Optimization of Methionyl tRNA-Synthetase Inhibitors for Treatment of Cryptosporidium Infection.

Cryptosporidiosis is one of the leading causes of moderate to severe diarrhea in children in low-resource settings. The therapeutic options for cryptosporidiosis are limited to one drug, nitazoxanide, which unfortunately has poor activity in the most needy populations of malnourished children and HIV-infected persons. We describe here the discovery and early optimization of a class of imidazopyridine-containing compounds with potential for treating Cryptosporidium infections. The compounds target the Cryptosporidium methionyl-tRNA synthetase (MetRS), an enzyme that is essential for protein synthesis. The most potent compounds inhibited the enzyme with Ki values in the low picomolar range. Cryptosporidium cells in culture were potently inhibited with 50% effective concentrations as low as 7 nM and >1,000-fold selectivity over mammalian cells. A parasite persistence assay indicates that the compounds act by a parasiticidal mechanism. Several compounds were demonstrated to control infection in two murine models of cryptosporidiosis without evidence of toxicity. Pharmacological and physicochemical characteristics of compounds were investigated to determine properties that were associated with higher efficacy. The results indicate that MetRS inhibitors are excellent candidates for development for anticryptosporidiosis therapy.

Measuring abdominal aortic diameters in routine abdominal computed tomography scans and implications for abdominal aortic aneurysm screening.

OBJECTIVE: This study aimed to determine the prevalence and relevance of incidental abdominal aortic aneurysm (AAA) on routine abdominal computed tomography (CT) and to audit the performance of radiologists to identify and report AAA. METHODS: A retrospective audit of all abdominal CT scans performed on men and women ≥50 years at Dunedin Public Hospital between January 2013 and September 2014 was carried out. All CT scans for planning of AAA treatment or follow-up were excluded. The maximal anterior-posterior diameter of the infrarenal abdominal aorta was measured in both the sagittal and transverse planes on the picture archiving and communication system. The radiologist reports were analyzed. All detected AAAs were reviewed for clinical relevance. RESULTS: A total of 3332 scans were performed, of which 86 scans were excluded, resulting in a total cohort of 3246. There were 187 incidental AAAs detected with a prevalence of 5.8%. The prevalence was 8.7% in men and 3.1% in women. Whereas the prevalence increased with age, a significant number were detected in those younger than 65 years, with a prevalence of 1.5%. Of the 187 AAAs, 122 (65%) were reported by radiologists: 100% reporting rate in AAAs ≥50 mm, 87% in AAAs ≥40 to 49 mm, and 52% in AAAs ≥30 to 39 mm. Of these, 15% were specifically recommended for referral to a vascular service. Of the incidentally detected AAAs, 72% were considered to be clinically relevant, which is an overall 4.1% prevalence of AAAs with an ability to benefit. In addition, all 3246 subjects avoided the need for further AAA screening. CONCLUSIONS: There is a high prevalence of AAAs (5.8%) and clinically relevant AAAs (4.1%) detected on routine abdominal CT. As an opportunistic approach, it is a simple and effective way to detect AAAs and to broaden traditional screening criteria to include women and those younger than 65 years in our region. Furthermore, large numbers of subjects with normal aortic diameters are identified who will not need to be screened. Consequently, we consider routine diagnostic abdominal CT to be an important adjunct to national and community AAA screening strategies.

Surgical peripheral iridotomy creation during intraocular surgery by intraocular diathermy probe-a novel technique.

A novel technique for the creation of surgical iridotomies using a bipolar diathermic probe is described. In a cohort comprising 19 eyes of 18 patients, a 100% patency rate was achieved, with no intra- or postoperative complications.

DMEK with endophotocoagulation and cyst wall removal for corneal endothelial decompensation due to iris cyst.

PURPOSE: Iris cysts may arise secondary to surgical or nonsurgical trauma, potentially leading to corneal decompensation via mechanical injury to the adjacent endothelium. However, no well-established protocol exists for the treatment for corneal edema arising therefrom. OBSERVATIONS: A 58-year-old white male presented with an iris mass of his left eye; it occupied 1/3rd the anterior chamber volume and directly contacted the corneal endothelium. The cornea was diffusely edematous, and best corrected visual acuity (BCVA) measured 20/70 (0.3). Corneal endothelial decompensation secondary to iris cyst was diagnosed. Treatment consisted of endophotocoagulation and vitrectomy probe removal of the cyst wall, with Descemet membrane endothelial keratoplasty (DMEK) also performed as a single, combined procedure. The patient subsequently experienced a resolution of his corneal edema and disappearance of his iris cyst, without recurrence of either condition. BCVA improved to 20/25 (0.8). CONCLUSIONS AND IMPORTANCE: Iris cyst may be a rare cause of corneal decompensation. Viable treatment may entail a single-stage procedure involving endophotocoagulation and vitrectomy probe application to the cyst wall combined with DMEK.