Lymphoid Tissue Damage in HIV-1 Infection Depletes Naïve T Cells and Limits T Cell Reconstitution after Antiretroviral Therapy

Highly active antiretroviral therapy (HAART) can suppress HIV-1 replication and normalize the chronic immune activation associated with infection, but restoration of naïve CD4+ T cell populations is slow and usually incomplete for reasons that have yet to be determined. We tested the hypothesis that damage to the lymphoid tissue (LT) fibroblastic reticular cell (FRC) network contributes to naïve T cell loss in HIV-1 infection by restricting access to critical factors required for T cell survival. We show that collagen deposition and progressive loss of the FRC network in LTs prior to treatment restrict both access to and a major source of the survival factor interleukin-7 (IL-7). As a consequence, apoptosis within naïve T cell populations increases significantly, resulting in progressive depletion of both naïve CD4+ and CD8+ T cell populations. We further show that the extent of loss of the FRC network and collagen deposition predict the extent of restoration of the naïve T cell population after 6 month of HAART, and that restoration of FRC networks correlates with the stage of disease at which the therapy is initiated. Because restoration of the FRC network and reconstitution of naïve T cell populations are only optimal when therapy is initiated in the early/acute stage of infection, our findings strongly suggest that HAART should be initiated as soon as possible. Moreover, our findings also point to the potential use of adjunctive anti-fibrotic therapies to avert or moderate the pathological consequences of LT fibrosis, thereby improving immune reconstitution

CXCR5⁺ follicular cytotoxic T cells control viral infection in B cell follicles

During unresolved infections, some viruses escape immunological control and establish a persistant reservoir in certain cell types, such as human immunodeficiency virus (HIV), which persists in follicular helper T cells (TFH cells), and Epstein-Barr virus (EBV), which persists in B cells. Here we identified a specialized group of cytotoxic T cells (TC cells) that expressed the chemokine receptor CXCR5, selectively entered B cell follicles and eradicated infected TFH cells and B cells. The differentiation of these cells, which we have called 'follicular cytotoxic T cells' (TFC cells), required the transcription factors Bcl6, E2A and TCF-1 but was inhibited by the transcriptional regulators Blimp1, Id2 and Id3. Blimp1 and E2A directly regulated Cxcr5 expression and, together with Bcl6 and TCF-1, formed a transcriptional circuit that guided TFC cell development. The identification of TFC cells has far-reaching implications for the development of strategies to control infections that target B cells and TFH cells and to treat B cell–derived malignancies

Near-infrared spectroscopy-derived tissue oxygen saturation in battlefield injuries: a case series report

BACKGROUND: Near-infrared spectroscopy technology has been utilized to monitor perfusion status in animal models of hemorrhagic shock and in human traumatic injury. To observe the effectiveness of such a device in a combat setting, an FDA-approved device was used in conjunction with standard resuscitation and therapy of wounded patients presenting to the 228(th )Combat Support Hospital (CSH), Company B, over a three-month period. MATERIALS AND METHODS: These observations were performed on patients presenting to the 228(th )CSH, Co B, at Forward Operating Base Speicher, outside of Tikrit, Iraq, between the dates of June 15 and September 11, 2005. We utilized the Inspectra™ 325 tissue oxygen saturation (StO(2)) monitor (Hutchinson Technology, Inc; Hutchinson, MN, USA) with the probe placed on the thenar eminence or on another appropriate muscle bed, and used to monitor StO(2 )during early resuscitation and stabilization of patients. RESULTS: During the above time period, 161 patients were evaluated at the CSH as a result of traumatic injury and the device was placed on approximately 40 patients. In most patients, StO(2 )readings of greater than 70% were noted during the initial evaluation. No further information was collected from these patients. In 8 patients, convenience samples of StO(2 )data were collected along with pertinent physiologic data. In these patients, StO(2 )levels of below 70% tracked with hypotension, tachycardia, and clinical shock resulted in increases in StO(2 )after resuscitation maneuvers. CONCLUSION: Near-infrared spectroscopy-derived StO(2 )reflected and tracked the resuscitation status of our patients with battlefield injuries. StO(2 )has significant potential for use in resuscitation and care of patients with battlefield injuries

Correction: Fucoidans inhibit the formation of post-operative abdominal adhesions in a rat model.

[This corrects the article DOI: 10.1371/journal.pone.0207797.]

Fucoidans inhibit the formation of post-operative abdominal adhesions in a rat model.

PURPOSE:Fibrin clot is essential for post-operative abdominal adhesion formation. Fucoidans, sulfated polysaccharides, inhibit fibrin clot formation. In addition, they inhibit inflammation and fibrosis, which also play important roles in adhesion formation. The purpose of this study was to evaluate fucoidans' potential for inhibiting post-operative abdominal adhesions and measure their effects on systemic coagulation parameters when administered intraperitoneally (IP). METHODS AND MATERIALS:Female Sprague Dawley rats were studied. A 2.5x2.5cm full thickness segment of abdominal wall was excised. The skin edges were approximated. This model induces extensive adhesions and allows objective quantitation. Three fucoidans were evaluated- Sigma Fucoidan Crude (SFC), Fucus vesiculosis 95% (Sigma) and, Peridan. One protocol involved continuous infusion into the abdomen from a subcutaneous osmotic pump. Alternatively, boluses of the solutions were injected IP at the end of the operation. Rats were sacrificed a week later. Adhesion extent was scored. Systemic coagulation effects of fucoidans were also evaluated. INR and aPTT were measured following IP injection of the fucoidan solutions and after 7 days of continuous infusion. RESULTS:Animals given a continuous infusion of either SFC or Peridan yielded adhesion reduction of 80 to 90% from control. Bolus Peridan had no discernable influence on adhesion formation, but a single bolus of SFC caused significant adhesion reductions. Peridan resulted in prompt aPTT elevations which fell to nearly normal by 5 hours. The maximum peak value after SFC injection was seen in 15 hours. The maximal INR elevations were around 2. Measurement of INR and aPTT after a week of continuous infusion of either Peridan or SFC, were always in the normal control range. The third agent, Sigma, frequently yielded intraperitoneal infection found at autopsy. CONCLUSIONS:These findings indicate that selected fucoidans infused intraperitoneally for a week after abdominal operations reduce adhesion extent by up to 90%

Metabolomics in COPD Acute Respiratory Failure Requiring Noninvasive Positive Pressure Ventilation

We aimed to investigate whether metabolomic analysis can discriminate acute respiratory failure due to COPD exacerbation from respiratory failure due to heart failure and pneumonia. Since COPD exacerbation is often overdiagnosed, we focused on those COPD exacerbations that were severe enough to require noninvasive mechanical ventilation. We enrolled stable COPD subjects and patients with acute respiratory failure requiring noninvasive mechanical ventilation due to COPD, heart failure, and pneumonia. We excluded subjects with history of both COPD and heart failure and patients with obstructive sleep apnea and obstructive lung disease other than COPD. We performed metabolomics analysis using NMR. We constructed partial least squares discriminant analysis (PLS-DA) models to distinguish metabolic profiles. Serum (p=0.001, R2 = 0.397, Q2 = 0.058) and urine metabolic profiles (p<0.001, R2 = 0.419, Q2 = 0.142) were significantly different between the four diagnosis groups by PLS-DA. After excluding stable COPD patients, the metabolomes of the various respiratory failure groups did not cluster separately in serum (p=0.2, R2 = 0.631, Q2 = 0.246) or urine (p=0.065, R2 = 0.602, Q2 = −0.134). However, several metabolites in the serum were reduced in patients with COPD exacerbation and pneumonia. We did not find a metabolic profile unique to COPD exacerbation, but we were able to clearly and reliably distinguish stable COPD patients from patients with respiratory failure in both serum and urine

In-theater Peritoneal Dialysis for Combat-related Renal Failure

BACKGROUND: Complications of renal failure may prevent timely evacuation of injured soldiers. Conventional renal replacement therapy is not available in forward surgical units. METHODS: Records of in-theater improvised peritoneal dialysis (IPD) in level III hospitals or forward surgical units in Iraq or Afghanistan were reviewed to determine the following: cause of renal failure and associated injuries; type of dialysate, peritoneal access, and exchange technique; and patient outcome. These data were used to propose method for IPD using commonly available materials. RESULTS: IPD is described in four patients. Abdominal or chest drains were used with either improvised dextrose-electrolyte solution or commercial dialysate. Exchanges were successful, despite fresh surgical wounds including full laparotomy, removed excess fluid and restored acid and electrolyte balance, but did not correct azotemia. Open abdominal packing prevented continuation of IPD after 48 hours. Two patients fully recovered, one died, and one patient with a poor prognosis was lost to follow-up. CONCLUSION: IPD can be delivered effectively using readily available materials in forward surgical units and level III combat support hospitals

In-theater Peritoneal Dialysis for Combat-related Renal Failure

BACKGROUND: Complications of renal failure may prevent timely evacuation of injured soldiers. Conventional renal replacement therapy is not available in forward surgical units. METHODS: Records of in-theater improvised peritoneal dialysis (IPD) in level III hospitals or forward surgical units in Iraq or Afghanistan were reviewed to determine the following: cause of renal failure and associated injuries; type of dialysate, peritoneal access, and exchange technique; and patient outcome. These data were used to propose method for IPD using commonly available materials. RESULTS: IPD is described in four patients. Abdominal or chest drains were used with either improvised dextrose-electrolyte solution or commercial dialysate. Exchanges were successful, despite fresh surgical wounds including full laparotomy, removed excess fluid and restored acid and electrolyte balance, but did not correct azotemia. Open abdominal packing prevented continuation of IPD after 48 hours. Two patients fully recovered, one died, and one patient with a poor prognosis was lost to follow-up. CONCLUSION: IPD can be delivered effectively using readily available materials in forward surgical units and level III combat support hospitals