Design and implementation of clinical trials of antimicrobial drugs and devices used in periodontal disease treatment

The design and implementation of clinical trials (CTs) carried out to evaluate antimicrobial and anti-infective drugs and devices are one of the most difficult challenges in contemporary periodontal research and product development. The overwhelming amount of evidence which has established a microbial etiology for periodontitis is the basis for developing and testing antimicrobial treatments. Well-designed antimicrobial CTs start with a carefully crafted hypothesis and a protocol which explicitly integrates the requirements of the patient, the clinician, the sponsor, and regulatory authorities. Surrogate variables for effectiveness must be clinically relevant, scientifically sound, and statistically valid. Currently, clinical attachment level measurements and alveolar bone assessments are accepted as proof of effectiveness. Indication and claim support of the antimicrobial product guide the design and implementation of the CT. Adverse microbiologic consequences, such as lack of antimicrobial susceptibility, wrong spectrum, incorrect dosage, non-compliance, and drug interference, must be monitored. Successful CTs balance a large group of variables used to screen, randomize, and assign subjects to experimental and control groups to ensure that prognostic and risk factors are properly accounted for.     

Analysis of the roles of antilipopolysaccharide and anti-cholera toxin immunoglobulin A (IgA) antibodies in protection against Vibrio cholerae and cholera toxin by use of monoclonal IgA antibodies in vivo

Secretory immunoglobulin A (IgA) antibodies (sIgA) directed against cholera toxin (CT) and surface components of Vibrio cholerae are associated with protection against cholera, but the relative importance of specific sIgAs in protection is unknown. A monoclonal IgA directed against the V. cholerae lipopolysaccharide (LPS), secreted into the intestines of neonatal mice bearing hybridoma tumors, was previously shown to provide protection against a lethal oral dose of 10(7) V. cholerae cells. We show here that a single oral dose of 5 to 50 micrograms of the monoclonal anti-LPS IgA, given within 2 h before V. cholerae challenge, protected neonatal mice against challenge. In contrast, an oral dose of 80 micrograms of monoclonal IgA directed against CT B subunit (CTB) failed to protect against V. cholerae challenge. A total of 80 micrograms of monoclonal anti-CTB IgA given orally protected neonatal mice from a lethal (5-micrograms) oral dose of CT. Secretion of the same anti-CTB IgA antibodies into the intestines of mice bearing IgA hybridoma backpack tumors, however, failed to protect against lethal oral doses of either CT (5 micrograms) or V. cholerae (10(7) cells). Furthermore, monoclonal anti-CTB IgA, either delivered orally or secreted onto mucosal surfaces in mice bearing hybridoma tumors, did not significantly enhance protection over that provided by oral anti-LPS IgA alone. These results demonstrate that anti-LPS sIgA is much more effective than anti-CT IgA in prevention of V. cholerae-induced diarrheal disease.     

Hypomagnesemia following correction of metabolic acidosis: a case of hungry bones

Severe symptomatic hypomagnesemia (0.15 mmol/L [0.3 mEq/L]) and hypocalcemia (1.47 mmol/L [5.9 mg/dL]) occurred in a 4-week-old infant coincidental with correction of a severe renal tubular acidosis with alkali therapy. The patient had no evidence of gastrointestinal abnormality and magnesium (Mg) intake was adequate for age and weight. Extreme renal conservation of Mg was observed, supporting the presence of Mg depletion. We suggest that Mg depletion in this infant occurred due to acidosis-induced bone demineralization and that symptomatic hypomagnesemia was precipitated by rapid remineralization accompanying correction of systemic acidosis. This patient represents a novel case of hungry bone syndrome (HBS). Since HBS has not been described previously in patients with acidosis undergoing therapy, several other factors may have contributed to this patient's severe hypomagnesemia, namely, prematurity, twin status, severity of acidosis, rapidity of correction of acidosis, catch-up growth and calcium supplementation. Clinicians should be vigilant for HBS in infants with severe acidosis undergoing alkali therapy.     

Occupational lead exposure and hearing loss

Studies of adults, children, and laboratory animals suggest an association between lead exposure and hearing loss. A causal relationship might direct mandated medical surveillance of lead-exposed workers to include audiometric testing. A cross-sectional, computerized dataset was obtained from a private occupational health screening company to examine the relationship between blood lead level and hearing loss. Audiometry and blood lead results were available for 183 workers. A statistically significant correlation was found between blood lead level and an elevated hearing threshold at 400 Hz (P = 0.03); no other frequencies showed such a correlation. This finding suggests either an interaction between nose exposure and lead, interaction of other exposure factors (such as cigarette smoking), or that factors other than biomechanical ones render the organ of Corti more susceptible at 4000 Hz. Further evaluation of these questions should be undertaken. Computerized databases created for worker surveillance may be a source for data useful for examining other causal connections in occupational settings.     

The use of quantitative bacteriologic assessment of bone

A new sub-class of binding protein-dependent transporter with specificity for a broad range of polar amino acids has been identified by sequence comparison, in Rhizobium leguminosarum, Rhodobacter capsulatus, Escherichia coli and Pseudomonas fluorescens. Southern blotting and PCR analysis has shown that transporters from this new sub-class are widely distributed in Gram-negative bacteria, including, in addition to the above, Citrobacter freundii, Erwinia carotovorum and Rhizobium meliloti. ABC transporters of polar amino acids can be divided into two groups: those with narrow solute specificity and the newly identified sub-class with broad solute specificity. The binding and inner membrane proteins from transporters with a broad solute specificity are larger by approximately 30% than those with a narrow solute specificity. Multiple alignment of the inner membrane proteins from all sequenced polar amino acid transporters indicates there is an N-terminal conserved region that may be involved in solute specificity. A conserved arginine or lysine at residue 30 of this region is changed to glutamate in arginine transporters. Residue 53 also has a strong correlation with the charge on the transported solute, with basic amino acid transporters replacing an aliphatic amino acid at this position with a negatively charged amino acid. The general amino acid permease from R. leguminosarum, which will transport aliphatic as well as basic and acidic amino acids, juxtaposes two prolines at residues 52 and 53 of the N-terminal conserved region.