Interleukin 7 and T cell receptor signals regulate homeostasis of CD4 memory cells

Immunological memory depends on the long-term maintenance of memory T cells. Although the factors that maintain CD8 T cell memory are well understood, those responsible for CD4 memory are not well defined. We have shown here that interleukin 7 (IL-7) was an important survival factor for CD4 memory T cells that together with T cell receptor (TCR) signals regulated homeostasis of the CD4 memory population in lymphopenic conditions and in the intact immune system. Thus, IL-7 contributes to the maintenance of all naive and memory T cell subsets, and therefore controls the overall size of the T cell pool.     

The deltaccr5 mutation conferring protection against HIV-1 in Caucasian populations has a single and recent origin in Northeastern Europe

The chemokine receptor CCR5 is encoded by the CMKBR5 gene located on the p21.3 region of human chromosome 3, and constitutes the major co- receptor for the macrophage-tropic strains of HIV-1. A mutant allele of the CCR5 gene, Delta ccr5 , was shown to provide to homozygotes with a strong resistance against infection by HIV. The frequency of the Delta ccr5 allele was investigated in 18 European populations. A North to South gradient was found, with the highest allele frequencies in Finnish and Mordvinian populations (16%), and the lowest in Sardinia (4%). Highly polymorphic microsatellites (IRI3.1, D3S4579 and IRI3.2, D3S4580 ) located respectively 11 kb upstream and 68 kb downstream of the CCR5 gene deletion were used to determine the haplotype of the chromosomes carrying the Delta ccr5 variant. A strong linkage disequilibrium was found between Delta ccr5 and specific alleles of the IRI3.1 and IRI3.2 microsatellites: >95% of the Delta ccr5 chromosomes carried the IRI3.1-0 allele, while 88% carried the IRI3.2-0 allele. These alleles were found respectively in only 2 or 1.5% of the chromosomes carrying a wild-type CCR5 gene. From these data, it was inferred that most, if not all Delta ccr5 alleles originate from a single mutation event, and that this mutation event probably took place a few thousand years ago in Northeastern Europe. The high frequency of the Delta ccr5 allele in Caucasian populations cannot be explained easily by random genetic drift, suggesting that a selection advantage is or has been associated with homo- or heterozygous carriers of the Delta ccr5 allele.      

Equol and other compounds from bovine urine as monoamine oxidase inhibitors

Summary Equol, its methylated derivative, and a carbazole, all isolated from bovine urine, are relatively potent inhibitors of monoamine oxidase with IC₅₀ values of 158, 28, and 16M respectively (using 83M tyramine as substrate). The probable dietary origin of these compounds suggests that natural monoamine oxidase inhibitors may be more widespread than had previously been suspected.     

Short-termin vivo stability of endothelial-lined polyester elastomer and polytetrafluoroethylene grafts

A fibronectin substrate will significantly enhance the strength of endothelial cell attachment on grafts constructed of polyester elastomer (PE) and polytetrafluoroethylene (e-PTFE). This experiment was undertaken to determine the short-termin vivo stability of endothellum on these fibronectin coated surfaces. Eight mongrel dogs underwent bilateral carotid artery replacement with both graft materlals. All grafts were inoculated with 2,000 cells/mm² using cultured autogenous venous endothelium labelled with Indium-111-oxine. The Indium-111 label in the grafts was measured immediately prior to implantation, after 1 hour ofin vivo perfusion, and at explantation after 24 hours. The percentage of inoculated cells attached to the grafts before perfusion was simillar for both materials, 93.3±3.0% versus 92.2±7.2%, for PE and e-PTFE respectively. All grafts were patent at one hour after implantation. PE grafts were found to have 93.8±3.9 % of the attached cells present at one hour while e-PTFE grafts had only 54.5 ± 10.8 % remaining, p<.001. After 24 hours, 5/8 (62.5%) e-PTFE grafts and 2/8 (25.0 %) PE grafts remained patent, p=.13. Of the patent grafts however, endothelial cell retention was still superior on the PE grafts with 78.0±0.6% of the attached cells remaining compared to only 24.5±6.1% on e-PTFE, p<.001. Occluded PE grafts had fewer cells remaining at 24 hours than patent ones, 78.0±0.6% versus 31.1±32.8%, respectively, p=.13. Histologically, patent PE grafts demonstrated nearly confluent endothelial monolayers while e-PTFE had patches of endothelial cells surrounded by, a platelet-fibrin carpet. We conclude that short-term patency appears to be determined by the extent of endothelial retention on PE but not e-PTFE.     

Mitigating disparity in children with acute appendicitis: Impact of patient-driven protocols

PurposePrevious reports in the literature demonstrate racial and ethnic disparities for children diagnosed with acute appendicitis, with minorities experiencing worse outcomes. At our institution, we have developed an evidence based patient driven protocol for children following laparoscopic appendectomy. However, the influence of such protocol on mitigating racial and ethnic disparities in outcomes remains unknown. The purpose of our study is to assess the impact of our protocol by evaluating the influence of race and ethnicity on surgical outcomes among children treated for acute appendicitis.Material and methodsA retrospective review of prospectively collected data was conducted. Children undergoing a laparoscopic appendectomy at our freestanding children's hospital between December 2015 and July 2017 were included. Demographic data, post-operative length of stay, same day discharge rates and hospital readmission rates were abstracted from patient medical records. Patients were classified by their race and ethnic background. Comparative analysis was performed in STATA with a p value < .05 determined as significant.ResultsA total of 786 children were included, with the majority being either White (70%, n = 547), Black (8%, n = 62) or Hispanic (17%, n = 133); 569 patients (72%) were found to have non-perforated appendicitis. There was no statistically significant difference in the rates of same day discharge among White, Black or Hispanic children respectively (88% vs. 77% vs. 86%, p = .126). Of the 217 children with perforated appendicitis, Hispanic children had increased rates of perforation (41%, n = 55) compared to White and Black children respectively (23%, n = 128 and 29%, n = 18, p = .001). However, average post-operative length of stay were similar among White, Black and Hispanic children (96 h vs. 95 h vs. 98 h, p = .015). On multivariate analysis, the only significant risk factor for an elevated post-operative length of stay was the presence of a perforation.ConclusionOur evidence based patient driven protocol effectively mitigates racial and ethnic disparities found in children with acute appendicitis. Further prospective investigation into the role of such patient-driven protocols to mitigate healthcare disparities is warranted.Levels of EvidenceTherapeutic study; Level 3.     

Periadventitial dissection of the superior mesenteric artery for locally advanced pancreatic cancer: Surgical planning with the “halo sign” and “string sign”

Most patients diagnosed with pancreatic cancer are classified as nonoperative candidates based on the contemporary guidelines of resectability. The advent of more potent control of systemic disease using neoadjuvant chemotherapy has enabled more aggressive operative interventions. In our multidisciplinary practice, patients with Stage III, locally advanced pancreatic cancer and superior mesenteric artery (SMA) encasement are now carefully triaged with high quality, preoperative imaging to determine if they can be considered candidates for operative resection with periadventitial dissection of the SMA. Patients displaying a “halo sign,” where the encased SMA remains fully patent and free from arterial invasion, are now candidates for SMA periadventitial dissection. This procedure involves the surgical stripping of the infiltrated neurolymphatic tissue off the SMA leaving behind a bare “skeletonized artery.” Alternatively, the “string sign” involving the SMA confers a more likely case of arterial invasion, where a complete oncologic resection cannot be achieved successfully. This method of patient selection in case of SMA involvement abandons the traditional metrics of circumferential degrees of the arterial encasement to guide surgical decisions. Our institutional approach has allowed us to meaningfully expand our operative methods of resection with the potential for improved longitudinal outcomes to pancreatic cancer patients who were deprived historically from the more effective and possibly curative treatment.