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.

A third life for burimamide. Discovery and characterization of a novel class of non-opioid analgesics derived from histamine antagonists.

Burimamide, a histamine (HA) derivative with both H2- and H3-blocking properties, induces antinociception when injected into the rodent CNS. Several related compounds share this property, and structure-activity studies have shown that this new class of analgesics is distinct from known HA antagonists. The prototype, named improgan, shows a preclinical profile of a highly effective analgesic, with activity against thermal, mechanical and inflammatory nociception after doses that do not alter motor balance or locomotor activity. Improgen analgesia is not blocked by opioid antagonists and is observed in opioid receptor knock-out mice. Unlike morphine, improgan does not induce tolerance after daily dosing. Extensive in vitro pharmacology studies have excluded known histaminergic, opioid, serotonergic, GABAergic and adrenergic receptor mechanisms, as well as 50 other sites of action. The improgan-like analgesic activity of some HA congeners suggests an analgesic action on a novel HA receptor, but further studies are required to substantiate this. Studies in progress are characterizing the sites and mechanisms of action of improgan, and developing brain-penetrating derivatives that could be useful for clinical pain.

Epidemiologic evidence for a causal relation between vaccination and fibrosarcoma tumorigenesis in cats.

Within the past 2 years, a putative causal relationship has been reported between vaccination against rabies and the development of fibrosarcomas at injection sites in cats. A retrospective study was undertaken, involving 345 cats with fibrosarcomas diagnosed between January 1991 and May 1992, to assess the causal hypothesis. Cats with fibrosarcomas developing at body locations where vaccines are typically administered (n = 185) were compared with controls (n = 160) having fibrosarcomas at locations not typically used for vaccination. In cats receiving FeLV vaccination within 2 years of tumorigenesis, the time between vaccination and tumor development was significantly (P = 0.005) shorter for tumors developing at sites where vaccines are typically administered than for tumors at other sites. Univariate analysis, adjusted for age, revealed associations between FeLV vaccination (odds ratio [OR] = 2.82; 95% confidence interval [CI] = 1.54 to 5.15), rabies vaccination at the cervical/interscapular region (OR = 2.09; 95% CI = 1.01 to 4.31), and rabies vaccination at the femoral region (OR = 1.83; 95% CI = 0.65 to 5.10) with fibrosarcoma development at the vaccination site within 1 year of vaccination. Multivariate analysis, adjusted for age and other vaccines, also revealed increased risks after FeLV (OR = 5.49; 95% CI = 1.98 to 15.24) and rabies (OR = 1.99; 95% CI = 0.72 to 5.54) vaccination.(ABSTRACT TRUNCATED AT 250 WORDS)

Relationship of maternal to neonatal colonization with coagulase-negative staphylococci.

Infections with coagulase-negative staphylococci (C-S) have become problems of major clinical importance among very low birthweight infants in neonatal intensive care units. Colonization with slime-producing strains of C-S may be a risk factor for these infants in the development of invasive infections. The present study evaluated the maternal genital tract as a possible source for neonatal colonization with C-S. Specific objectives were to determine the incidence of vaginal colonization with C-S in pregnant women with special reference to slime-producing strains and whether transmission of C-S occurs from mother to infant during the process of vaginal delivery. Antenatal vaginal cultures were done on 465 women at different gestations of pregnancy. Additionally, 101 women and their newborn infants were cultured after vaginal delivery. Fifty-one percent of women were colonized with C-S during pregnancy, and no significant differences in colonization rates by trimester were found. Slime-positive isolates from pregnant women increased significantly from the first to the third trimester (40 to 68%; chi-square, 11.21, p less than 0.005). However, the proportion of slime-positive strains among the 30 infants who were colonized with C-S at birth was 40% (12 of 30). Although 30 infants were colonized with C-S at birth, only three were shown to have acquired the organism by maternal transmission determined by similarity of species, biotype, antibiotic sensitivity pattern, slime production, phage type, and plasmid pattern profile. Therefore 27 infants (26% of the total) most likely acquired C-S from environmental sources, including nursery attendants.(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation of coagulase-negative staphylococcal isolates from serial nasopharyngeal cultures of premature infants.

The present study was undertaken to determine whether very low birth weight infants in a neonatal intensive care unit became colonized with virulent strains of coagulase-negative staphylococci (C-S) over time (i.e., those characterized as Staphylococcus epidermidis, slime positive, and/or multiply antibiotic resistant), and if so, whether the initial colonizing strains developed these characteristics or whether the strains themselves changed. Nasopharyngeal (NP) cultures were obtained weekly on 28 very low birth weight (less than 1750 g) infants hospitalized for a mean of 8 wk (range 4-15 wk). There were 105 isolates of C-S recovered from 96 cultures that were characterized by species, biotype, antibiotic susceptibility pattern, and slime production (screening parameters). Isolates from the same infant with highly similar screening parameters then underwent phage typing and plasmid analysis to increase the likelihood of establishing strain identity. C-S colonization rose from 12% on admission to 75% by wk 2, then gradually declined to 30% by wk 6 and remained stable through wk 10. There were no significant differences among C-S isolates from wk 1 compared with wk 10 of hospital stay with respect to distribution of species, slime positive, or multiply antibiotic resistant strains. One biotype of S. epidermidis was recovered from 46% of study infants, but only one infant was colonized with a predominant biotype of S. epidermidis throughout hospitalization. Thirteen pairs of isolates recovered from 12 of the infants on two or more wk were found to be identical by phage typing and plasmid analysis. Only seven of these 13 pairs of isolates had concordant results for all the screening parameters.(ABSTRACT TRUNCATED AT 250 WORDS)

The emergency department diagnosis of Trichomonas vaginitis.

Trichomonas vaginalis is a common cause of vaginitis in emergency department patient populations. While the diagnosis of this condition is usually on the basis of wet-mount microscope slide preparations, other diagnostic technology exists. We studied the accuracy of the traditional wet-mount technique as compared with detection using direct immunofluorescence and culture techniques in ED patients with the presenting complaint of vaginal discharge. Of 157 patients evaluated, the wet-mount technique detected 27 cases of Trichomonas, compared with 35 cases diagnosed by direct immunofluorescence and 52 cases detected by culture. This represents a false-negative rate for the wet-mount technique of 51%; the false-negative rates for direct immunofluorescence and culture technique were 36% and 5%, respectively. Our study suggests that the wet-mount technique is relatively insensitive in the detection of Trichomonas vaginitis.

Septicaemia in a granulocytopenic patient caused by Corynebacterium striatum.

A 64 year old woman with metastatic endometrial carcinoma was admitted to the hospital after three grand mal seizures. Blood cultures yielded Corynebacterium striatum. The patient responded to parenteral ampicillin therapy. This is believed to be the first case of sepsis caused by this organism.

Molecular analyses of conjugative, gentamicin-resistance plasmids from staphylococcal clinical isolates.

Gentamicin-resistant Staphylococcus aureus and Staphylococcus epidermidis strains which were isolated from infants with staphylococcal bacteremia were analyzed for the presence of self-transmissible gentamicin-resistance (Gmr) plasmids. Conjugative GMr plasmids of approximately 43.8-63 kilobases (kb) were found in all S. aureus strains. Inter- and intra-species transfer of Gmr plasmids by conjugation was observed from S. aureus to S. aureus and to S. epidermidis recipient strains. However, neither inter- nor intra-species transfer of gentamicin resistance by conjugation was observed with nine out of nine S. epidermidis donor strains which were mated with either S. epidermidis or S. aureus recipient strains. These conjugative Gmr plasmids were unable to comobilize a smaller (15-kb) plasmid present in all but two S. aureus clinical isolates. Many of the conjugative Gmr plasmids also carried genetic determinants for kanamycin, tobramycin, neomycin, and ethidium bromide resistance, and for beta-lactamase synthesis. EcoRI restriction endonuclease digests of the S. aureus Gmr conjugative plasmids revealed three different digestion patterns. Four EcoRI restriction endonuclease digestion fragments of 15, 11.4, 6.3, and 4.6 kb in size were common to all plasmids. These plasmids and conjugative Gmr staphylococcal plasmids from other geographical regions shared restriction digestion fragments of similar molecular weights. DNA hybridization with biotinylated S. aureus plasmid pIZ7814 DNA revealed a high degree of homology among these plasmids. A 50.9-kb plasmid from one of the nonconjugative S. epidermidis clinical isolates showed homology with the probe DNA but lacked a portion of a 6.3-kb fragment which was present in all conjugative plasmids and believed to carry much genetic information for conjugation.

Colonization with slime-positive coagulase-negative staphylococci as a risk factor for invasive coagulase-negative staphylococci infections in neonates.

Mucocutaneous cultures obtained at admission and subsequent weekly nasopharyngeal cultures were obtained on 182 infants in the neonatal intensive care unit (NICU) over 3 months to assess whether a relationship existed between colonization with coagulase-negative staphylococci and invasive infection, particularly with respect to slime production. Nasopharyngeal colonization by coagulase-negative staphylococci occurred in a mean of 58% of infants weekly, with an equal prevalence of slime-positive and slime-negative isolates over time. Colonization of the nasopharynx on admission increased from 8.9% of those admitted within the first day of life to 33% of those admitted thereafter (p less than 0.005). The presence of slime-positive coagulase-negative staphylococci on admission was not predictive of later patterns of colonization with respect to slime. Of infants not colonized on admission who had subsequent cultures, 72% became colonized with coagulase-negative staphylococci that were equally likely to be slime-positive or slime-negative. The incidence of invasive infections was 4.4%. Infants with slime-positive mucocutaneous colonization were more likely to develop invasive coagulase-negative staphylococci disease than infants with slime-negative or no colonization (8.4% versus 1.1%; p less than 0.025). The incidence of slime-positive coagulase-negative staphylococci isolates from blood cultures was 6/7 (86%) whereas those from mucocutaneous cultures was 131/260 (50%) (p = 0.06). Colonization with slime-positive coagulase-negative staphylococci is a significant risk factor for developing invasive coagulase-negative staphylococci disease and these organisms are responsible for the majority of coagulase-negative staphylococci invasive infections.

Enzymatic modification of glycocalyx in the treatment of experimental endocarditis due to viridans streptococci.

The presence of abundant surface polysaccharide, or glycocalyx, on viridans streptococci has been associated with failure to eradicate the organism from experimental cardiac vegetations during penicillin treatment. The role of glycocalyx in retarding sterilization was tested by in vivo administration of dextranase, an endohydrolase that attacks internally situated alpha (1-6) linkages. Dextranase and penicillin, either singly or in combination, were used to treat experimental endocarditis. After two days of therapy, 100% of animals treated with penicillin or dextranase alone had infected vegetations, whereas only 25% treated with penicillin and dextranase had infected vegetations (P less than .01). After five days of therapy, 100% of the animals treated with penicillin had infected vegetations, versus none that were treated with penicillin and dextranase (P less than .01). We conclude that glycocalyx acts to retard antibiotic activity in vegetations and that partial enzymatic digestion of the glycocalyx facilitates penicillin sterilization of the infected valve.

Characteristics of coagulase-negative staphylococci from infants with bacteremia.

Twenty-nine infants were identified as having coagulase-negative staphylococcal (C-S) bacteremia. Fourteen infants had pneumonia and 10 had central line-associated bacteremia. Twenty-four of 29 (83%) had invasion of the mucocutaneous barrier at the time the positive blood culture was drawn. Clinical signs and symptoms were nonspecific. Apnea/bradycardia was the most prevalent clinical feature, occurring in 20 (69%) infants. Staphylococcus epidermidis was the most frequent blood culture isolate, occurring in 21 (72%) cases. Slime production by C-S blood culture isolates occurred in 23 (79%) cases. There was no prevalent antibiotic resistance pattern, phage type or plasmid profile among blood culture isolates from infants with bacteremia. Mucocutaneous isolates of C-S from infants with bacteremia were compared with those from infants without invasive disease. Infants with bacteremia had a significantly higher percentage of slime-producing organisms (75% vs. 58%, P = 0.027) and a significantly higher percentage of S. epidermidis species (79% vs. 53%, P = 0.001) than isolates from infants without bacteremia. Our data support the relationship of slime production and the S. epidermidis species of C-S as virulence factors in infants with foreign bodies. Testing C-S for slime production is a relatively simple laboratory procedure which may be an additional aid in the evaluation of their clinical significance.

Endocarditis caused by beta-lactamase-producing Haemophilus influenzae.

We have described a case of tricuspid valve endocarditis caused by beta-lactamase-producing H influenzae that responded well to four weeks of cefamandole therapy.

Infective endocarditis of a bicuspid aortic valve caused by Hansenula anomala.

Infective endocarditis due to Hansenula anomala developed on a bicuspid aortic valve in a 40-year-old man. H. anomala, an ascomycetous yeast, may be a member of the normal flora of the throat and alimentary tract in humans but has not been previously known to be pathogenic in humans. A past history of intravenous drug use may have contributed to the development of disease in this patient.

Pulmonary aspergillosis and the importance of oxalate crystal recognition in cytology specimens.

A 62-year-old man, previously healthy but alcoholic, and who was clinically thought to have bacterial pneumonia, presented with a pulmonary infiltrate in the right apex, and suddenly died of exsanguinating hemoptysis. Sputum cultures yielded Aspergillus niger and Candida krusei while sputum cytology revealed numerous birefringent crystals in a background of acute inflammatory exudate. Autopsy findings showed invasive aspergillosis with a large mycetoma-containing cavity in the lung that was associated with localized massive oxalosis. This case further substantiates the fact that the presence of calcium oxalate crystals in pulmonary biopsy and cytology specimens can be regarded as an important diagnostic aid in the diagnosis of pulmonary aspergillosis due to A niger.

Acremonium kiliense osteomyelitis of the calvarium.

A 35-year-old man with osteomyelitis of the calvarium, from which Acremonium kiliense was consistently isolated, was successfully treated with amphotericin-B and ketoconazole in addition to craniectomy. Subsequent acrylic cranioplasty produced a good cosmetic result.

Perforated granulomatous colitis caused by Histoplasma capsulatum.

A 57-year-old man who presented with an acute abdomen and clinically was thought to have perforated colonic diverticulitis, was found to have transmural granulomatous inflammation and perforation of colon that was caused by Histoplasma capsulatum. Although involvement of any part of the gastrointestinal tract may occur with disseminated histoplasmosis, the complication of intestinal perforation requiring emergency surgery (particularly in the colon) is extremely rare and warrants this case report with discussion of the various clinicopathologic features of gastrointestinal histoplasmosis and the occurrence of primary intestinal histoplasmosis.

Clinical significance of serotype, biotype, and beta-lactamase production of respiratory isolates of Hemophilus influenzae.

The correlation between clinical significance and serotype, biotype, and beta-lactamase production of 101 respiratory isolates of Hemophilus influenza from nonbacteremic patients was determined. Six of 33 (18.2%) isolates from patients with definite or probable infection were serotypable; only two of 67 (3%) isolates from colonized patients were serotypable. Eight-seven and one-half per cent of the serotypable strains were biotypes I or IV; 78.8% of nonserotypable strains were biotypes II, III, or V. Biotype distribution among isolates from patients with definite or probable infection were similar to isolates from colonized patients. beta-lactamase production was not helpful in evaluating clinical significance. Nonserotypable H. influenzae is an important cause of nonbacteremic pneumonia in elderly men.