The gene encoding a newly discovered protein, chorein, is mutated in chorea-acanthocytosis.

Chorea-acanthocytosis is a neurodegenerative disorder with peripheral red cell acanthocytosis. Linkage of chorea-acanthocytosis to chromosome 9q21 has been found. We refined the locus region and identified a previously unknown, full-length cDNA encoding a presumably structural protein, which we called chorein. We found a deletion in the coding region of the cDNA leading to a frame shift resulting in the production of a truncated protein in both alleles of patients and in single alleles of obligate carriers.

Improvement of meal-related symptoms and epigastric pain in patients with functional dyspepsia treated with acotiamide was associated with acylated ghrelin levels in Japan.

BACKGROUND: The aim of this study is to clarify whether acotiamide and rabeprazole combination therapy can improve clinical symptoms, gastric emptying, and satisfaction with treatment in functional dyspepsia (FD) patients more effectively than acotiamide or rabeprazole monotherapy alone. We also aimed to determine whether acotiamide affects these changes via its effect on gastric emptying and appetite-related hormones such as ghrelin. METHODS: We used Rome III criteria to evaluate upper abdominal symptoms and anxiety by the State-Trait Anxiety Inventory (STAI). Gastric motility was evaluated by the (13) C-acetate breath test. Eighty-one FD patients were treated with acotiamide (300 mg/day) (n = 35), acotiamide (300 mg/day) and rabeprazole (10 mg/day) (n = 28), or rabeprazole (10 mg/day) (n = 18) for a period of 4 weeks and followed after 4 weeks of no treatment. Adenocorticotropic hormone (ACTH), cortisol, leptin and ghrelin levels were measured in all FD patients. KEY RESULTS: Acotiamide and rabeprazole combination therapy significantly improved postprandial distress syndrome (PDS)-like symptoms (p = 0.018, p = 0.04 and p = 0.041, respectively) and epigastric pain (p = 0.024) as wells as STAI-state scores (p = 0.04) compared to rabeprazole monotherapy. Both acotiamide monotherapy, and acotiamide taken in combination with rabeprazole, significantly (p = 0.001 and p = 0.02, respectively) improved satisfaction with treatment, compared to rabeprazole monotherapy. Acotiamide and rabeprazole combination therapy had no significant effect on ACTH and cortisol levels in FD patients. Of interest, acotiamide monotherapy, and acotiamide and rabeprazole combination therapy, significantly (p < 0.0001 and p = 0.018, respectively) increased acylated ghrelin/total ghrelin ratios and significantly (p = 0.04) improved impaired gastric emptying compared to rabeprazole monotherapy. CONCLUSIONS & INFERENCES: Further studies are warranted to clarify how acotiamide treatment improves clinical symptoms in FD patients.

Tirilazad pretreatment improves early cerebral metabolic and blood flow recovery from hyperglycemic ischemia.

Acidosis may augment cerebral ischemic injury by promoting lipid peroxidation. We tested the hypothesis that when acidosis is augmented by hyperglycemia, pretreatment with the 21-aminosteroid tirilazad mesylate (U74006F), a potent inhibitor of lipid peroxidation in vitro, improves early cerebral metabolic recovery. In a randomized, blinded study, anesthetized dogs received either tirilazad mesylate (1 mg/kg plus 0.2 mg/kg/h; n = 8) or vehicle (n = 8). Hyperglycemia (400-500 mg/dl) was produced prior to 30 min of global incomplete cerebral ischemia. Intracellular pH and high energy phosphates were measured by phosphorus magnetic resonance spectroscopy. During ischemia, microsphere-determined CBF decreased to 8 +/- 4 ml min-1 100 g-1 and intracellular pH decreased to 5.6 +/- 0.2 in both groups. During the first 20 min of reperfusion, ATP partially recovered in the vehicle group to 57 +/- 21% of baseline, but then declined progressively in association with elevated intracranial pressure. By 30 min, ATP recovery was greater in the tirilazad group (77 +/- 35 vs. 36 +/- 19%), although postischemic hyperemia was similar. By 45 min, the tirilazad group had a higher intracellular pH (6.5 +/- 0.5 vs. 5.9 +/- 0.6) and a lower intracranial pressure (18 +/- 6 vs. 52 +/- 24 mm Hg). By 180 min, blood flow and ATP were undetectable in seven of eight vehicle-treated dogs, whereas ATP was > 67% and pH was > 6.7 in six of eight tirilazad-treated dogs. Thus, tirilazad acts during early reperfusion to prevent secondary metabolic decay associated with severe acidotic ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)

A specific thrombin inhibitor (argatroban) ameliorated cerebral blood flow in the patients with acute cerebral infarction.

Argatroban, one of the arginine derivatives, has been reported to have a safe and potent antithrombin action. This compound is active in several animal models of thrombosis and also has been shown to improve general neurological symptomatology, general subjective symptomatology and general daily behavior in the patients with acute thrombosis. This was considered to reflect remarkable improvement of microcirculation. No published clinical data, however, exist on the effect of argatroban on cerebral blood flow (CBF) change during acute stroke. Three patients with acute cerebral infarction were subjected to this study. Intravenous argatroban injection (2.5 mg/hr) was continued in 48 hours. Regional CBF (rCBF) was measured before and after injection of argatroban using Xe-CT method. Argatroban increased CBF not only in the injured side hemisphere or penumbra, but also contralateral side of lesion in the patients with acute cerebral infarction.

Abstinence from drink ameliorated cerebral blood flow and vasoreactivity in patients with chronic alcoholism.

High dose ethanol consumption is a risk factor for both ishemic and hemorrhagic cerebrovasucular disease. This link between heavy drinkers and the risk factor of stroke has been considered as hypertension, liver dysfunction, abnormality of platelet function or other unknown mechanisms. Recently some of the experimental study suggest that direct action of ethanol on the inhibition of the synthesis/release of nitric oxide from endothelium and neurons may contribute to this link. Few studies in this field, however, were performed clinically. We examined cerebral blood flow (CBF) and vaso-reactivity in the patients with chronic alcoholism on abstinence from drink. CBF of nine male patients were measured by use of stable Xe-CT method before and after acetazolamide load. Regional CBF increased in second measurement after abstinence, but there were no significant changed statistically. However, %vaso-reactivity in right ACA and MCA significantly improved. We considered that large brain vessels dilated then small vessels could response to acetazolamide.

Intracellular pH during reperfusion influences evoked potential recovery after complete cerebral ischemia.

BACKGROUND AND PURPOSE: Increasing ischemic duration delays recovery of intracellular pH and depresses recovery of somatosensory evoked potentials. We tested whether manipulation of the rate of pH recovery influences evoked potential recovery after complete ischemia. METHODS: Four groups of eight anesthetized dogs underwent 12 minutes of complete ischemia followed by 4 hours of reperfusion with either 1) normocapnia, 2) normocapnia and acetazolamide (25 mg/kg at reperfusion plus 12.5 mg/kg per hour, 3) hypocapnia, or 4) hypercapnia. Intracellular pH was measured by phosphorus magnetic resonance spectroscopy, and intracellular bicarbonate was calculated using sagittal sinus partial pressure of CO2 during reperfusion. RESULTS: In the normocapnic control group, intracellular pH decreased from 7.10 +/- 0.04 (+/- SEM) to 6.13 +/- 0.08 during ischemia and recovered to 6.90 +/- 0.08 by 30 minutes of reperfusion. Bicarbonate also largely recovered (9.9 +/- 1.6 mM). With acetazolamide pH (6.51 +/- 0.10) and estimated bicarbonate (4.8 +/- 1.3 mM) remained depressed at 30 minutes and did not fully recover until 60-75 minutes. However, percent recovery of somatosensory evoked potential amplitude at 4 hours of reperfusion was less with acetazolamide (23 +/- 4%) than in the control group (52 +/- 5%). With hypercapnic reperfusion, which delayed pH recovery but not bicarbonate recovery, evoked potential recovery was also depressed (27 +/- 5%). With hypocapnic reperfusion, which delayed bicarbonate recovery but not pH recovery, evoked potential recovery (52 +/- 6%) was not depressed compared with controls. Recovery of adenosine triphosphate and oxygen consumption was similar among groups. CONCLUSIONS: Delayed recovery of intracellular pH with or without delayed recovery of bicarbonate during reperfusion further impairs somatosensory evoked potential recovery independent of recovery of high-energy phosphates. Persistence of acidosis during reperfusion can contribute to postischemic electrophysiological deficit.

Effect of the 21-aminosteroid tirilazad on cerebral pH and somatosensory evoked potentials after incomplete ischemia.

BACKGROUND AND PURPOSE: Postischemic evoked potential recovery correlates with acidosis during ischemia and early reperfusion. Acidosis promotes lipid peroxidation in vitro. We tested the hypothesis that the 21-aminosteroid tirilazad mesylate (U74006F), an inhibitor of lipid peroxidation in vitro, ameliorates somatosensory evoked potential recovery and acidosis during reperfusion after severe incomplete cerebral ischemia. METHODS: Cerebral perfusion pressure was reduced to 11 +/- 1 mm Hg (+/- SEM) for 30 minutes by cerebral ventricular fluid infusion in anesthetized dogs. Cerebral intracellular pH and high-energy phosphates were measured by magnetic resonance spectroscopy. Dogs were randomized to receive vehicle (citrate buffer; n = 8) or tirilazad (1 mg/kg; n = 8) before ischemia in a blinded study. RESULTS: Cerebral blood flow was reduced to 6 +/- 1 mL/min per 100 g during ischemia, resulting in nearly complete loss of high-energy phosphates and an intracellular pH of 6.0-6.1 in both groups. Initial postischemic hyperemia was similar between groups but lasted longer in the vehicle group. Tirilazad accelerated mean recovery time of intracellular pH from 31 +/- 5 to 15 +/- 3 minutes and of inorganic phosphate from 13 +/- 2 to 6 +/- 1 minutes. Recovery of somatosensory evoked potential amplitude was greater with tirilazad (49 +/- 3%) than vehicle (33 +/- 6%). Fractional cortical water content was less with tirilazad (0.819 +/- 0.003) than vehicle (0.831 +/- 0.002). CONCLUSIONS: Tirilazad attenuates cerebral edema and improves somatosensory evoked potential recovery after incomplete ischemia associated with severe acidosis. Accelerated pH and inorganic phosphate recovery indicates that this antioxidant acts during the early minutes of reperfusion.

Pupillary light reflex in patients with hemispheric cerebrovascular disease.

Pupillary dynamics were investigated in 41 patients with hemispheric CVD by means of computerized open-loop videopupillography. The patients were alert and showed either abnormal high- or low-density areas on CT scan. Fourteen cases were examined in the acute stage (within 7 days from onset), 28 cases in the subacute stage (between 8 and 28 days) and 11 cases in the chronic stage (over 29 days). In the acute stage, the parasympathetic nervous functions (maximum velocity and acceleration of pupillary constriction) were hyporeactive and showed no significant differences between the ipsilateral and contralateral side of the lesion. In the subacute stage, these functions were significantly more hyperreactive on the ipsilateral side than on the contralateral side, that is, the parasympathetic functions of the healthy hemisphere became significantly improved in comparison with those in the acute stage. In the chronic stage, no significant differences were observed between the two sides. In contrast, the sympathetic nervous function (maximum velocity of dilatation) showed no differences with respect to either laterality or the time course after onset. The above data suggest that bilateral parasympathetic hypofunctions exist in the acute stage of hemispheric CVD, with an ipsilateral improvement of these functions with the passage of time, and that such autonomic dysfunctions may play some role in the pathophysiology of CVD.

Effect of bifemelane on the intracellular pH and energy state of the ischemic brain.

4-(o-Benzylphenoxy)-N-methylbutylamine hydrochloride (bifemelane, CAS 90293-01-9, Celeport) has been reported to exert a protective effect on the brain against ischemic insults. However, the underlying mechanism of this action has not yet been fully elucidated. The effects of bifemelane on the intracellular pH (pHi) and energy metabolism of the ischemic brain were examined in Mongolian gerbils using in vivo 31P nuclear magnetic resonance spectroscopy. Transient global ischemia was produced by clipping both common carotid arteries for 45 min, and the brain was reperfused by releasing the clips. Bifemelane (10 or 20 mg/kg) or normal saline was administered intraperitoneally 30 min prior to the ischemia. During the ischemia, adenosine triphosphate (ATP) and phosphocreatine (PCr) were markedly reduced in association with an increase in inorganic phosphate (Pi) and decrease in pHi in both the control and bifemelane groups. The extents of energy disturbance and intracellular acidosis in the three groups were identical. After reperfusion, ATP, PCr, Pi and pHi recovered towards the pre-ischemic levels in all the groups. In the bifemelane groups, the recovery of pHi was significantly faster than in the control group. Of the two bifemelane groups, the 20 mg/kg group showed more excellent pHi recovery as compared to the 10 mg/kg group. The energy recovery in the three groups were almost identical, although the 20 mg/kg group showed some tendency towards faster recovery as compared to the control group. The present results suggest that bifemelane may accelerate recovery of the pHi after cerebral ischemia. Such an action may contribute to the cerebral protective effects of this drug against ischemic insults.

Effects of pentoxifylline on cerebral blood flow, metabolism, and evoked response after total cerebral ischemia in dogs.

OBJECTIVE: To test the hypothesis that pentoxifylline improves recovery of cerebral electrical activity and metabolic function after a transient cerebral global ischemia by improving cerebral blood flow during the reperfusion period. DESIGN: Randomized, controlled, prospective study. SETTING: University research laboratory. SUBJECTS: Forty male beagle dogs. INTERVENTIONS: Six control dogs received pentoxifylline (40 mg/kg bolus followed by infusion at 0.2 mg/kg/hr) without ischemia. Thirteen dogs received Ringer's lactate solution with 12 mins of cerebral global ischemia (by aortic occlusion). Nine dogs received pentoxifylline before ischemic insult. Six dogs received pentoxifylline on reperfusion, and six dogs received pentoxifylline 30 mins after reperfusion. MEASUREMENTS AND MAIN RESULTS: Total and regional cerebral blood flow, cerebral oxygen consumption, and somatosensory evoked potentials were measured during 180 mins of reperfusion. Pentoxifylline did not affect cerebral blood flow, oxygen consumption, or somatosensory evoked potentials without ischemia. Pretreatment with pentoxifylline resulted in attenuated postischemic hyperemia at 10 mins of reperfusion (94 +/- 15 vs. 133 +/- 11 [SEM] mL/min/100 g; p < .05), but there was no difference in total cerebral blood flow or oxygen consumption during later points of reperfusion. Pentoxifylline treatment during reperfusion resulted in no recovery of cerebral blood flow or oxygen consumption. All ischemic groups demonstrated a rapid ablation of somatosensory evoked potential amplitude and there were no differences in the decrement of the amplitude on ischemia. At 180 mins of reperfusion, somatosensory evoked potentials recovered to the following percentages of the baseline control values: 28 +/- 4% in dogs treated with Ringer's lactate solution; 58 +/- 4% in the pentoxifylline pretreated group (p < .05); 40 +/- 5% in dogs receiving pentoxifylline at reperfusion (p > .05); and 53 +/- 8% in dogs receiving pentoxifylline at 30 mins of reperfusion (p < .05). CONCLUSIONS: Pentoxifylline treatment improves recovery of cerebral electrical function after complete transient cerebral global ischemia by a mechanism that does not involve improvement in cerebral blood flow or global oxygen consumption.

Sodium, ATP, and intracellular pH transients during reversible complete ischemia of dog cerebrum.

We tested the hypotheses that with the onset of cerebral ischemia, massive cellular sodium influx does not occur until adenosine triphosphate is fully depleted and that on reperfusion, neuronal sodium efflux does not occur until adenosine triphosphate is fully restored. We examined the temporal relationships among transcellular sodium, energy metabolism, and intracellular pH with sodium and phosphorus magnetic resonance spectroscopy in a new, hemodynamically stable, brain stem-sparing model of reversible, complete cerebral ischemia in eight anesthetized dogs. Inflation of a neck tourniquet after placement of glue at the tip of the basilar artery resulted in decreased blood flow to the cerebrum from 29 +/- 5 to 0.3 +/- 0.5 ml/min/100 g. Medullary blood flow was not significantly affected, and arterial blood pressure was unchanged. Sodium signal intensity decreased and did not lag behind the fall in adenosine triphosphate. After 12 minutes of ischemia, reperfusion resulted in a more rapid recovery of sodium intensity (12.4 +/- 4.8 minutes) than either adenosine triphosphate (16.5 +/- 3.7 minutes) or intracellular pH (38.9 +/- 1.8 minutes). Because intracellular sodium has a weaker signal than extracellular sodium, the decreased sodium intensity is interpreted as sodium influx and indicates that sodium influx does not require full depletion of adenosine triphosphate. Rapid recovery of sodium intensity during early reperfusion may represent sodium efflux, although increased plasma volume and sodium uptake from plasma may also contribute. If our interpretation of the sodium signal is correct, delayed recovery of adenosine triphosphate may be due to the utilization of adenosine triphosphate for the restoration of transcellular sodium gradient.

Shift reagent enhanced concurrent 23Na and 1H magnetic resonance spectroscopic studies of transcellular sodium distribution in the dog brain in vivo.

The intracellular to extracellular sodium distribution is one of the primary determinants of action potentials necessary for the electrical function of organs such as brain, heart and skeletal muscle. The ability of shift reagent enhanced 23Na MRS to directly measure the intracellular and extracellular sodium distribution in brain is controversial and centers on the relative contributions of bulk magnetic susceptibility and hyperfine interactions to the observed chemical shifts. In this study, infusion of dysprosium (III) triethylenetetraminehexacetate (Dy(TTHA)-3), resulted in a 23Na MRS spectrum of dog brain with two well resolved peaks at 9 and 0.4 ppm. The 9 ppm peak corresponded to the resonance seen in aspirated blood. After disruption of the blood brain barrier, the single peak at 0.4 ppm split into two peaks at 3 and 0 ppm. The ability of Dy(TTHA)-3 enhanced 23Na MRS to follow global changes in brain sodium distribution was tested during cardiac arrest. The expected rapid Na influx into the intracellular space produced a marked decrease in the 3 ppm signal and a parallel increase in the 0 ppm peak. This is consistent with the assignment of the 3 ppm peak as interstitial sodium and the 0 ppm peak as intracellular sodium.