Anemia due to coadministration of renin-angiotensin-system inhibitors and PPARγ agonists in uncomplicated diabetic patients.

Therapy with either angiotensin converting enzyme inhibitors and angiotensin receptor blockers (ACEI/ARB) or thiazolidinediones (TZD) is associated with dose-dependent decrements in hematocrit and hemoglobin levels. We aimed to investigate the impact of the coadministration of TZD and ACEI/ARB on hematocrit and hemoglobin values in uncomplicated patients with type 2 diabetes mellitus and normal serum creatinine.Data from patients with type 2 diabetes currently followed, were reviewed and patients treated with ACEI/ARB and/or TZD were identified. For the purpose of this study the following 4 groups of 30 stable non-anemic diabetic patients each matched for age, gender, and BMI were formed. Group ACEI/ARB included patients on ACEI/ARB without TZD, group TZD included patients on TZD and antihypertensive agents other than ACEI/ARB, group ACEI/ARB/TZD consisted of patients on combined therapy with ACEI/ARB and TZD and the control group C included patients never exposed to ACEI/ARB or TZD. Clinical and laboratory data were collected prior to initiation of treatment and after 6 months.Neither hematocrit nor hemoglobin showed any significant change from baseline at the end of the study in group C. In both group ACEI/ARB and group TZD a small, but statistically significant reduction in hematocrit (~ 1% point) and hemoglobin levels (~ 0.3 g/dl) was seen. A greater statistically and clinically important reduction in hematocrit (~ 3% points) and hemoglobin (~ 1 g/dl) levels was observed in group ACEI/ARB/TZD. Furthermore, incident anemia at the end reached 7% in group TZD and 23% in group ACEI/ARB/TZD.Coadministration of RAS inhibitors and PPAR-γ agonists should be considered in the differential diagnosis of hematocrit lowering and anemia in uncomplicated type 2 diabetic patients with normal serum creatinine. Further studies are required to clarify the mechanism(s), the cardiovascular consequences and the cost utility of anemia workup in such patients.

Hematocrit-lowering effect following inactivation of renin-angiotensin system with angiotensin converting enzyme inhibitors and angiotensin receptor blockers.

Several clinical and experimental observations suggest that an intact and activated renin-angiotensin system (RAS) may be an important determinant of erythropoiesis in a variety of clinical conditions, including hypertension, chronic renal insufficiency or failure, chronic obstructive pulmonary disease, and congestive heart failure. Accordingly, RAS inactivation may confer susceptibility to the hematocrit-lowering effects of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Indeed, a dose-dependent decrease in hematocrit is observed within the first month of such therapy. In the majority of patients with hypertension decreases in hematocrit values after RAS inactivation are small and not clinically important. In extreme conditions, however, such as erythrocytosis after successful renal transplantation, secondary polycythemia of chronically hypoxemic COPD patients, erythrocytosis associated with renovascular hypertension, severe cardiac or renal failure, the hematocrit-lowering effect of angiotensin-converting enzyme inhibitors and angiotensin receptor blocker may be profound and even lead to or worsen anemia. Hematocrit reaches its nadir value within three months, and then it remains stable during long-term observations. After discontinuation of RAS blockade, hematocrit values rise gradually over the next three to four months towards the pretreatment levels. The mechanism(s) related to this phenomenon is not yet fully understood, but angiotensin II seems to be responsible for inappropriately sustaining secretion of erythropoietin despite hematocrit elevation and capable to directly stimulate the erythroid progenitors in bone marrow to produce erythrocytes.

Cephalosporins in surgical prophylaxis.

Controlled clinical trials have shown that antimicrobial prophylaxis can lower the incidence of infection after certain operations, thus reducing morbidity, hospital stay, antibiotic usage and mortality due to sepsis. An effective prophylactic regimen should be directed against the most likely infecting organisms, but need not be active against every potential pathogen. Infection can be prevented when effective concentrations are present in the blood and the tissue during and shortly after the procedure. Therefore, antimicrobial prophylaxis should begin just before the operation: beginning earlier is unnecessary and potentially dangerous, beginning later is less effective. A single-dose prophylaxis after the induction of anesthesia is sufficient. If surgery is delayed or prolonged, a second dose is advisable if an antimicrobial drug with a short half-life is used. Postoperative administration is unnecessary and is harmful. Cephalosporins are considered to be the drug of choice, because they offer fewer allergic reactions. From the first generation cephalosporins, cefazolin has been widely recommended with success. From the second generation cephalosporins, cefuroxime, cefamandole and cefoxitin are increasingly recommended. Their antistaphylococcal activity is somewhat less strong but their activity against gram-negative bacteria is stronger. In addition, cefoxitin has good activity against anaerobes. Third generation cephalosporins, such as cefotaxime, cefoperazone, ceftriaxone, ceftazidime or ceftizoxime are generally not recommended for surgical prophylaxis. Despite these recommendations, they have been accepted by the medical community and are today in use in many countries as the most common drugs in surgical prophylaxis. Ceftriaxone in particular, is far exceeding the sales of any other drug for prophylaxis. Contra-indications, limitations, additional or other drugs and practical recommendations for specific procedures are discussed and the results of several prospective randomized studies are presented.

Association between activation of the renin-angiotensin system and secondary erythrocytosis in patients with chronic obstructive pulmonary disease.

PURPOSE: An association between activation of the renin-angiotensin system and enhanced erythropoiesis has been observed in patients with several diseases, including congestive heart failure and hypertension. Our goal was to examine whether the renin-angiotensin system is associated with secondary erythrocytosis in patients with chronic obstructive pulmonary disease (COPD). SUBJECTS AND METHODS: Plasma renin activity, plasma aldosterone concentration, serum erythropoietin level, and serum angiotensin converting enzyme (ACE) activity were measured in 12 patients with COPD and secondary erythrocytosis [mean (+/-SD) hematocrit of 53% +/- 3%] and in 12 matched controls with COPD who did not have erythrocytosis (hematocrit 45% +/- 5%). All patients had chronic hypoxemia (PaO2 <60 mm Hg). RESULTS: Both plasma renin and aldosterone levels were threefold greater in patients with secondary erythrocytosis compared to controls. No difference in erythropoietin levels was observed between patients with or without secondary erythrocytosis. Renin levels (r = 0.45; P = 0.02) but not erythropoietin levels (r = 0.15; P = 0.47) were correlated with hematocrit in the entire sample. Renin levels and PaO2 were the only variables independently and significantly associated with hematocrit values in a multiple linear regression model. CONCLUSION: Activation of the renin-angiotensin system is associated with the development of secondary erythrocytosis in chronically hypoxemic patients with COPD. The exact mechanism is not yet fully understood, but angiotensin II may be responsible for inappropriately sustained erythropoietin secretion or direct stimulation of erythroid progenitors.

Relationship between left ventricular hypertrophy and plasma renin activity in chronic hemodialysis patients.

Left ventricular hypertrophy (LVH) is very common in uremic patients. It was shown previously that hemodialysis patients are chronically exposed to the extremes of plasma renin activity due to differences in the original renal disease. Because nonhemodynamic factors seem to play a fundamental role in the development of LVH, the present study was undertaken to investigate the relationship between the predialysis renin level and the echocardiographically determined cardiac structure in stable hemodialysis patients, matched for other parameters known to participate in the development of LVH, such as age; gender; body mass index; interdialytic weight gain; heart rate; systolic, diastolic, and mean arterial BP; hematologic and biochemical profile; vascular access; adequacy of dialysis; nutritional status; and period of follow-up. Thirty-three such patients were stratified in three groups according to predialysis renin levels: group A (n = 11), with renin levels < or = 1 ng.ml-1.h-1; group B (n = 9), with renin levels between 1 and 4 ng.ml-1.h-1; and group C (n = 13), with renin levels > or = 4 ng.ml-1.h-1. LVH with disproportionate septal thickening was directly related to the degree of renin-angiotensin system activation, and values for interventricular septum thickness, posterior wall thickness, interventricular septum thickness/posterior wall thickness ratio, left ventricular mass, and left ventricular mass index were all significantly correlated with predialysis renin levels. Because angiotensin II promotes growth in both fibroblasts and cardiac myocytes, these relationships suggest that elevated renin levels may be causally associated with the development of LVH in chronic hemodialysis patients.

Low-dose amiodarone-related complications after cardiac operations.

OBJECTIVE: High-dose preoperative amiodarone therapy has been implicated as a risk factor for serious complications after cardiac operations. To investigate the effect of preoperative low-dose amiodarone treatment on early postoperative outcome after cardiac operations, we prospectively studied 88 patients. METHODS: Forty-four patients were receiving amiodarone (mean daily dose +/- standard deviation, 205 +/- 70 mg/day) and 44 patients were controls matched in pairs. The following parameters were recorded after the operation in all patients: (1) the ratio of oxygen tension to inspired oxygen fraction on arrival in the intensive care unit and 2, 4, 6, 10, 14, 18, and 22 hours thereafter; (2) the occurrence of acute respiratory distress syndrome; (3) early postoperative cardiac complications; and (4) the type and number of inotropic agents or vasopressors (or both) needed. RESULTS: No difference in the ratio of oxygen tension to inspired oxygen fraction was noted at the various time intervals between amiodarone-treated patients and control patients. Overall, only one patient had acute respiratory distress syndrome in the amiodarone group, but he had multiple other factors known to predispose to acute lung injury. Several cardiac complications, such as pulmonary edema, temporary pacing, and need for intraaortic balloon pump counterpulsation, were observed more frequently in amiodarone-treated patients than in control patients. In addition, amiodarone-treated patients required more frequent inotropic support (73% vs 43%, p = 0.003) and more inotropic drugs or vasopressors (or both) per patient than did control patients (1.4 +/- 1.1 vs 0.6 +/- 0.8, p = 0.002). CONCLUSION: Preoperative low-dose amiodarone therapy does not seem to be related to significant postoperative lung toxicity, but it is associated with various cardiac complications and an increased need for more intense inotropic support after cardiac operations. These findings may be related to the drug's depressant effect on the myocardium.

Clinical outcome and immunology of postoperative arginine, omega-3 fatty acids, and nucleotide-enriched enteral feeding: a randomized prospective comparison with standard enteral and low calorie/low fat i.v. solutions.

In a prospective randomized trial in patients undergoing major abdominal surgery, the impact of a new enteral formula supplemented with arginine, omega-3 fatty acids, and nucleotides (A, n = 14) on immunological parameters was compared with a standard enteral formula (B, n = 14) and a low calorie/low fat intravenous solution (C, n = 13). Four days postoperatively, a statistically significant decrease in total leukocyte count (A, 9.0 +/- 2.9; B, 8.0 +/- 2.4; C, 11.1 +/- 3.5 x 10(6) cells/mL; A versus C, B versus C; p < 0.05), higher percentage of lymphocytes (A, 14.3 +/- 4.9; C, 8.2 +/- 6.1; p < 0.05), and decreased median CRP levels (A, 80.4 [69.9]; B, 70 [74]; C, 88.5 [142] in mg/L; A versus C, p < 0.05; B versus C; p < 0.05) were observed in the enteral nutrition groups. The expression of activated surface antigen HLA-DR was diminished on CD14+ cells over 4 d (A, 58.2 [39.2]; B, 52.2 [36.2]; C, 76.6 [25.2] in %; A versus C, p < 0.05; B versus C, p < 0.05) and 8-10 d (A, 37.9 [31.4]; C, 58.5 [37.6]; p < 0.05) postoperatively. Significantly enhanced median phagocytic activity of CD14+ monocytes and granulocytes was observed in group C 8-10 days postoperatively (A, 83.3 [11.8]; B, 71.6 [34.1]; C, 87.4 [10.8]; A versus B, B versus C, p < 0.05; and A, 75.7 [10.0]; B, 69.0 [37.8]; C, 80.0 [10.1] in %, B versus C, p < 0.05, respectively). Postoperative hospital and intensive care unit stay was similar among the three groups; however, infectious complications were less frequent in group A (A versus C, p = 0.15). Thus, a modified enteral nutritional support and supplementation may influence the immune competence toward a more efficient defense response.

The T cell antigen receptor CD3:CD4 molecular complex is diminished on the surface of pulmonary lymphocytes.

CD4, a 55-kd cell surface glycoprotein, binds to class II major histocompatibility complex (MHC) (Ia) antigens and functions as a coreceptor for the T cell antigen receptor (Ti alpha beta)-CD3 complex. We have observed that critical elements of the T cell antigen multireceptor complex, including Ti alpha beta, CD3, CD4, but not CD8, were diminished on CD45RO+ pulmonary T lymphocytes but not CD45RO+ peripheral blood T lymphocytes (PBL). Epitopes mapping from the first (D1) to the fourth (D4) extracytoplasmic Ig-like domains of CD4 were expressed to a lesser degree on pulmonary T cells than on PBL (P = 0.002). CD4 expression on pulmonary T cells did not increase after 72 hours of ex vivo culture in complete medium but was restored toward control levels by stimulation with phytohemagglutinin, anti-CD3, or interleukin-2. CD4 mRNA isolated from lung T cells and PBL co-migrated on Northern blots and the total levels of CD4 mRNA were comparable, suggesting that diminished CD4 expression by pulmonary T cells might reflect a posttranscriptional change. To determine whether CD4bright T cells convert with mitogen stimulation to CD4dim cells, PBLs were stimulated with immobilized anti-CD3, anti-CD4, or a molecularly engineered anti-CD3:CD4 bispecific monoclonal antibody and the ratio of the CD4:CD3 mean fluorescence staining intensities was calculated at days 3 and 13. The CD4:CD3 ratio decreased primarily for cells stimulated with anti-CD3:CD4, suggesting that co-ligation of CD3 and CD4 is required for the generation of CD4dim T cells. We conclude that diminished Ti alpha beta-CD3:CD4 expression is a characteristic of T cells in lung that is not shared by peripheral blood T cells in vivo, and speculate that this change reflects T cell activation in a millieu of limited interleukin-2 availability.

A phase II trial of interleukin-2 and interferon alfa-2a in patients with advanced renal cell carcinoma.

PURPOSE: A phase II trial that used a regimen of interleukin-2 (IL-2) and interferon alfa-2a (IFN-alpha) was undertaken to evaluate the efficacy of this combination in the treatment of metastatic renal cell carcinoma. PATIENTS AND METHODS: Thirty-four assessable patients were treated with one to two induction cycles of IL-2 administered by continuous intravenous (IV) infusion at a dose of 3 x 10(6) U/m2/d [corrected] for 4 days per week plus IFN-alpha administered by subcutaneous injection at a dose of 5 x 10(6) U/m2/d [corrected] for 4 days per week for 3 consecutive weeks. A maintenance regimen of IL-2 2 x 10(6) U/m2/d [corrected] given by continuous IV infusion for 5 days per week plus IFN-alpha subcutaneously at a dose of 6 x 10(6) U/m2/d [corrected] that was given 3 days per week for 3 weeks was administered for one to five cycles. Twenty-eight patients (82%) completed one to two induction cycles, and 14 patients (41%) received maintenance doses. RESULTS: Major responses were achieved in four patients (12%), which included one complete response (CR) in a bone metastasis. Responses were observed in patients both with and without prior nephrectomy as well as in a primary tumor. Toxicity was moderately severe and included two treatment-related deaths. CONCLUSIONS: In view of the minimal antitumor activity and associated toxicity, the combination of IL-2 and IFN-alpha in this trial cannot be recommended. The investigation of new cytokines and the identification of biologic prognostic factors for a response to immunologic therapy are essential.

Most human pulmonary infiltrating lymphocytes display the surface immune phenotype and functional responses of sensitized T cells.

Pulmonary infiltrating lymphocytes (PIL) isolated directly from human lung were examined for their surface immune phenotype by monoclonal antibody staining and cytofluorimetry. In order to purify PIL, resected lungs were enzymatically digested with collagenase and DNase and subjected to density centrifugation and nylon-wool column separation. In some cases, CD4+ lymphocytes were further purified with alpha CD8 and complement. The majority of pulmonary lymphocytes were CD2+ (87 +/- 1%) and CD3+ (73 +/- 4%). Virtually all of the CD3+ PIL were Ti alpha beta+. Greater than 90% of both CD4+ or CD8+ PIL were CD45RO+ and CD45RA-, consistent with prior antigen sensitization in vivo. A subset of CD4+ PIL (34 +/- 4%) expressed Leu8, the human congener of the murine MEL-14 lymphocyte homing receptor, whereas most homologous CD4+ peripheral blood lymphocytes were Leu8+ (75 +/- 8; P less than 0.01). HLA-DR surface antigens were expressed by 45 +/- 5% of CD4+ PIL versus 9 +/- 1% of CD4+ peripheral blood lymphocytes (P less than 0.001). There was no significant difference in the percentage of low-affinity interleukin-2 (IL-2) receptor-positive CD4+ lymphocytes in lung and blood (9 +/- 3% versus 13 +/- 2%). Analysis of the DNA synthetic cell cycle showed that approximately 5% of blood CD4+ lymphocytes and approximately 25% of CD4+ PIL were in S/G2/M. Compared to homologous blood T cells, purified PIL displayed enhanced proliferative responses to IL-2 and diminished responses to the lectin phytohemagglutinin. Lectin-stimulated PIL showed greater secretion of interferon-gamma and IL-2 than did blood lymphocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

Endogenous regulation of rat brain mast cell serotonin release.

Mast cells are involved in allergic reactions where they release numerous vasoactive and other mediators in response to IgE and antigen. They are also activated by neuropeptides and are found in close contact with neurons. Mast cell heterogeneity has now been documented for mucosal mast cells and connective tissue mast cells. Rat brain mast cells were studied in a perfusion system and were shown to release serotonin in response to the mast cell secretagogue compound 48/80 (C48/80). High-potassium neuronal depolarization also released serotonin, but this was calcium dependent, not associated with beta-hexosaminidase, and was unaffected by prior treatment with C48/80. Neuronal depolarization, however, was associated with somatostatin secretion and substantially reduced subsequent C48/80 stimulation, an effect abolished by neonatal treatment of the animals with capsaicin. Perfusion with somatostatin and substance P also induced brain mast cell serotonin release. C48/80 stimulation of combined thalamic and hypothalamic slices after neuronal depolarization substantially reduced the C48/80 effect, suggesting the possible presence of endogenous inhibitors released from the hypothalamus. Finally, the alpha 2-receptor agonist clonidine had a slight stimulatory effect. These results indicate that brain mast cell serotonin release may be regulated by endogenous neurotransmitters and/or neuromodulators.