Maternal high fat diet consumption reduces liver alpha7 nicotinic cholinergic receptor expression and impairs insulin signalling in the offspring.

The activation of nicotinic acetylcholine receptor α7 subunit (α7nAChR) has been associated to anti-inflammatory response in macrophages. High-fat diet (HFD) consumption during pregnancy and lactation impairs the cholinergic anti-inflammatory pathway in liver and white adipose tissue of offspring. In order to evaluate the relationship between damage in the cholinergic anti-inflammatory pathway and insulin resistance (IR) development, the liver of offspring of obese dams was investigated. Additionally, the capacity of α7nAChR activation to reduce IR induced by saturated fatty acid was investigated in hepatoma cell line. Initially, female mice were subjected to either standard chow (SC) or HFD during pregnancy and lactation period. After weaning, only male offspring from HFD dams (HFD-O) and SC dams (SC-O) were fed with the SC diet. Hepatic α7nAChR expression was downregulated, and hepatic TNF-α, IL-1ß, and pIKK level, but not pJNK, were elevated in the HFD-O compared to SC-O mice. Besides, hepatic expression of TNF-α in response to lipopolysaccharide (LPS) was higher in HFD-O than SC-O mice. Insulin-stimulated phosphorylation of the AKT was lower in HFD-O compared to SC-O. Additionally, insulin-stimulated phosphorylation of the AKT in KOα7Alb-Cre mice fed HFD was lower than WT mice fed HFD. In hepatoma cell line, palmitate increased IL-6 and TNF-α expressions and pJNK level. These effects were accompanied by reduced capacity of insulin to stimulate AKT phosphorylation. PNU or nicotine reduced cytokine expression and JNK activation, but improved insulin resistance induced by palmitate. Our results suggest that maternal obesity impairs hepatic α7nAChR expression and AKT phosphorylation in the offspring. In vitro studies suggest that α7nAChR activation has potential to reduce deleterious effect of saturated fatty acids on insulin signalling.

Synthesis of new cyano-substituted analogues of Tröger's bases from bromo-derivatives. A stereochemical dependence of long-range (n JHH , n = 4, 5, and 6) proton-proton and proton-carbon (n JCH , n = 1, 2, 3, 4, and 5) coupling constants of these compounds.

A free-catalyst microwave-assisted cyanation of brominated Tröger's base derivatives (2a-f) is reported. The procedure is simple, efficient, and clean affording the nitrile compounds (3a-e, I) in very good yields. Complete assignment of 1 H and 13 C chemical shifts of 2a-f, I and 3a-d, I was achieved using gradient selected 1D nuclear magnetic resonance (NMR) techniques (1D zTOCSY, PSYCHE, DPFGSE NOE, and DEPT), homonuclear 2D NMR techniques (gCOSY and zTOCSY), and heteronuclear 2D NMR techniques (gHSQCAD/or pure-shift gHSQCAD, gHMBCAD, bsHSQCNOESY, and gHSQCAD-TOCSY) with adiabatic pulses. Determination of the long-range proton-proton coupling constants n JHH (n = 4, 5, 6) was accomplished by simultaneous irradiation of two protons at appropriate power levels. In turn, determined coupling constants were tested by an iterative simulation program by calculating the 1 H NMR spectrum and comparing it to the experimental spectrum. The excitation-sculptured indirect-detection experiment (EXSIDE) and 1 H-15 N CIGARAD-HMBC (constant time inverse-detection gradient accordion rescaled heteronuclear multiple bond correlation) were applied for determination of long-range carbon-proton coupling constants n JCH (n = 2, 3, and 4) and for assignment of 15 N chemical shift at natural abundance, respectively. DFT/B3LYP optimization studies were performed in order to determine the geometry of 2c using 6-31G(d,p), 6-311G(d,p), and 6-311 + G(d,p) basis sets. For calculation of 1 H and 13 C chemical shifts, n JHH (n = 2, 3, 4, 5, and 6), and n JCH (n = 1, 2, 3, and 4) coupling constants, the GIAO method was employed at the B3LYP/6-31G(d,p), B3LYP/6-31+G(d,p), B3LYP/6-311+G(d,p), B3LYP/6-311++G(2d,2p), B3LYP/cc-pVTZ), and B3LYP/aug-cc-pVTZ) levels of theory. For the first time, a stereochemical dependence magnitude of the long-range n JHH (n = 4, 5, and 6) and n JCH (n = 1, 2, 3, 4, and 5) have been found in bromo-substituted analogues of Tröger's bases.

Simultaneous Diagnosis of Acute Crohn's Disease and Endometriosis in a Patient Affects HIV.

This is the case report of a 45-year-old woman affected by HIV, who was hospitalized for diffuse abdominal pain, constipation, and weight loss present for over one month. A colonoscopy showed the presence of a nontransitable stenosis of the ascending colon. A right hemicolectomy was performed. The histological examination reports CD with outbreaks of endometriosis. CD and the HIV infection may coexist in the same individual and it seems that HIV reduces the relapse rate in IBD patients. CD and intestinal endometriosis can also occur simultaneously. The diagnosis is often only made after surgical resection of the diseased segment. These patients were more likely to have stricturing CD but endometriosis does not seem to impact the natural history of CD.

3-T magnetic resonance imaging simultaneous automated multimodal approach improves detection of ambiguous visual hippocampal sclerosis.

BACKGROUND AND PURPOSE: To evaluate if an automatic magnetic resonance imaging (MRI) processing system may improve detection of hippocampal sclerosis (Hs) in patients with mesial temporal lobe epilepsy (MTLE). METHODS: Eighty consecutive patients with a diagnosis of MTLE and 20 age- and sex-matched controls were prospectively recruited and included in our study. The entire group had 3-T MRI visual assessment of Hs analysed by two blinded imaging epilepsy experts. Logistic regression was used to evaluate the performances of neuroradiologists and multimodal analysis. RESULTS: The multimodal automated tool gave no evidence of Hs in all 20 controls and classified the 80 MTLE patients as follows: normal MRI (54/80), left Hs (14/80), right Hs (11/80) and bilateral Hs (1/80). Of note, this multimodal automated tool was always concordant with the side of MTLE, as determined by a comprehensive electroclinical evaluation. In comparison with standard visual assessment, the multimodal automated tool resolved five ambiguous cases, being able to lateralize Hs in four patients and detecting one case of bilateral Hs. Moreover, comparing the performances of the three logistic regression models, the multimodal approach overcame performances obtained with a single image modality for both the hemispheres, reaching a global accuracy value of 0.97 for the right and 0.98 for the left hemisphere. CONCLUSIONS: Multimodal quantitative automated MRI is a reliable and useful tool to depict and lateralize Hs in patients with MTLE, and may help to lateralize the side of MTLE especially in subtle and uncertain cases.

Diffusion tensor MRI changes in cerebellar structures of patients with familial essential tremor.

OBJECTIVE: The aim of our study was to investigate the microstructural integrity of brain regions functionally involved in the tremor loop in patients with familial essential tremor (FET), using diffusion tensor imaging (DTI). METHODS: Twenty-five patients with FET, 15 patients with Parkinson disease (PD), and 15 healthy subjects were studied. DTI was performed to measure fractional anisotropy (FA) and mean diffusivity (MD) in various regions of interest: red nucleus, dentate nucleus (DN), cerebellar white matter, middle (MCP) and superior cerebellar peduncle (SCP), and ventrolateral thalamus. RESULTS: In patients with FET, FA values in the DN (median 0.19, range 0.13-0.23) were reduced (p < 0.001) compared with patients with PD (median 0.37, range 0.32-0.58) and healthy controls (median 0.36, range 0.33-0.40). In patients with FET, FA was also reduced (p = 0.003) and MD values increased (p < 0.001) in the SCP compared with patients with PD and healthy controls. Among patients with FET, those with longer disease duration showed FA values in the DN lower than those with shorter disease duration (p = 0.018). Patients with FET could be completely distinguished from both patient with PD and healthy controls using FA values of the DN alone. CONCLUSION: Neuroimaging evidence of microstructural changes consistent with neurodegeneration was found in the dentate nucleus (DN) and SCP of patients with familial essential tremor. This suggests that neurodegenerative pathology of cerebellar structures may play a role in essential tremor. Further studies are needed to assess the role of fractional anisotropy and mean diffusivity changes in DN and SCP in the differential diagnosis of essential tremor and Parkinson disease, which may present similar clinical signs at the onset of disease.

Temporal lobe abnormalities on brain MRI in healthy volunteers: a prospective case-control study.

OBJECTIVE: To prospectively assess the frequency of mesiotemporal abnormalities seen on brain MRI in healthy subjects in comparison with patients with temporal lobe epilepsy (TLE). METHODS: Ninety-nine consecutive patients (48 women, mean age 36.1 +/- 16.1 years; range 10 to 75) with TLE and 51 healthy volunteers (26 women, mean age 39.3 +/- 10.8 years) prospectively underwent the same MRI protocol, specific for TLE. Images were reviewed independently by 2 neuroradiologists blinded to clinical information. Cortical atrophy and signal intensities in the amygdala, hippocampus, cingulate gyrus, subcallosal area, insula, temporal parietal, and occipital lobe were graded relative to cortical signal intensity in the frontal lobe. Intrarater and interrater reliability were also assessed. RESULTS: Interrater and intrarater measurements demonstrated consistent and repeatable results. Forty-seven of 99 (47.5%) patients showed either unilateral or bilateral major T2/fluid-attenuated inversion recovery hyperintensities of the hippocampus, and 19 patients (19.2%) showed hippocampal atrophy seen at T1/inversion recovery sequences. In the controls, 15/51 (29.4%) individuals had unilateral or bilateral hyperintensities, which did not differ from the rate of occurrence in patients (p = 0.08). Conversely, unilateral hippocampal atrophy was found in 1 control, which was significantly different (p = 0.005) from the rate of occurrence in patients. Hyperintensity plus structural hippocampal atrophy were only seen in patients. CONCLUSIONS: On brain MRI, either unilateral or bilateral hippocampal hyperintensities are frequently encountered in healthy volunteers. Conversely, hippocampal atrophy, especially when associated with concomitant hyperintensity, was seen exclusively in the epilepsy group, indicating that the combination of these 2 variables represents the strongest and most reliable indicator of epilepsy.

Cognitive deficits in multiple sclerosis patients with cerebellar symptoms.

BACKGROUND: Cerebellar dysfunction is common in patients with multiple sclerosis (MS). However, neuropsychological studies of this clinical feature are lacking. OBJECTIVE: We investigate the neuropsychological features in relapsing-remitting MS (RR-MS) patients with and without cerebellar dysfunction. METHODS: Twenty-one RR-MS patients with cerebellar dysfunction (RR-MSc), characterized by prevalent ataxic gait and nystagmus, and 21 RR-MS patients without any cerebellar manifestation (RR-MSnc) pair-matched for demographical and clinical variables were studied. All patients from each group underwent an extensive battery of neuropsychological tests. Magnetic resonance imaging analysis included hyperintense fast fluid-attenuated inversion-recovery lesion load in the whole brain as well as in the four lobes separately. RESULTS: Any significant differences were detected in total and regional lesion load measurements between the two groups. RR-MSc group performed equally as well as the RR-MSnc group on many of the cognitive exploration measures. Nevertheless, the RR-MSc group performed more poorly than the RR-MSnc group on attention tests (Symbol Digit Modalities Test) and verbal fluency tests (Controlled Oral Word Association Test); neither of the test results proved to be affected by regional lesion loads. CONCLUSION: These results highlight the importance of considering cognitive deficits associated with the presence of cerebellar symptoms in RR-MS.

The DRD2 TaqIA polymorphism associated with changed midbrain volumes in healthy individuals.

The human DRD2 gene is located on chromosome 11q22-q23 and contains one specific functional polymorphism called TaqIA, which characteristically presents two alleles referred to as A1 and A2. Evidence indicates that the A1 allele impacts brain dopaminergic function and may confer an increased risk of developing Parkinson's disease. However, possible morphological changes underlying such genetic variant remain to be clarified. The aim of this study was to provide an in vivo demonstration of changes in brain structures associated with the TaqIA polymorphism of the DRD2 gene. Optimized voxel-based morphometry (VBM) was applied to high-resolution MR brain images of 70 healthy controls divided into two groups according to their DRD2 genotype (A1/A2, n = 15; A2/A2, n = 55). Compared with individuals' homozygous for the A2 allele, the A1 carriers had significantly smaller areas of a specific part of the midbrain, encompassing the substantia nigra bilaterally. Our findings showed an association of the DRD2 TaqIA polymorphism with the changed volumes of a specific subcortical region strongly involved in the dopaminergic system.

Cerebellar atrophy in essential tremor using an automated segmentation method.

BACKGROUND AND PURPOSE: Essential tremor (ET) is a slowly progressive disorder characterized by postural and kinetic tremors most commonly affecting the forearms and hands. Several lines of evidence from physiologic and neuroimaging studies point toward a major role of the cerebellum in this disease. Recently, voxel-based morphometry (VBM) has been proposed to quantify cerebellar atrophy in ET. However, VBM was not originally designed to study subcortical structures, and the complicated anatomy of the cerebellum may hamper the automatic processing of VBM. The aim of this study was to determine the efficacy and utility of using automated subcortical segmentation to identify atrophy of the cerebellum and other subcortical structures in patients with ET. MATERIALS AND METHODS: We used a recently developed automated volumetric method (FreeSurfer) to quantify subcortical atrophy in ET by comparing results obtained with this method with those provided by previous evidence. The study included T1-weighted MR images of 46 patients with ET grouped into those having arm ET (n = 27, a-ET) or head ET (n = 19, h-ET) and 28 healthy controls. RESULTS: Results revealed the expected reduction of cerebellar volume in patients with h-ET with respect to healthy controls after controlling for intracranial volume. No significant difference was detected in any other subcortical area. CONCLUSIONS: Volumetric data obtained with automated segmentation of subcortical and cerebellar structures approximate data from a previous study based on VBM. The current findings extend the literature by providing initial validation for using fully automated segmentation to derive cerebellar volumetric information from patients with ET.

Essential head tremor is associated with cerebellar vermis atrophy: a volumetric and voxel-based morphometry MR imaging study.

BACKGROUND AND PURPOSE: Our aim was to investigate the presence of brain gray matter (GM) abnormalities in patients with different forms of essential tremor (ET). MATERIALS AND METHODS: We used optimized voxel-based morphometry (VBM) and manually traced single region-of-interest analysis in 50 patients with familial ET and in 32 healthy subjects. Thirty patients with ET had tremor of the arms (a-ET), whereas the remaining 20 patients had both arm and head tremor (h-ET). RESULTS: VBM showed marked atrophy of the cerebellar vermis in the patients with h-ET with respect to healthy subjects (P(corrected) < .001). Patients with a-ET showed a trend toward a vermal GM volume loss that did not reach a significant difference with respect to healthy controls (P(uncorrected) < .01). The region-of-interest analysis showed a reduction of the cerebellar volume (CV) in the h-ET group (98.2 +/- 13.6 mm(3)) compared with healthy controls (110.5 +/- 15.5 mm(3), P < .012) as well as in the entire vermal area (790.3 +/- 94.5 mm(2), 898.6 +/- 170.6 mm(2), P < .04 in h-ET and control groups, respectively). CONCLUSIONS: Atrophy of the cerebellar vermis detected in patients with h-ET strongly supports the evidence for the involvement of the cerebellum in the pathophysiology of ET. The lack of a significant CV loss observed in patients with a-ET suggests that a-ET and h-ET might represent distinct subtypes of the same disease.

MRI evidence of mesial temporal sclerosis in sporadic "benign" temporal lobe epilepsy.

OBJECTIVE: To determine whether there is MRI-detectable mesial temporal sclerosis (MTS) in patients with sporadic benign temporal lobe epilepsy (BTLE). METHODS: Brain MRIs were obtained from 101 consecutive, unrelated patients (51 women; mean age 37.3 +/- 17.5 years; range 10 to 83 years) with BTLE, who reported rarely or never having had seizures at the time of long-term (> 2 years) follow-up. The mean age at seizure onset was 22.3 +/- 17.4 years; the mean duration of epilepsy was 16.4 +/- 14.1 years. MRI diagnosis of MTS was based on the occurrence of hippocampal formation atrophy on T1 slices, an increased mesial temporal signal intensity alteration on fluid-attenuated inversion-recovery (FLAIR) or T2 images, or both. RESULTS: Thirty-nine of 101 patients (38.6%) had MRI evidence of unilateral MTS (19/39 left MTS, 20/39 right MTS), which correlated with the epileptiform activity. Hyperintense FLAIR and T2 signal with or without atrophy was observed in 24 of 39 individuals. There was no difference between patients with or without MRI-detected MTS in age at onset and duration of epilepsy. Family history of epilepsy or febrile convulsions (FCs) was more frequent in patients with MRI-detected MTS (36%) as compared with patients with normal MRI (22.7%), but the difference was not significant. Antecedent FCs were more frequent (p = 0.03) in patients with MRI-detected MTS (9/39; 23%) vs those with normal MRI (5/62; 8%). CONCLUSIONS: MRI-detected mesial temporal sclerosis is often encountered in patients with sporadic benign temporal lobe epilepsy.

A novel Notch3 gene mutation not involving a cysteine residue in an Italian family with CADASIL.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary cerebrovascular disease leading to accumulating neurologic deficits and dementia. CADASIL has been linked to nucleotide substitutions and deletions in the Notch3 gene. All the mutations described until now lead to unpaired cysteine residue in the epidermal growth factor-like repeats. The authors report a family with CADASIL carrying a deletion in the Notch3 gene that did not involve a cysteine residue.

The role of hysteroscopy in early diagnosis of endometrial cancer.

The aim of this retrospective study was to compare stage, disease-free survival and overall survival in patients suffering from endometrial cancer who underwent hysteroscopy and those who did not. Between January 1, 1990 and June 30, 2001, 181 patients were referred to our Gynaecologic Department for primary endometrial carcinoma; from clinical charts we reviewed the personal and pathological data of all patients. Patients were divided into two groups: those with hysteroscopy (69 patients) and those without (112 patients). Endometrial biopsy was performed at the end of hysteroscopy. We compared symptoms at diagnosis, stage and survival. Hysteroscopy demonstrates a high diagnostic accuracy for endometrial cancer. In our case series we obtained a sensitivity of 93.10%, specificity of 99.96%, positive predictive value of 98.18% and negative predictive value of 99.85%; when hysteroscopy was associated with endometrial biopsy the sensitivity was 96.55% and specificity 100%. In this study we had a significant difference in stage Ia; in the group with hysteroscopy, stage Ia cases were 23.2% while in the group without, stage Ia cases were 15.2%. Survival in stage Ia only was 100% and 91.7%, respectively, at three and five years. In conclusion hysteroscopy was found to have a very important role in the early diagnosis of endometrial cancer, especially when it is limited to the mucosal surface.

A short-term temperature forecaster based on a novel radial basis functions neural network.

Many applications dealing with electric load forecasting in buildings require temperature prediction. A new method for short-term temperature forecasting based on a Radial Basis Functions Neural Network, initialized by a Regression Tree, is presented. In this method, each terminal node of the tree contributes one hidden unit to the RBF network. The forecaster uses the current coded hour and the temperature as inputs, and predicts the next hour temperature. The results demonstrate this predictor can be used for load forecasting.

beta-carotene at high concentrations induces apoptosis by enhancing oxy-radical production in human adenocarcinoma cells.

This is the first report demonstrating a relationship between apoptosis induction and changes of intracellular redox potential in the growth-inhibitory effects of high concentrations of beta-carotene in a tumor cell line. beta-Carotene inhibited the growth of human WiDr colon adenocarcinoma cells in a dose- and time-dependent manner, induced apoptosis, and blocked Bcl-2 expression. These effects were accompanied by an enhanced production of intracellular reactive oxygen species (ROS). The addition of the antioxidant alpha-tocopherol blocked both the pro-oxidant and the growth-inhibitory effects of the carotenoid. These findings suggest that beta-carotene may act as an inductor of apoptosis by its pro-oxidant properties.

Quercetin inhibits p21-RAS expression in human colon cancer cell lines and in primary colorectal tumors.

Immunocytochemical studies have revealed that 10 microM quercetin reduced the steady state levels of p21-ras proteins in both colon cancer cell lines and primary colorectal tumors. These findings were confirmed by Western blot and flow cytometric analysis showing that the inhibition of p21-ras expression by quercetin was time- and concentration-dependent. Twenty-four-hour treatment with 10 microM quercetin reduced p21-ras levels to about 50% of control values. Quercetin was similarly effective in inhibiting the expression of K-, H-, and N-ras proteins. Moreover, the effect of quercetin on ras oncogene expression was not dependent on the cell cycle position of colon cancer cells and appeared to be specific and not merely a consequence of overall inhibition of protein synthesis. Northern blot analysis revealed that quercetin produced in colon cancer cells an early (30 min) reduction of the steady state levels of K-, H-, and N-ras mRNAs. This reduction was also present after 6 hr of flavonoid treatment. These effects of quercetin suggest a possible chemopreventive role for this compound in colorectal carcinogenesis.

Beta-carotene antagonizes the effects of eicosapentaenoic acid on cell growth and lipid peroxidation in WiDr adenocarcinoma cells.

The effects of combinations between eicosapentaenoic acid (EPA) and beta-carotene on cell growth and lipid peroxidation were investigated in human WiDr colon adenocarcinoma cells. EPA alone was able to inhibit the growth of WiDr cells in a dose- and time-dependent manner. Such an inhibition involved fatty acid peroxidation, as shown by the remarkable increase in the levels of Malondialdehyde (MDA) in EPA-treated cells. Beta-carotene was capable of reducing the growth inhibitory effects of EPA and the levels of MDA in a dose- and a time-dependent manner. In addition, EPA increased beta-carotene consumption in WiDr cells. This study provides evidence that beta-carotene can antagonize the effects of EPA on colon cancer cell growth and lipid peroxidation.