Influence of ultra-low dose Aprotinin on thoracic surgical operations: a prospective randomized trial

<p>Abstract</p> <p>Background</p> <p>The blood saving effect of aprotinin has been well documented in cardiac surgery. In thoracic surgery, very few recent studies, using rather high doses of aprotinin, have shown a similar result. In a randomized prospective trial, we have tested the influence of aprotinin using an ultra-low dose drug regime.</p> <p>Methods</p> <p>Fifty-nine patients, mean age 58 ± 13.25 years (mean ± SD) undergoing general thoracic procedures were randomized into placebo (Group A) and treatment group (Group B). The group B (n = 29) received 500.000 IU of aprotinin after induction to anesthesia and a repeat dose immediately after chest closure. A detailed protocol with several laboratory parameters was recorded. Patients were transfused when perioperative Ht was less than 26%.</p> <p>Results</p> <p>The two groups were similar in terms of age, gender, diagnosis, pathology, co-morbidity and operations performed. The mean drainage of the first and second postoperative day in group B was significantly reduced (412.6 ± 199.2 vs. 764.3 ± 213.9 ml, p < 0.000, and 248.3 ± 178.5 vs. 455.0 ± 274.6, p < 0.001). Similarly, the need for fresh frozen plasma transfusion was lower in group B, p < 0.035. Both the operation time and the hospital stay were also less for group B but without reaching statistical significance (84.6 ± 35.2 vs 101.2 ± 52.45 min. and 5.8 ± 1.6 vs 7.2 ± 3.6 days respectively, p < 0.064). The overall transfusion rate did not differ significantly. No side effects of aprotinin were noted.</p> <p>Conclusion</p> <p>The perioperative ultra-low dose aprotinin administration was associated with a reduction of total blood losses and blood product requirements. We therefore consider the use of aprotinin safe and effective in major thoracic surgery.</p

Evaluation of the short‐, mid‐, and long‐term effects of tofacitinib on lymphocytes in patients with rheumatoid arthritis

Objective: Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA). Altered lymphocyte cell counts and a potential association with increased infection rates have been reported in RA patients treated with JAK inhibitors. This analysis was undertaken to evaluate the short-, mid-, and long-term effects of tofacitinib on lymphocytes and infection rates in patients with RA. Methods: In this post hoc analysis, absolute lymphocyte counts (ALCs) were obtained from phase III studies (12–24 months; n = 717–958) and phase I/II/III/long-term extension studies of tofacitinib (≤117 months) (All RA population; n = 7,061); lymphocyte subset counts (LSCs) were from phase II studies (1.5–6 months’ exposure; n = 236–486), an ORAL Sequel vaccine substudy (~22 months; n = 198), and an ORAL Sequel lymphocyte substudy (~50 months; n = 55–1,035) of tofacitinib. The reversibility of ALC/LSC changes was evaluated. The relationship of ALC and LSC to infections was analyzed in the All RA population. The value of monitoring ALC alone was assessed by examining correlations between ALCs and LSCs. Results: Tofacitinib treatment resulted in an initial increase in ALC versus pretreatment baseline, which gradually declined to steady state by ~48 months. CD4+ and CD8+ T cell counts decreased over long-term treatment, and ALC and LSC changes were reversible upon treatment cessation. Patients with ALCs of <500 cells/mm 3 had an increased risk of serious infections. There was no strong association between CD4+ T cell, CD8+ T cell, B cell, or natural killer cell counts and serious infection incidence rates. ALC and CD4+ or CD8+ T cell counts correlated well (R = 0.65–0.86). Conclusion: Our findings indicate that monitoring of ALC alone appears to be adequate to assess infection risk in tofacitinib-treated patients with RA

Comparison of quality-of-care measures in U.S. patients with end-stage renal disease secondary to lupus nephritis vs. other causes

BACKGROUND: Patients with end-stage renal disease (ESRD) due to lupus nephritis (LN-ESRD) may be followed by multiple providers (nephrologists and rheumatologists) and have greater opportunities to receive recommended ESRD-related care. We aimed to examine whether LN-ESRD patients have better quality of ESRD care compared to other ESRD patients. METHODS: Among incident patients (7/05–9/11) with ESRD due to LN (n = 6,594) vs. other causes (n = 617,758), identified using a national surveillance cohort (United States Renal Data System), we determined the association between attributed cause of ESRD and quality-of-care measures (pre-ESRD nephrology care, placement on the deceased donor kidney transplant waitlist, and placement of permanent vascular access). Multivariable logistic and Cox proportional hazards models were used to estimate adjusted odds ratios (ORs) and hazard ratios (HRs). RESULTS: LN-ESRD patients were more likely than other ESRD patients to receive pre-ESRD care (71% vs. 66%; OR = 1.68, 95% CI 1.57-1.78) and be placed on the transplant waitlist in the first year (206 vs. 86 per 1000 patient-years; HR = 1.42, 95% CI 1.34–1.52). However, only 24% had a permanent vascular access (fistula or graft) in place at dialysis start (vs. 36%; OR = 0.63, 95% CI 0.59–0.67). CONCLUSIONS: LN-ESRD patients are more likely to receive pre-ESRD care and have better access to transplant, but are less likely to have a permanent vascular access for dialysis, than other ESRD patients. Further studies are warranted to examine barriers to permanent vascular access placement, as well as morbidity and mortality associated with temporary access, in patients with LN-ESRD

Successful Treatment of Hemolysis and Severe Anemia without Transfusion in a Jehovah’s Witness PNH Patient with the Terminal Complement Inhibitor Eculizumab.

Abstract In hemolytic paroxysmal nocturnal hemoglobinuria (PNH) patients, hemoglobin levels are typically maintained by transfusions, without which severe anemia can occur. The terminal complement inhibitor eculizumab was previously shown to effectively control intravascular hemolysis and the need for transfusions in PNH patients. We now report on compassionate use of eculizumab in a severely anemic Jehovah’s Witness PNH patient. RF is a 61 year old Hispanic woman with a 10 year history of PNH and s/p nephrectomy. In Jan 2004 she was hospitalized for a severe hemolytic paroxysm with jaundice, weakness, lower abdominal pain, vomiting, hemoglobinuria, LDH of 15,000 IU/L, hemoglobin (Hgb) of 5–6 g/dL, and 40–50,000/mm3 platelets. Flow cytometry showed 41% RBC and 70% granulocyte PNH clone sizes. To her prednisone (80 mg qd), Procrit 40,000 U thrice per week and coumadin 2.5 mg qd were added. In Feb, she improved somewhat after high dose IVIG but remained icteric and had a bed-chair existence. In mid-March, her Hgb was 5.1 g/dL, LDH 5000 IU/L, and haptoglobin &lt;26 mg/dL. Walking 5–10 feet resulted in shortness of breath and tachycardia. From Apr through Oct she generally stabilized with chronic fatigue, a bed-chair existence, LDH in the 3–4000’s IU/L, and 80–100,000 platelets/mm3; prednisone was now 20 mg qd. Her Hgb decreased from 5–7 g/dL through mid Jul, to 4–6 g/dL through Oct. She then worsened during a febrile illness: Hgb dropped to 3.6 g/dL. An investigator sponsored IND was granted by the FDA and the local Institutional Review Board approved the single patient open label trial; the patient was consented for use of eculizumab. Eculizumab therapy (600 mg/week for four weeks, then 900 mg on week 5 and every other week thereafter) was initiated on Nov 2 at which time she had severe hemoglobinuria, Hgb of 4.1 g/dL, LDH of 4326 IU/L, haptoglobin of &lt;26 mg/dL and reticulocyte count of 250,000; she was bed-wheel chair bound, using supplemental O2. One week after the first dose, she noted clear urine, her Hgb rose almost 2 g to 5.4 g/dL, LDH dropped to 1019 IU/L, haptoglobin increased to 46 mg/dL, and she was no longer icteric. She was now able to walk short distances. At two weeks her LDH was 473 IU/L. Within a month was able to walk several blocks without difficulty. After 6 weeks of eculizumab therapy, her Hgb had risen to 9.3 g/dL and her LDH was in the normal range. Flow cytometry in Jan 2005 showed a 95% PNH RBC clone size. Her Procrit was converted to Aranesp. From Jan to early Mar her Hgb ranged from 8.1 to 9.1 g/dL with LDH remaining in the normal range; in Mar her Hgb dropped to 6.5 g/dL but without hemoglobinuria or intravascular hemolysis (LDH remained &lt; 250 IU/L), and PNH RBC clone size was 90%. There was no evidence of GI blood loss. Though fatigued, she was still able to perform her normal daily routines. In Apr she was hospitalized with a Klebsiella UTI with a Hgb of 3.7 g/dL, but recovered to 6.6–8.0 g/dL after the resolution of the infection and initiation of IV iron supplementation. Currently, she is on Aranesp 300 mcg q2wk, prednisone 15 mg qd, oral and IV iron, folate, and 900 mg eculizumab q2wk. Her LDH is normal and Hgb is 8 g/dL. She has no hemoglobinuria, feels well, performs her daily routines and is “leading a normal life”. This case report demonstrates that intravascular hemolysis can cause severe anemia in PNH, and that eculizumab can rapidly improve Hgb through resolution of hemolysis and protection of the PNH RBC clone.</jats:p

Characterization of RT6-Bearing Rat Lymphocytes. II. Developmental Relationships of RT6 -

The derivation of RT6(+) T cells from postthymic RT6(-) T cells in weanling rats was formally demonstrated by the intravenous transfer (“parking”) of highly purified populations of RT6(-) lymph node T cells into thymectomized, irradiated, and bone-marrow-reconstituted (TXBM) RT6(+) and RT7 alloantigen-disparate recipients. Parallel experiments in irradiated and bonemarrow- reconstituted rats, and in rats whose RT6(+) T cells had been depleted by injection of DS4.23 anti-RT6.1 mAb, suggested that the transit time between the pre-RT6(+) and the RT6(+) T-cell compartments approximated 4-5 days. A more precise estimate of the transit time was made by linear regression analysis of the generation of RT6(+) T cells in rats that were treated with DS4.23 mAb at timed intervals after thymectomy. This study indicated that 50% of the pre-RT6 T cells differentiated into RT6(+) cells within 4 days, 75% within 8 days, and more than 90% within 16 days. Despite the apparent absence of pre-RT6(-) T cells 3 weeks after thymectomy, numerous RT6(-) T cells persisted for at least 10 weeks in thymectomized rats, even after treatment with DS4.23 mAb. Moreover, these RT6(+) T cells failed to generate RT6(+) T cells after transfer into adoptive hosts. Quantitative and phenotypic analyses indicated that this population of “true” RT6(-) T cells: (1) constitutes approximately 50% of the total RT6(-) T cells normally found in control rats; (2) contains CD4 and CD8 subsets; (3) expresses both the CD5 pan-T-cell antigen (which is absent from NK cells) and the R73 α/β TCR constant-region determinant; and (4) lacks sIgM. Hence, the present results indicate that the “true” RT6(-) and the RT6(+) T-cell subsets have stable antigenic phenotypes and represent developmentally discrete populations of postthymic cells in normal rats. This is supported by associated phenotypic and functional studies that suggest that the “true” RT6(-)T-cell subset contains antigenically naive and/or autoreactive clonotypes, whereas the RT6(+) T-cell subset contains memory and/or regulatory cells. It remains to be determined whether the “true” RT6(-) and the RT6(+) subsets represent separate lineages of T cells or a single lineage at different stages of activation or maturation

Differential expression of integrins on human thymocyte subpopulations

Integrins represent a candidate group of cell surface receptors that may control the homing and population of the thymus by T-cell precursors and the subsequent migration of developing thymocytes through the thymic architecture. We have used multiparameter flow cytometric methods to characterize the expression of several members of the integrin family (alpha 3 beta 1, alpha 4 beta 1, alpha 5 beta 1, alpha 6 beta 1, and alpha L beta 2) on thymocyte subpopulations and have correlated integrin expression with other well-defined thymocyte differentiation markers. alpha 4 beta 1 was expressed by all thymocytes, but expression was highest on CD4-CD8- double-negative (DN) cells, high on CD+CD8+ double-positive (DP) cells, and lowest on mature single-positive (SP) cells, alpha 3 beta 1, alpha 5 beta 1, and alpha 6 beta 1 were present on 13%, 63%, and 26% of thymocytes, respectively, with maximal levels of expression on DN and SP cells, and low levels of expression on DP cells. Simultaneous analysis of alpha 4 beta 1, alpha 5 beta 1, and CD3 expression suggested a pathway of T-cell differentiation in the thymus in which the majority of the DN cells were alpha 4 beta 1hi alpha 5 beta 1hi, the DP cells alpha 4 beta 1hi alpha 5 beta 1lo/-, and the most mature SP cells were alpha 4 beta 1int. The stage-specific expression of integrins strongly implies their functional involvement during T-cell maturation in the thymus.</jats:p