Phase I/II study of the toxicity, pharmacokinetics, and activity of the HIV protease inhibitor SC-52151

A significant restriction was demonstrated in the ability of herpes simplex virus type 1 virion host shutoff (vhs) mutant viruses to invade the corneal epithelium. Viral replication and invasion was confined to the areas of the cornea which were scarified prior to infection. Differences between wild-type and vhs mutant replication in corneas in vivo were 100- to 1000-fold at all timepoints postinfection. Smaller but still significant growth restrictions were observed in cultured corneal cells. This difference between in vitro and in vivo is not likely to be due to differences in cell cycle status since vhs-induced RNA degradation can occur in both cycling and noncycling cells in vitro. The vhs function is therefore important for invasion of the cornea and secondarily the nervous system and is thereby required for efficient establishment of latency.     

Significance of spikes recorded on intraoperative electrocorticography in patients with brain tumor and epilepsy

PURPOSE: Patients with medically intractable epilepsy due to brain tumors may undergo resective surgery for treatment of both the tumor and the epilepsy. In this instance, the extent of surgical resection is sometimes guided by spikes recorded on intraoperative electrocorticography (ECoG). Whether spikes recorded by electrocorticography imply active epileptogenicity has not been addressed adequately. METHODS: We performed preresection and postresection electrocorticography on 36 patients with brain tumor and seizures. There were 31 low-grade gliomas, 4 high grade gliomas, and 1 dysembryonic neuroepithelial tumor. Patients had resection of the tumor to normal tissue margins only. No additional surgery was performed, based on electrocorticography findings. Patients were divided into 2 groups: Group I (no seizures or rare seizures after resection) and Group II (recurrent seizures). Recorded spikes were analyzed for spike distribution and spike discharge rate. RESULTS: On preresection ECoG, 85% of patients in Group I and 88% of patients in Group II had spikes. In Group I, 70% of patients had spikes over the tumor bed, and 63% of patients had spikes in the surrounding tissue. In Group II, 55% of patients had spikes over the tumor bed and 89% of patients had spikes in the surrounding tissue. Spike distribution and discharge rate did not correlate with outcome. On postresection ECoG, 60% of patients in Group I and 67% of patients in Group II had residual spikes. In Group I, 46% of patients had spikes along the margin of resection and 26% of patients had extramarginal spikes. In Group II, 50% had spikes along the margin of resection and 67% of patients had extramarginal spikes. CONCLUSIONS: The difference in spike distribution in the extramarginal area between the 2 groups was not statistically significant, but showed a trend toward a relationship between postresection spikes and seizure recurrence.     

Memory improvement following cardiac transplantation

Seventeen patients with severe cardiomyopathy underwent neuropsychological evaluation prior to and at least 1 year after successful heart transplantation. Study candidates were screened, and individuals with a history of stroke, cardiac arrest, or medical and neurological conditions which might affect brain function were excluded. Pre-transplant testing revealed normal intelligence and normal attentional, language, and executive abilities but impaired recent memory. Following heart transplant, memory functioning improved significantly, reaching normal levels. Other cognitive abilities remained unchanged. Results suggest that cardiomyopathy is associated with mesial temporal dysfunction, possibly attributable to inadequate or reduced cerebral blood flow and related hypometabolism. This cerebral dysfunction is potentially reversible following successful transplantation, which restores cardiac output and cerebrovascular perfusion.     

Effects of nalmefene, CG3703, tirilazad, or dopamine on cerebral blood flow, oxygen delivery, and electroencephalographic activity after traumatic brain injury and hemorrhage

Hemorrhage after traumatic brain injury (TBI) in cats produces significant decreases in cerebral oxygen delivery (DcereO2) and electroencephalographic (EEG) activity. To determine whether effective treatments for the separate insults of TBI and hemorrhagic shock would also prove effective after the clinically relevant combination of the two, we measured the effects of a kappa-opiate antagonist (nalmefene), an inhibitor of lipid peroxidation (tirilazad), a thyrotropin-releasing hormone analog (CG3703), a clinically useful pressor agent (dopamine) or a saline placebo on cerebral blood flow (CBF), and EEG activity after TBI and mild hemorrhagic hypotension. Cats (n = 40, 8 per group) were anesthetized with 1.6% isoflurane in N2O:O2 (70:30) and prepared for fluid-percussion TBI and microsphere measurements of CBF. Cats were randomized to receive nalmefene (1 mg/kg), tirilazad (5 mg/kg), CG3703 (2 mg/kg), dopamine (20 microg x kg(-1) x min[-1]) or a saline placebo (2 ml, 0.9% NaCl). Animals were injured (2.2 atm), hemorrhaged to 70% of preinjury blood volume, treated as just described and resuscitated with a volume of 10% hydroxyethyl starch equal to shed blood. CBF was determined and EEG activity recorded before injury, after hemorrhage, and 0, 60, and 120 min after resuscitation (R0, R60, and R120). CBF increased significantly after resuscitation (R0) in the nalmefene- and CG3703-treated groups. CBF did not differ significantly from baseline in any group at R60 or R120. DcereO2 was significantly less than baseline in the saline-, dopamine-, and tirilazad-treated groups at R60 and in the dopamine-, tirilazad-, and CG3703-treated groups at R120. EEG activity remained unchanged in the nalmefene-treated group but deteriorated significantly at R60 or R120 compared to baseline in the other groups. Nalmefene and CG3703 preserved the hyperemic response to hemodilution (otherwise antagonized by TBI), and nalmefene prevented the deterioration in DcereO2 and EEG activity that occurs after TBI and hemorrhage.     

Chronic interleukin-6 alters NMDA receptor-mediated membrane responses and enhances neurotoxicity in developing CNS neurons

Recent studies show that the cytokine interleukin-6 (IL-6) is expressed at elevated levels in the CNS in several disease states and contributes to the neuropathological process. The mechanisms through which IL-6 exerts its CNS effects are primarily unknown. We have investigated the pathophysiological effects of IL-6 on developing CNS neurons using a culture model system and a chronic treatment paradigm. Here, we show, using current- and voltage-clamp recordings, that chronic IL-6 treatment of developing cerebellar granule neurons increases the membrane and current response to NMDA and that these effects are the primary mechanism through which IL-6 produces an enhanced calcium signal to NMDA. We also show that calcium influx through voltage-sensitive calcium channels contributes to the enhanced calcium signal to NMDA in the IL-6-treated neurons in a developmentally regulated manner and that the membrane depolarization to NMDA is more sensitive to the NMDA receptor antagonist ifenprodil in the IL-6-treated neurons compared with control neurons at a late developmental stage, consistent with a larger proportion of NMDA receptors containing the NMDAR2B subunit in the IL-6-treated neurons. Additional studies show that IL-6 treatment reduces the number of granule neurons in culture and enhances neurotoxicity involving NMDA receptors. These results support a pathological role for IL-6 in the CNS and indicate that NMDA receptor-mediated functions are likely to play a critical role in neuropathological changes observed in CNS diseases associated with elevated CNS levels of IL-6.     

Further analysis of the reliability of the posterior tangent lateral lumbar radiographic mensuration procedure: concurrent validity of computer-aided X-ray digitization

OBJECTIVE: To investigate the reliability of a specific method of radiographic analysis of the geometric configuration of the lumbopelvic spine in the sagittal plane, and to investigate the concurrent validity of a computer-aided digitization procedure designed to replace the more tedious and time-consuming manual measurement process. DESIGN: A blind, repeated-measures design was used. The results of radiographic measures derived through the traditional manual marking method were compared with measures derived by computer-aided digitization of lateral lumbopelvic radiographs. SETTING: Private chiropractic clinic. MAIN OUTCOME MEASURES: Pearson's product-moment correlation coefficients, paired sample t tests and intraclass correlation co-efficients (ICC) were used to examine intraexaminer reliability, and repeated measures of analysis of variance were used to examine interexaminer reliability for relative rotation angles for T12-L1, L1-L2, L2-L3, L3-L4, L4-L5, L5-S1, overall lordosis measurement [absolute rotation angle (ARA)] from L1-L5 and Cobb angle of overall lordosis measured from the inferior surface of T12 to the superior surface of S1, Ferguson's sacral base angle to horizontal, angle of pelvic tilt (arcuate angle) to horizontal and anteroposterior thoracic translation (Sz) in millimeters. RESULTS: ICC estimates for intraexaminer reliability were in the range of 0.96-0.98 for the L1-L5 ARA, a range of 0.87-0.99 for the arcuate angle measurement, 0.83-0.94 for the Ferguson's angle measurement, 0.88-0.95 for the Cobb angle measurement from the inferior surface of T12 compared with the superior surface of S1 and 0.98-1.00 for the translation measurement of the lower thoracic spine to S1 (Sz). The intersegmental measurement's (T12-L1, L1-L2, L2-L3, L3-L4, L4-L5, L5-S1) correlations ranged from a low of 0.55 to a high of 0.97. Examination of these findings suggests that the reliability for the three doctors is acceptable with only the T12-L1 intersegmental measure falling below 0.70 for the least experienced examiner. Average ICC of interexaminer reliability for manual and computer-aided digitizing examiners were the following: 0.96 for the L1-L5 ARA; 0.84 for the arcuate angle measurement; 0.82 for the Ferguson's angle measurement; 0.88 for the Cobb angle measurement; 1.00 for the Sz translation measurement; and values of 0.65, 0.73, 0.74, 0.75, 0.89 and 0.81 for relative rotation angle measurements T12-L1, L1-L2, L2-L3, L3-L4, L4-L5 and L5-S1, respectively. CONCLUSION: The data tend to support the reliability of this method of radiographic analysis of the geometric configuration of the lumbopelvic spine as viewed on lateral lumbopelvic radiographs. The additional data presented here tend to support the concurrent validity of the computer-aided digitization method of analysis inasmuch as the measures determined by the digitizing examiners are essentially identical to those determined by the manual method plus or minus the average standard error of measure of each value.     

Erythrocyte Na/K ATPase activity and diabetes: relationship with C-peptide level

The purpose of this study is to clarify the volume effect of epidural saline injection 20 min after spinal anesthesia. Thirty patients undergoing combined spinal and epidural anesthesia for orthopedic surgery were randomly divided into two groups: a control group (n = 15) and a saline group (n = 15). In the control group, 2% lidocaine 3 ml with 0.4% tetracaine was injected into the subarachnoid space from L 4-5 interspace using Durasafe (Becton Dickinson, USA) and saline was not injected into the epidural space. In the saline group, saline 10 ml was injected through an epidural catheter 20 min after spinal anesthesia. The levels of analgesia 20 min after spinal anesthesia were not significantly different between the groups. However, the levels of analgesia 3, 5, 10, 40 and 100 min after epidural saline injection in the saline group were significantly higher than those in the control group (P < 0.05). The highest analgesic level was obtained 10 min after epidural saline injection and reached to T 4.3 +/- 1.1. In conclusion, epidural saline injection increases the analgesic level 20 min after spinal anesthesia because of the volume effect.     

Cell-associated viral RNA expression during acute infection with HIV type 1

The mechanism of decline in viremia following acute infection with HIV is unknown. To characterize this process virologically, the expression of viral RNAs was analyzed in samples of peripheral blood mononuclear cells (PBMCs) from a patient who experienced a 100-fold decline in plasma viremia over a 13-day period prior to the initiation of antiretroviral therapy. Cell-associated viral RNA declined in association with the decline in plasma virus. During the initial 7 days of observation, plasma viremia declined more than 10-fold with no change in the ratio of unspliced to multiply spliced mRNAs. The efficiency of viral gene expression did not decline during the study period and varied from 380 to 2800 unspliced RNA copies per productively infected cell. Together, these data indicate no change in the relative proportion of cells in late- and early-stage gene expression during the initial decline and provide evidence against shortening of the viral replication cycle by immune surveillance. However, the prevalence of productively infected cells declined markedly during the 13 days of observation, from 1 in 250 to 1 in 25,000 PBMCs. These data are compatible with depletion of available target cells during the initial decline in viremia. As the level of plasma virus stabilized after 8 days of observation, the ratio of unspliced to multiply spliced mRNAs rose; this rise was due to a relatively greater decline in multiply spliced mRNA. These data suggest the possible onset of a blockade to new infection events (for example, by neutralizing antibody or chemokines), causing an increase in the relative proportion of cells in late-stage gene expression. They may also be explained, however, by the persistence of cell-associated virions together with the near disappearance of productively infected cells from the circulation.