and [Hg(L(3))](ClO(4))(2) x MeCN (10) have also been characterized by X-ray crystallography. The optical response of L(1)-L(3) to the presence of the above-mentioned metal ions has been investigated in MeCN/H(2)O (1:1 v/v) and H(2)O solutions. All three ligands show a stronger "OFF-ON" CHEF (chelation enhancement of fluorescence) effect in the Zn(II) complexes than in the Cd(II) complexes in both media. The results have been examined by considering the ratio I(rel)(Zn(II))/I(rel)(Cd(II)), within the emerging idea that the relative strength of the CHEF effect for the small Zn(II) ion as compared to larger Cd(II) ion might be determined by steric crowding in the corresponding complexes with quinoline-based fluorescent chemosensors.

Displacements of articular fragments are not always visible on initial radiographs of acute distal radius fractures. Despite the wide use of CT scan, it may be useful to know a simple index that could suggest an articular displaced fracture from the initial standard radiographs. The authors describe an articular sagittal index (ASI) of the distal radius and provide reference values from a study of 100 healthy volunteers. An increase of the ASI index suggests a displaced articular distal radius fracture with possible impaction.

Background: Neuropsychological deficits in patients with multiple sclerosis (MS) have been shown to be associated with the major pathological substrates of the disease, ie, inflammatory demyelination and neurodegeneration. Double inversion recovery sequences allow cortical lesions (CLs) to be detected in the brain of patients with MS. Modern postprocessing techniques allow cortical atrophy to be assessed reliably., Objective: To investigate the contribution of cortical gray matter lesions and tissue loss to cognitive impairment in patients with relapsing-remitting MS., Design: Cross-sectional survey., Setting: Referral, hospital-based MS clinic. Patients Seventy patients with relapsing-remitting MS., Main Outcome Measures: Neuropsychological performance was tested using the Rao Brief Repeatable Battery of Neuropsychological Tests, version A. Patients who scored 2 SDs below the mean normative values on at least 1 test of the Rao Brief Repeatable Battery of Neuropsychological Tests, version A, were considered to be cognitively impaired. A composite cognitive score (the cognitive impairment index) was computed. T2 hyperintense white matter lesion volume, contrast-enhancing lesion number, CL number and volume, normalized brain volume, and normalized neocortical gray matter volume were also assessed., Results: Twenty-four patients with relapsing-remitting MS (34.3%) were classified as cognitively impaired. T2 hyperintense white matter lesion volume and contrast-enhancing lesion number were not different between cognitively impaired and cognitively unimpaired patients. Cognitively impaired patients had a higher CL number (P = .01) and volume (P < .001) and decreased normalized brain volume (P = .02) and normalized neocortical gray matter volume (P = .002) when compared with cognitively unimpaired patients. Multivariate analysis revealed that age (beta = 0.228; P = .02), CL volume (beta = 0.452; P < .001), and normalized neocortical gray matter volume (beta = 0.349; P < .001) were independent predictors of the cognitive impairment index (r(2) = 0.55; F = 23.903; P < .001)., Conclusion: The burden of CLs and tissue loss are among the major structural changes associated with cognitive impairment in relapsing-remitting MS.

Background: In primary progressive multiple sclerosis (PPMS), a discrepancy exists between the modest brain white matter (WM) lesion burden and the severity of neurologic disability. Double-inversion recovery (DIR) sequences have improved MRI sensitivity in the detection of cortical lesions (CLs) in patients with relapsing-onset MS., Objective: This 2-year longitudinal study was designed to assess the frequency, extent, and rate of formation of CLs in PPMS and their relationship with T2 lesion volume (LV), gray matter (GM) atrophy, and disability., Methods: Forty-eight patients with PPMS underwent clinical and magnetic resonance examinations at baseline and after 2 years. The number and volume of CLs, WM T2 LV, and GM fraction (GMf) were assessed at baseline and at follow-up., Results: At baseline, CLs were detected in 81.2% of patients with PPMS. At least one new CL was found in 28 patients during the follow-up. In patients with PPMS, CL and T2 WM LVs increased over the follow-up. At baseline, CL number and volumes were significantly correlated with T2 WM LV, GMf, disease duration, and Expanded Disability Status Scale score, as well as with increasing GM atrophy and disability during the follow-up. A multivariate analysis showed that CL volume at baseline was an independent predictor of percentage GM volume change and disability accumulation during the subsequent 2-year period., Conclusions: Cortical lesions are a frequent finding in primary progressive multiple sclerosis. The extent of such abnormalities is associated with the extent of cortical atrophy and clinical disability, and is able to predict their changes over a medium time period.

Acetylcholine (ACh) and N-methyl-D aspartate receptors (NMDARs) interact in the regulation of multiple important brain functions. NMDAR activation is indirectly modulated by ACh through the activation of muscarinic or nicotinic receptors. Scant information is available on whether ACh directly interacts with the NMDAR. By using a cortical brain slice preparation we found that the application of ACh and of other drugs acting on muscarinic or nicotinic receptors induces an acute and reversible reduction of NMDAR-mediated currents (I(NMDA)), ranging from 20 to 90% of the control amplitude. The reduction displayed similar features in synaptic I(NMDA) in brain slices, as well as in currents evoked by NMDA application in brain slices or from acutely dissociated cortical cells, demonstrating its postsynaptic nature. The cholinergic inhibition of I(NMDA) displayed an onset-offset rate in the order of a second, and was resistant to the presence of the muscarinic antagonist atropine (10 microM) in the extracellular solution, and of G-protein blocker GDP(beta)S (500 microM) and activator GTP(gamma)S (400 microM) in the intracellular solution, indicating that it was not G-protein dependent. Recording at depolarized or hyperpolarized holding voltages reduced NMDAR-mediated currents to similar extents, suggesting that the inhibition was voltage-independent, whereas the reduction was markedly more pronounced in the presence of glycine (20 microM). A detailed analysis of the effects of tubocurarine suggested that at least this drug interfered with glycine-dependent NMDAR-activity. We conclude that NMDAR-mediated current scan be inhibited directly by cholinergic drugs, possibly by direct interaction within one or more subunits of the NMDAR. Our results could supply a new interpretation to previous studies on the role of ACh at the glutamatergic synapse., (Copyright 2008 Wiley-Liss, Inc.)

Objective: The purpose of the study was to compare and contrast the initial presenting demographic, clinical, neuroimaging, and laboratory features in a cohort of children affected from multiple sclerosis (MS) or acute disseminated encephalomyelitis (ADEM)., Methods: A 12-year prospective study was conducted in 68 pediatric patients (age

Background: Using double inversion recovery (DIR) MRI, cortical lesions can be seen in the brain of patients with multiple sclerosis (MS). The burden of such lesions seems to be well correlated with the severity of MS-related disability., Objective: To investigate whether the extent of cortical damage in patients with benign MS (BMS) might contribute to explain their favorable clinical status., Methods: Forty-eight patients with BMS (Expanded Disability Status Scale [EDSS] score < or =3.0 and disease duration > or =15 years) and 96 patients with non-disabling, early relapsing-remitting (RR) MS (EDSS score < or =3.0 and disease duration < or =5 years) were studied. Brain MRI, including a DIR and a fluid-attenuated inversion recovery (FLAIR) sequence, was acquired at baseline and after 12 months. On DIR images, intracortical (ICL) and cortical-subcortical lesions (CSL) were identified and their number and volume calculated. Total white matter (WM) lesion volume was quantified on FLAIR images., Results: Compared with early RRMS, patients with BMS had lower number of ICL at both study time points (P < or = 0.001 for both comparisons). At one-year follow-up, a significant increase of ICL and CSL number and total volume was observed only in early patients with RRMS. The number and volume of cortical lesions was not correlated with WM lesion volume. Total ICL number at baseline, total cortical lesion volume at baseline, and total cortical lesion volume change were independent predictors of MS phenotype., Conclusion: In patients with BMS, the selective sparing of the cortex from disease-related focal pathology might be one of the factors associated to their favorable clinical status, independently of the (possible) accrual of WM lesions.

The underlying cellular mechanisms leading to frontal cortical hypofunction (i.e., hypofrontality) in schizophrenia remain unclear. Both hypoactive and hyperreactive prefrontal cortical (PFC) states have been reported in schizophrenia patients. Recent proton magnetic resonance spectroscopy studies revealed that antipsychotic-naïve patients with first psychotic episode exhibit a hyperactive PFC. Conversely, PFC activity seems to be diminished in patients chronically exposed to conventional antipsychotic treatments, an effect that could reflect the therapeutic action as well as some of the impairing side effects induced by long-term blockade of dopamine transmission. In this review, we will provide an evolving picture of the pathophysiology of schizophrenia moving from dopamine to a more glutamatergic-centered hypothesis. We will discuss how alternative antipsychotic strategies may emerge by using drugs that reduce excessive glutamatergic response without altering the balance of synaptic and extrasynaptic normal glutamatergic neurotransmission. Preclinical studies indicate that acamprosate, a FDA approved drug for relapse prevention in detoxified alcoholic patients, reduces the glutamatergic hyperactivity triggered by ethanol withdrawal without depressing normal glutamatergic transmission. Whether this effect is mediated by a direct modulation of NMDA receptors or by antagonism of metabotropic glutamate receptor remains to be determined. We hypothesize that drugs with similar pharmacological actions to acamprosate may provide a better and safer approach to reverse psychotic symptoms and cognitive deficits without altering the balance of excitation and inhibition of the corticolimbic dopamine-PFC system. It is predicted that schizophrenia patients treated with acamprosate-like compounds will not exhibit progressive cortical atrophy associated with the anti-dopaminergic effect of classical antipsychotic exposure.

Cortical lesions (CLs) can be detected in the majority of patients with established multiple sclerosis (MS), but little is known about their evolution over time. This study was performed to investigate the short-term MRI evolution of CLs, with the ultimate aim to achieve a better in vivo understanding of their nature. Seven hundred and sixty-eight CLs from 107 MS patients (76 with relapsing-remitting [RR] and 31 with secondary progressive [SP] MS) were followed with brain MR examinations, including a double inversion recovery (DIR) sequence, every 6 months for 1 year. CLs' number, volume and morphological features were assessed at each time-point. Six hundred and eighty CLs (88.5%) remained morphologically unchanged during the follow-up period, while 74 (9.6%) showed an increase in size. Only 6 (0.8%) CLs seen at baseline (all in RRMS patients) disappeared at follow-up MRI scans. No enlarging CLs spread into the subcortical white matter. No CLs ever showed gadolinium enhancement. At baseline, the mean number of CLs was higher in SPMS than in RRMS patients (p<0.001), whereas the mean number of new CLs per patient after 1 year did not differ between the two groups. Over a one-year period, CLs can increase their number and size in a relevant proportion of MS patients, without spreading into the subcortical white matter or showing inflammatory features similar to those of white matter lesions. The short-term rate of CLs accumulation does not seem to vary according to the clinical stage of MS.

Objectives: Previous imaging reports showed over-activation of fronto-limbic structures in bipolar patients, particularly in response to emotional stimuli. In this study, for the first time, we used perfusion weighted imaging (PWI) to analyze lobar cerebral blood volume (CBV) in bipolar disorder to further explore the vascular component to its pathophysiology., Methods: Fourteen patients with DSM-IV bipolar disorder (mean age+/-SD=49.00+/-12.30 years; 6 males, 8 females) and 29 normal controls (mean age+/-SD=45.07+/-10.30 years; 13 males, 16 females) were studied. PWI images were obtained following intravenous injection of paramagnetic contrast agent (Gadolinium-DTPA), with a 1.5 T Siemens magnet using an echo-planar sequence. The contrast of enhancement (CE), was calculated pixel by pixel as the ratio of the maximum signal intensity drop during the passage of contrast agent (Sm) by the baseline pre-bolus signal intensity (So) (CE=Sm/So*100) for frontal, temporal, parietal, and occipital lobes, bilaterally, on two axial images. Higher CE values correspond to lower CBV and viceversa., Results: Bipolar patients had significantly lower CE values in left frontal and temporal lobes (p=0.01 and p=0.03, respectively) and significantly inverse laterality index for frontal lobe (p=0.017) compared to normal controls. No significant correlations between CE measure and age or clinical variables were found (p>0.05)., Conclusion: This study found increased left frontal and temporal CBV in bipolar disorder. Fronto-temporal hyper-perfusion may sustain over-activation of these structures during emotion modulation, which have been observed in patients with bipolar illness.

This study investigated the possible prognostic factors for relapse, and the diagnostic criteria for multiple sclerosis and related disorders, in pediatric acute disseminated encephalomyelitis. The study population comprised 24 Italian children with a mean age at onset of 6.9 years, and a mean follow-up time of 52.8 months (range, 12-180). Clinical, neurophysiologic, spinal-fluid, neuroradiologic, and outcome features were investigated. All patients but 2, who were reclassified as exhibiting clinically isolated syndromes, fulfilled the new classification criteria for acute disseminated encephalomyelitis recently proposed by the International Pediatric Multiple Sclerosis Study Group. Three patients relapsed after 3 months, 2 years, and 8 years, respectively. By the second attack, the diagnosis of multiple sclerosis, as well as of multiphasic disseminated encephalomyelitis, could be rendered using the revised criteria of McDonald et al. Long-term follow-up seemed to confirm a chronic disease course in 2 children. We could not identify features at onset to predict outcomes of patients. However, early in follow-up, the appearance of oligoclonal immunoglobulin G bands in spinal fluid and the persistence of visual-evoked potential abnormalities were associated with poor outcomes.

Introduction: Epilepsy is three to six times more frequent in MS than in the general population. Previous studies based on conventional magnetic resonance (MR) imaging have suggested a possible correlation between cortical inflammatory pathology and epileptic seizures. However, pure intracortical lesions (ICLs) are unlikely to be demonstrated with conventional MR. We applied the double inversion recovery (DIR) sequence in relapsing remitting MS (RRMS) patients with or without epileptic seizures in order to clarify the relationship between ICLs and epilepsy in MS in vivo., Methods: Twenty RRMS patients who had epileptic seizures (RRMS/E) during the course of the disease were studied for the presence of ICLs. A group of 80 RRMS patients with no history of seizures and matched for gender, age, disease duration, Expanded Disability Status Scale (EDSS) grading, and T2 lesion volume (T2-WMLV) was selected as reference population. ICLs were detected by applying the DIR sequence., Results: ICLs were observed in 18/20 (90%) RRMS/E and in 39/80 (48%) RRMS (p = 0.001). RRMS/E showed five times more ICLs (7.2 +/- 8.4) than RRMS (1.5 +/- 2.4; p = 0.015). The total ICLs volume was 6 times larger in RRMS/E than in RRMS (1.2 +/- 1.7 cm3 versus 0.2 +/- 0.2 cm3, p = 0.016). No significant difference was observed between RRMS and RRMS/E with regard to the number and volume of juxtacortical lesions and T2-WMLV., Discussion: Our findings indicate that RRMS/E have more extensive cortical inflammation than RRMS patients with no history of epilepsy. Inflammatory ICLs may be responsible for epilepsy in MS.

Background: A significant inflammatory pathologic disorder in the cortex of patients with multiple sclerosis (MS) has been demonstrated by ex vivo studies., Objective: To determine the frequency, time of appearance, and clinical relevance of intracortical lesions (ICLs) in MS in vivo., Design: Double inversion recovery sequence study., Setting: Multiple Sclerosis Centre of the Veneto Region. Patients We enrolled 380 patients (116 with clinically isolated syndrome [CIS], 163 with relapsing-remitting MS [RRMS], and 101 with secondary progressive MS [SPMS]) and 40 age- and sex-matched healthy volunteers between May 1, 2005, and December 31, 2006., Main Outcome Measures: We assessed the frequency and number of ICLs and brain parenchyma fraction, white matter T2 lesion volume, and clinical disability., Results: Although never observed in healthy volunteers, ICLs were detected in 58% of patients (36% of patients with CIS, 64% of patients with RRMS, and 73% of patients with SPMS). The number of ICLs was higher in patients with SPMS than in those with CIS or RRMS (P <.001), and patients with ICLs had a higher Expanded Disability Status Scale score (P = .004), a higher white matter T2 lesion volume (P = .008), a lower brain parenchyma fraction (P = .009), and a higher frequency of IgG oligoclonal bands (IgGOBs) (P <.001) than patients without ICLs. Patients positive for IgGOBs had more ICLs than patients negative for IgGOBs (P = .02). The number of ICLs correlated with the Expanded Disability Status Scale score (r = 0.48, P <.001), white matter T2 lesion volume (r = 0.38, P = .001), and brain parenchyma fraction (r = -0.47, P = .001). A significant association between ICLs and male sex was observed., Conclusions: Although more frequent in patients with SPMS, ICLs were observed from the early disease stages. The ICLs were more frequently detected in patients with IgGOBs and were associated with a higher clinical disability score and male sex. The ICLs may help to define MS clinical heterogeneity and prognosis in clinical settings.

Introduction: Increasing evidence suggests relevant cortical gray matter pathology in patients with Multiple Sclerosis (MS), but how early this pathology begins; its impact on clinical disability and which cortical areas are primarily affected needs to be further elucidated., Methods: 115 consecutive patients (10 Clinically Isolated Syndrome (CIS), 32 possible MS (p-MS), 42 Relapsing Remitting MS (RR-MS), 31 Secondary Progressive MS (SP-MS)), and 40 age/gender-matched healthy volunteers (HV) underwent a neurological examination and a 1.5 T MRI. Global and regional Cortical Thickness (CTh) measurements, brain parenchyma fraction and T2 lesion load were analyzed., Results: We found a significant global cortical thinning in p-MS (2.22 +/- 0.09 mm), RR-MS (2.16 +/- 0.10 mm) and SP-MS (1.98 +/- 0.11 mm) compared to CIS (2.51 +/- 0.11 mm) and HV (2.48 +/- 0.08 mm). The correlations between mean CTh and white matter (WM) lesion load was only moderate in MS (r = -0.393, p = 0.03) and absent in p-MS (r = -0.147, p = 0.422). Analysis of regional CTh revealed that the majority of cortical areas were involved not only in MS, but also in p-MS. The type of clinical picture at onset (in particular, pyramidal signs/symptoms and optic neuritis) correlated with atrophy in the corresponding cortical areas., Discussion: Cortical thinning is a diffuse and early phenomenon in MS already detectable at clinical onset. It correlates with clinical disability and is partially independent from WM inflammatory pathology.

Blood in the urine (hematuria) can originate from any site along the urinary tract and may be the only sign of renal or vesical malignancy. Therefore, literature recommends for the evaluation of any case of macroscopic or microscopic hematuria. Our aim was to define the diagnostic role of multidetector CT urography (MDCTu) in the evaluation of this symptom through the analysis of 181 consecutive patients from January 2003 to March 2006.

We measured pharmacologically isolated GABAergic currents from layer II/III neurons of the rat auditory cortex using patch-clamp recording. Activation of muscarinic receptors by muscarine (1 microM) or oxotremorine (10 microM) decreased the amplitude of electrically evoked inhibitory postsynaptic currents to about one third of their control value. Neither miniature nor exogenously evoked GABAergic currents were altered by the presence of muscarinic agonists, indicating that the effect was spike-dependent and not mediated postsynaptically. The presence of the N- or P/Q-type Ca(2+) channel blockers omega-conotoxin GVIA (1 microM) or omega-AgaTx TK (200 nM) greatly blocked the muscarinic effect, suggesting that Ca(2+)-channels were target of the muscarinic modulation. The presence of the muscarinic M(2) receptor (M(2)R) antagonists methoctramine (5 muM) or AF-DX 116 (1 microM) blocked most of the muscarinic evoked inhibitory postsynaptic current (eIPSC) reduction, indicating that M(2)Rs were responsible for the effect, whereas the remaining component of the depression displayed M(1)R-like sensitivity. Tissue preincubation with the specific blockers of phosphatidyl-inositol-3-kinase (PI(3)K) wortmannin (200 nM), LY294002 (1 microM), or with the Ca(2+)-dependent PKC inhibitor Gö 6976 (200 nM) greatly impaired the muscarinic decrease of the eIPSC amplitude, whereas the remaining component was sensitive to preincubation in the phospholipase C blocker U73122 (10 microM). We conclude that acetylcholine release enhances the excitability of the auditory cortex by decreasing the release of GABA by inhibiting axonal V-dependent Ca(2+) channels, mostly through activation of presynaptic M(2)Rs/PI(3)K/Ca(2+)-independent PKC pathway and-to a smaller extent-by the activation of M(1)/PLC/Ca(2+)-dependent PKC.

Purpose: The purpose of this study was to define the indications, diagnostic accuracy and limitations of second-generation sonographic contrast agents in the evaluation of patients with renal trauma., Materials and Methods: Between March 2004 and April 2005, 277 patients with blunt abdominal trauma were evaluated. Twenty-eight out of 277 patients had renal lesions, the severity of which was graded according to the organ injury severity scale of the American Association for the Surgery of Trauma (AAST). All the patients enrolled in the study had minor trauma and were evaluated with baseline ultrasound (US), contrast-enhanced US after injection of a second-generation contrast agent (SonoVue) and, if positive, with multiphasic multidetector computed tomography (MDCT)., Results: Five out of 28 traumatic parenchymal lesions with perirenal fluid collection were identified at baseline US. All 28 renal parenchymal lesions, with or without perirenal or retroperitoneal haematoma, were identified at contrast-enhanced US. Multiphase MDCT confirmed all the cases that were positive at contrast-enhanced US and demonstrated the integrity of the urinary tract in the delayed phase., Conclusions: Our experience confirmed the diagnostic accuracy of second-generation sonographic contrast material both for diagnosis and for appropriate patient management. In particular, contrast-enhanced sonography proved to be a reliable technique for the evaluation and follow-up of low-grade renal injuries. Its main advantage is reduced radiation exposure, as fewer MDCT examinations are needed, whereas its limitation is the high cost of the technique if used in unselected patients.

Prolonged exposure to environmental enrichment (EE) induces behavioral adaptation accompanied by detectable morphological and physiological changes. Auditory EE is associated with an increased auditory evoked potential (AEP) and increased auditory gating in the primary auditory cortex. We sought physiological correlates to such changes by comparing synaptic currents in control vs. EE-raised rats, in a primary auditory cortex (AI) slice preparation. Pharmacologically isolated glutamatergic or GABA(A)-receptor-mediated currents were measured using perforated patch whole-cell recordings. Glutamatergic AMPA receptor (AMPAR)-mediated excitatory postsynaptic currents (EPSCs) displayed a large amplitude increase (64+/-11% in EE vs. control) accompanied by a rise-time decrease (-29+/-6% in EE vs. control) and decrease in pair pulse ratio in layer II/III but not in layer V. Changes in glutamatergic signaling were not associated with changes in the ratio between N-methyl-D aspartate-receptor (NMDAR)-mediated vs. AMPAR-mediated components, in amplitude or pair pulse ratio of GABAergic transmission, or in passive neuronal properties. A realistic computational model was used for integrating in vivo and in vitro results, and for determining how EE synapses correct for phase error of the inputs. We found that EE not only increases the mean firing frequency of the responses, but also improves the robustness of auditory processing by decreasing the dependence of the output firing on the phase difference of the input signals. We conclude that behavioral and electrophysiological differences detected in vivo in rats exposed to an auditory EE are accompanied and possibly caused by selective changes in cortical excitatory transmission. Our data suggest that auditory EE selectively enhances excitatory glutamatergic synaptic transmission in layer II/III without greatly altering inhibitory GABAergic transmission.

Accumulating evidence indicates that dopamine and D1 receptor ligands modulate N-methyl D-aspartate (NMDA) receptors through a variety of D1 receptor-dependent mechanisms. In this study, we reveal a distinct D1 receptor-independent mechanism by which NMDA receptors are modulated. Using the human embryonic kidney (HEK) cell recombinant system and dissociated neurons, we have discovered that dopamine and several D1 ligands act as voltage-dependent, open-channel blockers for NMDA receptors, regardless of whether they are agonists or antagonists for D1 receptors. Analysis of structural and functional relationships of D1 ligands revealed the elements that are critical for their binding to NMDA receptors. Furthermore, using D1 receptor knockout mice, we verified that this channel-blocking effect was independent of D1 receptors. Finally, we demonstrated that D1 ligands functionally interact with Mg(2+) block through multiple sites, implying a possible role of the direct channel block under physiological conditions. Our results suggest that the direct inhibition of NMDA receptors by dopamine D1 receptor ligands is due to the channel pore block rather than receptor-receptor interactions.

The aim of the present study was to determine the effect of a cholesterol-rich diet on learning performance and monitor possible related changes in synaptic function. To this purpose, we compared controls with rats fed with a cholesterol-enriched diet (CD). By using a Morris water-maze paradigm, we found that CD rats learned a water-maze task more quickly than rats fed with a regular diet (RD). A longer period of this diet tended to alter the retention of memory without affecting the improvement in the acquisition of the task. Because of the importance of the hippocampus in spatial learning, we hypothesized that these behavioral effects of cholesterol would involve synaptic changes at the hippocampal level. We used whole-cell patch-clamp recording in the CA1 area of a hippocampal rat slice preparation to test the influence of the CD on pre- and postsynaptic function. CD rats displayed an increase in paired-pulse ratio in both glutamatergic synapses (+48 +/- 9%) and GABAergic synapses (+41 +/- 8%), suggesting that the CD induces long-lasting changes in presynaptic function. Furthermore, by recording NMDA-receptor-mediated currents (I(NMDA)) and AMPA-receptor-mediated currents (I(AMPA)) in the same set of cells we found that CD rats display a lower I(NMDA)/I(AMPA) ratio (I(NMDA)/I(AMPA) = 0.75 +/- 0.32 in RD versus 0.10 +/- 0.03 in CD), demonstrating that cholesterol regulates also postsynaptic function. We conclude that a cholesterol-rich diet affects learning speed and performance, and that these behavioral changes occur together with robust, long-lasting, synaptic changes at both the pre- and postsynaptic level.

Purpose: The aim of this paper is to present our experience in the percutaneous management of high-flow priapism with transcatheter embolisation and gelfoam., Materials and Methods: We present three clinical cases in which an acute trauma caused the development of high-flow priapism. After differing initial management, all cases underwent arteriography, followed by demonstration of the arterial-lacunar fistula and embolisation with gelfoam., Results: Near immediate detumescence after the procedure confirmed the success of embolisation, which was supported by clinical and instrumental follow-up., Discussion: In high-flow priapism, the best therapeutic solution remains transcatheter arterial embolisation, with ultra-selective catheterisation by microcatheter and embolisation of the pudendal artery only, which is responsible for the post-traumatic arterial-lacunar fistula. This manoeuvre is not always technically easy, and requires experience and remarkable dexterity. Technical failure is always possible owing to the spasm of a peripheral arteriole that cannot be resolved with papaverine, and to the possible rehabilitation by the downstream contralateral circulation. Furthermore, the apprehension of the operator carrying out the procedure in this anatomical context may make the immediate result seem satisfactory, even if it is not optimal. All these considerations stress the need for a rigorous clinical and instrumental follow-up to guide later diagnostic and therapeutic choices.

Acetylcholine and dopamine are simultaneously released in the cortex at the occurrence of novel stimuli. In addition to a series of excitatory effects, acetylcholine decreases the release of glutamate acting on presynaptic muscarinic receptors. By recording evoked excitatory postsynaptic currents in layers II/III neurons of the auditory cortex, we found that activation of muscarinic receptors by oxotremorine reduces the amplitude of glutamatergic current (A(oxo)/A(ctr) = 0.53 +/- 0.17) in the absence but not in the presence of dopamine (A(oxo)/A(ctr) = 0.89 +/- 0.12 in 20 microM dopamine). These data suggested that an excessive sensitivity to dopamine, such as postulated in schizophrenia, could prevent the decrease of glutamate release associated with the activation of cholinergic corticopetal nuclei. Thus, a possible mechanism of action of antipsychotic drugs could be through a depression of the glutamatergic signal in the auditory cortex. We tested the capability of haloperidol, clozapine and lamotrigine to affect glutamatergic synaptic currents and their muscarinic modulation. We found that antipsychotics not only work as dopamine receptor antagonists in re-establishing muscarinic modulation, but also directly depress glutamatergic currents. These results suggest that presynaptic modulation of glutamate release can account for a dual route of action of antipsychotic drugs.

Purpose: To evaluate the accuracy of second generation contrast enhanced US (Sonovue) in the diagnosis and staging of traumatic hepatic lesions, compared with conventional US and spiral CT., Material and Methods: A total of 203 patients (127 males, 76 females, mean age 36 years) with isolated abdominal trauma were examined with conventional and contrast enhanced US (Sonovue, Bracco, Italy) between March 2002 and February 2003. The sonographic contrast agent was administered at a dose of 2 ml/10-15", repeated twice. CT examinations were performed with single- (Rhota, Esaote Biomedica, Italy) or multislice spiral CT with administration of contrast agent. The presence and number of lesions, hepatic capsular involvement, size and sonographic pattern were evaluated., Results: Conventional US demonstrated hepatic lesions in 27 patients, in 3 cases it identified 2 foci (30 lesions, size 2-8 cm). Contrast enhanced US (CEUS) revealed another 2 lesions and in 4 patients it identified lesions not shown at conventional US (size 2-5 cm). Capsular involvement was detected in 14 cases (11 with conventional US). The sonographic pattern of the lesions at conventional US was hypo-anechoic in 19 cases, and hyperechoic in 11. In CEUS all the lesions appeared strongly hypoechoic against a strongly hyperechoic parenchyma, with clear borders and larger size as compared with conventional US., Conclusions: In isolated blunt abdominal trauma CEUS is more accurate than conventional US in determining the number and size of lesions and detecting capsular involvement. This has a strong impact on diagnosis as the number of false negatives is reduced and on prognosis as the lesions are more accurately graded, and there is close correlation with spiral CT. CEUS can be used as a first approach in mild isolated abdominal trauma, in paediatric patients and in the follow-up, whereas CT is the method of choice in severe trauma and in multiple traumas.

The neural circuits of the auditory cortex are a substrate for the dual purpose of representing and storing the auditory signal on one hand, and sending its relevant features to other cortical and subcortical areas on the other hand. The ability to process and transform the signal crucially depends on achievement of the neuronal spike threshold following spatiotemporal summation of the synaptic signals. We used patch-clamp recording in a thin slice preparation to compare neuronal responses to current injection of layer II/III and layer V neurons. We found that while the two classes of neurons do not differ in passive neuronal properties, layer II/III neurons possess a lower firing threshold relative to layer V neurons (-44.8 +/- 2.4 mV vs. -34.3 +/- 4.0 mV). We speculate that a lower spiking threshold in layer II/III neurons might favor local intracolumnar activation for representation and storage of the auditory information whereas a more positive spiking threshold for layer V neurons may prevent unnecessary cortical spread of a scarcely processed signal.

Recommendations to decrease the nursing shortage often identify the need to strengthen nurses' autonomy and control in hospitals but do not describe specific mechanisms to accomplish this goal. The Nurse Practices Committee provides a forum for staff nurses and nurse executives at Robert Wood Johnson University Hospital to jointly make decisions about resource allocation. Committee members agree that this work has strengthened relationships by fostering mutual understanding, respect, and trust. As a result, nursing management and staff partners can advocate for patients and nurses with a single, more powerful voice.

Purpose: The use of CT volume-rendering techniques allows the evaluation of visceral organs without the need for endoscopy. Conventional endoscopic evaluation of the bladder is limited by the invasiveness of the technique and the difficulty exploring the entire bladder. Virtual evaluation of the bladder by three-dimensional CT reconstruction offers potential advantages and can be used in place of endoscopy. This study investigates the sensitivity of virtual CT in assessing lesion of the bladder wall to compare it with that of conventional endoscopy, and outlines the indications, advantages and disadvantages of virtual CT-pneumocystography., Materials and Methods: Between September 2001 and May 2002, 21 patients with haematuria and positive cystoscopic findings were studied. After an initial assessment by ultrasound, the patients underwent pelvic CT as a single volumetric scan after preliminary air distension of the bladder by means of 12 F Foley catheter. The images were processed on an independent workstation (Advantage 3.0 GE) running dedicated software for endoluminal navigation. The lesions detected by endoscopy were classified as sessile or pedunculated, and according to size (more or less than 5 mm). Finally, the results obtained at virtual cystoscopy were evaluated by two radiologists blinded to the conventional cystoscopy results., Results: Thirty lesions (24 pedunculated, 6 sessile) were detected at conventional cystoscopy in 16 patients (multiple polyposis in 3 cases). Virtual cystoscopy identified 23 lesions (19 pedunculated and 4 sessile). The undetected lesions were pedunculated <5 mm (5 cases) and sessile (2 cases). One correctly identified pedunculated lesion was associated with a bladder stone., Discussion: Good quality virtual images were obtained in all of the patients. In only one patient with multiple polyposis the quality of the virtual endoscopic evaluation was limited by the patient's intolerance to bladder distension, although identification of the lesions was not compromised. The overall sensitivity was 77%; this was higher for pedunculated lesions (79%) than for sessile lesions (50%). The virtual technique is less invasive and tends to be associated with fewer complications than is conventional cystoscopy. It also demonstrated a good sensitivity for evaluating pedunculated lesions, allowing evaluation of the bladder base and anterior wall, sites that are commonly poorly accessible at conventional cystoscopy. Further advantages of the virtual technique include the possibility of accurately measuring the extent of the lesion and obtaining virtual images even in patients with severe urethral obstruction and active bleeding. The limitations include the inability to obtain tissue for histologic examination or to perform endoscopic resection of pedunculated lesions. The technique is less sensitive than conventional cystoscopy in the detection of sessile lesions or very small polyps (<5 mm). Furthermore, diffuse wall thickening reduces bladder distension thereby preventing optimal evaluation. The most valuable indication appears to be the follow-up of treated wall lesions., Conclusions: Virtual CT-pneumocystoscopy can replace conventional cystoscopy in cases with pedunculated lesions when there is no need for biopsy, when the lesions are located at the bladder base or when cystoscopic instrumentation cannot be introduced into the bladder due to stenosis. Virtual pneumocystoscopy can also be used in the follow-up of treated polypoid lesions in association with pelvic CT-angiography.

Sound features are blended together en route to the central nervous system before being discriminated for further processing by the cortical synaptic network. The mechanisms underlying this synaptic processing, however, are largely unexplored. Intracortical processing of the auditory signal was investigated by simultaneously recording from pairs of connected principal neurons in layer II/III in slices from A1 auditory cortex. Physiological patterns of stimulation in the presynaptic cell revealed two populations of postsynaptic events that differed in mean amplitude, failure rate, kinetics and short-term plasticity. In contrast, transmission between layer II/III pyramidal neurons in barrel cortex were uniformly of large amplitude and high success (release) probability (Pr). These unique features of auditory cortical transmission may provide two distinct mechanisms for discerning and separating transient from stationary features of the auditory signal at an early stage of cortical processing.

In this study we analyzed the effect of 4-aminopyridine (4-AP) on free cytosolic calcium concentration ([Ca(2+)](i)) in basal conditions, after stimulation with neurotransmitters, and during capacitative calcium entry. Using fura-2 ratiometric calcium imaging, we found that 4-AP increased [Ca(2+)](i) in type I astrocytes, neurons, and in skeletal muscle cells. The [Ca(2+)](i) elevation induced by 4-AP was concentration-dependent and consisted of two phases: the first was dependent on intracellular calcium mobilization, and the second was dependent on extracellular calcium influx. 4-AP also increased the second messenger inositol trisphosphate in both neurons and astrocytes. In astrocytes, 4-AP treatment potentiated the sustained phase of the [Ca(2+)](i) elevation induced by ATP and bradykinin. In addition, capacitative calcium entry was potentiated severalfold by 4-AP, in astrocytes and muscle cells but not in neurons. These effects of 4-AP were completely and promptly reversible. 4-AP blocked voltage-sensitive K(+) currents in astrocytes. However, voltage-sensitive K(+) channel blockers inhibiting these currents did not affect agonist-induced calcium transients or capacitative calcium entry, indicating that 4-AP effects on [Ca(2+)](i) were not caused by the blockade of voltage-gated K(+) channels. We conclude that 4-AP is able to affect calcium homeostasis at multiple levels, from increasing basal [Ca(2+)](i) to potentiating capacitative calcium entry. The potentiation of capacitative calcium entry in astrocytes or muscle cells may explain some of the therapeutic activities of 4-AP as a neurotransmission enhancer.

Histamine-containing neurons of the tuberomammilary nucleus project to the hippocampal formation to innervate H1 and H2 receptors on both principal and inhibitory interneurons. Here we show that H2 receptor activation negatively modulates outward currents through Kv3.2-containing potassium channels by a mechanism involving PKA phosphorylation in inhibitory interneurons. PKA phosphorylation of Kv3.2 lowered the maximum firing frequency of inhibitory neurons, which in turn negatively modulated high-frequency population oscillations recorded in principal cell layers. All these effects were absent in a Kv3.2 knockout mouse. These data reveal a novel pathway for histamine-dependent regulation of high-frequency oscillations within the hippocampal formation.

Electrical coupling is a widespread feature of developing neuronal circuits and it contributes to the generation of patterned activity. In the developing rat hippocampus, release of GABA by coactive hilar interneurones generates widespread synchronized activity. Here it is shown that hilar interneurones strongly rectify in the outward direction when depolarized. This depolarization-induced hyperpolarization, abolished by gap junction uncouplers, is modulated by nitric oxide. This phenomenon might represent a current-shunting mechanism of the excess current by providing functional inhibition at a developmental stage when GABA is excitatory. Spatial buffering of the current might represent an osmotic mechanism for growth and differentiation.

The establishment of synaptic connections and their refinement during development require neural activity. Increasing evidence suggests that spontaneous bursts of neural activity within an immature network are mediated by gamma-aminobutyric acid via a paradoxical excitatory action. Our data show that in the developing hippocampus such synchronous burst activity is generated in the hilar region by transiently coupled cells. These cells have been identified as neuronal elements because they fire action potentials and they are not positive for the glial fibrillary acidic protein staining. Oscillations in hilar cells are "paced" by a hyperpolarization-activated current, with properties of Ih. Coactivated interneurons synchronously release GABA, which via its excitatory action may serve a neurotrophic function during the refinement of hippocampal circuitry.

The whole cell configuration of the patch clamp technique was used to study the mechanisms of induction of long term depression (LTD) occurring at the mossy fibre-CA3 synapse between postnatal (P) day 6 and P13. In control conditions, when two pulses were delivered to the mossy fibres with an interval of 50 ms a potentiation of the EPSC evoked by the second pulse associated with a reduction in the number of failures was observed. Tetanization of the mossy fibres induced LTD of the responses to the first and second stimulus without affecting the paired pulse facilitation. Loading the postsynaptic cell with BAPTA prevented the induction of LTD but did not modify the paired pulse facilitation, suggesting that LTD induction occurs at the postsynaptic site.

The effect of thyrotropin-releasing hormone (TRH), a neuropeptide physiologically present in the mammalian hippocampus, on spontaneous, miniature and evoked GABAergic postsynaptic currents was investigated using whole-cell patch-clamp recording from pyramidal cells and interneurons of the rat hippocampal thin slice preparation. Bath application of 10 microM TRH induced an increase in the frequency of spontaneous postsynaptic currents from 1.07 +/- 0.68 to 3.16 +/- 0.73 Hz in pyramidal neurons and interneurons of the stratum lacunosum-moleculare (SL-M). In tetrodotoxin solution TRH did not change miniature postsynaptic currents. Application of TRH to minislices containing only the CA1 region still produced an increase in the spontaneous postsynaptic current frequency, indicative of an action by TRH upon a GABAergic circuitry. Paired recordings from one pyramidal cell and one stratum lacunosum moleculare interneuron displayed synchronous events whose frequency rose after TRH application, suggestive of a common, TRH-sensitive input. In a small subset of cells TRH induced the appearance of highly rhythmic large postsynaptic currents at a frequency of approximately 2 Hz, as confirmed by autocorrelation analysis. Postsynaptic currents electrically evoked by focal stimulation of stratum lacunosum-moleculare were depressed from 90 +/- 27 to 44 +/- 15 pA after application of TRH. This phenomenon was solely due to an increase in the number of synaptic failures. It is proposed that the effect of TRH on the GABAergic system was primarily exerted on a subset of interneurons controlling the activity of pyramidal cells as well as stratum lacunosum-moleuclare interneurons.

Patch-clamp technique was used in the CA1 region of the hippocampal rat slice preparation in order to perform a comparison between synaptic GABAergic spontaneous postsynaptic currents (sPSCs) recorded from pyramidal cells (PCs) of stratum pyramidale (SP) and interneurons of stratum-lacunosum moleculare (SL-M INs). GABAergic sPSCs from PCs and from SL-M INs displayed similar frequency (0.75 +/- 0.26 Hz vs. 0.53 +/- 0.11 Hz, respectively), amplitude (34.6 +/- 5.0 pA vs. 39.6 +/- 4.1 pA), rise-time (2.9 +/- 0.4 ms vs. 3.2 +/- 0.3 ms), and decay-time (31.7 +/- 1.5 vs. 32.3 +/- 2.4). Agonists of receptors for endogenously released transmitters were bath-applied to induce variations in the frequency of sPSCs. Spontaneous PSC frequency increased after carbachol and trans-1-aminocyclopentane-1,3-dicarboxilic acid (t-ACPD), whereas it decreased after 5-hydroxy-tryptamine (5-HT) and baclofen in both classes of cells. Cross-correlation analysis of double-patch recordings (one PC and one SL-M IN) revealed 4.4 times as many coincident events as would be expected at random. The ratio between measured and random coincidences did not vary when the sPSCs frequency was increased. These results suggest that the same class of spontaneously active GABAergic cells impinge both on PCs and on SL-M INs, exerting control over them by varying the level of released GABA.

Chloride-cation Transporter Blockers (CTBs) furosemide and ammonium were used to test the effects of changes in the internal [Cl-] on the spontaneous and miniature GABAergic post-synaptic currents (PSCs) of CA3 pyramidal cells of rat hippocampal slices with the whole-cell patch technique. Application of CTBs in the presence of kynurenic acid raised (65 +/- 21%) the frequency of GABAergic spontaneous PSCs leaving unchanged the miniature frequency, indicating that the increase in synaptic activity was caused by interneurone firing. Partial removal of external chloride yielded the same effect, suggesting that ECl contributes to the resting potential of interneurones. PSC rise times were prolonged and their mean amplitude was lowered by furosemide as well as the response to exogenous muscimol, confirming that furosemide exerts some GABAA receptor antagonism.

The monosynaptic field excitatory postsynaptic potentials (EPSPs) evoked in the optic tectum of the frog (Rana remporaria) in vitro by different patterns of stimulation of the contralateral optic nerve were studied using extracellular recording. Pulse trains at frequencies of less than or equal to 0.033 Hz elicited field potentials of stable amplitude, whereas in the range 0.33-1.0 Hz EPSPs showed a depression in the first few responses subsequent to the first one, followed by a partial recovery and a final decline to a steady level. When the interpulse interval was less than 200 ms, paired-pulse monosynaptic facilitation was found. Decrease in the external Ca2+ concentration, or in the stimulation intensity or application of picrotoxin reversibly produced a monotonically decreasing EPSP amplitude, suggesting that a local neuronal circuit was controlling the development of synaptic fatigue. A simple model based on the combined effects of depletion of excitatory transmitter stores plus activation of a local inhibitory circuit was found to provide a simulation which closely resembled the experimentally observed pattern of synaptic fatigue. The present study suggests that an inhibitory synaptic process contributed to the non-monotonic decay of excitatory transmission in the frog optic tectum, following repetitive stimulation of the optic nerve.

A series of oligosaccharides was prepared from hyaluronate by depolymerisation with bovine testicular hyaluronidase. Complete assignment of the 1H and 13C NMR spectra was obtained for the disaccharide, the tetrasaccharide, and the NaBH4-treated tetrasaccharide, by using various 1D and 2D NMR methods. The 1H assignments for the tetrasaccharide differ from the incomplete data reported recently (ref. 11). The 13C NMR spectra of the aqueous di-, tetra-, hexa-, and octa-saccharides of this series show that all resonances, apart from those subject to obvious end effects, have chemical shifts comparable to those of the corresponding resonances of hyaluronate in D2O. The observed 13C chemical shifts suggests that cooperative intramolecular hydrogen bonds probably play a minor role in determining the conformation of hyaluronate in water.

The 1H- and 13C-NMR spectra of the ethyl and benzyl esters and the tetrabutylammonium and tetraethylammonium salts of hyaluronic acid [[symbol: see text]2)-beta-D-GcpA+-1----3)-beta-D-GlcpNAc-(1[symbol: see text]n] in Me2SO-d6 have been assigned using 1D and 2D techniques. The chemical shifts of the resonance of GlcNAc C-3 suggest that the relative orientations of the monosaccharides at the (1----3) linkage in the esters and salts are different. Small differences in the chemical shifts of the resonance GlcA C-4 suggest only a slight conformational variation around the (1----4) linkage. The 13C-NMR data also suggest similarities in conformation between the esters in Me2SO-d6 and the salts in water. The chemical shifts of the 1H resonances for NH and OH groups and their temperature dependence for the esters and salts in Me2SO reveal markedly stronger inter-residue hydrogen bonds between the carboxyl and NH groups and between HO-4 of GlcA and O-5 of GlcNAc for the salts. The 3J2,NH values indicate a slightly different orientation for the acetamido group. For solutions in Me2SO, the higher segmental flexibility of the esters is supported by the line widths, whereas the reduced viscosity for the tetrabutylammonium salt showed a sigmoidal concentration dependence and suggests association of chains which could contribute to the segmental rigidity. The linear concentration dependence for the benzyl ester suggests a higher overall flexibility without chain association.

The localization of substance P in the human post-mortem brainstem is studied by the indirect immunofluorescence technique. Positive neuronal cell bodies, nerve fibers and terminals are unevenly present over both sensory and effector areas and nuclei. The pattern of distribution of substance P in the human brainstem, similar to that seen in the laboratory animals, supports the hypothesis of a neurotransmitter role of this compound in man.