Tacrolimus Therapeutic Drug Monitoring in Stable Kidney Transplantation and Individuation of CYP3A5 Genotype.

The posology of tacrolimus (TAC) is usually guided by its therapeutic drug monitoring. Some patients reach target concentrations (CTs) quickly, others more slowly. In a retrospective study, 20 kidney transplant recipients were included (mean age, 50.7 ± 14.1 years; weight 64.0 ± 14.2 kg; patients clinically stable for over a year). We studied cytochrome CYP3A5 genotype, in particular CYP3A5 6986A>G, the most important polymorphism related to the metabolism of TAC (wild genotype CYP3A5 *1 genotype, and CYP3A5 *3 variants). One year after transplantation, the CTs were 5.0 to 8.0 ng/mL. The patients were divided into group A (TAC doses < 6.0 mg/d) and group B (TAC doses > 6.0 mg/d). All were tested for the CYP3A5 gene sequence to characterize their polymorphism. Patients with CYP3A5 *1/*1 and *1/*3 were extensive metabolizers, and those with CYP3A5 *3/*3 were poor metabolizers. In group A and group B, the average TAC doses at the time of therapeutic drug monitoring were 3.0 ± 1.4 ng/mL (0.05 ± 0.03 mg/kg) and 12.8 ± 3.7 ng/mL (0.2 ± 0.1 mg/kg), respectively (P < .001). Group A was the poor metabolizers genotype, while in group B, the extensive metabolizers genotype was present. Patients with the CYP3A5 *1/*1 or *1/*3 genotype required 1.5 to 2 times higher doses than patients *3/*3 to reach CT. This genetic test allows clinicians to know, before the kidney transplant, the patient's TAC metabolism pattern and then to optimize the drug exposure.

Plasticity of the human visual brain after an early cortical lesion.

In adults, partial damage to V1 or optic radiations abolishes perception in the corresponding part of the visual field, causing a scotoma. However, it is widely accepted that the developing cortex has superior capacities to reorganize following an early lesion to endorse adaptive plasticity. Here we report a single patient case (G.S.) with near normal central field vision despite a massive unilateral lesion to the optic radiations acquired early in life. The patient underwent surgical removal of a right hemisphere parieto-temporal-occipital atypical choroid plexus papilloma of the right lateral ventricle at four months of age, which presumably altered the visual pathways during in utero development. Both the tumor and surgery severely compromised the optic radiations. Residual vision of G.S. was tested psychophysically when the patient was 7 years old. We found a close-to-normal visual acuity and contrast sensitivity within the central 25° and a great impairment in form and contrast vision in the far periphery (40-50°) of the left visual hemifield. BOLD response to full field luminance flicker was recorded from the primary visual cortex (V1) and in a region in the residual temporal-occipital region, presumably corresponding to the middle temporal complex (MT+), of the lesioned (right) hemisphere. A population receptive field analysis of the BOLD responses to contrast modulated stimuli revealed a retinotopic organization just for the MT+ region but not for the calcarine regions. Interestingly, consistent islands of ipsilateral activity were found in MT+ and in the parieto-occipital sulcus (POS) of the intact hemisphere. Probabilistic tractography revealed that optic radiations between LGN and V1 were very sparse in the lesioned hemisphere consistently with the post-surgery cerebral resection, while normal in the intact hemisphere. On the other hand, strong structural connections between MT+ and LGN were found in the lesioned hemisphere, while the equivalent tract in the spared hemisphere showed minimal structural connectivity. These results suggest that during development of the pathological brain, abnormal thalamic projections can lead to functional cortical changes, which may mediate functional recovery of vision.

Interpersonal sensitivity and persistent attenuated psychotic symptoms in adolescence.

Interpersonal sensitivity defines feelings of inner-fragility in the presence of others due to the expectation of criticism or rejection. Interpersonal sensitivity was found to be related to attenuated positive psychotic symptom during the prodromal phase of psychosis. The aims of this study were to examine if high level of interpersonal sensitivity at baseline are associated with the persistence of attenuated positive psychotic symptoms and general psychopathology at 18-month follow-up. A sample of 85 help-seeking individuals (mean age = 16.6, SD = 5.05) referred an Italian early detection project, completed the interpersonal sensitivity measure and the structured interview for prodromal symptoms (SIPS) at baseline and were assessed at 18-month follow-up using the SIPS. Results showed that individuals with high level of interpersonal sensitivity at baseline reported high level of attenuated positive psychotic symptoms (i.e., unusual thought content) and general symptoms (i.e., depression, irritability and low tolerance to daily stress) at follow-up. This study suggests that being "hypersensitive" to interpersonal interactions is a psychological feature associated with attenuated positive psychotic symptoms and general symptoms, such as depression and irritability, at 18-month follow-up. Assessing and treating inner-self fragilities may be an important step of early detection program to avoid the persistence of subtle but very distressing long-terms symptoms.

CD55 is a HIF-2α marker with anti-adhesive and pro-invading properties in neuroblastoma.

CD55 has been revealed to have an important role in tumor genesis, and presence of small populations of cells with strong CD55 expression would be sufficient to predict poor prognosis of several tumors. In our study we revealed that CD55 is a novel target of hypoxia-inducible factor HIF-2α in neuroblastoma (NB) cells. We show that HIF-2α expression is sufficient to sustain stem-like features of NB cells, whereas CD55 protein upon HIF-2α expression contributes to growth of colonies and to invasion of cells, but not to stemness features. Interestingly, in NB tissues, CD55 expression is limited to quite a small population of cells that are HIF-2α positive, and the gene expression of CD55 in the NB data set reveals that the presence of CD55(high) affects prognosis of NB patients. The functional characterization of CD55-positive populations within heterogeneous NB monoclonal cell lines shows that CD55 has pro-invading and anti-adhesive properties that might provide the basis for the ability of solid tumors to survive as microscopic residual disease. The easy accessibility to CD55 membrane antigen will offer the possibility of a novel antibody approach in the treatment of recurrent tumors and will provide a ready target for antibody-based visualization in NB diagnosis and prognosis.

A low-cost and versatile system for projecting wide-field visual stimuli within fMRI scanners.

We have constructed and tested a custom-made magnetic-imaging-compatible visual projection system designed to project on a very wide visual field (~80°). A standard projector was modified with a coupling lens, projecting images into the termination of an image fiber. The other termination of the fiber was placed in the 3-T scanner room with a projection lens, which projected the images relayed by the fiber onto a screen over the head coil, viewed by a participant wearing magnifying goggles. To validate the system, wide-field stimuli were presented in order to identify retinotopic visual areas. The results showed that this low-cost and versatile optical system may be a valuable tool to map visual areas in the brain that process peripheral receptive fields.

Brain connectivity is altered by extreme physical exercise during non-REM sleep and wakefulness: indications from EEG and fMRI studies.

Brain connectivity is associated to behavioral states (e.g. wake, sleep) and modified by physical activity although, to date, it is not clear which components (e.g. hypothalamus-pituitary-adrenal axis hormones, cytokines) associated to the exercise are involved. In this pilot study, we used extreme exercise (UltraTriathlon) as a model to investigate physical-activity-related changes of brain connectivity. We studied post-race brain synchronization during wakefulness and sleep as well as possible correlations between exercise-related cytokines/hormones and synchronization features. For wakefulness, global synchronization was evaluated by estimating from fMRI data (12 athletes) the brain global connectivity (GC). GC increased in several brain regions, mainly related to sensory-motor activity, emotional modulation and response to stress that may foster rapid exchange of information across regions, and reflect post-race internally-focused mental activity or disengagement from previous motor programs. No significant correlations between cytokines/hormones and GC were found. For sleep (8 athletes), synchronization was evaluated by estimating the local-(cortical) and global-related (thalamo- cortical) EEG features associated to the phenomenon of Sleep Slow Oscillations (SSO) of NREM sleep. Results showed that: power of fast rhythms in the baseline preceding the SSO increased in midline and parietal regions; amplitude and duration of SSOs increased, mainly in posterior areas; sigma modulation in the SSO up state decreased. In the post race, IL-10 positively correlated with fast rhythms baseline, SSO rate and positive slope; IL-1ra and cortisol inversely correlated with SSO duration; TNF-α and C-reactive protein positively correlated with fast rhythm modulation in the SSO up state. Sleep results suggest that: arousal during sleep, estimated by baseline fast rhythms, is increased; SSO may be sustained by cortical excitability, linked to anti-inflammatory markers (IL-10); thalamo-cortical entrainment, (sigma modulation), is impaired in athletes with higher inflammatory markers.

De Novo Solid Tumors After Kidney Transplantation: Is It Time for a Patient-Tailored Risk Assessment? Experience From a Single Center.

BACKGROUND: Progress in immunosuppressive therapy and perioperative techniques has improved the survivals of both grafts and patients. The patient, however, is exposed to the risks of aging and side effects of immunosuppression. De novo tumors are the 2nd cause of death in the organ transplant population. The aim of this study was to evaluate whether the current accepted guidelines for the pre-transplantation study and the post-transplantation follow-up have been effective, in our kidney transplant population, regarding early detection and treatment, improving prognosis, and reducing mortality of some curable neoplastic diseases. METHODS: We considered de novo tumors in kidney transplant patients from 1995 to 2010 (n = 636) excluding hematologic and nonmelanoma skin tumors from our study. RESULTS: There were 64 de novo tumors in 59 patients out of 636 kidney transplant patients; 29.68% were urogenital cancer, 26.56% gastrointestinal cancer, 12.5% melanoma, 6.25% lung cancer, 6.25% biliopancreatic cancer, 4.68% visceral Kaposi sarcoma, 4.68% breast cancer, 4.68% thyroid cancer, 1 pleural mesothelioma, 1 meningioma, 1 merkeloma. Twenty patients died because of cancer. Ten patients had a late de novo tumor diagnosis, when the stage of tumor was advanced and not suitable for curative treatment. CONCLUSIONS: Because of the increased neoplastic risk, we consider it mandatory to carry out a meticulous screening and to implement pre-transplantation study concerning this increased neoplastic risk population to detect a subgroup of patients presenting the highest risk to improve their outcome.

Ultra-high-field MR imaging in polymicrogyria and epilepsy.

BACKGROUND AND PURPOSE: Polymicrogyria is a malformation of cortical development that is often identified in children with epilepsy or delayed development. We investigated in vivo the potential of 7T imaging in characterizing polymicrogyria to determine whether additional features could be identified. MATERIALS AND METHODS: Ten adult patients with polymicrogyria previously diagnosed by using 3T MR imaging underwent additional imaging at 7T. We assessed polymicrogyria according to topographic pattern, extent, symmetry, and morphology. Additional imaging sequences at 7T included 3D T2* susceptibility-weighted angiography and 2D tissue border enhancement FSE inversion recovery. Minimum intensity projections were used to assess the potential of the susceptibility-weighted angiography sequence for depiction of cerebral veins. RESULTS: At 7T, we observed perisylvian polymicrogyria that was bilateral in 6 patients, unilateral in 3, and diffuse in 1. Four of the 6 bilateral abnormalities had been considered unilateral at 3T. While 3T imaging revealed 2 morphologic categories (coarse, delicate), 7T susceptibility-weighted angiography images disclosed a uniform ribbonlike pattern. Susceptibility-weighted angiography revealed numerous dilated superficial veins in all polymicrogyric areas. Tissue border enhancement imaging depicted a hypointense line corresponding to the gray-white interface, providing a high definition of the borders and, thereby, improving detection of the polymicrogyric cortex. CONCLUSIONS: 7T imaging reveals more anatomic details of polymicrogyria compared with 3T conventional sequences, with potential implications for diagnosis, genetic studies, and surgical treatment of associated epilepsy. Abnormalities of cortical veins may suggest a role for vascular dysgenesis in pathogenesis.

Brain white matter involvement in hereditary spastic paraplegias: analysis with multiple diffusion tensor indices.

BACKGROUND AND PURPOSE: The hereditary spastic paraplegias are a group of genetically heterogeneous neurodegenerative disorders, characterized by progressive spasticity and weakness of the lower limbs. Although conventional brain MR imaging findings are normal in patients with pure hereditary spastic paraplegia, microstructural alteration in the cerebral WM can be revealed with DTI. Concomitant investigation of multiple intrinsic diffusivities may shed light on the neurobiologic substrate of the WM degeneration pattern in patients with pure hereditary spastic paraplegia across the whole brain. MATERIALS AND METHODS: Tract-based spatial statistics analysis was performed to compare fractional anisotropy and mean, axial, and radial diffusivities of the WM skeleton in a group of 12 patients with pure hereditary spastic paraplegia and 12 healthy volunteers. Data were analyzed counting age and sex as nuisance covariates. The threshold-free cluster-enhancement option was applied, and the family-wise error rate was controlled by using permutation tests for nonparametric statistics. RESULTS: In pure hereditary spastic paraplegia, group widespread fractional anisotropy decreases and radial diffusivity and mean diffusivity increases (P < .05, corrected) were found. No voxelwise difference was observed for the axial diffusivity map. Percentage of voxels within the WM skeleton that passed the significance threshold were 51%, 41.6%, and 11.9%, respectively, for radial diffusivity, fractional anisotropy, and mean diffusivity clusters. An anteroposterior pattern with preferential decrease of fractional anisotropy in the frontal circuitry was detected. CONCLUSIONS: In patients with pure hereditary spastic paraplegia, alterations in multiple DTI indices were found. Radial diffusivity seems more sensitive to hereditary spastic paraplegia-related WM pathology and, in line with the lack of axial diffusivity changes, might indicate a widespread loss of myelin integrity. A decrease of fractional anisotropy alone in the frontal circuitry may reflect subtle disruption of the frontal connections.

BOLD human responses to chromatic spatial features.

Animal physiological and human psychophysical studies suggest that an early step in visual processing involves the detection and identification of features such as lines and edges, by neural mechanisms with even- and odd-symmetric receptive fields. Functional imaging studies also demonstrate mechanisms with even- and odd-receptive fields in early visual areas, in response to luminance-modulated stimuli. In this study we measured fMRI BOLD responses to 2-D stimuli composed of only even or only odd symmetric features, and to an amplitude-matched random noise control, modulated in red-green equiluminant colour contrast. All these stimuli had identical power but different phase spectra, either highly congruent (even or odd symmetry stimuli) or random (noise). At equiluminance, V1 BOLD activity showed no preference between congruent- and random-phase stimuli, as well as no preference between even and odd symmetric stimuli. Areas higher in the visual hierarchy, both along the dorsal pathway (caudal part of the intraparietal sulcus, dorsal LO and V3A) and the ventral pathway (V4), responded preferentially to odd symmetry over even symmetry stimuli, and to congruent over random phase stimuli. Interestingly, V1 showed an equal increase in BOLD activity at each alternation between stimuli of different symmetry, suggesting the existence of specialised mechanisms for the detection of edges and lines such as even- and odd-chromatic receptive fields. Overall the results indicate a high selectivity of colour-selective neurons to spatial phase along both the dorsal and the ventral pathways in humans.

Preemptive liver-kidney transplantation in von Gierke disease: a case report.

Type 1a glycogen storage disease (GSD 1a), or von Gierke disease, is a rare, autosomal-recessive disease caused by a deficiency of glucose-6-phosphatase, which leads to glycogen accumulation in the liver, kidney, and intestinal mucosa. Clinical manifestations include hypoglycemia, growth retardation, hepatomegaly, lactic acidemia, hyperlipidemia, and hyperuricemia. Long-term complications include renal disease, gout, osteoporosis, pulmonary hypertension, short stature, and hepatocellular adenomas, which may undergo malignant transformation. Herein we have described the management and the clinical course of a GSD1a patient who underwent simultaneous preemptive liver- kidney transplantation (SPLKT), which solved the liver and renal disease. We confirmed the rapid normalization of glucose metabolism, and correction of hyperlipemia after liver transplantation. In our opinion uremic patients with GSD 1a with or without adenomas must be considered for SPLKT. To our knowledge this is the fifth case of SPLKT and the first preemptive one to be described in the literature.

Pregnancy after kidney transplantation: two transplantation centers--Vicenza-Udine experience.

BACKGROUND: Pregnancy after kidney transplant has become possible thanks to the recent surgical and pharmacological breakthrough. MATERIALS AND METHODS: We performed a retrospective study including all childbearing women transplanted in our centers after 1997. The following variables were analyzed: type of nephropathy, patient age when dialysis started, age at transplantation, time between dialysis and transplantation and between transplantation and baby birth. We also considered immunosuppressive therapy, type of delivery, baby weight, Apgar score, and mother and baby follow-up. RESULTS: We followed up 13 pregnancies in 12 patients who were diagnosed with chronic pyelonephritis (n = 4), postpartum cortical necrosis (n = 1), immunoglobulin A GN (n = 4), diabetic nephropathy (n = 1), unknown nephropathy (n = 2). All patients received a cadaveric donor kidney. They were treated with calcium antagonists and alfamethyldopa for their high blood pressure. We observed 9 mother complications: nonnephrotic proteinuria (n = 1), urinary tract Infection (n = 1), pre-eclampsia (n = 4), internal placenta detachment (n = 1) and spontaneous abortions (n = 2); 4 fetal complications: IUGR (n = 2), acute distress respiratory syndrome (n = 1), Klinefelter syndrome (n = 1) and preterm births (n = 4). In 2 cases the child weight was lower when compared to the gestational age, and 5 babies were admitted to the neonatal intensive care unit. The mother's follow-up showed no acute rejection episodes. Breastfeeding was discouraged due to the transmission of immunosuppressive medications into breast milk. We did not observe significant disease upon child follow-up. CONCLUSION: Our data were in agreement with the literature confirming that pregnancy after kidney transplant though possible carries elevated risks. Patients therefore are referred to highly specialized centers where obstetricians, nephrologists, intensivists, and neonatologists provide surveillance and treatment.

An integrated fMRI, SEPs and MEPs approach for assessing functional organization in the malformed sensorimotor cortex.

PURPOSE: Malformations of cortical development are often accompanied by an abnormal cortical pattern. Due to its propensity to involve discrete cortical areas, polymicrogyria represents an interesting model for assessing the reorganization of cortical function in relation to the disrupted anatomy. Functional MRI, TMS and SEPs can provide a highly complementary, multimodal approach to map noninvasively the functional rearrangement of sensorimotor functions in the polymicrogyric cortex, and to obtain a coherent modelling. We report here an illustrative case which is included in a patients series under study using a block design 3T fMRI, short-latency SEPs as identified on the basis of their latency, polarity, and scalp distribution and an assessment of the area and volume of the motor maps and the relative position of the center of gravity and hot spot. RESULTS: A 15 years old girl, with drug-resistant epilepsy and left perisylvian polymicrogyria that was part of a large epileptogenic network including also the mesial aspect of the left frontal lobe, exhibited a normal distribution of somatomotor responses in the expected anatomic sites, with a dissociation between motor functions, which were slightly impaired in the malformed hemisphere, and bilaterally normal sensory responses. In this patient, a large resection of epileptogenic zone, sparing eloquent areas as previously identified, should be planned in order to improve seizure outcome. CONCLUSIONS: An integrated fMRI, TMS and SEP mapping approach helps defining the relationship between epileptogenic zones and somatomotor areas. Studies of greater number of patients will be necessary in order to identify the general rules that determine the functional representation in the malformed cortex.

Physical training effects in renal transplant recipients.

INTRODUCTION: Several studies demonstrated the benefits of rehabilitation in uraemic patients. This study evaluates physical and psychosocial effects of exercise on renal transplant recipients (RTRs). PATIENTS AND METHODS: Eight RTRs were evaluated before and after an exercise training consisting of thirty 40-minute sessions, three times a week, performed with the interval training technique. RESULTS: Hospital Anxiety and Depression Scale (HADS) significantly decreased (p<0.04 and <0.008, respectively). Quality of life mean scores (SF-36 test) significantly increased (p<0.000). No differences were recorded for muscle and fat mass, maximal explosive power of the lower limbs, alkaline and acid phosphatase, parathormone (PTH), myoglobin, lipoprotein-A, glomerular filtration rate (GFR), at rest heart rate, and cardiac troponin. IL-6 decreased from 2.8±0.6 to 1.7±0.5 pg/mL (p<0.01). Resting MAP fell from 112±4 to 99±3 mmHg (p<0.02). The metabolic threshold rose from 33±4 to 43±5% (p<0.033). The blood lactate level at peak exercise increased from 5.2±0.9 to 6.2±0.7 mmol/L (p<0.012). The maximum oxygen uptake increased from 1200±210 to 1359±202 mL/min (p<0.05), iso-load oxygen uptake decreased from 1110±190 to 1007±187 mL/min (p<0.034). The maximum working capacity increased from 90±14 to 115±15 watts (p<0.000). CONCLUSION: This study suggests that an appropriate dose of physical training is a useful, safe and non-pharmacologic contribution to RTR treatment.

Sudden Sensorineural Hearing Loss: MR Imaging.

Hearing loss greater than 30 dB over three contiguous pure-tone frequencies occurring within a three day period is defined as sudden hearing loss. It is usually sensorineural (SSNHL), unilateral and appears as an otologic emergency. SSNHL has many possibile etiologies such as: labyrinthine viral infection, ischemic or hemorrhagic illness, trauma, immuno-mediated inner ear disease, tumor, inner ear malformation, and an imbalance between perilymphatic and endolymphatic fluid pressure. Nevertheless in almost 80% of cases SSNHL belongs to the idiopathic category because the etiology is unknown. The aim of this study was to test the diagnostic impact of two MR devices. Fifteen cases of SSNHL studied with a 1.5 T unit in our hospital between January 2006 and December 2008 within two weeks of the onset were retrospectively evaluated. Since January 2009 three more patients affected by SSNHL have been scanned with a 3T MR unit. We discuss the diagnostic sensitivity, clinical usefulness and the cost-benefit ratio of the MR systems.

Diffusion tensor MRI and MR spectroscopy in long lasting upper motor neuron involvement in amyotrophic lateral sclerosis.

Upper motor neuron (UMN) dysfunction in Amyotrophic Lateral Sclerosis (ALS) is not easy to identify clinically: Diffusion Tensor Imaging (DTI) and single-voxel Magnetic Resonance Spectroscopy (H-MRS) can identify markers of UMN involvement. The aim of this study was to correlate brain DTI and MRS data with clinical parameters in ALS patients (PALS). We studied 32 PALS using Magnetic Resonance Imaging. The subjects were subdivided into definite/probable (D/P) and possible/suspected (P/S). DTI indices included Fractional Anisotropy (FA) and averaged Apparent Diffusion Coefficient (avADC). Anatomical areas were sampled by positioning regions of interest along corticospinal tracts, from the precentral cortex to the bulb. H-MRS voxels were localized bilaterally in precentral regions. D/P-PALS showed significantly lower FA values than healthy controls in almost all regions, whereas P/S-PALS FA values were significantly lower only in the left precentral gray matter (GM), right precentral white matter (WM), cerebral peduncles (CP), left hemipons, and left bulbar pyramid (BP). Significantly higher avADC values were observed in the D/P-PALS right precentral GM, precentral WM, right semioval center-posterior limb of the internal capsule (SC-PLIC), and left CP; and in the precentral WM, right SC-PLIC, left CP, and right hemipons of P/S-PALS. With increasing disability, only D/P-PALS showed significantly reduced FA values in the left precentral WM and hemipons, and increased avADC values in the precentral WM. Significantly lower N-acetylaspartate (NAA)/creatine-phosphocreatine complex (Cr) and higher choline (Cho)/Cr and myoinositol (mI)/Cr ratios were found in D/P-PALS, while only higher Cho/Cr and mI/Cr ratios were found in P/S-PALS. Our data highlight the usefulness of DTI and H-MRS in assessing UMN involvement. Given FA sensitivity and specificity, despite the small number of PALS, our findings support its use as a diagnostic marker in D/P-PALS.

Phenylketonuria: white-matter changes assessed by 3.0-T magnetic resonance (MR) imaging, MR spectroscopy and MR diffusion.

PURPOSE: This study evaluated the sensitivity of a 3.0-Tesla (T) magnetic resonance imaging (MRI) in measuring cerebral phenylalanine using proton magnetic resonance spectroscopy and in assessing MR-documented white-matter changes by means of diffusion studies (diffusion-weighted imaging, apparent diffusion coefficient map; diffusion tensor imaging) in patients with phenylketonuria. MATERIALS AND METHODS: Thirty-two patients with the classical clinical and biochemical deficits of phenylketonuria underwent biochemical (blood phenylalanine), genotypic (phenylalanine hydroxylase gene) and radiological investigation by means of MRI, proton magnetic resonance spectroscopy and diffusion magnetic resonance imaging with a 3.0-T scanner. RESULTS: Periventricular and subcortical white-matter changes were detected on all MR scans. In 29/32 patients, proton magnetic resonance spectroscopy easily documented abnormal signal elevation at 7.36 ppm, corresponding to phenylalanine, despite its low concentration. Phenylalanine signal amplitude relative to the creatine/phosphocreatine signal increased linearly with blood phenylalanine values (r 0.7067; p<0.001). Diffusion MRI demonstrated hyperintensity in the areas exhibiting MRI changes as well as decreased apparent diffusion coefficient values, but fractional anisotropy indices were normal. CONCLUSIONS: The high signal, together with better spectral, spatial, contrast and temporal resolution, makes the 3.0-T MR the most suitable technique in the study of the phenylketonuria. In particular, the multimodal approach with MRI, proton magnetic resonance spectroscopy and diffusion magnetic resonance imaging can provide more information than previous studies performed with low-field systems.

HAND1 gene expression is negatively regulated by the High Mobility Group A1 proteins and is drastically reduced in human thyroid carcinomas.

HMGA1 proteins exert their major physiological function during embryonic development and play a critical role in neoplastic transformation. Here, we show that Hand1 gene, which codes for a transcription factor crucial for differentiation of trophoblast giant cells and heart development, is upregulated in hmga1 minus embryonic stem cells. We demonstrate that HMGA1 proteins bind directly to Hand1 promoter both in vitro and in vivo and inhibit Hand1 promoter activity. We have also investigated HAND1 expression in human thyroid carcinoma cell lines and tissues, in which HMGA proteins are overexpressed, with respect to normal thyroid; an inverse correlation between HMGA1 and HAND1 expression was found in all thyroid tumor histotypes. A correlation between HAND1 gene repression and promoter hypermethylation was found in anaplastic carcinomas but not in other thyroid tumor histotypes. Therefore, we can hypothesize that HMGA1 overexpression plays a key role on HAND1 silencing in differentiated thyroid carcinomas and that promoter hypermethylation occurs in later stages of thyroid tumor progression. Finally, the restoration of the HAND1 gene expression reduces the clonogenic ability of two human thyroid carcinoma-derived cell lines, suggesting that HAND1 downregulation may have a role in the process of thyroid carcinogenesis.