Radiographic Outcomes, Union Rates, and Complications Associated With Plantar Implant Positioning for Midfoot Arthrodesis.

BACKGROUND: Midfoot arthrodesis has long been successfully included in the treatment paradigm for a variety of pathologic foot conditions. A concern with midfoot arthrodesis is the rate of nonunion, which historically has been reported between 5% and 10%. Plantar plating has also been noted to be more biomechanically stable when compared to traditional dorsal plating in previous studies. Practical advantages of plantar plating include less dorsal skin irritation and the ability to correct flatfoot deformity from the same medial incision. The purpose of this study is to report the arthrodesis rate, the success of deformity correction, and the complications associated with plantar-based implant placement for arthrodesis of the medial column. METHODS: A retrospective review was undertaken of all consecutive patients between 2012 and 2019 that underwent midfoot arthrodesis with plantar-positioned implants. Radiographic outcomes and complications are reported on 62 patients who underwent midfoot arthrodesis as part of a correction for hallux valgus deformity, flatfoot deformity, degenerative arthritis, Lisfranc injury, or Charcot neuroarthropathy correction. RESULTS: Statistically significant improvement was seen in the lateral talus-first metatarsal angle (Meary angle) and medial arch sag angle for patients treated for flatfoot deformity correction. In patients treated for hallux valgus deformity, there was a reduction in the intermetatarsal angle from 15.4 to 6.8 degrees. The overall nonunion rate was 6.45% in all patients. The rate of nonunion was higher at the NC joint compared to the TMT joint and with compression claw plates. One symptomatic nonunion required revision surgery (1.7%). There were no nonunions when excluding neuroarthropathy patients and smokers. The odds ratio (OR) for nonunion in patients with neuroarthropathy was 6.05 (P < .05), and in active smokers the OR was 2.33 (P < .05). CONCLUSION: Plates placed on the plantar bone surface for midfoot arthrodesis achieved and maintained deformity correction with rare instances of symptomatic hardware for a variety of orthopedic conditions. An overall clinical and radiographic union rate of 94% was achieved. The radiographic union rate improved to 100% when excluding both neuroarthropathy patients and smokers. The incidence of nonunion was higher in smokers, neuroarthropathy patients, naviculocuneiform joint fusions, use of compression claw plates, and when attempting to fuse multiple joints. Incisional healing complications were rarely seen other than in active smokers. LEVEL OF EVIDENCE: Level IV, case series.

A retrospective review of 112 patients undergoing arthroscopic suprascapular nerve decompression.

BACKGROUND: Arthroscopic suprascapular nerve release has yielded good results previously. However, comprehensive literature is still lacking. PURPOSE: This study assessed results of suprascapular nerve release in patients with intractable shoulder pain with confirmed suprascapular neuropathy. METHODS: Retrospectively reviewed patients undergoing suprascapular nerve release. Patients were evaluated with VAS scores and supraspinatus/infraspinatus strength. RESULTS: 112 patients were included showing reduction in VAS pain scores from the initial visit to final follow up. Additionally, improvement in both supra/infraspinatus strength occurred. There were no major complications. CONCLUSION: This series demonstrates improvement in pain and strength following suprascapular nerve release with limited risk. LEVEL OF EVIDENCE: IV.

Whole body vibration therapy: a novel potential treatment for type 2 diabetes mellitus.

There is a worsening epidemic of obesity and diabetes in the world. Life style interventions including dietary changes and increase in exercise can improve glucose metabolism and health in general. However, standard exercise programs are strenuous, time-consuming, and thus have low long-term compliance issues. We tested the feasibility of using high frequency, low amplitude whole body vibration (WBV) therapy to improve glucose metabolism in young type 2 diabetic (T2DM) mice. We also aimed to investigate the postulated anti-inflammatory and cytoprotective properties of WBV. Male db/db and db/m mice were exposed to high frequency, low-amplitude WBV. Outcome parameters comprised of body weight, hemoglobin A1c (HbA1c) level, as well as interleukin (IL)-17 (a marker of helper T cells), forkhead box P3 (Foxp3; a marker of regulatory T cells), and gammaH2AX (an index of DNA injury) expression. Furthermore, a 24 h metabolic cage study was carried out immediately after the WBV protocol and fluid intake, urine excretion and urine osmolality were determined. WBV did not affect body weight but improved HbA1c levels in db/db mice. Vibrated db/db mice demonstrated less fluid intake and urine excretion but better urinary concentrating ability than their non-vibrated controls. Pro-inflammatory changes were significantly reduced, as indicated by reduced IL-17 but increased Foxp3 expression. WBV reduced gammaH2AX in db/db mice suggestive of cytoprotective effect. However, WBV was largely without significant effects on assessed parameters in db/m mice. Collectively, our findings suggest that daily, short duration WBV may improve glycemic control, polydipsia, polyuria, and urine osmolality in T2DM in association with reduced inflammation. Thus, WBV may be a viable adjunctive treatment strategy in T2DM.

Pharmacological reversal of histone methylation presensitizes pancreatic cancer cells to nucleoside drugs: in vitro optimization and novel nanoparticle delivery studies.

We evaluated the potential of an investigational histone methylation reversal agent, 3-deazaneplanocin A (DZNep), in improving the chemosensitivity of pancreatic cancer to nucleoside analogs (i.e., gemcitabine). DZNep brought delayed but selective cytotoxicity to pancreatic cancer cells without affecting normal human pancreatic ductal epithelial (HPDE) cells. Co-exposure of DZNep and gemcitabine induced cytotoxic additivity or synergism in both well- and poorly-differentiated pancreatic cell lines by increased apoptosis. In contrast, DZNep exerted antagonism with gemcitabine against HPDE cells with significant reduction in cytotoxicity compared with the gemcitabine-alone regimen. DZNep marginally depended on purine nucleoside transporters for its cytotoxicity, but the transport dependence was circumvented by acyl derivatization. Drug exposure studies revealed that a short priming with DZNep followed by gemcitabine treatment rather than co-treatment of both agents to produce a maximal chemosensitization response in both gemcitabine-sensitive and gemcitabine-resistant pancreatic cancer cells. DZNep rapidly and reversibly decreased trimethylation of histone H3 lysine 27 but increased trimethylation of lysine 9 in an EZH2- and JMJD1A/2C-dependent manner, respectively. However, DZNep potentiation of nucleoside analog chemosensitization was found to be temporally coupled to trimethylation changes in lysine 27 and not lysine 9. Polymeric nanoparticles engineered to chronologically release DZNep followed by gemcitabine produced pronounced chemosensitization and dose-lowering effects. Together, our results identify that an optimized DZNep exposure can presensitize pancreatic cancer cells to anticancer nucleoside analogs through the reversal of histone methylation, emphasizing the promising clinical utilities of epigenetic reversal agents in future pancreatic cancer combination therapies.

Novel C-1 substituted cocaine analogs unlike cocaine or benztropine.

Despite a wealth of information on cocaine-like compounds, there is no information on cocaine analogs with substitutions at C-1. Here, we report on (R)-(-)-cocaine analogs with various C-1 substituents: methyl (2), ethyl (3), n-propyl (4), n-pentyl (5), and phenyl (6). Analog 2 was equipotent to cocaine as an inhibitor of the dopamine transporter (DAT), whereas 3 and 6 were 3- and 10-fold more potent, respectively. None of the analogs, however, stimulated mouse locomotor activity, in contrast to cocaine. Pharmacokinetic assays showed compound 2 occupied mouse brain rapidly, as cocaine itself; moreover, 2 and 6 were behaviorally active in mice in the forced-swim test model of depression and the conditioned place preference test. Analog 2 was a weaker inhibitor of voltage-dependent Na+ channels than cocaine, although 6 was more potent than cocaine, highlighting the need to assay future C-1 analogs for this activity. Receptorome screening indicated few significant binding targets other than the monoamine transporters. Benztropine-like "atypical" DAT inhibitors are known to display reduced cocaine-like locomotor stimulation, presumably by their propensity to interact with an inward-facing transporter conformation. However, 2 and 6, like cocaine, but unlike benztropine, exhibited preferential interaction with an outward-facing conformation upon docking in our DAT homology model. In summary, C-1 cocaine analogs are not cocaine-like in that they are not stimulatory in vivo. However, they are not benztropine-like in binding mechanism and seem to interact with the DAT similarly to cocaine. The present data warrant further consideration of these novel cocaine analogs for antidepressant or cocaine substitution potential.

Synthesis and applications of masked oxo-sulfinamides in asymmetric synthesis.

This short perspective reports on the synthesis and applications of a class of chiral amino carbonyl compounds, masked oxo-sulfinamides where the amine is protected with an N-sulfinyl moiety and the carbonyl group is protected as the ketal or 1,3-dithiane. These polyfunctionalized chiral building blocks are prepared by addition of organometallic reagents to masked oxo-sulfinimines (N-sulfinyl imines) or the addition of oxo-organometallic reagents and lithio-1,3-dithianes to sulfinimines. Because unmasking of the amino and carbonyl groups results in cyclic imines, these chiral building blocks are particularly useful for the asymmetric synthesis of functionalized nitrogen heterocycles, including prolines, pipecolic acids, pyrrolidines, homotropinones, tropinones, and tropane alkaloids such as cocaine and C-1 cocaine analogues.

Enantioselective synthesis of cocaine C-1 analogues using sulfinimines (N-sulfinyl imines).

The first examples of cocaine analogues having substituents (methyl, ethyl, n-propyl, n-pentyl, and phenyl) at the C-1 position of the cocaine tropane skeleton were prepared by heating sulfinimine-derived α,ß-unsaturated pyrrolidine nitrones. In the presence of the Lewis acid Al(O(t)Bu)(3) the nitrones undergo an intramolecular [3 + 2] cycloaddition to give tricyclic isoxazolidines that were transformed in three steps to the cocaine analogues. In the absence of the Lewis acid, lactams were formed resulting from rearrangement of the nitrone to an oxaziridine. A novel Pd- and base-promoted rearrangement of methanesulfonate salts of isoxazolidine to bridge bicyclic[4.2.1]isoxazolidines was discovered.

Asymmetric synthesis of anti-α-substituted ß-amino ketones from sulfinimines.

Previously unknown, enantiopure, ß-amino ketones were prepared in modest yield by addition of lithium reagents to N-sulfinyl anti-α-substituted ß-amino Weinreb amides. Grignard reagents failed to add to these Weinreb amides in contrast to the syn-α-substituted isomers which did. The anti-α-substituted ß-amino Weinreb amides were prepared by addition of LiN(OMe)Me to the corresponding N-sulfinyl anti-α-substituted ß-amino esters because α-alkylation of N-sulfinyl ß-amino Weinreb amide enolates resulted in poor diastereoselectivities.

Asymmetric total synthesis of (S)-(+)-cocaine and the first synthesis of cocaine C-1 analogs from N-sulfinyl ß-amino ester ketals.

Sulfinimine-derived α,ß-unsaturated pyrrolidine nitrones, on heating with Al(O-t-Bu)(3), undergo a highly stereoselective intramolecular [3 + 2] cycloaddition to give tricyclic isoxazolidines, which are transformed in three-steps to give C-1 substituted cocaine analogs.

Asymmetric synthesis of cyclic cis-beta-amino acid derivatives using sulfinimines and prochiral Weinreb amide enolates.

Cyclic cis-beta-amino Weinreb amides, valuable building blocks for the asymmetric synthesis of cyclic beta-amino acids derivatives, are readily prepared via ring-closing metathesis of sulfinimine-derived N-sulfinyl beta-amino diene Weinreb amides. These unsaturated cyclic cis-beta-amino Weinreb amides are valuable building blocks for the asymmetric synthesis of cyclic beta-amino acid derivatives.

Asymmetric synthesis of substituted homotropinones from N-sulfinyl beta-amino ketone ketals. (-)-Euphococcinine and (-)-adaline.

Sulfinimine-derived N-sulfinyl beta-amino ketone ketals on heating with NH(4)OAc:HOAc undergo a four-step intramolecular Mannich cyclization cascade reaction to give homotropinones, such as (-)-euphococcinine, in excellent yields as single isomers.

Total synthesis of (5R,6R,8R,9S)-(-)-5,9Z-indolizidine 221T using sulfinimine-derived N-sulfinyl beta-amino ketones.

The first total asymmetric synthesis of the poison frog alkaloid (-)-221T, a 5,6,8-trisubstituted indolizidine is described. The key core piperidine ring was constructed via an acid catalyzed intramolecular cascade Mannich cyclization reaction of a N-sulfinyl syn-alpha-methyl beta-amino ketone and crotonaldehyde. The beta-amino ketone was prepared via the reaction of prochiral lithium Weinreb amide enolate with an enantiopure N-2,4,6-triisopropylphenylsulfinyl imine.

Asymmetric synthesis of substituted tropinones using the intramolecular mannich cyclization reaction and acyclic N-sulfinyl beta-amino ketone ketals.

Sulfinimine-derived, enantiopure N-sulfinyl beta-amino ketone ketals on hydrolysis give dehydropyrrolidine ketones that on treatment with (Boc)(2)O/DMAP afford substituted tropinones in good yield.

Vinylaluminum addition to sulfinimines (N-sulfinyl imines). Asymmetric synthesis of anti-alpha-alkyl beta-amino esters.

Addition of vinylaluminum NMO reagents to N-(p-toluenesufinyl)- and N-(2-methypropanesulfinyl)-derived sulfinimines gives N-sulfinyl aza-Morita-Baylis-Hillman products (dr = 7:1 to 12:1) that result from addition of the reagent from the least hindered direction. Hydrogenation of the aza-MBH adducts with a Rh(I) catalyst affords anti-alpha-substituted N-sulfinyl-beta-amino esters in good yield and high dr (10:1 to 21:1).

Asymmetric synthesis of (2S,3R)-(-)-epi-CP-99,994 using sulfinimine-derived anti-2,3-diamino esters.

A differentially protected C-3 N-sulfinyl, C-2 N,N-(diphenylmethylene) 2,3-diamino ester was employed in the synthesis of the amino piperidine (2S,3R)-(-)-epi-CP-99,994. Key steps in the synthesis included the chemoselective hydrolysis of the C-2 N,N-(diphenylmethylene) group and its reprotection as a dibenzylamino group.

Asymmetric synthesis of acyclic 1,3-amino alcohols by reduction of N-sulfinyl beta-amino ketones. Formal synthesis of (-)-pinidinol and (+)- epipinidinol.

Stereoselective reduction of acyclic N-sulfinyl beta-amino ketones with (LiEt(3)BH) and Li(t-BuO)(3)AlH, respectively, gave anti- and syn-1,3-amino alcohols with excellent selectivity. A formal asymmetric synthesis of the hydroxy piperidine alkaloids (-)-pinidinol and (+)-epipinidinol from a common N-sulfinyl beta-amino ketone ketal precursor was developed. The pinidinol piperidine ring was formed via a novel acid-catalyzed cascade reaction of a N-sulfinylamino silyl protected alcohol ketal.

Asymmetric synthesis of cis- and trans-2,5-disubstituted pyrrolidines from 3-oxo pyrrolidine 2-phosphonates: synthesis of (+)-preussin and analogs.

Pyrrolidine enones, derived from 3-oxo pyrrolidine 2-phosphonates and a HWE reaction with aldehydes, on Luche reduction give pyrrolidine allylic alcohols. The alcohols on hydrogenation (Pd/H2) give cis-2,5-disubstituted pyrrolidines and on treatment with TFA-NaBH3CN undergo a hydroxy directed reduction to trans-2,5-disubstituted pyrrolidines.

Synthesis of polysubstituted pyrroles from sulfinimines (N-sulfinyl imines).

Polysubstituted 2-carboxylate and 2-phosphonate pyrroles are prepared by aromatization of the corresponding 3-oxo 2-carboxylate and 2-phosphonate NH-pyrrolidines using air. Reaction of electrophiles with 3-oxo pyrrolidine dianions readily introduces substituents, regioselectively at C-4 in these pyrrolidines.

alpha-Amino 1,3-Dithioketal Mediated Asymmetric Synthesis of Piperidines (L-733,060) and Tetrahydrofuran Glycines.

Sulfinimine-derived alpha-amino 1,3-dithianes, alpha-amino carbonyl chiral building blocks, are utilized in asymmetric syntheses of (+)-(tetrahydrofuran-2-yl)glycine and the 2,3-disubstituted piperidine (+)-L-733,060.