APOE genotypes in African American female multiple sclerosis patients.

Multiple sclerosis (MS) is a chronic inflammatory CNS disorder, resulting in progressive neurological dysfunction. The disease has a higher incidence in Caucasian Americans (CA) than African Americans (AA); however, the latter may have a more aggressive disease course. We used cluster analysis to determine whether there is a difference in disease progression between the races and whether the APOE AND APOC1 genotypes influence the disease progression. AA female patients were younger and had a higher progression index and MS severity score than CA female MS patients. AA females who were APOE 4/4, 2/4, or 2/3 and APOC1 AA had a younger age-of-onset, had primarily a relapsing remitting disease course, with a higher progression index and MS severity score, as assessed by cluster analysis. Cluster analysis also indicated that CA female patients were of two groups. One group was younger, had the APOE 3/3 genotype with relapsing remitting less severe disease. The second CA group was older, had the APOE 3/4 or 2/3 genotypes with more of the secondary progressive more severe disease phenotype. Thus, the AA MS female patients who were APOE 4 carriers had an earlier age-of-onset and more severe disease course than CA MS female patients.

Age-related decrease in vulnerability to excitatory amino acids in the nucleus basalis.

The present study investigated the effects of nucleus basalis magnocellularis (NBM) lesions in young (3 months), adult (9 months), and aged (24 months) rats by injections of either NMDA or AMPA upon performance of a delayed alternation task on a T maze. During phase 1 of testing, the interchoice interval (ICI) was 5 s and each rat was given 10 trials per day during phase 2, the ICI was 30 s across 10 trials per day; during phase 3, the ICI was 5 s across 20 trials per day. Analyses of variance revealed (a) a significant effect of age during phase 1 (i.e., 24-month-old rats performed worse than 3-month-old rats); (b) a significant effect of age and lesion in phase 2 (i.e., the lesions impaired choice accuracy equally in all age groups when the ICIs were 30 s); (c) a significant effect of age and lesions, and a significant interaction in phase 3 (i.e., young rats were more impaired by the lesions than were aged rats.

Choline acetyltransferase activity and vesamicol binding in Rett syndrome and in rats with nucleus basalis lesions.

The decline in choline acetyltransferase activity has been identified previously within the brains of patients with Rett syndrome and Alzheimer's disease. The level of [3H]vesamicol binding to a terminal vesicular acetylcholine transporter is inversely related to the decline in cortical choline acetyltransferase activity in Alzheimer's disease, which may be due to compensatory processes within surviving cholinergic terminals. In order to investigate whether similar cholinergic compensatory processes are present in the Rett syndrome brain and are altered by normal aging, we investigated the density of cholinergic vesicular transporters in (i) the brains of Rett syndrome patients, and (ii) young and old rats with experimentally-induced cholinergic cell loss. In Rett syndrome, a significant decline in choline acetyltransferase activity within the putamen and thalamus was directly correlated with a decline in [3H]vesamicol binding. In both young and old rats, basal forebrain lesions decreased cortical choline acetyltransferase activity significantly, while [3H]vesamicol binding was unchanged. In contrast to young and old lesioned rats and patients with Alzheimer's disease, cholinergic cells in the brains of patients with Rett syndrome do not compensate for the loss of cholinergic cells by increasing acetylcholine vesicular storage.

Vitamin A modulation of xenobiotic-induced hepatotoxicity in rodents.

Vitamin A (VA, retinol) has been shown to modulate cells of the immune system. When rats are pretreated with VA (75 mg/kg/day) for 7 days, there is greatly potentiated liver damage upon subsequent exposure to hepatotoxicants such as CCl4. This potentiated damage can be blocked by superoxide dismutase or catalase, suggesting that reactive oxygen species are playing a major role in the increased liver injury. The studies reported here examined VA-induced modulation of CCl4 hepatotoxicity in different strains of male rats, female rats, and different strains of male mice. Also, the role of VA-induced weight loss on potentiation of CCl4 injury was investigated. Rats or mice were dosed with VA (retinol) at 75 mg/kg/day, po, for 7 days. In an additional VA dose-response study, mice were given VA at 18.8, 37.5, or 75 mg/kg/day, po, for 7 days. On day 8 they were given a dose of CCl4 which elicited mild hepatic damage. On day 9 they were necropsied. Male and female Sprague-Dawley rats, and male Fischer-344 and athymic nude rats pretreated with VA had an approximately 10-fold increase in liver damage as compared to vehicle controls. Pretreatment of male Balb/C, C3H/HeJ, Swiss-Webster, or athymic nude mice resulted in a marked reduction of CCl4-induced hepatic damage. In the dose-response study in mice, increasing doses of VA elicited increasing amounts of protection from CCl4-induced liver injury. Paired feeding studies revealed that VA-induced weight loss (or decreased weight gain) had no effect on subsequent VA-induced potentiation (rats) or protection (mice) from hepatic damage caused by CCl4.(ABSTRACT TRUNCATED AT 250 WORDS)

Results and patterns of perioperative myocardial infarction.

Myocardial injury during a variety of cardiac surgical operations was determined in 57 patients by serial electrocardiograms (ECG's), serial determinations of serum creatine phosphokinase (CPK), and perioperative and postoperative technetium-99m stannous pyrophosphate (PYP) scans. ECG evidence of injury developed in four patients, whereas positive localized injury by PYP scan developed in ten. Twenty-one patients had elevated CPK enzymes postoperatively. The localization of injury by PYP scan correlated with ECG evidence of infarction in only one of four patients. Localized left ventricular injury by PYP scan without new Q waves on the ECG was common (5/12) in patients undergoing aortic valve replacement with perfusion of the coronary arteries. The injury in patients with congenital heart disease occurred at sites of ventricular incision or suggested possible air embolization of the coronary arteries. Perioperative infarction is frequently segmental and nontransmural and occurs in patients with coronary, valvular, and congenital heart disease.

Nitric oxide formation does not underlie the memory deficits produced by ibotenate injections into the nucleus basalis of rats.

Basal forebrain (BF) injections of ibotenic (IBO) acid impair memory, whereas quisqualic (QUIS) acid injections do not. The authors investigated whether the cytotoxicity and differential behavioral effects of IBO and QUIS in rats depend on the generation of nitric oxide (NO). Injections of IBO or sodium nitroprusside (NP), but not QUIS, significantly increased BF NO formation, as determined by guanosine 3,5-cyclic monophosphate levels. IBO, alone or coinjected with methylene blue (MB), and QUIS, alone or coinjected with NP, decreased cortical choline acetyltransferase (ChAT) activity and the number of ChAT-positive BF neurons. The BF levels of galanin or neuropeptide Y were unchanged in all lesion groups. QUIS, but not IBO, dose-dependently destroyed NO-producing BF cells. Injections of IBO, with or without MB, impaired choice accuracy in a T-maze alternation task. The results suggest that the generation of NO in the BF does not underlie the spatial working memory deficit produced by IBO.

Investigations of neurotoxicity and neuroprotection within the nucleus basalis of the rat.

The present study investigated the specific ways by which cytotoxicity due to glutamate receptor stimulation could be attenuated by the administration of agonists and antagonists of the ionotropic and metabotropic glutamate receptors within the nucleus basalis magnocellularis (NBM) of rats as measured by cortical choline acetyltransferase activity. The results of these studies suggest that (1) the cytotoxicity of ibotenate to NBM cholinergic cells is not dependent upon stimulation of metabotropic glutamate receptors, but results from activation of N-methyl-D-aspartate (NMDA) receptors, (2) the cytotoxicity of quisqualate to cholinergic cells within the NBM is not dependent upon stimulation of NMDA or metabotropic receptors, and (3) the cytotoxicity of NMDA was prevented by administration (i.p.) of the un-competitive NMDA antagonist memantine (30 mg/kg), resulting in plasma levels of 2.5 micrograms/ml, a concentration known to block efficiently NMDA receptors in vitro. Finally, performance of a food-motivated, delayed-alternation task on a T-maze was impaired by injections of NMDA into the NBM, but was prevented by co-administration of NMDA with memantine.

Effects of excitatory amino acid lesions upon neurokinin B and acetylcholine neurons in the nucleus basalis of the rat.

The nucleus basalis magnocellularis (NBM) contains cholinergic neurons that project to the neocortex and is densely innervated by excitatory amino acid-containing terminals. A dysfunction in the balance of excitatory inputs or an alteration in the sensitivity of NBM cells to glutamate may underlie the selective vulnerability to aging. Some large NBM neurons contain neurokinin B (NKB) mRNA. The present study investigated whether alpha-2-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA) or N-methyl-D-aspartate (NMDA) differentially destroy NKB-containing, NKB-receptive, or cholinergic NBM cells, and whether this vulnerability is altered by aging. Injections of AMPA or NMDA significantly decreased neocortical ChAT activity, as compared to control levels, across all three age groups, with no interaction between lesion and age group. The results of in situ hybridization histochemistry and NKB receptor studies suggest that NKB-containing neurons in the NBM, and the neurons they innervate, are not vulnerable to NMDA or AMPA in either young or old rats. While NKB mRNA-positive cells were diffusely distributed throughout the basal forebrain, only a small proportion of the large NBM cells contained NKB mRNA. The results suggest that NKB does not extensively colocalize with acetylcholine within the basal forebrain of rats and that NBM NKB neurons do not directly innervate cholinergic cells.

MK-801, memantine and amantadine show neuroprotective activity in the nucleus basalis magnocellularis.

The activation of glutamate receptors by endogenuous glutamate has been implicated in the processes that underlie cell loss associated with ischemia and trauma and in the development of some neurodegenerative diseases. The antagonism of NMDA-sensitive glutamate receptors may therefore have therapeutic applications. The present study compared the side effects and neuroprotective potency of 1-aminoadamantane hydrochloride (amantadine), 1-amino-3,5-dimethyladamantane hydrochloride (memantine), and (+)-5-methyl-10,11-dihydro-5H-debenzocyclhepten-5,10-imine maleate ((+)-MK-801) against NMDA injected directly into the nucleus basalis magnocellularis of rats. Each drug significantly attenuated the loss of nucleus basalis magnocellularis cholinergic cells. The ED50s were respectively 0.077, 2.81 and 43.5 mg/kg for (+)-MK-801, memantine and amantadine, giving a relative potency ratio of 1:36:565. The ratio of the ED50 for the side effects observed, including ataxia, myorelaxation and stereotypy, and the ED50 for neuroprotective ability, was highest for memantine and the lowest for (+)-MK-801. The results suggest that a potential neuroprotective action of NMDA receptor antagonists, memantine and amantadine in particular, can be seen at low doses lacking side effects.

In vitro growth suppression by adenoviral transduction of p21 and p16 in squamous cell carcinoma of the head and neck: a research model for combination gene therapy.

OBJECTIVES: To determine the duration of expression of the cell cycle regulators p21 and p16 and the effect of these 2 genes both alone and in combination on the growth of squamous cell carcinoma of the head and neck cell lines in vitro. EXPERIMENTAL METHODS AND DESIGN: Cells were transduced via an adenoviral vector with p21 (Ad5CMV-p21), p16 (Ad5CMV-p16), or both. Western blotting was performed to determine duration of expression of the protein products of the transduced p21 and p16 genes. In vitro growth assays and cell cycle analyses were performed on transduced cells. RESULTS: Transduced gene products were detected up to day 12 after infection. Western blotting showed high levels of p21 and p16 in transduced cells. Growth suppression was observed in squamous cell carcinoma of the head and neck cell lines transduced with Ad5CMV-p21, Ad5CMV-p16, or both, but the combination of p21 and p16 did not achieve significantly greater growth suppression than that seen in cells transduced with Ad5CMV-p16 alone. Cell cycle analysis demonstrated that the percentage of cells arrested at G1 stage in the cells transduced with Ad5CMV-p16 was similar to that in the cells transduced with both Ad5CMV-p21 and Ad5CMV-p16. No significant in vivo growth suppression was observed in tumor nodules treated with Ad5CMV-p16. CONCLUSIONS: Although p21 and p16 are believed to function as cell cycle regulators of cyclin-dependent kinases, we observed no additive or synergistic effect when using them in combination. The expression of transduced p21 and p16 gene products up to days 9 and 12, respectively, was consistent with the growth suppression and cell cycle arrest observed. This work provides information on the previously uncharacterized duration of p21 and p16 transgene product expression and also lends insight into the interaction of these 2 cell cycle regulators in squamous cell carcinoma of the head and neck.

Gene therapy for head and neck cancer. Comparing the tumor suppressor gene p53 and a cell cycle regulator WAF1/CIP1 (p21).

OBJECTIVE: To compare the efficacy of the tumor suppressor gene wild-type p53 with that of cell-cycle regulator WAF1/CIP1 as single-agent gene therapy for squamous cell carcinoma of the head and neck. EXPERIMENTAL METHODS AND DESIGN: Recombinant cytomegalovirus-promoted adenoviruses containing the wild-type p53 or WAF1/CIP1 (p21) genes were transiently introduced into squamous cell carcinoma of the head and neck cell lines. Standard Western blot analysis was used to determine expression in these cells of the proteins encoded by these genes. A nude mouse xenograft model of squamous cell carcinoma of the head and neck was used to investigate the in vivo efficacy of the repeated gene therapy interventions. RESULTS: Western blot analysis showed marked induction of the WAF1/CIP1 tumor suppressor gene product by both the p21 adenovirus and the wild-type p53 adenovirus (as a secondarily transcribed product). In vitro growth curves demonstrated that the wild-type p53 adenovirus significantly inhibited cell growth in these cell lines, whereas direct induction of the p21 gene product did not. Repeated infection with wild-type p53 adenovirus significantly reduced the size of established subcutaneous tumors, whereas infection with a replication-defective viral control did not. CONCLUSION: Wild-type p53 adenovirus exhibits substantial in vitro and in vivo tumor suppressor activity in squamous cell carcinoma of the head and neck cell lines. This tumor suppression is not a function of the induced WAF1/CIP1 (p21) transcriptional product. Further studies are required to investigate the potential for induction of apoptosis by gene therapy.

Cochlear implantation in patients with compromised healing.

BACKGROUND: The indications for cochlear implantation (CI) are continually evolving and, as experience accumulates, the relative contraindications for CI continue to decrease. However, there is little information regarding CI in patients who may be considered to be at risk for poor wound healing due to immunosuppression or intercurrent disease. OBJECTIVE: To assess and report the complication rates, postoperative course, postimplant rehabilitation, and long-term performance of patients considered at risk due to presumably impaired healing capability. We hypothesized that these patients had outcomes similar to other implanted patients. METHODS: This is a retrospective chart review of 277 patients who have received CI at the University of Miami Ear Institute between 1990 and 1999. The clinical courses of 6 patients on immunosuppressive medications and 7 patients with diseases believed to be associated with poor healing are reported. RESULTS: Long-term follow-up (mean, 33 months) showed postoperative complication rates, performance, and rehabilitation compliance that were similar to published reports of noncompromised patients. CONCLUSION: CI of selected patients with potentially reduced healing capabilities is safe and effective.

Reactive oxygen species in the progression of CCl4-induced liver injury.

Pretreatment of rats with large doses of vitamin A (retinol) dramatically increased the hepatotoxicity of carbon tetrachloride (CCl4). Experiments were performed to elucidate the mechanism of this potentiation. Hypervitaminosis A was produced by oral administration of retinol, 250,000 IU/kg for seven days. CCl4 was then administered at a dose of 0.15 ml/kg, ip. This large dose of vitamin A did not enhance the biotransformation of CCl4, but did produce a 4-fold increase in CCl4-induced lipid peroxidation, as assessed by ethane exhalation. Because vitamin A has been shown to activate macrophages, it was hypothesized that this increased lipid peroxidation and liver injury resulted from the release of reactive oxygen species from activated Kupffer cells. By using a chemiluminescence assay, an enhanced release of free radicals was detected in Kupffer cells isolated from vitamin A pretreated rats. In addition, Kupffer cells from vitamin A pretreated rats displayed enhanced phagocytic activity in vitro, towards sheep red blood cells. In vivo, vitamin A pretreated rats cleared carbon particles from the blood 2-3 times faster than non-pretreated rats. In vivo administration of superoxide dismutase (SOD) 2 hr after CCl4 exposure did not influence CCl4 toxicity in control rats but did block the enhanced ethane exhalation and also the potentiation of CCl4 liver injury in vitamin A treated rats. Administration of methyl palmitate, an inhibitor of Kupffer cell function, did not inhibit CCl4 toxicity in control rats, but did effectively block enhanced ethane exhalation and potentiation of CCl4 injury in vitamin A treated rats. We conclude that potentiation of CCl4 hepatotoxicity by hypervitaminosis A is mediated in part by reactive oxygen species released from activated Kupffer cells.

Patterns of maxillofacial injuries in powered watercraft collisions.

Because of the widespread popularity of water sports, plastic and reconstructive surgeons can expect to manage an increasing number of injuries associated with these activities, particularly those related to powered watercraft vehicles. Although seat belts for motorists and helmets for motorcyclists may be efficacious, such devices currently do not serve a similar role in powered watercraft sports. In this study, a retrospective chart review of 194 consecutive patients who presented to the University of Miami/Jackson Memorial Hospital (Level I trauma center) as a result of powered watercraft collisions is presented. The purpose of this investigation was to assess the incidence, cause, demographics, and available management options for head and neck injuries secondary to powered watercraft. Identified were 194 patients who presented because of watersports-related injuries during the period January 1, 1991, through December 31, 1996. From this group, 81 patients (41.8 percent) sustained injuries directly attributable to powered watercraft collisions, including 41 personal watercraft collisions (50.6 percent), 39 boat collisions (48.1 percent), and 1 airboat collision (1.2 percent). The patient population, as expected, tended to be young and male with an average age of 29 years (range, 8 to 64 years old). Interestingly, 41 of the patients (50.6 percent) who presented to this trauma center as a result of powered watercraft collisions also sustained associated head and neck trauma. Of 74 injuries 24 were facial fractures (32.4 percent), 18 were facial lacerations (24.3 percent), 14 were closed head injuries (18.9 percent), 8 were skull fractures (10.8 percent), 4 were scalp lacerations (5.4 percent), 4 were C-spine fractures (5.4 percent), 1 was an ear laceration (1.4 percent), and 1 was a fatality (1.4 percent). Le Fort fractures were the most commonly identified facial fracture in this series. The number of these injuries seen in hospital emergency rooms will most likely increase in the future as the popularity of water-related recreational activities becomes even more widespread. Based on these findings, it is strongly recommended that future efforts be directed toward the prevention of these injuries through patient education and the eventual development of efficacious and safe protective equipment.

Treatment of neonatal necrotizing tracheobronchitis with extracorporeal membrane oxygenation and bronchoscopy.

Necrotizing tracheobronchitis has recently been described as a complication of mechanical ventilation of newborns with respiratory failure. Despite the use of bronchoscopy, 45% of the reported patients to date have died. In this study, we report the use of extracorporeal membrane oxygenation (ECMO) to stabilize two patients with necrotizing tracheobronchitis. While supported by bypass, both patients underwent prolonged bronchoscopies with removal of extensive amounts of tracheal debris. ECMO provided efficient oxygenation in the face of near total airway occlusion, and permitted far more extensive bronchoscopic debridement and lavage than would have been possible if the lungs were required for oxygenation. In addition, ECMO provided a period of lung "rest" during which ventilator settings were reduced, thus minimizing further barotrauma and allowing for lung and airway healing. Both patients recovered without significant respiratory sequelae. ECMO and bronchoscopy are effective forms of therapy for patients with life-threatening necrotizing tracheobronchitis when conventional modalities of treatment have failed.

Relationship among weight change, body condition and reproductive performance of range beef cows.

A 5-yr study involving 45 to 78 pregnant Hereford range cows each year evaluated relationships among prepartum nutrition, body condition scores, BW changes and reproductive performance. Four prepartum nutritional treatments were imposed. One group of cows were fed to maintain (M) their November BW until calving in March and April. The other three groups of cows were fed to lose about 5% of their November BW by 8 wk before parturition, then to maintain BW (LM), lose an additional 5% of their BW (LL) or gain 5% of their BW (LG). After calving, all cows were fed to maintain BW. Body condition scores and BW were recorded every 14 d throughout the trial. Linear regression analyses were conducted to examine treatment effects on BW, body condition score and measures of reproductive performance. A discriminant analysis was performed on pregnancy rate and percentage of cows with ovarian luteal activity by 85 d after parturition. The M cows had a greater pregnancy rate (71%) than cows on other treatment groups. The LL cows had a reduced pregnancy rate (42%) compared with LM (51%) and LG (58%) cows. Prepartum nutritional treatment did not affect the days from parturition to conception. Precalving body condition score and November to January BW changes influenced pregnancy rate (P less than .001). A cubic response curve described the relationship between pregnancy rate and precalving body condition score for cows with condition scores of 3 through 7.(ABSTRACT TRUNCATED AT 250 WORDS)

Bilateral peritonsillar abscess: case report and presentation of its clinical appearance.

Although there is no consensus on its incidence, bilateral peritonsillar abscess is an unusual variant of an otherwise relatively common otolaryngologic disease. A bilateral peritonsillar abscess can be differentiated from other oropharyngeal pathology with a detailed physical examination and complementary imaging. Its diagnosis should always be considered in patients who have signs and symptoms that are suggestive of peritonsillar abscess but whose intraoral examination yields atypical findings, as well as in patients with marked distress or trismus. This article describes the case of a young man who came to the emergency room with bilateral peritonsillar abscess. The author believes that this report contains the only published photograph of the intraoral appearance of this condition.

Repair of a large septal perforation with a radial forearm free flap: brief report of a case.

We treated a 38-year-old man who had a large septal perforation that had been caused by chronic nasal inhalation of cocaine. We were able to repair the perforation with a left radial forearm free flap. Long-term followup indicates a successful closure of the defect and a natural thinning of the flap. The patient remains symptom-free more than 2 years following surgery.

Unraveling the complex nature of prostate cancer stem cells.

The identification of distinct prostate cancer stem cell biomarkers is necessary as researchers attempt to isolate, characterize, and therapeutically target these tumor initiating cells. However, in reading the current literature it is frequently difficult to discern which biomarkers and cellular characteristics identify prostate cancer stem cells as opposed to the general population of prostate cancer cells or normal prostate stem cells. Within this review, we address this issue by dissecting out the cell surface markers, adhesion and cytoskeletal proteins, signaling pathways, epigenetic modifications, and the effects of androgens that are specific to and help to define the prostate cancer stem cell.

Modulation of 1,2-dichlorobenzene hepatotoxicity in the Fischer-344 rat by a scavenger of superoxide anions and an inhibitor of Kupffer cells.

The hepatotoxicity of 1,2-dichlorobenzene (1,2-DCB) was studied in Fischer-344 (F344) rats administered methyl palmitate (MP) to inhibit Kupffer cell function or superoxide dismutase (conjugated to polyethylene glycol, i.e., PEG-SOD) to scavenge superoxide anions. In rats not pretreated with phenobarbital (PB), administration of either MP or PEG-SOD dramatically reduced the severity of 1,2-DCB-induced liver injury. Both agents reduced the elevations in plasma ALT activities by 80%. PEG-SOD conferred protection when administered 2 hr before or 2 hr after 1,2-DCB. Light microscopic examination of H & E-stained liver sections confirmed that the reductions in plasma ALT activities reflected protection from hepatocellular injury. Interestingly, MP did not protect against 1,2-DCB-induced hepatotoxicity in PB-pretreated rats. The degree of inhibition of 1,2-DCB hepatotoxicity by PEG-SOD in PB-pretreated animals was also less than that in normal rats and was not significantly different. The lack of a significant inhibition of the PB-potentiated hepatotoxicity by both PEG-SOD and MP suggests that reactive oxygen species released from a nonparenchymal source were not as crucial to the 1,2-DCB hepatotoxicity in the PB-pretreated rats as in the normal rats. Our results using both MP and PEG-SOD support the hypothesis that reactive oxygen species released from Kupffer cells play a major role in the progression of 1,2-DCB hepatotoxicity in the F344 rat.