Epilepsy syndromes associated with hypothalamic hamartomas.

PURPOSE: Hypothalamic hamartoma (HH) related epilepsy presents with gelastic seizures (GS), other seizure types and cognitive deterioration. Although seizure origin in GS has been well established, non-GS are poorly characterized. Their relationship with the HH and cognitive deterioration remains poorly understood. We analyzed seizure type, spread pattern in non-GS and their relationship with the epileptic syndrome in HH. METHODS: We documented all current seizure types in six adult patients with HH-epilepsy with video-EEG monitoring, characterized clinical-electrographic features of gelastic and non-gelastic seizures and correlated these findings with cognitive profile, as well as MRI and ictal SPECT data. RESULTS: Only four seizure types were seen: GS, complex partial (CPS), tonic seizures (TS) and secondarily generalized tonic-clonic seizures (sGTC). An individual patient presented either CPS or TS, but not both. GS progressed to CPS or TS, but not both. Ictal patterns in GS/TS and in GS/CPS overlapped, suggesting ictal spread from the HH to other cortical regions. Ictal SPECT patterns also showed GS/TS overlap. Patients with GS-CPS presented a more benign profile with preserved cognition and clinical-EEG features of temporal lobe epilepsy. Patients with GS-TS had clinical-EEG features of symptomatic generalized epilepsy, including mental deterioration. CONCLUSIONS: Video-EEG and ictal SPECT findings suggest that all seizures in HH-related epilepsy originate in the HH, with two clinical epilepsy syndromes: one resembling temporal lobe epilepsy and a more catastrophic syndrome, with features of a symptomatic generalized epilepsy. The epilepsy syndrome may be determined by HH size or by seizure spread pattern.     

Pressure overload-induced transient oxidative stress mediates perivascular inflammation and cardiac fibrosis through angiotensin II.

Oxidative stress is implicated in the pathogenesis of various cardiovascular diseases. We have shown that in Wistar rats with a suprarenal aortic constriction (AC), pressure overload-induced transient perivascular inflammation (monocyte chemoattractant protein-1 [MCP-1] induction and macrophage accumulation) in the early phase is the determinant of reactive myocardial fibrosis and resultant diastolic dysfunction in the late phase. Thus, we investigated the role of reactive oxygen species production in cardiac remodeling in AC rats. Superoxide production and the footprint of lipid peroxidation were assessed using dihydroethidium staining and immunohistostaining against 4-hydroxy-2-nonenal (4-HNE), respectively. In sham rats, dihydroethidium and 4-HNE signals were scarcely found in the heart. At day 3, AC rats showed dihydroethidium signals mainly in the intramyocardial arterial wall, whereas modest 4-HNE staining was observed diffusely in the myocardium. These signals declined to lower levels by day 14 despite sustained hypertension. Chronic administration of a subdepressor dose of an angiotensin II type 1 receptor blocker candesartan reduced the pressure overload-induced dihydroethidium and 4-HNE signals at day 3. Moreover, candesartan decreased MCP-1 induction and macrophage infiltration at day 3 and prevented myocardial fibrosis at day 14, without affecting left ventricle and myocyte hypertrophy. In conclusion, acute pressure overload induced self-limited superoxide production mainly in the vascular wall. The reactive oxygen species production would contribute to the perivascular inflammation and subsequent myocardial fibrosis. Angiotensin II was suggested to have a pressure-independent effect on the reactive oxygen species production.     

Increased expression of gp91phox homologues of NAD(P)H oxidase in the aortic media during chronic hypertension: involvement of the renin-angiotensin system.

Although vascular cells express multiple members of the Nox family of nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase, including gp91phox, Nox1, and Nox4, the reasons for the different expressions and specific roles of these members in vascular injury in chronic hypertension have remained unclear. Thus, we quantified the mRNA expressions of these NAD(P)H oxidase components by real-time polymerase chain reaction and evaluated superoxide production and morphological changes in the aortas of 32-week-old stroke-prone spontaneously hypertensive rats (SHRSP) and age-matched Wistar Kyoto rats (WKY). The aortic media of SHRSP had an approximately 2.5-fold greater level of Nox4 mRNA and an approximately 10-fold greater level of Nox1 mRNA than WKY. The mRNA expressions of gp91phox and p22phox in SHRSP and WKY were comparable. SHRSP were treated from 24 weeks of age for 8 weeks with either high or low doses of candesartan (4 mg/kg/day or 0.2 mg/kg/day), or a combination of hydralazine (30 mg/kg/day) and hydrochlorothiazide (4.5 mg/kg/day). The high-dose candesartan or the hydralazine plus hydrochlorothiazide decreased the blood pressure of SHRSP to that of WKY, whereas the low-dose candesartan exerted no significant antihypertensive action. Media thickening and fibrosis, as well as the increased production of superoxide in SHRSP, were nearly normalized with high-dose candesartan and partially corrected with low-dose candesartan or hydralazine plus hydrochlorothiazide. These changes by antihypertensive treatment paralleled the decrease in mRNA expression of Nox4 and Nox1. These results suggest that blood pressure and angiotensin II type 1 receptor activation are involved in the up-regulation of Nox1 and Nox4 expression, which could contribute to vascular injury during chronic hypertension.     

PEUTZ‐JEGHERS SYNDROME ASSOCIATED WITH RENAL AND GASTRIC CANCER THAT DEMONSTRATED AN STK11 MISSENSE MUTATION

A 75‐year‐old male was admitted to the gastroenterology unit of Nagoya City University Hospital due to epigastralgia after surgical treatment for right renal cancer. Endoscopy revealed advanced type 1 gastric cancer in the corpus of the stomach and multiple polypoid lesions in the stomach and duodenum. X‐ray examination of the small intestine using barium showed multiple polyps in the upper jejunum. Faint pigmentation on the palm was also detected. Peutz‐Jeghers syndrome (PJS) was diagnosed, despite a lack of family history. Total gastrectomy, resection of part of the upper jejunum and intraoperative endoscopic polypectomy of duodenal polyps was performed. This is the second reported case of PJS associated with renal cancer. We also detected a missense mutation in the tumor suppressor gene STK11 that, when mutated, is causative for PJS.     

Effects of subacute toluene exposure on neuronal and glial marker proteins in rat brain

The behavior of marker proteins of neurons (gamma-enolase) and glial cells (alpha-enolase, beta-S100 protein and creatine kinase-B) was investigated quantitatively by using enzyme immunoassay systems in toluene-exposed rat brains. Three groups of animals were exposed to toluene vapor at 300 ppm, 1000 ppm, and 3000 ppm, respectively, 8 h/day, 6 days/week, for 2 weeks. After subacute repeated solvent exposure, both neuron-specific gamma-enolase and glial marker proteins displayed an overall concentration-dependent increase tendency in separate brain regions. In cerebrum, only the 3000 ppm group showed a significant increase in alpha-enolase by 27% and creatine kinase-B (CK-B) by 26%. alpha-Enolase and gamma-enolase exhibited a pronounced elevation in cerebellum relative to other brain regions, while beta-S100 protein appeared to be the most markedly altered marker in brainstem. The development of gliosis, which is a frequent phenomenon following CNS damage, is presumed to be responsible for the elevation of glial marker content. Energy metabolism disruption in brain tissues may also bring about the compensatory oversynthesis of glycolytic enzymes such as gamma-enolase, alpha-enolase and CK-B. The dose-dependent alteration patterns following toluene exposure suggest the feasibility of using these brain specific markers to evaluate solvent-induced CNS effects.     

Transient Brain Ischaemia Provokes Ca2+, PIP2 and Calpain Responses Prior to Delayed Neuronal Death in Monkeys

To clarify the mechanism of postischaemic delayed cornu Ammonis (CA)-1 neuronal death, we studied correlations among calpain activation and its subcellular localization, the immunoreactivity of phosphatidylinositol 4,5-bisphosphate (PIP₂) and Ca²⁺ mobilization in the monkey hippocampus by two independent experimental approaches: in vivo transient brain ischaemia and in vitro hypoxia-hypoglycaemia of hippocampal acute slices. The CA-1 sector undergoing 20 min of ischaemia in vivo showed microscopically a small number of neuronal deaths on day 1 and almost global neuronal loss on day 5 after ischaemia. Immediately after ischaemia, CA-1 neurons ultrastructurally showed vacuolation and/or disruption of the lysosomes. Western blotting using antibodies against inactivated or activated μ-calpain demonstrated μ-calpain activation specifically in the CA-1 sector immediately after ischaemia. This finding was confirmed in the perikarya of CA-1 neurons by immunohistochemistry. CA-1 neurons on day 1 showed sustained activation of μ-calpain, and increased immunostaining for inactivated and activated forms of μ- and m-calpains and for PIP₂. Activated μ-calpain and PIP₂ were found to be localized at the vacuolated lysosomal membrane or endoplasmic reticulum and mitochondrial membrane respectively, by immunoelectron microscopy. Calcium imaging data using hippocampal acute slices showed that hypoxia-hypoglycaemia in vitro provoked intense Ca²⁺ mobilization with increased PIP₂ immunostaining specifically in CA-1 neurons. These data suggest that transient brain ischaemia increases intracellular Ca²⁺ and PIP₂ breakdown, which will activate calpain proteolytic activity. Therefore, we suggest that activated calpain at the lysosomal membrane, with the possible release of biodegrading enzyme, will cause postischaemic CA-1 neuronal death.     

Monkey hippocampal neuron responses to complex sensory stimulation during object discrimination.

The purpose of this study was to investigate, during the performance of an object discrimination task, responses of neurons in the monkey hippocampal formation to the sight of several objects that have biological meaning, and compare these responses with those of amygdalar neurons studied previously using the same task. Neuronal activity in the hippocampal formation of conscious monkeys was recorded during performance of a task that led to presentation of familiar rewarding, familiar aversive, or unfamiliar objects. Of 864 neurons recorded in the hippocampal formation and adjacent cortices, 160 (18.5%) responded to the sight of a certain object(s). Responses to the sight of different kinds of objects were analyzed in detail. Nondifferential neurons (n = 73) responded to different objects with no significant difference in response magnitudes, and differential neurons (n = 87) responded to different objects with different response magnitudes. Of the differential neurons, 23 responded more strongly to rewarding objects than to other objects (rewarding-object-dominant neurons), but the magnitude of responses to objects did not necessarily correlates with the order of preferences to the objects as determined from observation of animal behavior. Aversive-object-dominant neurons (n = 13) responded more to aversive objects than to other objects. Unfamiliar-object-dominant neurons (n = 7) responded more to unfamiliar objects than to familiar objects. Selective neurons (n = 10) responded selectively to only one object or one category of objects. Fourteen of the rewarding- or averse-object-dominant neurons were tested in extinction or reversal trials. In 12 of 14 neurons, responses to a rewarding or aversive object did not change, or slightly weakened, in extinction or reversal trials. The results suggest the following. (1) Responses of rewarding- or aversive-object-dominant neurons may be involved in object-reward or object-aversion association. However, responses of many of these neurons might reflect past inputs to reinforcement rather than extant emotional processing. (2) Responses of unfamiliar-object-dominant neurons may be involved in recognition of objects based on their familiar or unfamiliar aspects. These results are further discussed and compared with responsiveness of amygdalar neurons.     

An experimental study on development of gallstone disease after curative gastrectomy for cancer--postoperative alteration of the composition of canine gallbladder bile after subtotal gastrectomy with truncal vagotomy]

In connection with gallstone (GS) formation after gastrectomy for cancer, we examined alteration of the composition of gallbladder bile after subtotal gastrectomy with truncal vagotomy. Of 11 mongrel dogs with cholecystostomy, 3 underwent B-I and 4 B-II gastrectomy. Four dogs without gastrectomy were served as controls. Bile was collected for 12 months. Bile acids were quantified by GLC. The bile was cultured for bacteriology. TBA did not significantly differ among the three groups of the dogs. In the two gastrectomized groups, CDA (a secondary bile acid) kept a higher level and CA (a primary bile acid) maintained a lower concentration compared with those in the controls. A remarkable increase of non-conjugated bile acids was recognized in both gastrectomized groups. Lithogenicity was low for all of the 3 groups. All but 1 control dog incurred bile infection that persisted long. Black pigment stones containing calcium bilirubinate developed in 1 of the 3 B-I and 2 of the 4 B-II dogs but none in the controls. The bile infection seemed to be involved in the development of GS. As the alteration of bile composition and GS occurred solely in the gastrectomized dogs, subtotal gastrectomy with truncal vagotomy might precipitate the GS formation.     

Change in body image of patients with alcohol dependence during treatment process]

In order to find useful information for the establishment of new treatment method to alcohol dependence, we investigated the change of the body image of patients with alcohol dependence before and after the treatment. HABIT (Haga Body Image Test), a questionnaire about body image developed in department of psychiatry in Kyoto Prefectural University of Medicine, was used to examine the change of body image between pre- and post-3-month conventional treatment program in 46 patients with alcohol dependence hospitalized into special institutions for treatment of the disease in Kyoto. Patients with poor outcome of the treatment showed improvement of body image on visceral function, feeling of appetite and outward appearance, while patients with good outcome indicated no significant change in these aspects. This finding likely suggests that the treatment would result in good outcome in patients having stable feeling of physical health, and the cognitive treatment approach about these aspects of body image should be performed on the patients with poor treatment outcome. On the other hand, the body image about motor function showed significantly higher score in the patients approach for the patients with poor outcome to become aware of their physical activity would be effective.