Reinstatler, Lael

Abstract Background Fungal infections of inflatable penile prostheses (IPPs) are inadequately understood in the literature. Aim To review a multi-institution database of IPP infections to examine for common patient and surgical factors related to IPP fungal infections. Methods This is a retrospective Institutional Review Board–approved analysis of 217 patients at 26 institutions who underwent salvage or device explant between 2001 and 2018. Patient data were compiled after an extensive record review. Outcomes 26 patients (12%) with fungal infections were identified. Results 23 of 26 patients (83%) with a fungal IPP infection were either diabetic or overweight. 15 patients had undergone primary IPP implantation, and the other 11 had previously undergone an average of 1.7 IPP-related surgeries (range 1–3; median 2). The average age at implantation was 63 years (range 31–92; median 63). 18 of the 26 patients with fungal infection had diabetes (69%), with a mean hemoglobin A1c (HbA1c) value of 8.4 (range 5.8–13.3; median 7.5). Twenty-two patients (85%) were overweight or obese. The mean body mass index for all patients was 30.1 kg/m2 (range 23.7–45 kg/m2; median 28.4 kg/m2), and that for diabetic patients was 30.8 kg/m2 (range 24.1–45 kg/m2, median 29.7 kg/m2). Ninety-one percent of implants were placed with intravenous antibiotics, consistent with current American Urological Association guidelines: an aminoglycoside plus first- or second-generation cephalosporin or vancomycin or ampicillin/sulbactam or piperacillin/tazobactam. 65% (17 of 26) of infected IPPs had only fungal growth in culture. No patient had concomitant immunosuppressive disease or recent antibiotic exposure before IPP implantation. Clinical Implications More than two-thirds of the fungal infections occurred in diabetic patients and 85% occurred in overweight or obese patients, suggesting that antifungal prophylaxis may be appropriate in these patients. Strengths & Limitations This is the largest series of fungal infections reported to date in the penile prosthesis literature. The overall number of such cases, however, remains small. Conclusion Fungal infections represent 12% of all penile prosthesis infections in our series and were seen mostly in diabetic or overweight patients, who may benefit from antifungal prophylaxis.

Insulin-degrading enzyme (IDE) is a ubiquitous zinc-metalloprotease that hydrolyzes several pathophysiologically relevant peptides, including insulin and the amyloid β-protein (Aβ). IDE is inhibited irreversibly by compounds that covalently modify cysteine residues, a mechanism that could be operative in the etiology of type 2 diabetes mellitus (DM2) or Alzheimer's disease (AD). However, despite prior investigation, the molecular basis underlying the sensitivity of IDE to thiol-alkylating agents has not been elucidated. To address this topic, we conducted a comprehensive mutational analysis of the 13 cysteine residues within IDE. Our analysis implicates C178, C812, and C819 as the principal residues conferring thiol sensitivity. The involvement of C812 and C819, residues quite distant from the catalytic zinc atom, provides functional evidence that the active site of IDE comprises two separate domains that are operational only in close apposition. Structural analysis and other evidence predict that alkylation of C812 and C819 disrupts substrate binding, whereas alkylation of C178 interferes with the apposition of active-site domains and subtly repositions zinc-binding residues. Unexpectedly, alkylation of C590 was found to activate hydrolysis of Aβ significantly, while having no effect on insulin, demonstrating that chemical modulation of IDE can be both bidirectional and highly substrate selective. Our findings resolve a long-standing riddle about the basic enzymology of IDE with important implications for the etiology of DM2 and AD. Moreover, this work uncovers key details about the mechanistic basis of the unusual substrate selectivity of IDE that may aid the development of pharmacological agents or IDE mutants with therapeutic value.