Small changes in enzyme function can lead to surprisingly large fitness effects during adaptive evolution of antibiotic resistance

In principle, evolutionary outcomes could be largely predicted if all of the relevant physicochemical variants of a particular protein function under selection were known and integrated into an appropriate physiological model. We have tested this principle by generating a family of variants of the tetracycline resistance protein TetX2 and identified the physicochemical properties most correlated with organismal fitness. Surprisingly, small changes in the Km(MCN), less than twofold, were sufficient to produce highly successful adaptive mutants over clinically relevant drug concentrations. We then built a quantitative model directly relating the in vitro physicochemical properties of the mutant enzymes to the growth rates of bacteria carrying a single chromosomal copy of the tet(X2) variants over a wide range of minocycline (MCN) concentrations. Importantly, this model allows the prediction of enzymatic properties directly from cellular growth rates as well as the physicochemical-fitness landscape of TetX2. Using experimental evolution and deep sequencing to monitor the allelic frequencies of the seven most biochemically efficient TetX2 mutants in 10 independently evolving populations, we showed that the model correctly predicted the success of the two most beneficial variants tet(X2)T280A and tet(X2)N371I. The structure of the most efficient variant, TetX2T280A, in complex with MCN at 2.7 Å resolution suggests an indirect effect on enzyme kinetics. Taken together, these findings support an important role for readily accessible small steps in protein evolution that can, in turn, greatly increase the fitness of an organism during natural selection

Evaluating the Role of Electroretinography in Patients with Optic Neuritis

Electroretinography (ERG) has potential as a quantitative and objective measure of retinal and optic nerve function for patients with optic neuritis (ON). Multi-focal (mf) ERG response represents cone and bipolar cell activity, whereas the photopic negative response (PhNR) is more specific to ganglion cell activity. This study will investigate the clinical utility of ERG in prognostication of visual outcomes. ERG might be utilized to assess early response to neuroprotective agents following ON onset, when structural methods such as optical coherence tomography (OCT) are confounded by edema

Large Orbital Pediatric Intraosseous Hemangioma

A five-year-old male presenting with progressive right facial swelling underwent multiple biopsies before being diagnosed with a polyostotic frontal-zygomatic primary intraosseous hemangioma. Intraosseous hemangiomas are rare, more frequently afflict adult females, and very rarely involve the orbit. Our case with bony destruction and surrounding soft tissue mass measured 5.3 cm in a child mimicked a more ominous malignancy. This case is unique with its rapid progression and largest reported size, leading to additional challenges such as difficulty in achieving an adequate tissue sample and in the surgical management with respect to significant blood loss in a small child

Rare Signet Ring Cell Adenocarcinoma of the Colon Metastasis to the Orbit

Metastases arising from primary tumors of the gastrointestinal tract are not commonly encountered in the orbit. Colorectal carcinomas are subcategorized based on morphological and genetic characteristics with these distinctions bearing therapeutic and prognostic significance. The behavior of these subcategories, including their propensity for orbital metastasis, differs, and clinicians treating these tumors must be aware of their metastatic profiles. This report describes a 51-year-old female with right upper lid swelling and ptosis ultimately found, what we believe to be, the first reported case of signet ring cell colon carcinoma metastasizing to the levator muscle and superior orbit. This case serves as a reminder to all clinicians to consider orbital metastasis even in malignancies not typically found in this location

Clinical image: Rare photographic documentation of uveal melanoma progression.

To present clinical images of a patient with neovascular glaucoma and hypermature cataract masking orbital extension of a uveal melanoma. Observations: A 67-year-old female was referred for neovascular glaucoma and found to have an intraocular tumor with massive orbital extension. She refused surgery and returned one year later with progression of the tumor with metastases and expired seven months later. Conclusions and importance: Unexplained glaucoma and cataract should be investigated for harboring underlying intraocular tumors to prevent delays in diagnosis. Providers also should obtain greater understanding of psychosocial and socioeconomic barriers to healthcare

Misdiagnosis of Bell's palsy: Case series and literature review

Although Bell's palsy is a common etiology for isolated facial paralysis, it is important clinicians perform a complete neurologic examination to avoid misdiagnosis. Multiple cranial neuropathy is often caused by tumor or infection