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Spirochetes of the genus Leptospira have previously been shown to use an unusual pathway to synthesize isoleucine. For reasons of convenience, we assume that only one unusual pathway is found in the genus, and we refer to it as the pyruvate pathway. We determined the distribution of this pyruvate pathway in representatives of the seven Leptospira DNA hybridization groups. Our method included labeling the representative strains with radioactive carbon dioxide and other radioactive precursors, fractionating the cells, and determining the specific activities (counts detected per nanomole) of the amino acids found in the protein fractions. On the basis of isoleucine biosynthesis, we found that the genus can be classified as follows: class I primarily, if not exclusively, uses the well-known threonine pathway; class II uses mostly the pyruvate pathway, with a minor amount of isoleucine being synthesized via the threonine pathway; and class III uses the pyruvate pathway exclusively. No relationship appears to exist between the degree of DNA hybridization and the classes of isoleucine biosynthesis. Although the precise intermediates on the pyruvate pathway are unknown, the origin of the carbon skeleton of isoleucine synthesized by this pathway is consistent with a borrowing of the leucine biosynthetic enzymes. However, we found that the pyruvate pathway is not controlled by leucine and that the two isoleucine pathways are independently regulated. Finding major and highly evolved multiple biosynthetic pathways of a specific amino acid within one genus is unique, and, conceivably, represents phylogenetic diversity within Leptospira.

Dental extractions in patients with leukemia are controversial, since they may lead to hemorrhage, delayed wound healing and infection. However, the retention of diseased teeth in these patients may also lead to infectious complications during chemotherapy. With adequate hematologic values and specific surgical techniques, 119 extractions were performed on 28 patients with acute nonlymphocytic leukemia. No serious adverse sequelae occurred, and the prevalence of other adverse affects was comparable with that in nonleukemic patients. It is concluded that with proper precautions, extractions can be performed on these patients.

Factors contributing to the succession of opportunistic pathogens at oral sites, including the periodontium, during myelosuppressive chemotherapy are poorly understood. This study examined the relation of periodontal disease to qualitative and proportional shifts in the oral microflora of 21 acute nonlymphocytic leukemia patients (7 male and 14 female, mean age (range) = 51.0 (25-81 years) observed during standardized myelosuppressive regimens. Supra- and subgingival microbial plaque specimens were individually collected from 2 contralateral oral sites (distobuccal of teeth 1-6 and 3-6) in each participant at hospital admission (day 1) and during point of maximal myelosuppression (day 14). Periodontal disease indices obtained at day 1 included site-specific measures of attachment loss and clinical assessment of disease status. Using a residualized change score analysis, periodontal disease status and attachment loss were positively correlated with increases in the proportional recovery of Staphylococcus sp. from supragingival sites and total yeast from supra- and subgingival sites. When age-related covariation in the microbial shifts was controlled in the analysis, periodontal disease status and attachment loss demonstrated no significant correlation with increases in total yeast at supragingival sites. These findings suggest that host factors such as periodontal disease may contribute to patterns of oral microbial successions during cancer chemotherapy.

Sixty patients were studied 180 to 500 days after allogeneic marrow transplantation to determine if late oral abnormalities were associated with the presence of chronic graft-v-host disease (GVHD). Lip and intraoral mucosal surfaces were evaluated for color, keratinization, atrophy, and erythema. Subjective complaints of oral pain and xerostomia were also recorded. Abnormalities were scored on a scale of 0 to 3 and tested for association with GVHD by chi 2 test. Oral manifestations most strongly associated with chronic GVHD included atrophy and erythema or lichenoid lesions of the buccal and labial mucosa and oral pain. Oral manifestations resembled several naturally occurring autoimmune disorders. Recognition of these changes can aid in the clinical diagnosis and assessment of established chronic GVHD.

The proper dental management of patients with leukemia is complicated by the compromised host defenses against infection. This compromised state is a result of the chemotherapeutic agents used in cancer treatment as well as the natural existing disease state. Infection remains the leading immediate cause of death in persons with leukemia. Previous reports have described oral complications secondary to this neoplasm and its medical management; however, relatively few studies of the incidence of systemic complications secondary to oral disease have been reported. This study analyzed the incidence of acute infectious episodes in patients with acute nonlymphocytic leukemia (ANLL). Thirty-eight patients were randomly selected for review; of these patients, twelve (32 percent) had identifiable acute oral infection associated with the presence of a febrile state (greater than 101 degrees F). Seven of the twelve (58 percent) had no other identifiable sources of infection. The periodontium was the oral site most frequently involved, followed by mucosal and periapical loci. Most acute oral infections were associated with profound granulocytopenia (less than 100/microliters). The data suggest that oral disease plays a clinically important role in the development of systemic complications in ANLL patients.

Aerobic and facultative gram-negative bacilli (GNB) have been reported to increase on various body surfaces in the seriously ill and debilitated patient. This study examined quantitative aspects of GNB succession at five oral sites in cancer patients before and during myelosuppressive chemotherapy. GNB concentrations increased sharply during chemotherapy at 25 to 50% of the oral sites in both acute nonlymphocytic leukemia and small-cell lung carcinoma patients. Most sites did not exhibit shifts of GNB to levels higher than 0.1% of the cultivable flora. When shifts occurred, all sites sampled in the mouth were usually affected and GNB usually represented more than 10% of the cultivable flora. Low levels of indigenous microflora were observed in most sites exhibiting GNB shifts. None of the subjects harboring high levels of GNB developed the symptoms of acute infection which are commonly observed in myelosuppressed patients. Although Pseudomonas aeruginosa and Klebsiella pneumoniae were recovered from some sites, most GNB were nonpathogenic species of Pseudomonas; Pseudomonas pickettii was the most frequently recovered.

Aspergillus infection can be a major cause of morbidity in immunocompromised patients, especially when there is pulmonary involvement. Diagnosis of aspergillosis is often complicated by the varied clinical presentation and compromised medical status of such patients. Four cases of head and neck Aspergillus infections in bone marrow transplant patients are presented. Involvement predominantly was limited to the oral cavity and/or sinuses, and in one case, the ear. Two cases were successfully managed with a combined antibiotic and surgical approach, and one case with antibiotics only. The fourth case was managed with antibiotics and surgery, but fatal hemorrhage secondary to sinus involvement developed.

Oral complications in cancer patients with chemotherapy-induced myelosuppression contribute to morbidity and mortality. However, guidelines for oral care to prevent such complications, including disorders involving the periodontium, are not clear. This study specifically analyzed the impact of a noninvasive oral examination versus invasive oral interventions (periodontal probing, dental scaling) prior to chemotherapy on subsequent development of fever and/or bacteremia in these patients. Medical and dental records were reviewed for 100 patients who had been assigned to receive either the invasive or noninvasive procedures prior to chemotherapy. Temperature values immediately before and up to 48 h after the oral intervention were recorded, and the occurrence of fever and/or bacteremia was documented for each group. There was no statistically significant difference in the incidence of fever and/or bacteremia between the two groups of patients. Although periodontal probing and dental scaling are procedures that invade mucosal barriers, such interventions did not appear significantly to affect the incidence of fever or bacteremia among persons in this study.

From the initiation of chemotherapy until attainment of complete remission, 22 newly diagnosed, hospitalized patients with acute nonlymphocytic leukemia were studied for the prevalence of periodontal disease at admission and for acute exacerbations during myelosuppressive chemotherapy. Consistent with a normal population, all patients had asymptomatic periodontal disease at admission. In these 22 patients, 47 acute infections developed, including 13 of periodontal origin. All but three acute periodontal infections occurred during pronounced granulocytopenia (less than 100 granulocytes per microliter). Although signs and symptoms of inflammation were minimal, all 13 episodes were associated with pain and fever. Asymptomatic periodontal disease is readily overlooked but can be easily diagnosed by thorough clinical and roentgenographic examination. Its occurrence in patients with acute leukemia and its acute exacerbation during granulocytopenia indicate that this oral infection is associated with considerable morbidity during the treatment of acute nonlymphocytic leukemia.

Aspergillosis typically occurs in patients with reduced host defenses; such patients include renal and marrow recipients as well as patients with chemotherapy-induced myelosuppression. Pulmonary structures are most frequently involved; non-pulmonary involvement (including sinus) has not been frequently reported. In the present study, paranasal sinusitis occurred in 52 myelosuppressed cancer patients treated over 5 years at the UMCC with chemotherapy. Twenty-one patients had Aspergillus sinusitis; Aspergillus spp., including flavus and niger, were directly recovered from sinus in 19 of the 21 infections. Two other patients were considered clinically, although not microbiologically, documented. Multiple predisposing factors for Aspergillus sinusitis during the 60 days prior to infection diagnosis appear to exist; these include: 1) granulocyte count less than 500 mm3 (mean duration, 42 days versus 14 days for sinusitis of other etiology; P less than 0.001); 2) prolonged hospitalization (mean duration, 22 days versus 14 days for patients with non-fungal sinusitis; P less than 0.001); and 3) prolonged antibiotic therapy (mean duration, 22 days versus 9 days; P less than 0.001). The Aspergillus sinusitis resolved in 18 of 21 patients following treatment with amphotericin B; however, 11 of 18 patients had infection recurrence that always developed when tumor recurred and chemotherapy was reinstituted.

Three cases involving the oral management of patients with acute leukemia are described. Of particular interest is that the patients had abnormal responses to oral disease, probably related to their compromised host defenses. Because of the difficulty in treating oral disease in leukemic persons while they are undergoing chemotherapy, it is extremely important that such patients have dental evaluations and, if possible, treatment prior to initiation of medical management for their neoplasia.

Dentures for the patient receiving cancer chemotherapy must be constructed and maintained carefully, using sound basic principles of denture construction and tissue management inherent in the highest level of prosthodontic treatment. The objective of removable prosthodontic therapy is to improve the patient's quality of life, enhance nutrition by reducing oral irritation and ulceration, and control the oral microbial populations associated with chemotherapy and the wearing of a denture.

The clinical course of an adult patient with relapsed acute myelogenous leukemia and leukemic infiltrate periapical to the dentition is described. While the oral symptoms were indicative of pulpal disease requiring dental therapy to resolve the patient's complaint, roentgenographic, dental pulp testing, and histologic analysis revealed extramedullary infiltrate apical to a mandibular molar. The findings developed coincident with relapse of leukemia; the medical and dental testing described above were essential in establishing an accurate diagnosis. While most oral leukemic infiltrates affect the gingiva, in this patient the infiltrate involved periapical tissue which was not clinically observable.

Paranasal sinusitis occurred in 52 immunosuppressed cancer patients treated over 5 years at the University of Maryland Cancer Center. Twenty-one patients had aspergillus sinusitis; Aspergillus sp, including flavus and niger were directly recovered from sinus in 19 of the 21 infections. Two other patients with sinus involvement and positive nose cultures for Aspergillus flavus or fumigatus and microbiologically documented pulmonary aspergillosis were considered clinically, although not microbiologically, documented. Predisposing factors for aspergillus sinusitis during the 60 days prior to infection diagnosis were granulocyte count less than 500 microliter (mean duration, 42 days versus 14 days for sinusitis of other etiology; P less than 0.001), prolonged hospitalization (mean duration, 22 days versus 14 days for patients with nonfungal sinusitis; P less than 0.001), and prolonged antibiotic therapy (mean duration, 22 days versus 9 days; P less than 0.001). Treatment with amphotericin B was initially successful for 18 of 21 patients; however, 11 of 18 patients had infection recurrence that always developed at time of tumor exacerbation and reinstitution or intensification of chemotherapy. These findings suggest that aspergillus sinusitis in cancer patients is seen in association with prolonged neutropenia and antibiotic therapy, is amenable to therapy, but tends to recur with relapse of malignancy.

The clinical course of an adult patient with acute lymphocytic leukemia and localized, rapidly progressive periodontal disease in a setting of marrow regeneration is described. Initial presentation of this condition was consistent with herpes simplex virus infection involving the gingiva; however, more extensive evaluation including radiographs, cultures and biopsy revealed necrotic tissue, nonspecific bacterial growth and acute gingival inflammation, with no evidence of viral infection. While most acute oral infections in chemotherapy patients occur during the development of marrow aplasia, this lesion initially developed late during the marrow recovery phase. The characteristics of this lesion are compared with those occurring in noncancer patients with rapidly progressive periodontitis and who have genetically governed neutrophil and/or lymphocyte defects.

Salivary and plasma concentrations of hexamethylene bisacetamide (HMBA) were studied to determine (1) how the concentrations of HMBA achieved in saliva compared with those required to induce differentiation in vitro, and (2) whether saliva might substitute for plasma as a biologic fluid on which to base dosage adjustment. Plasma and expectorated saliva were collected concomitantly from 16 patients receiving 5-day continuous infusions of HMBA. The concentrations of HMBA in each fluid were determined by gas chromatography. The patients displayed a range of periodontal disease from gingivitis to complete edentia, but periodontal disease status did not appear to influence the salivary behavior of HMBA, which mirrored that of the drug in plasma, with concentrations of HMBA increasing in both fluids during the first 12-16 h of infusion. Between 24 and 120 h, HMBA concentrations in saliva and plasma remained constant. In some patients, salivary HMBA concentrations lagged behind those in plasma during the first 6-8 h of infusion, but after that the salivary HMBA concentrations approximated those in the plasma. Salivary concentrations of HMBA between 0.96 and 2.56 mM were associated with nontoxic plasma concentrations of HMBA. Therefore, in patients with restricted venous access, saliva might be a suitable substitute for plasma if adaptive control-dosing schemes for HMBA are employed. Moreover, the concentrations of HMBA in saliva bathing the oral cavity are quantitatively comparable to those required for induction of cell differentiation in vitro.

This study characterized the subgingival microbial flora associated with 27 acute exacerbations of preexistent periodontal disease in 24 patients with chemotherapy-induced myelosuppression. All but two acute periodontal infections developed at low granulocyte levels (less than 1,000/microL). Suspected pathogens were detected in high concentrations in subgingival plaque specimens in 17 episodes of acute periodontal infection; a single pathogen was recovered in ten acute infections, and more than one pathogen was recovered in seven acute infections. Staphylococcus epidermidis, Candida albicans, S aureus, and Pseudomonas aeruginosa predominated, with combinations of these detected in some patients. Concomitant bacteremias developed in two of these patients. The subgingival microflora associated with ten acute periodontal infections was characterized by predominantly indigenous microorganisms, which in nine episodes were in abnormal proportions compared with microbial profiles in noncancer patients with similar degrees of periodontal disease. These data demonstrate that pathogens normally associated with infections in myelosuppressed cancer patients, as well as indigenous oral flora, are associated with acute periodontal infections during granulocytopenia. This finding is important, since this body site has not commonly been recognized as a source for acute infection in these patients.

The extent of incorporation of aspartate into dipicolinic acid and into various amino compounds was determined in Bacillus cereus at various times before, during, and near the end of synthesis of dipicolinic acid. The purpose of this study was to gain further information on the in vivo control of the biosynthesis of amino acids derived from aspartate. Control of the lysine biosynthetic pathway was of particular interest with regard to sporulation, owing to the important role of diaminopimelate and dipicolinate in the structure of the spore. As synthesis of dipicolinate was initiated, incorporation of carbon derived from aspartate was funneled preferentially into this compound as compared with others of the aspartate group. Incorporation into lysine essentially stopped just before the synthesis of dipicolinate began. This is consistent with the previously observed disappearance at this time of diaminopimelic acid decarboxylase in cell-free extracts. Synthesis of diaminopimelate continued during the time of synthesis of dipicolinate. The previous suggestion that diaminopimelate might exert negative control on one of the enzymes between dihydrodipicolinate and diaminopimelate is thus considered unlikely. The possibility is discussed that synthesis of dipicolinate is favored by an increase in the rate of synthesis of dihydrodipicolinate rather than by a block in its rate of utilization.

Changes in the endogenous intracellular amino acid pool and total free amino acid production in Bacillus licheniformis grown in minimal media were investigated. The total intracellular pool increased during exponential growth and then decreased rapidly after the end of growth. Most of the amino acids were present at low concentrations, but glutamate and alanine comprised 60 to 90% of the total intracellular free amino acid at most times during the growth cycle. It was concluded that, in addition to providing monomers for protein synthesis, the intracellular amino acid pool may be maintained for the storage of energy-providing metabolic intermediates and possibly as a balance to the ionic strength of the medium. The total free amino acid production by the cell was found to be dependent upon the composition of the salts medium as well as the culture age under conditions in which the carbon and nitrogen sources were the same. A 10-fold increase in extracellular amino acid was observed as the cells changed from vegetative to sporulation metabolism, mostly due to the extrusion of intracellular amino acid. The impact of this increase upon amino acid uptake and pulse-labeling studies using unwashed cells is discussed.