Mapping corpus callosum deficits in autism: an index of aberrant cortical connectivity.

BACKGROUND: Volumetric studies have reported reductions in the size of the corpus callosum (CC) in autism, but the callosal regions contributing to this deficit have differed among studies. In this study, a computational method was used to detect and map the spatial pattern of CC abnormalities in male patients with autism. METHODS: Twenty-four boys with autism (aged 10.0 +/- 3.3 years) and 26 control boys (aged 11.0 +/- 2.5 years) underwent a magnetic resonance imaging (MRI) scan at 3 Tesla. Total and regional areas of the CC were determined using traditional morphometric methods. Three-dimensional (3D) surface models of the CC were also created from the MRI scans. Statistical maps were created to visualize morphologic variability of the CC and to localize regions of callosal thinning in autism. RESULTS: Traditional morphometric methods detected a significant reduction in the total callosal area and in the anterior third of the CC in patients with autism; however, 3D maps revealed significant reductions in both the splenium and genu of the CC in patients. CONCLUSIONS: Statistical maps of the CC revealed callosal deficits in autism with greater precision than traditional morphometric methods. These abnormalities suggest aberrant connections between cortical regions, which is consistent with the hypothesis of abnormal cortical connectivity in autism.     

Central nervous system effects in acute thallium poisoning

We report the central nervous system manifestations, neuropsychological studies and brain magnetic resonance image (MRI) findings of two patients with acute thallium intoxication. Neurologically the patients suffered from confusion, disorientation, and hallucination in the acute stage, followed by anxiety, depression, lack of attention, and memory impairment, in addition to peripheral neuropathy. Neuropsychological tests revealed an impairment of memory function, including reversed digital span, memory registration, memory recall, memory recognition, similarity, proverb reasoning, and verbal fluency. High concentrations of thallium were found in the urine, blood, and drinking water of these two patients. Brain MRI showed lesions in the corpus striatum in one patient. During the follow-up periods, the clinical manifestations and neuropsychological studies showed a slowly progressive improvement, and a follow-up brain MRI 1.5 months later demonstrated a resolution of the lesions. We conclude that thallium intoxication might induce encephalopathy, and brain MRI studies demonstrated the acute-stage brain lesions in a severe intoxicated patient. In addition, neuropsychological tests also confirmed memory deficits, although the brain lesions in the corpus striatum might resolve.     

Event-related potentials elicited during a visual Go-Nogo task in adults with phenylketonuria.

OBJECTIVE: The aim of the present study was to examine the nature of previously reported deficits in sustained attention and response inhibition in adults with the developmental disorder, phenylketonuria (PKU). METHODS: This study used event-related potentials (ERPs) to examine the performance of PKU adults (n=9) and a matched control group (n=9) on a visual Go-Nogo task. RESULTS: Comparison of behavioural measures between the PKU and control groups failed to reach statistical significance, yet analysis of the ERPs showed statistically significant amplitude reductions in the P1 and N1 components elicited following presentation of stimuli, and a reduction in the amplitude of the N2 component elicited following presentation of Nogo stimuli. CONCLUSIONS: These results suggest that adults with PKU, despite being continuously treated from birth, manifest subtle impairments in distinct aspects of information processing including early sensory processing of visually presented information, as well as impairments in inhibitory functions. SIGNIFICANCE: The results contribute to an understanding of the neurophysiological mechanisms that are implicated in PKU and highlight the sensitivity of ERP techniques for the identification of the loci of information processing deficits in clinical groups.     

Degeneration of neuronal cell bodies following axonal injury in Wld(S) mice

The phenotype of Wld(S) ("slow Wallerian degeneration") mice demonstrates prolonged survival of injured axons. However, whether the Wld(S) mutation delays degeneration of the neuronal cell body following axonal injury is unclear. We used a retrograde model of axonal transport failure in Wld(S) mice to test whether the mutant Wld(S) protein has any beneficial effect on the neuronal cell body. Retrograde axonal transport was physically blocked by optic nerve crush and confirmed by the absence of Fluoro-Gold labeling in wild-type and in Wld(S) mice. After this axonal injury, there was marked protection of axonal degeneration in the Wld(S) phenotype, as confirmed by immunohistochemistry and electron microscopy. However, the Wld(S) protein, localized in the nucleus of retinal ganglion cells, did not prevent or delay degeneration of the retinal ganglion cell body, confirmed by TUNEL staining and Fluoro-Gold labeling. These results imply that, after axonal injury, Wallerian degeneration of axons and degeneration of the neuronal cell body have different mechanisms, which are autonomous and independent of each other. Although the Wld(S) phenotype can be used to demonstrate stable enucleate axons, the mutation is unlikely to protect neurons in neurodegenerative diseases in which there is failure of retrograde transport.     

The protective role of Smad7 in diabetic kidney disease: mechanism and therapeutic potential

OBJECTIVE

Although Smad3 has been considered as a downstream mediator of transforming growth factor-β (TGF-β) signaling in diabetes complications, the role of Smad7 in diabetes remains largely unclear. The current study tests the hypothesis that Smad7 may play a protective role and has therapeutic potential for diabetic kidney disease.

RESEARCH DESIGN AND METHODS

Protective role of Smad7 in diabetic kidney disease was examined in streptozotocin-induced diabetic mice that have Smad7 gene knockout (KO) and in diabetic rats given Smad7 gene transfer using an ultrasound-microbubble-mediated technique.

RESULTS

We found that mice deficient for Smad7 developed more severe diabetic kidney injury than wild-type mice as evidenced by a significant increase in microalbuminuria, renal fibrosis (collagen I, IV, and fibronectin), and renal inflammation (interleukin-1β [IL-1β], tumor necrosis factor-α [TNF-α], monocyte chemoattractant protein-1 [MCP-1], intracellular adhesion molecule-1 [ICAM-1], and macrophages). Further studies revealed that enhanced renal fibrosis and inflammation in Smad7 KO mice with diabetes were associated with increased activation of both TGF-β/Smad2/3 and nuclear factor-κB (NF-κB) signaling pathways. To develop a therapeutic potential for diabetic kidney disease, Smad7 gene was transferred into the kidney in diabetic rats by an ultrasound-microbubble-mediated technique. Although overexpression of renal Smad7 had no effect on levels of blood glucose, it significantly attenuated the development of microalbuminuria, TGF-β/Smad3-mediated renal fibrosis such as collagen I and IV and fibronectin accumulation and NF-κB/p65-driven renal inflammation including IL-1β, TNF-α, MCP-1, and ICAM-1 expression and macrophage infiltration in diabetic rats.

CONCLUSIONS

Smad7 plays a protective role in diabetic renal injury. Overexpression of Smad7 may represent a novel therapy for the diabetic kidney complication.Diabetic nephropathy is a major complication of diabetes (1–4). Approximately 20–40% of patients with type 1 or type 2 diabetes mellitus (DM) develop diabetic nephropathy (5,6). Diabetic nephropathy is characterized by excessive deposition of extracellular matrix (ECM) proteins in the mesangium and tubulointerstitium, thickness of basement membrane of the glomeruli, and loss of podocytes with the development of microalbuminuria and a decline of renal function (2,3,7). Both in vivo and in vitro studies have demonstrated that renal fibrosis and inflammation play an important role in the pathogenesis of diabetic kidney disease (2–4,7–10). Transforming growth factor-β (TGF-β) family is a crucial mediator in the development of diabetic nephropathy (11–15).It is now clear that after binding to its receptors, TGF-β signals through two critical downstream mediators, Smad2 and Smad3, to exert its biological activities such as ECM production. In addition, TGF-β₁ also induces an inhibitory Smad called Smad7, which negatively regulates activation of Smad2/3 by TGF-β receptor competition and degradation via the ubiquitin-proteasome degradation mechanism (16,17). Recent studies have demonstrated that overexpression of Smad7 is capable of inhibiting renal fibrosis and inflammation by blocking the activation of both TGF-β/Smad and nuclear factor-κB (NF-κB) signaling pathway (18–22). In contrast, deletion of Smad7 promotes renal fibrosis and inflammation (23), suggesting that Smad7 may be a key regulator and a therapeutic agent for renal fibrosis and inflammation (24). Although it has been reported that Smad3 is pathogenic in fibrosis including diabetic kidney disease (25,26), the role of Smad7 in diabetes complications remains unexplored, and it is unknown whether blockade of the TGF-β signaling pathway by Smad7 has therapeutic potential for diabetes complications. Thus, in the current study, we uncovered the role of Smad7 in diabetic kidney disease induced in Smad7 knockout (KO) mice and developed new therapeutic strategy for diabetic kidney complication by targeting the TGF-β/Smad pathway with ultrasound-microbubble-mediated Smad7 gene therapy.     

Papillary tubal hyperplasia: the putative precursor of ovarian atypical proliferative (borderline) serous tumors, noninvasive implants, and endosalpingiosis

In contrast to the controversy regarding the terminology and behavior of ovarian noninvasive low-grade serous tumors [atypical proliferative serous tumor (APST) and serous borderline tumor], little attention has been directed to their origin. Similarly, until recently, proliferative lesions in the fallopian tube had not been extensively studied. The recent proposal that ovarian high-grade serous carcinomas are derived from intraepithelial carcinoma in the fallopian tube prompted us to evaluate the possible role of fallopian tube in the genesis of low-grade serous tumors. We have identified a lesion, designated "papillary tubal hyperplasia (PTH)," characterized by small rounded clusters of tubal epithelial cells and small papillae, with or without associated psammoma bodies, that are present within the tubal lumen and which are frequently associated with APSTs. Twenty-two cases in this study were selected from a population-based study in Denmark of approximately 1000 patients with low-grade ovarian serous tumors in whom implants were identified on the fallopian tube. Seven additional cases were seen recently in consultation at The Johns Hopkins Hospital (JHH). These 7 cases were not associated with an ovarian tumor. PTH was found in 20 (91%) of the 22 cases in the Danish study. On the basis of this association of PTH with APSTs with implants and the close morphologic resemblance of PTH, not only to primary ovarian APSTs but also to noninvasive epithelial implants and endosalpingiosis, we speculate that the small papillae and clusters of cells from the fallopian tube implant on ovarian and peritoneal surfaces to produce these lesions. The 7 JHH cases of PTH that were not associated with an ovarian tumor support the view that PTH is the likely precursor lesion. We propose a model for the development of ovarian and extraovarian low-grade serous proliferations (APST, noninvasive epithelial implants, and endosalpingiosis) that postulates that all of these lesions are derived from PTH, which appears to be induced by chronic inflammation. If this hypothesis is confirmed, it can be concluded that low-grade and high-grade ovarian tumors develop from tubal epithelium and involve the ovary secondarily.     

Choroid Plexus as the Best Reference Region for Standardized Uptake Value Analysis on C11-Acetate PET/CT for Grading and Predicting Prognosis in Patients with Cerebral Gliomas

PurposeWe aimed to compare different reference regions and select one with the most clinical relevance on C11-acetate (ACE) positron emission tomography/computed tomography (PET/CT) in patients with cerebral glioma.MethodsWe retrospectively reviewed 51 patients with cerebral glioma who underwent baseline ACE PET/CT at diagnosis. Other than the standardized uptake value (SUV) of the primary tumor, SUVs of the reference regions including the normal gray matter, white matter, choroid plexus, and cerebellum were measured. Then, the SUV ratio (SUV_R = tumor SUV_max/reference region SUV_mean) was calculated. The effect of patient age on the SUV_mean of each reference was examined and the SUV_Rs of each reference region were compared between grades. age, sex, tumor size, histological grades, SUV_R, and the presence of isocitrate dehydrogenase (IDH) mutation were included for survival analyses.ResultsExcept for the cerebellum showing a mild negative correlation, we found no correlations between age and SUV_mean using the gray matter, white matter, and choroid plexus (r = − 0.280, P = 0.047). Only the SUV_R-choroid plexus was able to differentiate between the WHO grades (Grade II vs. III, P = 0.035; grade III vs. IV, P < 0.001; grade II vs. IV, P < 0.001). Multivariate Cox proportional hazards models found that the SUVR-choroid plexus and IDH mutation were statistically significant for predicting OS.ConclusionOf the different reference regions used for grading cerebral gliomas, the choroid plexus was found to be the most optimal. In addition, the SUV ratio is useful to predict the overall survival in the model with the choroid plexus as a reference region.     

HLA, MLR, P and Lewis antigens and living donor renal transplantation in a single centre in the Middle East

One hundred and fifty-one living donor renal transplants performed in a single centre in Kuwait were analysed for graft survival in relation to HLA matching, mixed lymphocyte reaction (MLR), P and Lewis antigens. There was a significant difference in graft survival (P = .05) but only at 3, 4 and 5 years between HLA identical (97%, 94%, 94%) and haploidentical combinations (83%, 81% and 79%), respectively. The zero haplotype matched combinations were not significantly different in graft survival from the identical or haploidentical groups. Compatibility or incompatibility for P or Lewis antigens did not influence graft survival. The MLR was significant (P = .05) with the MLR negative recipients having 100% graft survival at 4 years compared to 84% in the MLR positive group. In conclusion with an overall actuarial graft survival of 84% at 6 years none of the factors examined 'dramatically' influenced graft survival. The 'Centre Effect' is the main factor influencing graft survival in our Centre.     

Testicular lymphoma with bone/bone marrow metastases illustrated by scrotal sonography, spinal MRI, and total body Tc-99m HMDP and Tc-99m MIBI imagines

An 83-year-old man with testicular lymphoma demonstrated progressive scrotal enlargement with non-homogeneity sonographically and abnormally increased uptake in the scrotum of Tc-99m HMDP and Tc-99m MIBI scintigraphically. Extensive bone/bone marrow metastases were exhibited by Tc-99m MIBI and Tc-99m HMDP scintigraphies and MRI of the spine. In addition, focal/tubular activity of the femoral bone marrow on Tc-99m MIBI imaging was consistent with skeletal scintigraphic findings. It is emphasized that Tc-99m MIBI total body imaging enabled the demonstration of testicular lymphoma as increased uptake and the illustration of skeletal/bone marrow metastases as diffuse and/or focal increased uptake, especially focal/tubular MIBI activity of the femoral marrow.