Comparison of HEp-2 and Vero Cell Responses Reveal Unique Proapoptotic Activities of the Herpes Simplex Virus Type 1 α0 Gene Transcript and Product.

Previous studies have provided evidence suggesting a role for apoptosis in the control of Herpes Simplex Virus 1 (HSV-1) latency. HSV-1 induces and then later blocks apoptosis in infected cells. The immediate early viral gene α0, which synthesizes the ICP0 protein, is necessary and sufficient for HSV-1-induced apoptosis in human epithelial (HEp-2) cells. While previous research showed that ICP0 protein synthesis is not necessary for HSV-1-induced apoptosis in infected HEp-2 cells, circumstantial evidence suggested that it might be needed in infected African green monkey kidney (Vero) cells. In this study, we determined the specific aspects of α0 needed to trigger apoptosis in these two cell types. HEp-2 cells transfected with α0 expressing plasmids that generated either full-length, truncated, or no detectable (multiple stop codons) ICP0 protein died through apoptosis. This indicates that ICP0 protein is not necessary for α0-induced apoptosis and that α0 mRNA alone has apoptotic induction properties in HEp-2 cells. We next investigated the primary structure of α0's mRNA to better define its proapoptotic ability. Since α0 is one of the few HSV-1 genes that are spliced, we transfected cells with a plasmid expressing ICP0 from cDNA copy, pcDNAICP0. The cells transfected with pcDNAICP0 underwent apoptosis at a level equivalent to those transfected with the genomic copy of α0, which indicates that neither splicing events nor introns are required for the apoptotic function of α0 in HEp-2 cells. Next, we studied the ability of α0 to cause apoptosis in Vero cells. Since HSV-1-induced apoptosis in Vero cells requires protein synthesis early in infection, proteins synthesized with immediate early kinetics may facilitate apoptosis. Vero cells were transfected with plasmids producing either full-length ICP0 or ICP0 truncated at codon 212. Full-length ICP0, but not truncated ICP0, induced apoptosis in Vero cells. Together, these results suggest that α0 gene expression triggers apoptosis, but ICP0 protein is needed to facilitate apoptosis in Vero cells. In addition, ICP0's facilitation activity may lie in its carboxyl-terminated domain. Thus, our results demonstrate that α0's mRNA and protein possess proapoptotic properties. The requirement for ICP0 protein during HSV-dependent apoptosis appears to be cell type specific.

The Fate of the Fixed Syndesmosis Over Time.

BACKGROUND: A prior study demonstrated statistical widening of the syndesmosis within weeks of elective screw removal. However, no information is available as to the radiographic outcomes of screw retention. The aim of this study was to evaluate radiographic syndesmotic widening and talar shift over time in patients treated with syndesmotic screws and to compare screw removal with retention along with other potential risk factors that may have led to tibia-fibula diastasis after weightbearing. METHODS: One hundred sixty-six skeletally mature patients with ankle fractures and concomitant syndesmotic injuries were treated with syndesmotic reduction and screw fixation. The syndesmosis was evaluated intraoperatively either by a stress test or direct visualization. If the syndesmosis was incompetent, it was reduced and stabilized with syndesmotic screws to maintain reduction. Anteroposterior, mortise, and lateral radiographs at presentation, postoperatively, and at follow-up after weightbearing were evaluated. We measured the medial clear space (MCS), tibia-fibula overlap (OL), and tibia-fibula clear space (CS). Screws that were retained were graded as loose/broken or intact. RESULTS: The fibula shifted an insignificant amount on postoperative mortise radiographs after elective syndesmotic screw removal at 3 months or more after initial fixation, indicated by a slightly greater CS and lower OL. The MCS did not change from preoperative to postoperative screw removal. There was no change in the radiographic markers from the postoperative to final follow-up images in those whose screws became loose or broken. Likewise, there was no radiographic difference if screws remained intact versus those that were loose or broken. CONCLUSION: In contradistinction to prior work, we found that only very mild widening (0.5 mm) of the tibia-fibula space occurred after weightbearing following syndesmotic fixation. The removal of syndesmotic screws at 3 months resulted in a slightly lower OL (<1 mm) and greater CS (0.5 mm) on mortise radiographs than screw retention even if the retained screws loosened or broke. This was not associated with any talar subluxation, and these differences were not statistically significant. The mortise remained intact whether the syndesmotic screws were removed, were loosened or broken, or remained solid. LEVEL OF EVIDENCE: Level IV, retrospective case series.

Influence of treatment modality in outcomes for different stages of resectable esophageal adenocarcinomas.

BACKGROUND: There is no consensus on the most effective modality for the treatment of resectable esophageal adenocarcinomas (EAC). We theorized that treatment modality may influence survival differently depending on the stage of disease. METHODS: A single-institution, retrospective examination of resectable EAC between 2000 and 2008 was performed. Resectable EAC were stratified into early disease (stage 2a or less) and late disease (stage 2b or more) based on pretreatment endoscopic ultrasound (EUS). Patients with T4, >N2, and/or distant disease were excluded. RESULTS: A total of 156 patients were included in this study. Most patients were white (97 %), male (83 %), and over 60 years of age (51 %). Patients with early disease on pretreatment EUS exhibited improved overall survival compared to patients with late disease (P < 0.001). Irrespective of treatment modality, there were no significant differences in overall 5-year survival for patients with early or late disease. Early and late disease patients whose disease responded to neoadjuvant chemotherapy (NAC) had significantly improved overall survival compared to nonresponsive disease (P < 0.05). The only negative independent predictors of overall 5-year survival were late stage disease on pretreatment EUS (hazard ratio 2.402, 95 % confidence interval 1.24-4.67, P = 0.01) and late stage disease on final pathological stage (hazard ratio 2.29, 95 % confidence interval 1.22-4.31, P = 0.01). CONCLUSIONS: Our data lack statistical power but reveal no difference in survival with the addition of neoadjuvant therapies to surgery for early or late resectable EAC. However, patients with disease that responded to NAC had improved outcomes at 5 years for both groups. Therefore, the prognosis for patients undergoing NAC may be optimized by immediate surgical resection if neoadjuvant therapies do not result in a dramatic clinical response.

Does neoadjuvant chemotherapy improve outcomes for patients with gastric cancer?

BACKGROUND: The role of neoadjuvant and adjuvant therapy for gastric cancer remains undefined. We compared the outcomes for patients treated with surgery alone or with the addition of adjuvant or neaodjuvant treatment. METHODS: A single-institution, retrospective evaluation of a prospective database of gastric cancer patients treated from 2000 to 2008 was performed. RESULTS: Overall, 173 patients with gastric cancer underwent surgical extirpation. Of the 173 patients, 43% had early-stage disease (less than stage 2) and 57% had late-stage disease (stage 2 or greater; American Joint Committee on Cancer, 2010). The median survival from the date of diagnosis for those treated with neoadjuvant chemotherapy (NAC) (n = 35), adjuvant chemotherapy (n = 21), adjuvant chemoradiotherapy (n = 18), both NAC and adjuvant chemotherapy (n = 11), or surgery alone (n = 88) was 26.3, 17.3, greater than 60, greater than 60, and 50.3 months, respectively. The addition of NAC to surgery was detrimental to survival in those with early-stage disease (P = 0.002) and did not improve survival in those with late-stage disease (P = 0.687). For those with late-stage disease, surgery with adjuvant chemoradiotherapy exhibited the best overall survival compared with surgery alone (P = 0.021) or surgery with adjuvant chemotherapy (P = 0.01). Patients treated with NAC had a greater rate of R0 resection compared with surgery alone (P = 0.049). CONCLUSIONS: NAC for patients with gastric cancer does not significantly improve the overall outcomes for those with late-stage disease and could be detrimental to survival for those with early-stage disease. However, treatment with NAC resulted in an improved rate of R0 resection.

Ulnar nerve component to innervation of thumb carpometacarpal joint.

PURPOSE: Thumb carpometacarpal (CMC) joint arthritis is one of the most common problems addressed by hand surgeons. The gold standard of treatment for thumb CMC joint arthritis is trapeziectomy, ligament reconstruction and tendon interposition. Denervation of the thumb CMC joint is not currently used to treat arthritis in this joint due to the failure of the procedure to yield significant symptomatic relief. The failure of denervation is puzzling, given that past anatomic studies show the radial nerve is the major innervation of the thumb CMC joint with the lateral antebrachial nerve and the median nerve also innervating this joint. Although no anatomic study has ever shown that the ulnar nerve innervates the CMC joint, due to both the failure of denervation and the success of arthroscopic thermal ablation, we suspect that previous anatomic studies may have overlooked innervation of the thumb CMC joint via the ulnar nerve. METHODS: We dissected 19 formalin-preserved cadaveric hand-to-mid-forearm specimens. The radial, median and ulnar nerves were identified in the proximal forearm and then followed distally. Any branch heading toward the radial side of the hand were followed to see if they innervated the thumb CMC joint. RESULTS: Eleven specimens (58%) had superficial radial nerve innervation to the thumb CMC joint. Nine specimens (47%) had median nerve innervation from the motor branch. Nine specimens (47%) had ulnar nerve innervation from the motor branch. CONCLUSIONS: We believe this is the first study to demonstrate that the ulnar nerve innervates the thumb CMC joint This finding may explain the poor results seen in earlier attempts at denervation of the thumb CMC, but the more favorable results with techniques such as arthroscopy with thermal ablation.