Predictor of buckwheat allergy in children based on challenge test results: a retrospective observational study in Japan.

Summary: Background. Buckwheat (BW) is a major food allergen and one of the leading causes of food-induced anaphylaxis in Japan. The standard method of diagnosing food allergy is the oral food challenge (OFC). The BW-specific IgE (BW-sIgE) value is used to assess BW allergy but its utility is limited. Aim. The aim of the present study was to identify factors with predictive value for the diagnosis of BW allergy using the OFC. Methods. We evaluated 37 patients who were classified into the positive or negative group according to their OFC results. Results. Ten patients (27.0%) showed objective or persistent, moderate, subjective symptoms during the OFC. The positive group had a significantly higher BW-sIgE/total IgE ratio than the negative group (p less than 0.001), but the total IgE (p = 0.139) and BW-sIgE (p = 0.130) did not differ significantly. Receiver operator characteristic (ROC) analysis showed that the BW-sIgE/total IgE ratio had a larger area under the curve (AUC, 0.885) than BW-sIgE (AUC, 0.667). The statistically optimal cut-off was 0.0058 for the BW-sIgE/total IgE ratio, which corresponded to a clinical sensitivity and specificity of 90.0% and 81.5%, respectively. Conclusions. BW-sIgE/total IgE ratio may be more useful predictor of BW OFC results than BWs-IgE.

Acceptability and Feasibility of Integrating Point-of-Care Diagnostic Testing of Sexually Transmitted Infections into a South African Antenatal Care Program for HIV-Infected Pregnant Women.

Background: Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG), and Trichomonas vaginalis (TV) infections may increase the risk of vertical transmission of the human immunodeficiency virus (HIV). In resource-limited settings, symptomatic screening, and syndromic management of sexually transmitted infections (STIs) during pregnancy continue to be the standard of care. In the absence of diagnostic testing, asymptomatic infections in pregnant women go untreated. Objective: To describe the acceptability and feasibility of integrating diagnostic STI screening into first antenatal care visits for HIV-infected pregnant women. Methods: HIV-infected pregnant women were recruited during their first antenatal care visit from three antenatal care clinics in Tshwane District, South Africa, between June 2016 and October 2017. Self-collected vaginal swabs were used to screen for CT, NG, and TV with a diagnostic point-of-care (POC) nucleic acid amplification test. Those with STIs were provided treatment per South African national guidelines. Results: Of 442 eligible women, 430 (97.3%) agreed to participate and were tested. Of those with a positive STI test result (n = 173; 40.2%), 159 (91.9%) received same-day results and treatment; 100% of STI-infected women were treated within seven days. Conclusions: Integration of POC diagnostic STI screening into first-visit antenatal care services was feasible and highly acceptable for HIV-infected pregnant women.

High-throughput Toroidal Grating Beamline for Photoelectron Spectroscopy at CAMD.

A 5 meter toroidal grating (5m-TGM) beamline has been commissioned to deliver 28 mrad of bending magnet radiation to an ultrahigh vacuum endstation chamber to facilitate angle resolved photoelectron spectroscopy. The 5m-TGM beamline is equipped with Au-coated gratings with 300, 600 and 1200 lines/mm providing monochromatized synchrotron radiation in the energy ranges 25-70 eV, 50-120 eV and 100-240 eV, respectively. The beamline delivers excellent flux (~1014-1017 photons/sec/100mA) and a combined energy resolution of 189 meV for the beamline (at 1.0 mm slit opening) and HA-50 hemispherical analyzer was obtained at the Fermi level of polycrystalline gold crystal. Our preliminary photoelectron spectroscopy results of phenol adsorption on TiO2 (110) surface reveals the metal ion (Ti) oxidation.

Parent artery occlusion for posterior cerebral artery aneurysms.

SUMMARY: We review four cases of posterior cerebral artery (PCA) aneurysm, of which three showed intolerance of parent artery occlusion. In two, balloon test occlusion (BTO) indicated poor opacification of the PCA branches from the anastomoses, and therefore, permanent occlusion was not attempted.

Attenuation of focal ischemic brain injury in mice deficient in the epsilon1 (NR2A) subunit of NMDA receptor.

The role of glutamate neurotoxicity in cerebral ischemia has long been advocated but still remains controversial, because various glutamate receptor (GluR) antagonists showed inconsistent protective efficacy in brain ischemia models. To address this central issue of ischemic brain damage more directly, we used mutant mice deficient in the GluRepsilon1 (NR2A) subunit of NMDA receptor with or without additional heterozygous mutation in the GluRepsilon2 (NR2B) subunit. Those mutant mice, as well as their littermates, were subjected to focal cerebral ischemia by introducing a 6-0 nylon suture from left common carotid artery. Brain injury volumes after 2 hr of suture insertion, as evaluated by 2,3,5-triphenyltetrazolium chloride staining at 24 hr after ischemia, revealed significantly smaller injury size in GluRepsilon1 subunit knock-out mice compared with their wild-type littermates. The reduction in injury volume was not attributable to differences in body temperature or in blood flow during ischemia. Additional heterozygous GluRepsilon2 subunit disruption did not result in further reduction in injury volume. These data directly demonstrate relevance of NMDA receptor-mediated tissue injury after brain ischemia and provide evidence that GluRepsilon1 subunit is involved in these injurious mechanisms.

Angle-resolved UV photoelectron spectra (UPS) of thin films of perylene-3,4,9,10-tetracarboxylic dianhydride on MoS(2).

Angle-resolved UV photoelectron spectra (ARUPS) were measured for thin films of perylene-3,4,9,10-tetracarboxylic dianhydride (PTCDA) deposited on cleaved MoS(2) surfaces. The take-off angle (theta) dependence of the photoelectron intensity of the highest pi band showed a sharp maximum at theta = 32-34 degrees. A spectral feature of the binding energy at approximately 8.9 eV, which is believed to originate from a pi state, showed a remarkably different theta dependence from that of the pi band. A quantitative analysis of the observed theta dependencies clearly indicates that (a) the feature at approximately 8.9 eV originates from the oxygen 2p non-bonding states and (b) the molecules lie flat on the substrate surface.

Effect of L-arginine and NG-nitro-L-arginine on delayed neuronal death in the gerbil hippocampus.

To assess the role of nitric oxide (NO) in cerebral ischemia, we investigated the effect of L-arginine, a substrate of NO synthase (NOS), and NG-nitro-L-arginine (L-NNA), a NOS inhibitor, on neuronal death in the CA1 hippocampal region. Seventy-two Mongolian gerbils were used in the study. Both carotid arteries were occluded for 4 min to induce forebrain ischemia. Temporal muscle temperature was strictly maintained at 37.5 +/- 0.3 degrees C during the ischemia. L-arginine (10 and 100 mg kg-1) or L-NNA (1, 10 and 100 mg kg-1) was administered intraperitoneally 4 times: 30 min before, 3 h, 6 h and 24 h after induction of ischemia. Four days after ischemic insult, the animals were perfusion-fixed, and the neuronal densities in the medial, middle and lateral CA1 subfield were estimated. Average neuronal cell density of the control group was 2-3 mm in each subfield. L-arginine at doses of 10 and 100 mg kg-1 did not prevent neuronal death. L-NNA at doses of 1 and 10 mg kg-1 did not protect neuronal cells from ischemia either. However, in ischemia gerbils treated with 100 mg kg-1 L-NNA, the average neuronal cell density in the lateral CA1 subfield was 54.4 +/- 19.1, L-NNA (100 mg kg-1) significantly (p < 0.05) reduced the occurrence of neuronal death in the lateral CA1 subfield. The present results suggest that NO plays an important role in the development of neuronal injury after global ischemia.

Treatment of focal cerebral ischemia with synthetic oligopeptide corresponding to lectin domain of selectin.

BACKGROUND AND PURPOSE: Synthetic oligopeptides with amino acid sequences of the lectin domain of selectin block selectin-mediated cell adhesion in vitro, which may be applied to a therapeutic intervention to attenuate acute inflammatory reactions. To evaluate the efficacy of such treatment against ischemic brain injury, the effects of administering a selectin oligopeptide that selectively blocks selectin-mediated cell adhesion on histological outcome and on cerebral blood flow (CBF) were studied in models of rodent focal cerebral ischemia. METHODS: Spontaneously hypertensive rats were anesthetized with halothane. Permanent focal cerebral ischemia was induced by tandem left middle cerebral artery (MCA) and common carotid artery (CCA) occlusion. Focal cerebral ischemia with partial reperfusion was introduced by reperfusing the CCA after 2 hours of tandem MCA/CCA occlusion. A synthetic oligopeptide (amino acid residues 23-30 from N terminal) of E-selectin was dissolved in physiological saline and was injected intravenously at a dosage of 2 mg/kg or 10 mg/kg before artery occlusion. Control animals received equivalent volumes of physiological saline or 10 mg/kg of synthetic oligopeptide with a scrambled amino acid sequence. Twenty-four hours after the occlusion, seven coronal brain slices were stained with 2,3,5-triphenyltetrazolium chloride, and the volume of ischemic injury was calculated. In a separate set of animals, regional CBF was monitored with laser-Doppler flowmetry at the dorsolateral cerebral cortex during 2-hour ischemia and 30 minutes after partial reperfusion. RESULTS: The volume of ischemic injury did not differ among groups in permanent ischemia. In ischemia with partial reperfusion, 10 mg/kg selectin oligopeptide, but not the same dosage of scrambled oligopeptide, significantly reduced the volume of ischemic injury (95 +/- 13, 73 +/- 11, 55 +/- 6, and 111 +/- 14 mm3 for saline [n = 11]; 2 mg/kg [n = 10] and 10 mg/kg [n = 16] selectin oligopeptide and 10 mg/kg scrambled oligopeptide [n = 6], respectively; P < .01 by one-way ANOVA followed by the Tukey test). Laser-Doppler flowmetry demonstrated a larger increase in CBF after reperfusion of the CCA in the 10-mg/kg selectin oligopeptide group. CONCLUSIONS: Our data demonstrate that administration of a synthetic oligopeptide corresponding to the lectin domain of selectin decreases the size of ischemic injury after transient, but not after permanent, focal cerebral ischemia as evaluated at 24 hours after onset of ischemia. These effects were associated with an improved CBF at the dorsolateral cerebral cortex after partial reperfusion.

An immunosuppressant, FK506, protects hippocampal neurons from forebrain ischemia in the mongolian gerbil.

We examined whether an immunosuppressant, FK506, inhibits delayed neuronal death in the gerbil hippocampal CA1 sector after 5-min forebrain ischemia. After reperfusion, gerbils were injected intravenously with FK506. Gerbils in the early injection group were injected with FK506 immediately after reperfusion, and gerbils in the delayed injection group were injected with FK506 1 or 2 h postischemia. The body temperature of the FK506-treated gerbils in the normothermic group was maintained at 37.5-38.0 degrees C for 2 h postischemia. In the chronic survival group, neuroprotection was assessed after recovery for 45 days. Seven or 45 days after reperfusion, neuronal density in the CA1 was assessed following perfusion fixation. FK506 ameliorated cell death in the CA1 in a dose-dependent manner in every group, although it showed a hypothermic effect. FK506 is neuroprotective against forebrain ischemia in gerbils.

Second-look operation for recurrent colorectal cancer based on carcinoembryonic antigen and imaging techniques.

PURPOSE: The usefulness of postoperative carcinoembryonic antigen (CEA) monitoring and improvements in imaging techniques have renewed enthusiasm for second-look operations (SLO) as the most effective treatment for recurrent colorectal cancer by reresection following early detection. The aim of our study is to evaluate the role of CEA and imaging techniques-directed SLO. METHODS: Seven hundred fifty-six patients with Dukes Stages B and C, who had undergone curative resection, were monitored postoperatively using CEA and imaging techniques. An SLO was performed on any potentially resectable recurrence, and in addition, an SLO was done when a persistently rising CEA value was detected. RESULTS: Recurrence developed in 18.8 percent (142/756) of patients, and 90.8 percent (129/142) of the recurrences were detected within the first three years following curative resection. When comparing carcinomas of the colon with that of the rectum, the former were associated with significantly more hepatic and intraabdominal recurrences, whereas the latter had significantly more locoregional and pulmonary recurrences. Seventy-two patients underwent SLO. Of these patients, 54.2 percent (39/72) had all of their disease resected, and 1.4 percent (1/72) had no detectable disease at the SLO. Among the 142 patients with recurrence, 71 (50 percent) patients underwent SLO. The resectable group at SLO carried a significantly better survival than the unresectable recurrence group (41.3 vs. 5.2 percent; P<0.01). CONCLUSIONS: Complete removal of colorectal cancer recurrences by SLO, on the basis of postoperative, follow-up CEA and imaging technique findings, results in improved survival.

Blood flow-dependent functional recovery in a rat model of focal cerebral ischemia.

The reduction in focal infarct volume after L-arginine has been attributed to an increase in regional cerebral blood flow (rCBF) within ischemic tissue. We tested the hypothesis that L-arginine-induced rCBF increases precede the recovery of spontaneous electrical activity [electrocorticogram (ECoG)] in spontaneously hypertensive rats subjected to middle cerebral artery (MCA) occlusion. ECoG was recorded from the penumbral region of parietal cortex by a glass microelectrode inserted into 1-mm3 cortical tissue from which blood flow was sampled by laser-Doppler flowmetry. rCBF dropped to 21 +/- 8% of the preischemic level, and ECoG was depressed by 64 +/- 13% after distal MCA occlusion. L-Arginine infusion (300 mg/kg i.v.) increased rCBF in 14 out of 18 rats, and ECoG significantly recovered in seven rats in which rCBF exceeded 31% of preischemic flow. Increases in rCBF anticipated the functional improvement in every case. Saline (n = 6) or D-arginine (n = 5) administration was ineffective. These data demonstrate that increasing rCBF can promote functional recovery in the ischemic brain and suggest that early administration of L-arginine or other vasodilators may enhance tissue survival by increasing rCBF.

Distribution of metastatic lymph nodes in colorectal cancer by the modified clearing method.

PURPOSE: The aim of this study was to clarify the distribution of lymph node metastasis in colorectal cancer. We also examined the relationship between the primary tumor (T) and the regional node (N) categories of the TNM (primary tumor, regional nodes, metastasis) classification. METHOD: Lymph nodes of surgical specimens in 311 consecutive patients with colorectal cancer were studied using the modified clearing method. RESULTS: Lymph node metastasis was seen in 59.2 percent of the total cases. The upward metastasis rate was 30.7 percent. In the longitudinal spread, most of the lymph node metastasis was seen within 10 cm. On the oral side in rectal cancer, there was no metastasis beyond 4 cm. The lateral metastasis rate in rectal cancer was 8.8 percent and in the lower rectum, the rate of cancer within 6 cm from the anal verge or beyond pT3 was much higher. CONCLUSION: In the TNM classification, there was no significant difference between colon and rectal cancer except pT1 with rectal cancer. In the lower rectal cancer within 6 cm from the anal verge or beyond pT3, there is a high risk of lateral metastasis, and lateral lymph node dissection or radiation therapy should be performed.

Metastases from carcinoma of the colon and rectum detected in small lymph nodes by the clearing method.

A study of regional lymph node metastases was performed using the clearing method in 322 patients with carcinoma of the colon and rectum (140 with carcinoma of the colon and 182 with carcinoma of the rectum) who had undergone surgical resection. The mean number of nodes examined per patient was 76.4 and the metastatic rate (patients with metastases divided by the total of patients) was 61.4 percent, with a metastatic incidence (nodes with metastases divided by the total of examined nodes) of 6.4 percent for carcinoma of the colon using the clearing method. For carcinoma of the rectum, the mean number of nodes examined was 73.7 with a metastatic rate of 57.1 percent and a metastatic incidence of 7.1 percent. In contrast, node analysis by the conventional manual method resulted in a mean of 18.1 nodes being examined, with a metastatic rate and incidence of 42.1 and 12.8 percent, respectively, for carcinoma of the colon. Manual examination of lymph nodes in carcinoma of the rectum resulted in a mean of 21.2 nodes being examined, with a metastatic rate and incidence of 50.0 and 16.8 percent, respectively. Compared with the manual method, the clearing method provided a greater number of nodes, a higher metastatic rate and a lower metastatic incidence. These differences may be explained by the detection of metastatic regional nodes smaller than 4 millimeters in maximum diameter by the clearing method. By TNM classification there were more pN3 than pN2 lesions. The five year survival rate after curative resection was 78.5 percent for pN1 lesions, 45.7 percent for pN2 lesions and 45.4 percent for pN3 lesions for carcinoma of the colon and 72.7 percent for pN1 lesions, 75.0 percent for pN2 and 53.9 percent for pN3 lesions for carcinoma of the rectum. There was no significant survival difference between the patients with pN1, pN2 and pN3 carcinomas. The presence of regional nodes metastases should be examined in detail. Therapies and prognosis of carcinoma of the colon and rectum should be discussed based on accurate staging.

L-arginine infusion promotes nitric oxide-dependent vasodilation, increases regional cerebral blood flow, and reduces infarction volume in the rat.

BACKGROUND AND PURPOSE: We previously reported that L-arginine infusion increased pial vessel diameter by nitric oxide-dependent mechanisms, improved regional cerebral blood flow (rCBF) distal to middle cerebral artery (MCA) occlusion, and reduced infarction volume in spontaneously hypertensive rats when administered intraperitoneally before and after MCA occlusion. In this report we extend our findings (1) by examining the time course of L-arginine on rCBF and pial vessel diameter under basal conditions and on rCBF after MCA occlusion and (2) by reproducing the protective effect of L-arginine on infarct volume when given intravenously immediately after the onset of MCA occlusion in both normotensive and hypertensive models of focal cerebral ischemia. METHODS: Changes in pial vessel diameter (closed cranial window) and rCBF (laser-Doppler flowmetry) were measured over time after L-arginine infusion into anesthetized Sprague-Dawley rats. rCBF was also measured distal to MCA occlusion in a brain region showing rCBF reductions in the range of 80% of baseline. The effects of infusing L-arginine (300 mg/kg for 10 minutes beginning 5 minutes after occlusion) were assessed on infarction volume in Sprague-Dawley rats after proximal MCA occlusion and in spontaneously hypertensive rats after common carotid artery plus distal MCA occlusion. RESULTS: L-Arginine (300 mg/kg IV) elevated rCBF by 20% when measured in the dorsolateral cortex of Sprague-Dawley rats and caused L-nitroarginine-methyl ester-inhibitable increases in pial vessel diameter. L-Arginine (> or = 30 mg/kg IV) increased blood flow distal to MCA occlusion by 50%. These effects were sustained throughout the observation period (70 to 105 minutes). Changes in mean arterial blood pressure were not observed. L-Arginine (300 mg/kg IV) reduced infarction volume by 35% and 28% in Sprague-Dawley and spontaneously hypertensive rats, respectively, when examined 24 hours after vessel occlusion. CONCLUSIONS: These studies extend our previous findings by demonstrating that exogenous L-arginine induces sustained rCBF increases in normal brain as well as in a marginally perfused brain region distal to MCA occlusion. Our data in Sprague-Dawley rats support the conclusion that L-arginine-induced increases in rCBF can decrease infarction volume. We conclude that nitric oxide-mediated mechanisms increase rCBF and decrease infarction volume after MCA occlusion in both normotensive and hypertensive animals.

L-arginine dilates rat pial arterioles by nitric oxide-dependent mechanisms and increases blood flow during focal cerebral ischaemia.

L-Arginine (> or = 30 mg kg-1, i.v.), but not D-arginine (300 mg kg-1) administered 5 min after unilateral common carotid/middle cerebral artery occlusion increased regional cerebral blood flow (rCBF) within the dorsolateral ischaemic cortex in spontaneously hypertensive rats. L-Arginine (300 mg kg-1) increased rCBF from 22 +/- 2.7 to 33 +/- 4% of baseline as measured by laser-Doppler flowmetry. This increase may explain the ability of L-arginine to reduce infarct size following focal cerebral ischaemia, as reported previously. The mechanism appears to be mediated by nitric oxide since topical L-NAME (1 microM), a nitric oxide synthase inhibitor, decreased pial arteriole calibre from 115 +/- 2.2 to 106 +/- 0.9% of baseline following L-arginine infusion (300 mg kg-1).

L-arginine decreases infarct size caused by middle cerebral arterial occlusion in SHR.

L-Arginine, but not D-arginine, serves as a precursor for the synthesis of nitric oxide (NO), a potent dilator of cerebral blood vessels. We examined the effects of administering L-arginine (300 mg/kg ip) on the volume of infarction in two models of focal cerebral ischemia in spontaneously hypertensive rats (SHR). L-Arginine was administered before (16 and 3 h) and after (5 min and 2 h) vessel occlusion, and animals were killed 24 h later. L-Arginine treatment decreased infarct size in rats subjected to distal middle cerebral arterial (MCA) plus ipsilateral common carotid arterial (CCA) occlusion by 31% [147 +/- 12 (saline) vs. 101 +/- 9 mm3 (L-arginine), P < 0.05]. D-Arginine, administered according to the same dosage and protocol, was without effect. In the group subjected to proximal MCA occlusion, L-arginine decreased infarction size in the striatum by 28% [47 +/- 5 (saline) vs. 34 +/- 3 mm3 (L-arginine), P < 0.05] and neocortex by 11% [193 +/- 7 (saline) vs. 171 +/- 8 mm3 (L-arginine), P < 0.05]. Changes in blood pressure or other measured physiological parameters did not account for the observed differences. The possible use of L-arginine for the treatment of focal cerebral ischemia merits further investigation.

The significance of brain temperature in focal cerebral ischemia: histopathological consequences of middle cerebral artery occlusion in the rat.

The purpose of this study was to determine the effect of selective modulation of brain temperature in the experimental settings of permanent and reversible middle cerebral artery (MCA) occlusion in Sprague-Dawley rats. Three models of proximal MCA occlusion were used, in which the effect of brain-temperature modulations could be studied. These included (a) permanent MCA occlusion with an initial 30-min period of hypotension (30 or 36 degrees C x 4 h), (b) permanent MCA occlusion alone (30, 36, or 39 degrees C x 2 h), and (c) 2 h of reversible MCA occlusion (30, 36, or 39 degrees C x 2 h). In the transient MCA occlusion series, intra- and postischemic cortical blood flow was assessed using a laser-Doppler flowmeter placed over the dorsolateral cortex. After a 3-day survival, all rats were perfusion fixed for histopathological analysis and the determination of infarct volume. In animals with permanent MCA occlusion plus hypotension, no significant difference in infarct volume was demonstrated between the 30 and 36 degrees C groups. In rats with permanent MCA occlusion without hypotension, significant differences in infarct volume were again not demonstrable, but an interaction between infarct area and temperature class was shown by repeated-measures analysis, indicating that hypothermia altered the topographic pattern of the cortical infarct. With 2 h of reversible MCA occlusion, there was a statistically significant reduction in infarct volume in the 30 degrees C group compared to 39 degrees C rats. Although intra- and postischemic CBF were not significantly different among the three temperature groups, the cortical infarct volume was positively correlated with postischemic CBF. The postischemic CBF, in turn, was positively correlated to the intraischemic brain temperature and was negatively correlated to CBF during the ischemic period. These findings demonstrate that moderate manipulations of brain temperature have a greater influence on the resulting cortical infarction in the setting of transient focal ischemia than in the context of permanent vascular occlusion.

Sensorimotor and cognitive consequences of middle cerebral artery occlusion in rats.

Rats were subjected to either right proximal middle cerebral artery (MCA) occlusion or sham operation, and examined for an extended period on a battery of tests designed to measure simple motor function, sensorimotor integration and cognitive function. Rats with MCA occlusion showed extensive neuronal loss in the dorsolateral striatum and variable neuron loss in the parietal, temporal and frontolateral neocortex. MCA occluded animals exhibited significant impairments in tests of postural reflex, visual and tactile forelimb placing, locomotor coordination, and a test of simultaneous bilateral tactile extinction. The reflex and sensorimotor function deficits recovered to pre-operative levels by Day 30 post-ischemia. Five weeks following surgery, rats were tested in 2 versions of the Morris water task. Rats with MCA occlusion demonstrated significant impairments in their ability to navigate to a hidden platform, but were not significantly impaired on the visible (cued) version of the task. This general pattern of transient sensorimotor and reflex deficits, but with more persistent cognitive impairments, is similar to that seen in humans following MCA infarcts.

Calcium antagonists in the treatment of experimental cerebral ischemia.

Calcium ion functions widely as an intracellular messenger and regulator. Intracellular calcium dyshomeostasis occurs during hypoxic/ischemic cell injury, and pharmacological antagonism of calcium entry into neurons has been considered to be of potential therapeutic value. Calcium antagonists, in addition, tend to improve cerebral perfusion of both the normal and abnormal (post-ischemic) brain. Studies of these agents have shown variable degrees of cerebroprotection in focal and global ischemia models. (S)-Emopamil is a phenylalkylamine-type calcium channel blocker which also exhibits stereoselective antagonism of the serotonin S2 receptor and has excellent blood-brain barrier penetrability. Protection of hippocampal CA1 neurons has been demonstrated with pre-ischemic administration of (S)-emopamil in global ischemia models. Our laboratory has compared the efficacy of pre- vs. post-ischemic (S)-emopamil treatment on neuronal necrosis resulting from 10 min of transient normothermic global ischemia in the rat. (S)-Emopamil pre-treatment, 20 mg/kg i.p., 30 min prior to ischemia, with a second dose 2.5 h later, resulted in 1.8-2.4 fold increases in numbers of surviving CA1 pyramidal neurons. Post-ischemic administration was ineffective. Intracerebral microdialysis has revealed a partial attenuation of dopamine release with pre-ischemic (S)-emopamil administration. In focal cerebral ischemia (middle cerebral artery occlusion in the rat), our laboratory has demonstrated a marked reduction in cortical infarct volume with (S)-emopamil pre- or post-treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Postischemic (S)-emopamil therapy ameliorates focal ischemic brain injury in rats.

(S)-Emopamil is a calcium channel blocker of the phenylalkylamine class, having potent serotonin S2 antagonistic properties and high blood-brain barrier penetrability. Previous studies have documented cerebroprotective effect in animal models of both focal and global ischemia. The present study was undertaken to define the postischemic "window" of therapeutic efficacy for this agent. Sprague-Dawley rats were subjected to permanent proximal middle cerebral artery occlusion, combined with an initial 30-minute period of halothane-induced hypotension (50 mm Hg). (S)-Emopamil (20 mg/kg) was administered intraperitoneally either 20-30 minutes prior to middle cerebral artery occlusion or 1 hour, 2 hours, or 3 hours following occlusion. Treated groups received a second similar dose 2.5 hours later and twice daily for 2 days thereafter. Brains were perfusion-fixed on the third day. Planimetric analysis of hemotoxylin and eosin-stained coronal brain sections documented a cortical infarct averaging 72.9 +/- 33.3 mm3 (mean +/- SD) in untreated rats. Cortical infarct volume was reduced by 48% (to 37.6 +/- 27.6 mm3) when therapy was initiated 1 hour postischemia (p less than 0.05). When treatment was deferred to 2 hours postichemia, mean cortical infarct volume was reduced by 34%, but this difference did not attain statistical significance. Infarct volume in rats with treatment initiated at 3 hours postischemia was indistinguishable from that in controls. Striatal infarct volume was similar in all groups. These results document a postischemic therapeutic window of cerebroprotection for (S)-emopamil lying between 1 and 2 hours after middle cerebral artery occlusion.