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Objective To elucidate the novel biological functions of heparan sulfate (HS) by clinic-pathologically studying a patient with paroxysmal atrioventricular (AV) block. Patient A long-surviving male patient with Sanfilippo syndrome type A presented with paroxysmal AV block at age 33 years. He then survived another 2.5 years after the onset of paroxysmal AV block and pacemaker implantation. Methods and results His cardiac histopathological examination at autopsy showed HS storage in the cardiac conduction system (CCS), especially in the atrioventricular node (AVN)-His bundle branches. Conclusion HS storage in the CCS might trigger AV block, arising from below the AVN-His bundle branches. This is the first description to indicate that HS might be an essential constituent of life-long CCS plasticity and that its storage in the CCS results in AV block.

Background & Aims: Activins belong to the transforming growth factor-β superfamily. Recent studies have shown that activin and its natural antagonist, follistatin, are involved in tissue repair and inflammatory processes. The aim of this study was to determine whether neutralization of activins with follistatin would have an in vivo anti-inflammatory effect in several murine models of colitis. Methods: We assessed activin levels in the colitis induced by intracolonic administration of trinitrobenzene sulfonic acid (TNBS). We subsequently tested the effects of an intraperitoneal injection of follistatin before or after induction of TNBS colitis. We also examined the established colitis induced by oral dextran sulfate sodium (DSS) as well as the spontaneous colitis that develops in interleukin (IL)-10 gene-deficient (IL-10−/−) mice. Results: Levels of activin transcripts in the colon during the acute phase of TNBS colitis were up-regulated. Epithelial cells, infiltrating macrophages (Mϕ), and endothelial cells produced excess activin βA. Pretreatment with follistatin increased the survival rate of mice with TNBS colitis from 33% to 82% and decreased the plasma levels of IL-6 and amyloid A. Administration of follistatin also reduced the histologic score and tissue myeloperoxidase activity in established TNBS and DSS colitis and reduced the severity of the colitis in IL-10−/− mice. Based on results obtained from 3 mouse models and from in vitro experiments, follistatin promoted the proliferation of colonic epithelial cells. Conclusions: Neutralization of activins by follistatin promoted epithelial cell division and tissue repair, clearly suggesting a treatment modality for intestinal inflammation.

Background & Aims: T helper (Th) 1 and Th2 cell subsets significantly influence the pathological features of inflammation in the gastrointestinal tract in a distinct manner. It is now established that the transfer of CD4 + CD45RB Hi (RB Hi ) T cells to either severe combined immunodeficient (SCID) or recombinase activation gene 2–deficient (RAG −/− ) mice results in a severe granulomatous hypertrophic colitis mediated by Th1 cells. We have modified this approach to address the role of Th2 cells. Methods: RB Hi T cells from wild-type (Wt) mice or mice genetically predisposed to Th2 responses (interferon-γ–defective [IFN-γ −/− ]) with or without B cells were transferred to T cell receptor (TCR)-β and δ-chain–defective (TCR −/− ) or SCID mice. Results: Transfer of Wt RB Hi T cells induced wasting disease with severe colitis in the TCR −/− mice. In contrast, IFN-γ −/− RB Hi T cells induced severe weight loss and hypoalbuminemia without significant inflammation in the colon. The small intestine of these mice exhibited villus atrophy, a decrease in brush-border enzymes, reduced enterocyte proliferation, and an increased number of goblet cells. The presence of B cells was necessary for these changes, because SCID recipients required cotransfer of B cells, together with IFN-γ −/− RB Hi T cells for ileal lesions to develop. Treatment of TCR −/− recipients of IFN-γ −/− RB Hi T cells with anti–IL-4 mAb abrogated both the wasting disease and the villus atrophy. Conclusions: Dysregulated Th2 cells cause atrophic changes and goblet cell transformation in the small intestinal epithelium and wasting disease mediated by excess interleukin-4 and B cells. GASTROENTEROLOGY 2003;124:672-682

To clarify the pathophysiology of tonic spasms, 21 patients with West syndrome were analyzed using ictal and interictal single photon emission computed tomography (SPECT). We focused on whether ictal perfusion changes were observed in the focal cortical region. Eight of the patients studied showed definite focal cortical ictal hyperperfusion, indicating that there is a unique subset of West syndrome that can be classified as infantile localization-related epilepsy. Of those eight patients, only two showed asymmetric spasms, suggesting that seizure symptomatology in infants gives only limited information on the localization-related nature of epilepsy. Furthermore, the activation of subcortical structures by focal cortical regions might be attributable to the symmetric seizure phenomena. Thirteen patients showed a diffuse pattern in their ictal SPECTs; this probably included patients with diffuse hyperperfusion and those with no changes. The following have yet to be determined: (1) whether West syndrome is divided into subgroups based on the origin of spasms, in that some patients have the origin in the cortical hemisphere and some have the origin in structures other than the cortical hemisphere, such as the brain stem; (2) whether differences in ictal SPECT patterns reflect a unique nature of tonic spasms in West syndrome, where tonic spasms appear in clusters and the interval of each spasm is different among each patient.

Two children with influenza A-related encephalopathy were treated with a combination of mild hypothermia (deep body temperature of the forehead: 35 degrees C) and anticytokine agents (high-dose methylprednisolone and ulinastatin), while receiving amantadine. One of the cases exhibited acute necrotizing encephalopathy on computed tomography (CT). Although no severe complications occurred, correctable hypokalemia and hyperglycemia occurred in both cases. Both patients recovered without any neurological sequelae. Our therapeutic protocol appears to be effective for managing influenza A-related encephalopathy.

We used interictal single photon emission computed tomography (SPECT) on 40 patients with West syndrome to determine whether cortical perfusion abnormalities are closely related to the development of West syndrome and whether they are correlated with the long-term seizure prognosis or the developmental outcome. Localized cortical perfusion abnormalities were seen in 24 patients (60%), while 15 patients (38%) were classified as normal. The remaining patient showed hyperperfusion of the basal ganglia bilaterally. Of 24 patients with localized perfusion abnormalities, unifocal cortical hypoperfusion was present in 11, multifocal hypoperfusion in 10, multiple cortical hypo- and hyperperfusion in one, hyperperfusion of the bilateral frontal cortices and brain stem in one, and focal hyperperfusion in the residual frontal cortex in one. For statistical analysis, we focused on 26 patients (cryptogenic; 10, symptomatic; 16), who were followed for more than 2 years after the onset of tonic spasms (mean 5.0 years). The results showed that focal cortical perfusion abnormalities were not correlated with the long-term seizure prognosis, the developmental outcome, or the response to ACTH therapy. In agreement with previous reports, the results of interictal SPECT suggested that focal cortical lesions play an important role in the development of West syndrome. However, statistical analysis showed that the existence of cortical dysfunction as defined by SPECT did not predict the seizure prognosis or the developmental outcome.

Potassium bromide was tried for two children with daily convulsive focal motor seizures with unconsciousness and focal motor seizure status. The treatment resulted in complete cessation of the attacks. It has been reported that bromide is effective for generalized tonic-clonic seizures and not for complex partial seizures, such as convulsive focal motor seizures with unconsciousness. However, our experiences provide evidence that bromide is one of the useful therapeutic agents for intractable symptomatic localization-related epilepsy.