Pyrazinoic acid, the active form of the anti-tuberculosis drug pyrazinamide, and aromatic carboxylic acid analogs are protonophores.

Pyrazinoic acid is the active form of pyrazinamide, a first-line antibiotic used to treat Mycobacterium tuberculosis infections. However, the mechanism of action of pyrazinoic acid remains a subject of debate, and alternatives to pyrazinamide in cases of resistance are not available. The work presented here demonstrates that pyrazinoic acid and known protonophores including salicylic acid, benzoic acid, and carbonyl cyanide m-chlorophenyl hydrazone all exhibit pH-dependent inhibition of mycobacterial growth activity over a physiologically relevant range of pH values. Other anti-tubercular drugs, including rifampin, isoniazid, bedaquiline, and p-aminosalicylic acid, do not exhibit similar pH-dependent growth-inhibitory activities. The growth inhibition curves of pyrazinoic, salicylic, benzoic, and picolinic acids, as well as carbonyl cyanide m-chlorophenyl hydrazone, all fit a quantitative structure-activity relationship (QSAR) derived from acid-base equilibria with R2 values > 0.95. The QSAR model indicates that growth inhibition relies solely on the concentration of the protonated forms of these weak acids (rather than the deprotonated forms). Moreover, pyrazinoic acid, salicylic acid, and carbonyl cyanide m-chlorophenyl hydrazone all caused acidification of the mycobacterial cytoplasm at concentrations that inhibit bacterial growth. Thus, it is concluded that pyrazinoic acid acts as an uncoupler of oxidative phosphorylation and that disruption of proton motive force is the primary mechanism of action of pyrazinoic acid rather than the inhibition of a classic enzyme activity.

Risk factors for carcinoma ex pleomorphic adenoma in patients presenting with recurrence after resection of pleomorphic adenoma.

BACKGROUND: In patients presenting with recurrent pleomorphic adenoma (rPA), clinical evaluation can fail to recognize carcinoma ex PA (cxPA). We aim to identify the risk factors for cxPA. METHODS: This is a single institution retrospective case-control study from 2000 to 2015. CxPA was diagnosed based on surgical pathology. Demographics, clinical, and social histories were collected. RESULTS: A number of 13/106 (12.3%) patients were diagnosed with cxPA, of which only 4/13 (31%) had clinical features suspicious for malignancy. Compared to benign rPA, factors associated with cxPA included age >50 (odds ratio [OR] 6.67, 95% confidence interval [CI]: 1.71-25.98, P < .01), >10 pack-years of smoking history (OR 3.36, 95% CI: 1.01-11.14, P = .04), and the largest tumor being >2 cm on pathology (OR 4.42, 95% CI: 1.14-17.10, P = .03). CONCLUSIONS: In patients presenting with rPA, risk factors for malignant transformation include age >50, significant smoking history, and tumors larger than 2 cm. Clinical signs of malignancy such as rapid growth or pain are not always present.

Risk factors for subsequent recurrence after surgical treatment of recurrent pleomorphic adenoma of the parotid gland.

BACKGROUND: Recurrent pleomorphic adenoma (PA) can be a lifelong disease, and rates of subsequent recurrence are high. METHODS: Patients between 2000 and 2015 were identified. Primary outcome was subsequent recurrence after surgical salvage. RESULTS: Twenty-seven of 84 patients developed a subsequent recurrence. Risk factors for subsequent recurrence included a higher number of previous recurrences (P < .01), worse preoperative facial nerve function (P < .01), and deep parotid lesion(s) (P < .01). Interval since last surgery was protective (P < .01), specifically >10 years since last surgery (P < .01). For patients with a >10-year interval since their last surgery, the subsequent recurrence-free rate at 10 years follow-up was 80.2% vs 31.8%. CONCLUSIONS: For patients presenting with a >10-year interval since their last surgery, subsequent recurrence rates are low, which may allow for as needed surveillance recommendations. For patients presenting with recurrent PA and ≤10 years since their last surgery, a closer surveillance is warranted.

Recurrent pleomorphic adenoma of the parotid gland: A comparison of radiographic and pathologic tumor burden.

PURPOSE: To compare recurrent pleomorphic adenoma tumor burden as detected on magnetic resonance and computerized tomography imaging with postoperative histopathology. MATERIALS AND METHODS: 44 patients were identified at a tertiary medical center between 2000 and 2015. Patients were included if they had viewable preoperative imaging and a postoperative diagnosis of recurrent pleomorphic adenoma. Primary outcomes were differences in the number and size of lesions detected on imaging and pathology. RESULTS: The size in greatest dimension between pathology and imaging was not significant on aggregate MRI + CT (p = 0.78), MRI (p = 0.41), or CT (p = 0.69). There were more lesions found on pathology compared to both aggregate MRI + CT (p = 0.003) and CT alone (p = 0.014). The number of lesions between MRI and pathology failed to reach significance (p = 0.06). On univariate analysis, the interval between imaging and pathology (recurrent surgery) did not significantly affect the number of lesions detected (p = 0.18). On multivariable analysis, CT as the primary imaging modality and >1 recurrence was independently associated with greater inaccuracy with respect to number of lesions detected (p = 0.006; p = 0.008). CONCLUSION: The size of the largest lesion on pathology can be accurately determined with imaging. Compared to MRI, CT scans significantly underpredict the number of lesions found on pathology. MRI should be prioritized unless contraindications exist. These findings will help guide imaging choice, preoperative planning, and patient counseling.

The Rise of the Neophallus: A Systematic Review of Penile Prosthetic Outcomes and Complications in Gender-Affirming Surgery.

BACKGROUND: Penile prostheses are commonly used to achieve erectile rigidity after phalloplasty in trans masculine patients. Implantation poses significant challenges because of the delicate nature of the neophallus and lack of native erectile tissue. Many groups have developed novel phalloplasty and prosthesis insertion techniques, but none have proven superior. AIM: To analyze and aggregate reported characteristics and outcomes of penile prosthesis implantation in the trans masculine patient. METHODS: A comprehensive literature search of Medline, EMBASE, and Cochrane Registry databases was conducted for studies published through February 19, 2019, with multiple search terms related to penile prosthesis use in gender-affirming surgical procedures. OUTCOMES: Studies were included and tabulated if they reported prosthesis outcomes in patients who received a neophallus as part of a gender-affirming procedure. RESULTS: 23 journal articles met inclusion criteria from 434 references identified. All selected articles were either retrospective or case series/reports. A total of 1,056 patients underwent phalloplasty, and 792 received a penile prosthesis. Most (83.6%) of the prostheses were inflatable, whereas 16.4% were non-inflatable. The number of cylinders used for each prosthesis was 61.0% single-cylinder and 39.0% double-cylinder. The mean follow-up duration was 3.0 years. Of patients who received a prosthesis, 36.2% reported a prosthesis complication; at follow-up 60.0% of patients had their original implant present, and 83.9% reported achieving penetration. CLINICAL IMPLICATIONS: Prosthesis implantation in gender-affirming operations poses significant risk of complication, but it is still a reasonable and useful method to achieve rigidity necessary for sexual intercourse. STRENGTH & LIMITATION: This is the first study to aggregate all reported penile prosthesis characteristics and outcomes in trans masculine patients. This study was significantly limited by inconsistent reporting of demographics, sensation, urinary health, patient satisfaction, and penetrative sex. The lack of comparative studies precluded any meaningful meta-analytical comparison. CONCLUSIONS: There is a great need for a prosthesis designed to meet the specific needs of the trans masculine patient after phalloplasty. Standardized methods of reporting implant outcomes including sexual function, sensation, and patient satisfaction should be refined for future studies. This study can assist patients and surgeons about the risks and benefits of this procedure. Rooker SA, Vyas KS, DiFilippo EC, et al. The Rise of the Neophallus: A Systematic Review of Penile Prosthetic Outcomes and Complications in Gender-Affirming Surgery. J Sex Med 2019;16:661-672.

Mycobacterial MenJ: An Oxidoreductase Involved in Menaquinone Biosynthesis.

MenJ, annotated as an oxidoreductase, was recently demonstrated to catalyze the reduction (saturation) of a single double bond in the isoprenyl side-chain of mycobacterial menaquinone. This modification was shown to be essential for bacterial survival in J774A.1 macrophage-like cells, suggesting that MenJ may be a conditional drug target in Mycobacterium tuberculosis and other pathogenic mycobacteria. Recombinant protein was expressed in a heterologous host, and the activity was characterized. Although highly regiospecific in vivo, the activity is not absolutely regiospecific in vitro; in addition, the enzyme is not specific for naphthoquinones vs benzoquinones. Coenzyme Q-1 (a benzoquinone, UQ-1) was used as the lipoquinone substrate, and NADH oxidation was followed spectrophotometrically as the activity readout. NADPH could not be substituted for NADH in the reaction mixture. The enzyme contains a FAD binding site that was 72% occupied in the purified recombinant protein. Enzyme activity was maximal at 37 °C and pH 7.0; addition of divalent cations, EDTA, and reducing agents such as dithiothreitol to the reaction mixture had no effect on activity. The addition of detergents did not stimulate activity, and addition of saturating levels of FAD had relatively little effect on the observed kinetic parameters. These properties allowed the development of a facile assay needed to study this potential drug target, which is also amenable to high throughput screening. The Km values for UQ-1 using recombinant MenJ from Mycobacterium smegmatis or M. tuberculosis without saturating concentrations of FAD were found to be 52 ± 9.6 and 44 ± 4.8 µM, respectively, while the KmNADH values were determined to be 59 ± 14 and 64 ± 15 µM. The Km for MK-1, the menaquinone analogue of UQ-1, using recombinant MenJ from M. tuberculosis without saturating concentrations of FAD but in the presence of 0.5% Tween 80 was shown to be 30 ± 2.9 µM. Thus, this is the first report of a kinetic characterization of a member of the geranylgeranyl reductase family of enzymes.