Broadly-specific Cytotoxic T Cells Targeting Multiple HIV Antigens Are Expanded From HIV+ Patients: Implications for Immunotherapy

Antiretroviral therapy (ART) is unable to eradicate human immunodeficiency virus type 1 (HIV-1) infection. Therefore, there is an urgent need to develop novel therapies for this disease to augment anti-HIV immunity. T cell therapy is appealing in this regard as T cells have the ability to proliferate, migrate, and their antigen specificity reduces the possibility of off-target effects. However, past human studies in HIV-1 infection that administered T cells with limited specificity failed to provide ART-independent, long-term viral control. In this study, we sought to expand functional, broadly-specific cytotoxic T cells (HXTCs) from HIV-infected patients on suppressive ART as a first step toward developing cellular therapies for implementation in future HIV eradication protocols. Blood samples from seven HIV+ patients on suppressive ART were used to derive HXTCs. Multiantigen specificity was achieved by coculturing T cells with antigen-presenting cells pulsed with peptides representing Gag, Pol, and Nef. All but two lines were multispecific for all three antigens. HXTCs demonstrated efficacy as shown by release of proinflammatory cytokines, specific lysis of antigen-pulsed targets, and the ability to suppress HIV replication in vitro. In conclusion, we are able to generate broadly-specific cytotoxic T cell lines that simultaneously target multiple HIV antigens and show robust antiviral function.     

Stability of Intimate Partner Violence by Men across 12?Years in Young Adulthood: Effects of Relationship Transitions

The present study examined the stability of young men??s intimate partner violence (IPV) over a 12-year period as a function of relationship continuity or discontinuity. Multiwave measures of IPV (physical and psychological aggression) were obtained from 184 men at risk for delinquency and their women partners. The effects of relationship continuity versus transitions on change in IPV were examined using multilevel analyses. In general, men??s IPV decreased over time. Men??s physical aggression in their early 20s predicted levels of physical aggression about 7?years later, and men??s psychological aggression in their early 20s predicted levels of psychological aggression about 10?C12?years later. As hypothesized, higher stability in IPV was found for men who stayed with the same partners, whereas men experiencing relationship transitions showed greater change. The IPV of new partners was linked to the changes in men??s IPV that occurred with repartnering. There was less change in men??s IPV over time as men changed partners less frequently.     

Laparoscopic modified Sugarbaker technique results in superior recurrence rate

Background

Parastomal hernia (PH) is a frequent complication of stoma formation, occurring in 35?C50?% of patients. Recurrence after repair is common, ranging from 24 to 54?% of cases. We hypothesized that repair using a laparoscopic modified Sugarbaker technique (SB) would result in a superior recurrence rate when compared with other repairs.

Methods

An Institutional Review Board-approved retrospective review of patients who underwent PH repair between 2004 and 2011 was performed. We collected demographics, factors related to ostomy formation, risk factors for hernia, intraoperative and postoperative information, as well as the absence or presence of PH on their last physical examination or imaging study.

Results

Forty-nine PH repairs were performed: 33 (67?%) para-ileostomy and 16 (33?%) para-colostomy. Repairs included 14 laparoscopic modified SB, 19 laparoscopic keyhole, 11 ostomy re-sitings, and 5 open primary repairs. There was no statistically significant difference between groups when comparing age, BMI, smoking status, steroid use, ostomy type, location, primary diagnoses, or complication rate. Recurrence rates were 0?% for SB, 58?% for keyhole, 64?% for re-siting, and 20?% for open repair. When SB was compared with all groups, the incidence of recurrence was significantly lower (p?<?0.001) but follow-up was as well (7.2 vs 32.7?months). When analysis was restricted to the 28 repairs performed between 2009 and 2011, there was no significant difference between the groups in terms of demographics or follow-up period (7.2?months for SB group versus 11.8?months for all others), but again there was a significant difference in recurrence (0 of 14 for the SB group vs 8 of 14, p?<?0.01). In addition, there were no differences in postoperative complication rates among all techniques.

Conclusion

The modified SB technique may offer patients a significant decrease in the risk of recurrence compared with other PH repair techniques with no significant increase in postoperative complications.     

The ability of statins to inhibit bone resorption is directly related to their inhibitory effect on HMG-CoA reductase activity.

Statins, which are inhibitors of 3-hydroxy-3-glutaryl-coenzyme A (HMG-CoA) reductase, decrease the hepatic biosynthesis of cholesterol by blocking the mevalonate pathway. Nitrogen-containing bisphosphonate drugs also inhibit the mevalonate pathway, preventing the production of the isoprenoids, which consequently results in the inhibition of osteoclast formation and osteoclast function. Therefore, we hypothesized that statins could affect bone metabolism in vivo through effects on osteoclastic bone resorption. In vitro, cerivastatin inhibited the parathyroid hormone (PTH)-stimulated bone resorption. Using a panel of 40 statin analogs, which showed variable effects on HMG-CoA reductase activity, we found that the ability of compounds to inhibit bone resorption is directly related to HMG-CoA reductase activity. However, in the thyro-parathyrodectomy (TPTX) model for bone resorption in the rat in vivo, cerivastatin did not prevent experimentally induced increases in bone resorption. The lack of effect of cerivastatin in this model is not related to a limited penetration of the target tissue (bone marrow), because a significant effect on HMG-CoA reductase activity was demonstrated in the total rat bone marrow cell extracts of rats posttreatment in vivo. Furthermore, cerivastatin inhibited protein prenylation in osteoclasts isolated from the rabbit bone marrow of rabbits after treatment in vivo. In contrast to other studies, none of the statins tested showed anabolic effects in parietal bone explant cultures. Taken together, we conclude that statins inhibit bone resorption in vitro, which correlates directly with the potency of the compounds for inhibition of HMG-CoA reductase activity. However, cerivastatin does not affect bone resorption in the rat TPTX model in vivo.     

Bilateral popliteal vein aneurysms

An 82-year-old man was admitted with a left hip fracture sustained in a fall. The fracture was surgically repaired. Ipsilateral leg swelling developed over the following 2 weeks. A lower extremity venous duplex scan demonstrated isolated dilatation of the popliteal veins in both lower extremities. Chronic thrombosis was noted in both popliteal veins at the level of this dilatation. Initial duplex scanning also revealed acute thrombus in the left popliteal, posterior tibial, and peroneal veins. A repeat scan 1 week later identified propagation of thrombus into the superficial femoral vein. Popliteal vein aneurysms, although rare, can cause significant morbidity and mortality. The literature is also reviewed.Presented at the Second Annual Winter Meeting of the Peripheral Vascular Surgery Society, Breckenridge, Colo., January 25–27, 1992.