Actions of tacrine and galanthamine on histamine-N-methyltransferase.

Histamine-synthesizing neurons in the brain may play an important role in cognition, and a histaminergic deficit has been found in Alzheimer's disease (AD). The AD medication tacrine was previously shown to inhibit some forms of rodent histamine-N-methyltransferase (HNMT), but the effects of AD drugs have not been investigated on human HNMT activity. Presently, the effects of tacrine and galanthamine (another AD medication) were studied on the activity of several forms of human and rat HNMT. Tacrine (0.01-10 microM) inhibited both human and rat HNMT activity in a concentration-dependent manner, but was less potent on both human embryonic kidney and recombinant human brain HNMT than on rat kidney HNMT (IC50 values were 0.46 and 0.70 microM vs. 0.29 microM, respectively). Galanthamine (up to 10 microM) did not influence the activity of rat kidney or human HNMT. Tacrine, but not galanthamine, may achieve brain levels sufficient to influence histamine metabolism in some patients treated for AD.

Salivary gland lesions: a Jamaican perspective.

A retrospective analysis of the spectrum and relative frequency of salivary gland lesions diagnosed in the Department of Pathology, University of the West Indies, Kingston, Jamaica, between 1965 and 1994, is reported. Four hundred and sixty-four salivary gland biopsies were received. Of these 99 (21.3%) were non-neoplastic and the remaining 365 (78.7%) were neoplasms: 261 (71.5%) were benign and 104 (28.5%) malignant. Benign mixed tumour (BMT)/pleomorphic adenoma (PA) was the most common neoplasm (63.3%) while mucoepidermoid carcinoma (MEC) was the most common malignant neoplasm (9.6%), followed by adenoid cystic carcinoma (ACC) (7.4%). The increased frequency of MEC over ACC is at variance with other reported series but the preponderance of pleomorphic adenoma is consistent. In the major salivary glands, benign neoplasms predominate at a ratio of 3:1, while a higher proportion of minor salivary gland neoplasms was malignant, ratio 1.2:1 (p = 0.003). These data represent the first attempt to document the spectrum of disease related to oral and maxillofacial pathology in Jamaica.

Salivery gland lesions: a Jamaican perspective

A retrospective analysis of the spectrum and relative frequency of salivary gland lesions diagnosed inthe Department of Pathology, University of the West Indies, Kingston, Jamaica between 1965 and 1994, is reported. Four hundred and sixty-four salivary gland biopsies were received. Of these 99 (21.3 percent) were non-neoplastic and the remaining 365 (78.7 percent) were neoplasm: 261 (71.5 percent) were benign and 104 (28.5 percent) malignant. Benign mixed tumour (BTM)/ pleomomorphic adenoma (PA) was the most common neoplasm (63.3 percent) while mucoepidermoid carcinoma (MEC) was the most common malignant neoplasm (9.6 percent), followed by adenoid cystic carcinoma (ACC) (7.4 percent). The increased frequency of MEC over ACC is at variance with other reported series but the preponderance of pleomorphic adenoma is consistent. In the major salivary glands, benign neoplasms predominate at a rotio of 3:1, while a higher proportion of minor salivary gland neoplasms was malignant, ratio 1.2:1 (p=0.003). These data represent the first attemp to document the spectrum of disease related to oral and maxillofacial pathology in jamaica. (AU)

Salivary gland lesions: a Jamaican perspective

A retrospective analysis of the spectrum and relative frequency of salivary gland lesions diagnosed in the Department of Pathology, University of the West Indies, Kingston, Jamaica, between 1965 and 1994, is reported. Four hundred and sixty-four salivary gland biopsies were received. Of these 99 (21.3) were non-neoplastic and the remaining 365 (78.7) were neoplasms: 261 (71.5) were benign and 104 (28.5) malignant. Benign mixed tumour (BMT)/pleomorphic adenoma (PA) was the most common neoplasm (63.3) while mucoepidermoid carcinoma (MEC) was the most common malignant neoplasm (9.6), followed by adenoid cystic carcinoma (ACC) (7.4). The increased frequency of MEC over ACC is at variance with other reported series but the preponderance of pleomorphic adenoma is consistent. In the major salivary glands, benign neoplasms predominate at a ratio of 3:1, while a higher proportion of minor salivary gland neoplasms was malignant, ratio 1.2:1 (p = 0.003). These data represent the first attempt to document the spectrum of disease related to oral and maxillofacial pathology in Jamaica.

Effects of selected histamine H3 receptor antagonists on tele-methylhistamine levels in rat cerebral cortex.

The H3 antagonist thioperamide is thought to act on brain H3 autoreceptors to increase both the release and metabolism of neuronal histamine (HA). Our studies investigated the effects of several new brain-penetrating H3 antagonists on rat cerebral cortical levels of the HA metabolite tele-methylhistamine (t-MH). Animals were pretreated with H3 antagonists (0.3 to 30 mg/kg; 1-4 hr; i.p.) in the presence or absence of the monoamine oxidase inhibitor pargyline to prevent metabolism of t-MH. Cortical t-MH levels were measured by both radioimmunoassay (RIA) and gas chromatography-mass spectrometry (GC-MS). Pargyline (60 mg/kg; 1 hr; i.p.) produced an approximately 2-fold increase in t-MH levels as measured by either GC-MS or RIA. Thioperamide (+/- pargyline) increased t-MH levels as measured by both GC-MS and RIA. In contrast, neither 5-cyclohexyl-1-(4-imidazol-4-ylpiperidyl)pentan-1-one (GT-2016) (+/- pargyline), 4-(6-cyclohexylhex-cis-3-enyl)imidazole (GT-2227) (+/- pargyline), nor clobenpropit (minus pargyline) increased t-MH levels as measured by GC-MS. A good agreement was found between t-MH levels as determined by either RIA or GC-MS except after treatment with GT-2016, which increased apparent t-MH brain levels according to the former but not the latter method. Subsequent studies suggest the in vivo formation of a GT-2016 metabolite, which can cross-react in the t-MH RIA. Although all H3 receptor antagonists studied to date seem capable of enhancing brain HA release, only thioperamide presently was found to enhance cortical t-MH levels. Thus, H3 receptor antagonists may differentially affect HA release and turnover, and brain t-MH levels may not be reliable predictors of H3 agonist, partial agonist, or antagonist in vivo activity.

Sex differences in ibogaine antagonism of morphine-induced locomotor activity and in ibogaine brain levels and metabolism.

The present study demonstrates that the putative antiaddictive agent ibogaine produces more robust behavioral effects in female than in male rats and that these behavioral differences correlate with higher levels of ibogaine in the brain and plasma of female rats. There were no differences in basal locomotor activity between the sexes, and the response of rats to ibogaine differed between the sexes even in the absence of morphine. Five h after receiving ibogaine (40 mg/kg, i.p.). antagonism of morphine-induced locomotor activity was evident in female but not in male rats. Either 19 h after administration of ibogaine (10-60 mg/kg, i.p.), or one h after administration of noribogaine (5-40 mg/kg, i.p.), a suspected metabolite, antagonism of morphine was significantly greater in female than in male rats. Brain and plasma levels of ibogaine (1 h) and noribogaine (5 h), measured by gas chromatography-mass spectrometry, were greater in females as compared with males receiving the same dose of ibogaine. Levels of both ibogaine and noribogaine were substantially lower at 19 h than at earlier times after ibogaine administration, contrary to a previous study in humans. For both sexes, subcutaneous administration of ibogaine (40 mg/kg, i.p., 19 h) produced greater antagonism of morphine-induced locomotor activity than did a comparable intraperitoneal injection, consistent with previous studies from this laboratory demonstrating that the former route of administration produces higher levels of ibogaine in the brain. These data show that there are sex differences in the effects of ibogaine and that this may be due to decreased bioavailability of ibogaine in males as compared to females.

Changes in inflammatory mediators in experimental periodontitis in the rhesus monkey.

Ligature-induced periodontitis was monitored for 6 months in eight Macaca mulatta monkeys to examine clinical status, radiographic bone level, and crevicular fluid (CF) levels of prostaglandin E2 (PGE2), thromboxane B2 (TxB2), interleukin-1 beta (IL-1 beta), tumor necrosis factor alpha, and leukotriene B4 (LTB4). A split-mouth design was used, with eight ligated teeth and eight contralateral nonligated teeth which develop soft-chow-promoted (spontaneous) disease. Ligated sites experienced an average attachment loss of 0.94 mm per site and linear bone loss of 0.88 mm per site, with spontaneous-periodontitis sites experiencing approximately half the loss of ligated sites. The CF mediator levels showed increased levels of PGE2 and TxB2 at the ligated sites, as compared with the spontaneous sites, with no significant contralateral differences in the IL-1 beta or LTB4 responses. The concentrations of LTB4 in CF reached an early threefold peak over the baseline level at 1 month. By 2 months there was a statistically significant threefold elevation in CF-PGE2 in the ligated sites and a twofold elevation in the spontaneous sites as compared to the baseline level (P = 0.041 and 0.008, respectively). The monocyte product IL-1 beta increased sharply at 2 months and returned to the baseline level by 6 months at both ligated and nonligated sites. Tumor necrosis factor alpha in CF was below the limit of detection at all sites throughout the experiment (i.e., < 2 ng/ml). The selective elevation of both PGE2 and TxB2 in ligated sites, compared with levels in spontaneous sites, in the presence of similar levels of LTB4 and IL-1 beta provides further evidence that these molecules regulate the magnitude of the tissue-destructive response in progressive periodontitis.

Solitary infantile myofibromatosis of the mandible. Report of three cases.

Infantile myofibromatosis (IMF) is a benign localized (solitary) or generalized (multicentric) proliferation of fibroblastic tissue occurring exclusively in infants and children. Three cases of solitary IMF involving the posterior region of the mandible of young children are reported. These lesions manifested clinically as asymptomatic bony expansion and roentgenographically as circumscribed lytic areas. Microscopically these tumors showed a distinct zoning phenomenon of curving bundles or intertwining fascicles of plump, spindle-shaped cells at the periphery and solid sheets of less differentiated round cells in the center. Positive immunostaining for vimentin and actin, with the lack of desmin and S-100 protein reactivity, confirmed their myofibroblastic nature of these cells and supported the diagnosis of IMF. All three lesions were treated by curettage and the follow-up showed no incidence of recurrence or any other complications. As we demonstrate in these case reports, IMF should be included in the differential diagnosis of spindle cell neoplastic processes in children.

Ulcerative cholecystitis produced by 3-nitro-4-hydroxy-phenylarsonic acid toxicosis in turkey poults.

Naturally occurring ulcerative cholecystitis was present in a flock of 21-day-old turkey hens that were accidentally given at least 0.004% 3-nitro-4-hydroxy-phenylarsonic acid (3-NITRO) in their water for 2 days. Similar lesions were reproduced by administering 0.002% 3-NITRO to 2-day-old turkey poults for 6 days. Turkeys 31 days old were given up to 0.004% 3-NITRO in their water for 6 days, but no gall bladder ulcers were present in these poults. The toxicity to turkeys of 3-NITRO in the water appears to be age-dependent.

Effect of acute hypoxia and hypercapnic acidosis on the development of acetylstrophanthidin-induced arrhythmias.

The effect of acutely induced hypoxia, hypercapnic acidosis, and the combination of the two on the amount of acetylstrophanthidin (AS) required to produce cardiac arrhythmias was determined in anesthetized dogs. Each animal was studied during ventilation with room air and again during ventilation with gas mixtures of appropriate concentrations; 24 hr separated the study periods. AS was infused intravenously at a rate of 5 mug/kg per min. Significantly less AS was required to produce arrhythmias during hypoxia and hypercapnic acidosis together than during the period with normal arterial Po(2), Pco(2), and pH (10 animals). Included in this group were two animals which had undergone previous bilateral adrenalectomy and four animals in which heart rate was maintained at the same frequency during both study periods. A significant reduction in the toxic dose of AS also was demonstrated in eight animals, two with constant heart rate, during hypoxia with normal arterial Pco(2) and pH. Hypercapnic acidosis alone (eight animals) did not significantly alter the toxic dose of AS. After the administration of propranolol (six animals) or hexamethionium (six animals), no significant difference was observed between the toxic dose of AS during hypoxia and that during ventilation with room air. Thus although hypoxia and hypercapnic acidosis together do reduce the amount of AS required to produce arrhythmias, it is the hypoxia which exerts the predominant effect on the development of this increased sensitivity to AS. Furthermore, this effect of hypoxia occurs primarily as a result of reflexly augmented sympathetic stimulation of the heart.

Left ventricular function in patients with chronic obstructive pulmonary disease.

Left ventricular function was assessed in six patients with essentially normal cardiopulmonary function, in five patients with primary myocardial disease, and in 16 patients with chronic obstructive pulmonary disease by determining the response of the ventricle to an increased resistance to ejection. Studies were performed at the time of cardiac catheterization and increased resistance to left ventricular ejection was produced by the intravenous infusion of methoxamine. In the control patients, methoxamine produced an increase in stroke volume index (SVI), in stroke work index (SWI), and stroke power index (SPI), whereas left ventricular end-diastolic pressure (LVEDP) increased only moderately. In contrast SVI, SWI, and SPI fell, whereas LVEDP increased inordinately in the patients with myocardiopathy. The patients with chronic obstructive pulmonary disease responded to the infusion with an increase in SVI, SWI, SPI, and LVEDP comparable to the control patients. Furthermore, in this latter group of patients, a quantitatively similar response was observed in those with essentially normal resting hemodynamics, in those with resting pulmonary hypertension, and in those whose disease had progressed to the stage of right ventricular failure. This study provides no evidence that chronic obstructive pulmonary disease results in chronic impairment of left ventricular function, but on the contrary, has demonstrated that the left ventricle responds normally to an increased pressure load in these patients.