Open revascularization approach is associated with healing and ambulation after transmetatarsal amputation in patients with chronic limb threatening ischemia.

BACKGROUND: Transmetatarsal amputation (TMA) allows for maintenance of ambulatory function for patients with significant forefoot tissue loss. Effective revascularization is key to optimizing limb salvage for patients with chronic limb threatening ischemia (CLTI). We hypothesized that CLTI patients requiring TMA will have better healing and functional outcomes with open bypass than with endovascular revascularization. METHODS: Consecutive TMAs performed at three affiliated centers between 2008 and 2020 were retrospectively reviewed. The baseline characteristics, including WIfI (wound, ischemia, foot infection) stage, noninvasive vascular studies, healing, and ambulatory outcomes, were collected. Catheter-based angiographic images were evaluated using the GLASS (global limb anatomic staging system). The primary outcomes were TMA healing and community ambulation. The secondary outcomes were TMA that had healed at study end, any ambulatory function postoperatively, major amputation, and mortality. Descriptive statistics and univariate, multivariable, and Kaplan-Meier analyses were performed. RESULTS: A total of 346 TMAs had been performed in 318 patients, 209 of whom had had peripheral artery disease (PAD). The median follow-up was 2.5 years. Patients with PAD had had significantly lower rates of healing compared with those without PAD (64% vs 77%; P = .007). Revascularization was performed in 185 limbs, with 102 treated endovascularly and 83 with open surgery. The patients who had undergone endovascular surgery were significantly less likely to have had the TMA healed at any point (55% vs 76%; P = .003) and less likely to have remained healed at study end (49% vs 66%; P = .02). Patients with GLASS stage 3 anatomy were significantly more likely to have healed after open surgery (75% vs 45%; P = .003). Long-term ambulation data were available for 72% of the revascularized patients. Endovascular surgery was associated with a lower likelihood of community ambulation after TMA (34% vs 57%; P = .002). On multivariable analysis, open surgery was significantly associated with TMA healing (odds ratio, 2.8; P = .007) and ambulation (odds ratio, 2.9; P = .001). CONCLUSIONS: For patients with CLTI and significant tissue loss requiring TMA, an initial open approach to revascularization was associated with improved healing and higher rates of ambulation compared with endovascular interventions. The metabolic requirement for healing of a TMA in patients with CLTI might be better met by open revascularization.

mRNA structure regulates protein expression through changes in functional half-life.

Messenger RNAs (mRNAs) encode information in both their primary sequence and their higher order structure. The independent contributions of factors like codon usage and secondary structure to regulating protein expression are difficult to establish as they are often highly correlated in endogenous sequences. Here, we used 2 approaches, global inclusion of modified nucleotides and rational sequence design of exogenously delivered constructs, to understand the role of mRNA secondary structure independent from codon usage. Unexpectedly, highly expressed mRNAs contained a highly structured coding sequence (CDS). Modified nucleotides that stabilize mRNA secondary structure enabled high expression across a wide variety of primary sequences. Using a set of eGFP mRNAs with independently altered codon usage and CDS structure, we find that the structure of the CDS regulates protein expression through changes in functional mRNA half-life (i.e., mRNA being actively translated). This work highlights an underappreciated role of mRNA secondary structure in the regulation of mRNA stability.

Transformative learning: empathy and multicultural awareness in podiatric medical education.

BACKGROUND: Short-term medical missions are common in medical educational settings and could possibly affect student learning. Little research has been conducted about the potential of these missions on students' transformative learning, in particular as it relates to empathy and multicultural awareness. METHODS: Eight podiatric medical students who participated in short-term medical missions in 2008 and 2009 completed an electronic survey to investigate the effect of their experience as it relates to their learning. The empathy and multicultural awareness impact of the mission experience was emphasized. Qualitative questions in the survey were coded, themed, and triangulated with the quantitative responses. RESULTS: Six students (75%) "strongly agreed" that participating in the medical mission was a significant positive experience in their podiatric medical training. Six students felt that their experiences in serving these communities increased their personal awareness of multicultural/diversity needs in general. All of the students agreed that they will become better podiatric physicians because of their experiences in the medical missions. The qualitative data also indicate that the experience had an effect on the students' views of health care and increased empathy toward their patients. CONCLUSIONS: Short-term medical missions could play a significant role in the transformative learning experience in podiatric medical education. This could affect the empathy and multicultural awareness of podiatric medical students. Further and more extensive evaluations of the potential impact of short-term medical missions in podiatric medical education should be explored because it could influence curriculum and global health in the field of podiatric medicine.

Retinal pigment epithelial cell transplantation could provide trophic support in Parkinson's disease: results from an in vitro model system.

Transplantation of retinal pigment epithelial (RPE) cells in the basal ganglia could provide a novel cell-based therapy for Parkinson's disease by providing a constant source of dopamine replacement via the melanin synthetic pathway enzyme tyrosinase. We now demonstrate that human RPE cells also produce a neurotrophic effect on primary cultures of rat striatal (enkephalinergic) and mesencephalic (dopaminergic) neurons. Differentiation of RPE cells to a pigmented monolayer using a Ca(++)-switch protocol increased the potency of the neurotrophic effect on dopaminergic neurons. Conditioned medium derived from differentiated RPE cells increased neurite outgrowth in dopaminergic neurons by 125% compared to 25% for undifferentiated RPE cells. The neurotrophic effect was not due to tyrosinase activity. Differentiation of RPE cells doubled the production of pigment-derived epithelial factor (PEDF). However, PEDF accounted for only a portion of the neurotrophic effect as determined by depletion experiments and dose-response comparisons with purified PEDF, indicating that differentiation increased the production of other trophic factors as well. Conditioned medium from differentiated RPE cells also provided a neurotrophic effect on a subset of enkephalinergic striatal neurons increasing neurite outgrowth by 78%. Survival of enkephalinergic neurons in vitro was increased by RPE conditioned medium. In untreated cultures the number of enkephalinergic neurons declined 62% over a 2-week period compared to a 29% decline in RPE-treated cultures. These results indicate that transplantation RPE cells could potentially provide a dual benefit in Parkinson's disease producing both dopamine and neurotrophic support of the basal ganglia.