Low incidence of Pneumocystis carinii pneumonia in HIV patients receiving 300 mg pentamidine aerosol every 2 weeks

Summary The optimal dosage of pentamidine for prophylaxis of Pneumocystis carinii pneumonia (PcP) is unknown. We assessed the effects of 300 mg pentamidine inhaled every 2 weeks. Salbutamol was added for prevention of bronchoconstriction. A total of 128 consecutive HIV patients were enrolled, 21 of whom were excluded within 8 weeks; the remaining 107 patients, 66 on primary and 41 on secondary prophylaxis, were treated for 39 weeks (median; range 8–133). Two patients developed PcP. Side effects occurred in only 14 of 5082 inhalations. Three patients developed hypoglycemia after inhalations. Blood glucose levels determined in 34 patients before and after inhalation revealed a decline from 89 ± 23 mg/dl to 79 ±23 mg/dl (P < 0.005). A randomized prospective trial is necessary to evaluate the efficacy of 300 mg pentamidine inhaled every 4 or 2 weeks.Abbreviation PcP Pneumocystis carinii pneumonia     

Lymphocyte subsets in hemodialysis patients treated with recombinant human erythropoietin

We investigated whether recombinant human erythropoietin (rhEPO) therapy affected the lymphocyte subsets in patients on long-term maintenance hemodialysis (HD) with severe anemia. Before treatment, the numbers of peripheral blood lymphocyte, CD3⁺, CD4⁺, CD8⁺, and CD20⁺ cells were decreased in HD patients compared to those in healthy subjects, while the number of CD3⁺ HLA-DR⁺ cells was increased in HD patients compared to that in healthy subjects. Furthermore, the number of CD4⁺CD45RA⁺ (naive T) cells was markedly decreased in HD patients (112±77 vs 241±146/µl;P<0.01). The number of CD8⁺S6F1⁺ (cytotoxic T) cells in HD patients was also less than that in healthy subjects (247±104 vs 122±83/µl; NS). During a 6-month period of rhEPO therapy, we found that the low level of CD4⁺CD45RA⁺ cells gradually increased (from 112±18 to 163±24/µl;P<0.01) with the elevation of hematocrit values (from 21.5±1.7 to 28.2±3.5%;P<0.05). The number of CD3⁺HLA-DR⁺ cells decreased after 1 month of rhEPO therapy (from 93±14 to 46±13/µl) and gradually declined throughout the 6-month study period. In ourin vitro study, we demonstrated that no effects were observed on [³H]thymidine uptake in the T cell subsets at various concentrations of rhEPO. These results suggest that rhEPO-induced immunoregulation is mediated by an indirect stimulatory effect on the immune system, this stimulation being accompanied by an improvement in physical condition.     

Cellular and serological markers of disease activity in Indian patients with HIV/AIDS

There has been an exponential rise of HIV positive patients as observed at the surveillance center of Nehru Hospital. Most patients are poor and cannot afford repeated viral load assays. Therefore, there is a need to identify cost effective and reliable surrogate markers of disease activity. In the present study absolute number of CD4 cells, 2 micro-globulin, circulating necleosomes were studied in 30 patients of AIDS, 30 seropositives and 30 healthy controls. In addition viral load, P-24 assay, and TNFR-II assays were done in seropositive and AIDS patients.The mean CD4 cells in patients with AIDS were 69.66 ± 68.25 mm³ while in seropositives values was 370 ± 201.29 mm³. The mean CD4 cells in healthy controls were however 690 ± 198 mm³. The differences in all the groups were highly significant (p < 0.001). The mean CD4 values in Indians are significantly lower than reported from the west. The lower number of CD4 cells in healthy population is interpreted to be due to immune activation. The CD8 cell number in controls was 650 ± 207 mm³ this figure is also higher than that observed in the west. P-24 assay failed to delineate between seropositives and patients with AIDS. Although, 2 microglobulin levels were significantly higher in AIDS than in seropositives and higher in seropositives than in controls yet with the best possible cut off, it had a sensitivity of only 70% in delineating the two conditions. The correlation between CD4 cells and viral load was more significant when the CD4 cells were below 200 mm³. Five out of 30 patients with a CD4 of 300–600 mm³ had a viral load of over 1 × 10⁵ cop/ml. The difference in TNF R-II levels between seropositives and AIDS was however more impressive. With a cut off of 550 pg/ml it had a sensitivity of 95% in delineating HIV from AIDS. It is concluded that a combination of absolute number of CD4 cells and TNF R-II assay along with clinical evaluation may be used to monitor therapy in resource poor countries where frequent viral load assay is unaffordable.     

Graft survival and long-term renal function after sequential conventional cyclosporin a therapy in cadaver kidney transplantation — a prospective randomized trial

Summary In a prospective randomized trial 50 renal transplant patients (group A) received a sequential course of 14 days conventional immunosuppression (Lymphocytoglobuline (ALG), azathioprine, steroids) and cyclosporin and steroids thereafter, while 50 patients (group B) received the conventional immunosuppression for 7 days followed by cyclosporin and steroids. In the latter group ALG was tolerated for the whole period while in the first group conversion from conventional to cyclosporin A therapy had to be performed after a mean of 11 days, due to ALG intolerance. Actual patient survival rates 1 year posttransplant were 100% in both groups and graft survival rates 96% in group A and 86% in group B (P<0.05). There was a mean dialysis frequency per patient of 0.7±2.0 in group A and 1.8±3.4 in group B (P=0.064). Serum creatinine 1 year posttransplant was 1.8±0.8 mg/dl in group A and 2.2±1.4 in group B. A total of 58 patients had a serum creatinine of less than 2 mg/dl at the time of conversion to cyclosporin. These patients had a significantly better graft survival rate (98.3%) and serum creatinine 1 year posttransplant (1.6±0.5 mg/dl) than the 40 patients with a serum creatinine of more than 2 mg/dl at the time of conversion (85%; 2.4±1.4 mg/dl), indicating that a delayed onset of cyclosporin therapy might benefit the kidney in the immediate posttransplant period when it is susceptible to nephrotoxicity due to the damage from hypothermic storage.     

Is tube feeding with elemental diets a primary therapy of crohn's disease?

Summary Tube feeding (TF) with elemental diets was used as primary therapy in 25 patients with an acute phase of Crohn's disease (CD). Feed was infused continuously via a nasoduodenal tube in a dosage of 2600–3200 kcal/day. The Crohn's disease activity index (CDAI), the serum levels of a₁-antitrypsin, C-reactive protein (CRP) and haptoglobin were used as parameters for disease activity; the body weight and the serum levels of albumin, prealbumin and transferrin were parameters for the nutritional status. Disease activity could be reduced in the total group by TF shown by a reduction of CDAI from 269±72 to 174±103, a₁-antitrypsin from 449±160 to 378±147 mg/dl, CRP from 6.12±5.6 to 3.23±5.4 mg/dl and haptoglobin from 414±167 to 344±152 mg/dl. Nutritional status was improved (body weight 83±12% to 87±10% ideal body weight, prealbumin 20.2±7.7 to 29.7±9.5 mg/dl, and transferin 229±107 to 310±103 mg/dl). Albumin did not change significantly. In 15 patients the CDAI was reduced to levels below 150. These patients were characterized as responders. In ten patients a normalization of CDAI could not be achieved and therapy had to be changed. With a stepwise linear discriminant analysis it could be demonstrated that patients with colonic disease and fever do not react to TF, with a probability of 90%. We conclude that TF can be used as primary therapy for the acute phase of CD in patients with small bowel disease. In patients with colonic disease and fever it is not as effective.     

Neurological functional recovery after thymosin beta4 treatment in mice with experimental auto encephalomyelitis

In the present study, we hypothesized that thymosin beta 4 (Tbeta4) is a potential therapy of multiple sclerosis (MS). To test this hypothesis, SJL/J mice (n=21) were subjected to experimental autoimmune encephalomyelitis (EAE), an animal model of MS. EAE mice were treated with saline or Tbeta4 (6 mg/kg, n=10) every 3 days starting on the day of myelin proteolipid protein (PLP) immunization for total five doses. Neurological function, inflammatory infiltration, oligodendrocyte progenitor cells (OPCs) and mature oligodendrocytes were measured in the brain of EAE mice. Double immunohistochemical staining was used to detect proliferation and differentiation of OPCs. Tbeta4 was used to treat N20.1 cells (premature oligodendrocyte cell line) in vitro, and proliferation of N20.1 cells was measured by bromodeoxyuridine (BrdU) immunostaining. Tbeta4 treatment improved functional recovery after EAE. Inflammatory infiltrates were significantly reduced in the Tbeta4 treatment group compared to the saline groups (3.6±0.3/slide vs 5±0.5/slide, P<0.05). NG2⁺ OPCs (447.7±41.9 vs 195.2±31/mm² in subventricular zone (SVZ), 75.1±4.7 vs 41.7±3.2/mm² in white matter), CNPase⁺ mature oligodendrocytes (267.5±10.3 vs 141.4±22.9/mm²), BrdU⁺ with NG2⁺ OPCs (32.9±3.7 vs 17.9±3.6/mm²), BrdU⁺ with CNPase⁺ mature oligodendrocytes (18.2±1.7 vs 10.7±2.2/mm²) were significantly increased in the Tbeta4 treated mice compared to those of saline controls (P<0.05). These data indicate that Tbeta4 treatment improved functional recovery after EAE, possibly, via reducing inflammatory infiltrates, and stimulating oligodendrogenesis.     

The effect of long-term administration of α1-blocker prazosin on capillary density in cardiac and skeletal muscle

The effect of prazosin on heart and muscle blood flow and capillary density was studied in rats. In acute experiments, ₁-blocker prazosin almost trebled blood flow in fast skeletal muscles [tibialis anterior (TA) and extensor digitorum longus (EDL)], but did not affect coronary flow when infused i.v. at a dose of 0.5 g · ml^–1 · min^–1 for 30 min. Prazosin in an equivalent dose was then given orally over a period of 5 weeks to investigate its effect on capillarisation in heart and skeletal muscle. Capillary density (CD, capillaries · mm^–2), estimated in frozen sections stained for alkaline phosphatase, was similar in the hearts of prazosin-treated and control rats. Capillary/fibre ratio in skeletal muscles increased from 1.52±0.019 in control EDL to 1.69±0.01 (P<0.001) and from 1.56±0.04 in control TA to 2.16±0.04 (P<0.001). In TA, the increase was greater than in EDL both in the glycolytic periphery (from 1.30±0.13 to 1.75±0.11, P<0.025) and the oxidative core of the muscle (from 1.837±0.14 to 2.51±0.12, P<0.005). Unilateral crush of the lateral peroneal nerve and subsequent reinnervation over the next 7 weeks resulted in redistribution of fibre types from a typical mosaic pattern into groups composed of fibres of similar oxidative capacity. Capillary density as well as capillary/fibre ratio in purely glycolytic areas was lower when compared to supply of glycolytic fibres in normal muscles. Oral administration of prazosin over the whole period of reinnervation not only maintained the original level of capillarity associated with fast glycolytic fibres in control muscles, but considerably increased it. Thus long-term prazosin administration not only causes an increase in capillary supply in normal muscles but also prevents loss of capillaries during reinnervation. The fact that it only increases capillarisation in tissues where it increases flow further supports the hypothesis that capillary growth can be initiated by mechanical factors connected with high blood flow.     

Can intravenous beta blockade predict long-term haemodynamic benefit in chronic congestive heart failure secondary to ischaemic heart disease? A comparison between intravenous and oral carvedilol

Several studies in the past have shown the long-term beneficial effects of -blockers in congestive heart failure. Despite the interest in this mode of therapy, their clinical application has been limited due to their negative inotropic effect. A subset of the heart failure patients do not show any improvements with standard -blocker therapy. Carvedilol, a new, non-selective -blocking agent with concurrent -blocking properties, was evaluated in 17 patients with chronic heart failure secondary to ischaemic heart disease. All had resting left ventricular ejection fraction 45% and were maintained on diuretic therapy. Acute haemodynamic measurements were made after intravenous carvedilol (2.5–7.5 mg) and also after chronic therapy for 8 weeks (carvedilol 12.5–50 mg b.d.). Radionuclide ventriculography, ambulatory intra-arterial blood pressure monitoring and right heart catheterization were performed before and after 8 weeks of chronic therapy. Twelve patients completed the study and 5 were withdrawn. Symptomatic and haemodynamic improvement was demonstrated in 11 of the 12 patients after 8 weeks of therapy. Mean±standard error systolic intraarterial blood pressure (133 ± 6 to 114 ± 5 mmHg, P <0.005), heart=" rate=" (81=" ±=" 3=" to=" 61=" ±=" 1=" beats/min,=">P <0.0001), pulmonary=" artery=" wedge=" pressure=" (19=" ±=" 2=" to=" 12=" ±=" 1=" mmhg,=">P <0.001) and=" systemic=" vascular=" resistance=" (1748=" ±=" 115=" to=" 1497=" ±=" 89=" dynes/=">⁵/m², P < 0.02)=" were=" reduced=" with=" an=" increase=" in=" mean=" ±=" se=" of=" stroke=" volume=" index=" (31=" ±=" 1.8=" to=" 40=" ±=" 1.6=">²/beat, P < 0.0005)=" and=" left=" ventricular=" ejection=" fraction=" (25=" ±=" 3=" %=" to=" 32=" ±=" 3=" %,=">P < 0.01)=" after=" 8=" weeks=" of=" therapy=" with=" carvedilol.=" this=" is=" in=" contrast=" to=" the=" acute=" haemodynamic=" effects=" of=" carvedilol,=" which=" only=" showed=" a=" reduction=" in=" heart=" rate=" (81=" ±=" 3=" to=" 74=" ±=" 3=" beats/min,=">P < 0.0001),=" systolic=" intra-arterial=" blood=" pressure=" (133=" ±=" 6=" to=" 117=" ±6=" mmhg,=">P < 0.0005)=" and=" pulmonary=" artery=" wedge=" pressure=" (19=" ±=" 2=" to=" 14=" ±=" 2=" mmhg,=">P < 0.002)=" at=" 10=" min=" post-injection.=" the=" systemic=" vascular=" resistance,=" left=" ventricular=" ejection=" fraction=" and=" stroke=" volume=" index=" failed=" to=" show=" any=" significant=" improvement.=" thus=" intravenous=" carvedilol=" produces=" a=" reduction=" in=" filling=" pressure,=" which=" is=" maintained=" after=" chronic=" treatment.=" this=" property=" is=" clearly=" beneficial=" for=" chronic=" heart=" failure=" patients=" and=" differs=" from=" standard=">-blockers. The discrepancy of the haemodynamic changes between the acute and chronic long-term response to carvedilol lends further support to the concept of upregulation of -adrenoceptors in cognestive heart failure.     

Body Mass Index and CD4+ T-Lymphocyte Recovery in HIV-Infected Men with Viral Suppression on Antiretroviral Therapy

Abstract

Purpose: To better characterize the relationship between body mass index (BMI) and CD4+ T-lymphocyte recovery in HIV disease.Methods: We analyzed the association between baseline BMI and CD4+ T-lymphocyte increases, as well as the association between BMI and immune activation (CD38 and HLA-DR co-expression on CD4+ and CD8+ T-lymphocytes), in male HIV-infected patients who achieved viral suppression on antiretroviral therapy (ART).Results: Baseline BMI predicted change in CD4+ T-lymphocyte count at weeks 96 ( P = .03, n = 461) and 144 ( P = .005, n = 357) but not at week 48 ( P = .38, n = 558). Relative to men with a normal BMI, overweight and obese men had increases at week 144 that were 35 and 113 cells/ mm³ higher, respectively, while underweight men had CD4+ T-lymphocyte increases that were 94 cells/mm³ lower. No significant correlations between baseline BMI and cellular immune activation were seen.Conclusions: BMI predicts CD4+ T-lymphocyte gains in men started on ART.     

Nonhypnotic low-dose etomidate for rapid correction of hypercortisolaemia in cushing's syndrome

Summary We determined the adrenostatic potential of low-dose nonhypnotic etomidate in six patients with Cushing's syndrome (ectopic Cushing's syndrome,n=2; Cushing's disease,n=3; bilateral adrenal adenoma,n=1). Etomidate was given as a continuous infusion for 32 h in a dose of 2.5 mg/h (n=5) or 0.3 mg/kg/h (n=3), respectively. Saline was given during a control period. The responsiveness to exogenous ACTH was studied during placebo and 7 and 31 h after commencing etomidate by administration of 250 µg 1–24 ACTH i.v. Etomidate (2.5 mg/h) led to a consistent decrease in serum cortisol in all patients from a mean of 39.4±13.3 to 21.1±5.7 µg/dl after 7 h (P<0.05 compared with placebo). After 24 h cortisol was reduced further to a mean steady state concentration of 12.3±5.7 µg/dl (P<0.05). At the end of the infusion period the cortisol increase in response to ACTH was reduced but not abolished. In contrast, a dose of 0.3 mg/kg/h etomidate induced unresponsiveness of serum cortisol to exogenous ACTH within 7 h. However, sedation was observed in two out of three patients at this dose, while during etomidate in a dose of 2.5 mg/h no side effects were seen. We conclude that low-dose non-hypnotic etomidate reduces serum cortisol to within the normal range in patients with Cushing's syndrome. The possibility to dissociate the adrenostatic effect of etomidate from its hypnotic action, the absence of side effects, and the i.v. route suggest that etomidate in a dose of 0.04–0.05 mg/kg/h may become the drug of choice for rapid initial control of hypercortisolism.Abbreviations ACTH adrenocorticotrophic hormone - CD Cushing's disease - CS Cushing's syndrome     

Short-term effects of oral enoximone on hemodynamics,exercise capacity,anaerobic threshold,and arrhythmias in congestive heart failure

Summary Enoximone, a phosphodiesterase-inhibitor, is a potent inotropic vasodilator agent that causes a marked improvement in hemodynamics in patients with congestive heart failure. The acute effects of oral enoximone on rest and exercise hemodynamics, ejection fraction, aerobic metabolism, exercise capacity, and arrhythmias were studied in 11 patients with moderate to moderately severe dilative cardiomyopathy after 8 days of enoximone (100 mg tid) in addition to baseline therapy (diuretics and digitalis).The cardiac index increased from 2.44±0.45 to 2.72±0.50 l/min/m² (p<0.01) at rest and from 4.00±0.96 to 4.75±0.95 l/min/m² (p<0.005) during exercise. Pulmonary wedge pressure decreased from 16.8±7.3 to 12.5±6.5 mmHg (p<0.005) at rest and from 28.2±8.0 to 24.5±10.3 mmHg (p< 0.05) during exercise. Systemic vascular resistance decreased from 1608±243 to 1495±300 dynes*sec*cm^–5 (p<0.05) at rest and from 1152±155 to 1027±236 dynes*sec*cm^–5 (ns) during exercise. The anaerobic threshold, which was recorded simultaneously, increased from 13.2±2.7 to 15.5± 2.5ml/kg/min VO₂ (p<0.02). The radionuclide ventriculography ejection fraction improved from 21.7±5.0 to 28.1±9.1% (p<0.01) during exercise; the changes at rest were not significant (20.8±6.2 vs 25.8±8.4%). Exercise tolerance showed an increase of 16% (492±133 to 573±135 sec, p< 0.005). The resting heart rate remained unchanged (81.8±13.4 vs 81.8±11.9). Interestingly, 24-h Holter monitoring revealed more or new repetitive arrhythmias in 9/11 patients.Short-term therapy with oral enoximone enhances ventricular performance by increasing cardiac contractility and lowering vascular resistance, both of which extend exercise tolerance and improve aerobic metabolism. Potential proarrhythmic effects need further evaluation, however.Abbreviations AMP adenosine monophosphate - PDE phosphodiesterase - VCO₂ carbon dioxide production - VPB ventricular premature beat - VE minute ventilation - VO₂ oxygen uptake Dedicated to Professor Jahrmärker on the occasion of his seventieth birthday     

Sequential activation and production of matrix metalloproteinase-2 during breast cancer progression

The proteolytic processes are thought to be the critical point in tumor invasion and metastasis, mainly by matrix metalloproteinases (MMPs) and serine proteases. We measured the activity of MMP-2 from 28 normal, 12 benign and 126 breast cancer tissues using gelatin zymography. Inactive MMP-2 (72 kD) was expressed in 53.6% of the normal and 66.6% of the cancer tissues, respectively (P= 0.77), while active MMP-2 (62 kD) was expressed in 28.6% and 73.0%, respectively (P = 0.003). The enzymatic activity of active MMP-2 (62 kD) measured in the gel band area was 4.0 ± 7.2 mm² in normal breasts, 7.7 ± 9.8 mm² in benign breast diseases, 9.5 ± 8.5 mm² in ductal carcinoma in situ (DCIS), and 12.0 ± 13.7 mm² in invasive cancers. The MMP-2 activation ratio (62 kD/62 kD + 72 kD) was 0.12 ± 0.18 in normal tissues, 0.10 ± 0.20 in benign diseases, 0.61 ± 0.22 in DCIS, and 0.50 ± 0.28 in invasive cancers. In conclusion, MMP-2 activation was the main cause of the increased 62 kD MMP-2 activity during the early phase of breast cancer, while production of MMP-2 supplemented the increased 62 kD activity in the late phase. We suggest, therefore, that these differential expressions of MMP-2 activation and production during the different stages of breast cancer progression are potential therapeutic targets for biological or gene therapy under the concept of stage-oriented cancer treatment.[]     

Effect of pravastatin on metabolic parameters of apolipoprotein B in patients with mixed hyperlipoproteinemia

Summary 3-Hydroxy-3-methylgluratyl coenzyme A reductase inhibitors reduce plasma cholesterol in different forms of hyperlipoproteinemia. Although an increase in low-density lipoprotein (LDL) receptor activity is the proven mechanism of this therapy in familial hypercholesterolemia, the mechanism remains controversial in mixed hyperlipoproteinemia. A decreased production of apolipoprotein B (apoB) and/or an increased removal of lipoproteins could mediate the hypocholesterolemic effect of these drugs. The effect of pravastatin on the metabolism of apoB was evaluated in a randomized, double blind, placebo controlled, cross-over study in five men with mixed hyperlipoproteinemia. Metabolic parameters for apoB were determined using endogenous labeling with [1^t3C]leucine and [¹⁵N]glycine and multicompartmental modeling. During pravastatin therapy cholesterol, LDL cholesterol, apoB, and LDL apoB levels were significantly reduced (P < 0.01) by 18%, 20%, 27%, and 29%, respectively, while triglyceride and high-density lipoprotein cholesterol levels remained unchanged. Pravastatin therapy increased the fractional catabolic rate of very low density lipoprotein apoB from 3.9±0.6 to 5.1±1.7 per day (P = 0.08) and that of LDL apoB from 0.37±0.09 to 0.46±0.10 per day (P<0.01). The apoB production (placebo 35.2±11.9 mg/kg per day; pravastatin 25.8±8.7 mg/kg per day) and conversion of very low density lipoprotein apoB to LDL apoB (placebo 65%, pravastatin 57%) remained stable. Thus, also in mixed hyperlipoproteinemia 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors increase the catabolism of apoB-containing lipoproteins without significantly affecting the production of apoB.Abbreviations apoB apolipoprotein B - FCR fractional catabolic rate - HMG hydroxy-methylglutaryl - CoA coenzyme A - FH familial hypercholesterolemia - HDL high-density lipoprotein - IDL intermediate-density lipoprotein - LDL low-density lipoprotein - VLDL very low density lipoprotein Dedicated to Prof. Dr. G. Paumgartner on the occasion of his 60th birthday     

Soluble CD163, a Specific Macrophage Activation Marker,is Decreased by Anti‐TNF‐α Antibody Treatment in Active Inflammatory Bowel Disease

Activated macrophages shed the haemoglobin–haptoglobin scavenger receptor CD163 into the circulation as soluble(s)‐CD163. We measured sCD163 as an in vivo macrophage activation marker in patients with Crohn's disease (CD) or ulcerative colitis (UC) receiving antitumour necrosis factor (TNF)‐α antibody or prednisolone treatment. We also investigated the CD163 expression on circulating monocytes. 58 patients with CD, 40 patients with UC and 90 healthy controls (HC) were included. All patients had active disease at inclusion and were followed for 6 weeks of anti‐TNF‐α antibody or prednisolone treatment. We measured plasma sCD163 levels at baseline, 1 day, 1 week and 6 weeks after initiating treatment. CD163 expression on circulating CD14⁺ monocytes was measured in 21 patients with CD receiving anti‐TNF‐α antibody treatment. Baseline sCD163 levels were elevated in patients with CD [1.99 (1.80–2.18) mg/l] and in patients with UC [2.07 (1.82–2.32) mg/l] compared with HC [1.51 (1.38–1.63) mg/l] (P < 0.001). Anti‐TNF‐α antibody treatment induced a rapid decrease in sCD163 levels in patients with CD and in patients with UC 1 day after treatment initiation (P < 0.05). One week of prednisolone treatment did not induce a reduction in sCD163 levels. Anti‐TNF‐α treatment normalized sCD163 levels in patients with UC, whereas patients with CD exhibited sustained increased sCD163 levels. In patients with CD, CD163 expression on CD14⁺ monocytes was increased compared with HC. This study highlights that active CD and UC are associated with increased macrophage activation, as indicated by elevated sCD163 levels and monocytic CD163 expression. Anti‐TNF‐α antibody treatment induced a rapid decrease in sCD163 levels, suggesting a specific effect on macrophage activation in inflammatory bowel diseases.     

Human leukocyte response to an endurance race

Summary The response of circulating leukocytes (WBC's) with regard to changes in number, proportion of neutrophils versus lymphocytes and changes in lymphocyte function as well as proportions of T and B cells was studied in eleven men who ran a 20-mile race. A marked leukocytosis was noted 10–15 min after the race with the predominant increase being polymorphonuclear leukocytes (P<0.001). A significant rise in mean serum cortisol levels was also noted (P<0.001) which correlated with both the increase in total WBC's (P< 0.001) and granulocytes (P<0.001), but not lymphocytes. The increase in serum cortisol was inversely correlated with miles of prior training (P<0.001). An increase in lymphocytes from 1767±112/mm³ to 2431±202/mm³ was less than that previously described in short-term exercise. As with short-term exercise the most significant increase in lymphocytes was in B lymphocytes bearing surface immunoglobulin (P<0.0025). However, in contrast to short-term exercise lymphocytes maintained good in vitro response to the mitogen phytohemagglutinin.This study demonstrates that endurance racing produces a more marked granulocytosis and less lymphocytosis than short bouts of exercise. It is suggested that the degree of leukocytosis is stress dependent in that it was positively correlated with serum cortisol and inversely correlated with prior training.Supported in part by a joint fellowship from the National and Wisconsin Kidney Foundations     

Sustained low‐dose growth hormone therapy optimizes bioactive insulin‐like growth factor‐I level and may enhance CD4 T‐cell number in HIV infection

High‐dose recombinant human growth hormone (rhGH) (2–6 mg/day) regimes may facilitate T‐cell restoration in patients infected with human immunodeficiency virus (HIV) on highly active antiretroviral therapy (HAART). However, high‐dose rhGH regimens increase insulin‐like growth factor‐I (IGF‐I) to supra‐physiological levels associated with severe side effects. The present study investigated whether lower doses of rhGH may improve T‐cell restoration in patients infected with HIV following an expedient response of total and bioactive (i.e., free) IGF‐I. A previous 16‐week pilot‐study included six HIV‐infected patients on stable HAART to receive rhGH 0.7 mg/day, which increased total (+117%, P < 0.01) and free (+155%, P < 0.01) IGF‐I levels. The study was extended to examine whether continuous use of low‐dose rhGH (0.7 mg/day until week 60; 0.4 mg/day from week 60 to week 140) would maintain expedient IGF‐I levels and improve CD4 T‐cell response. Total and free IGF‐I increased at week 36 (+97%, P < 0.01 and +125%, P < 0.01, respectively) and week 60 (+77%, P = 0.01 and +125%, P < 0.01) compared to baseline levels (161 ± 15 and 0.75 ± 0.11 µg/L). CD4 T‐cell number increased at week 36 (+15%, P < 0.05) and week 60 (+31%, P = 0.01) compared to baseline levels (456 ± 55 cells/µL). Following rhGH dose reduction, total IGF‐I and CD4 T‐cell number remained increased at week 88 (+44%, P = 0.01 and +33%, P < 0.01) and week 140 (+46%, P = 0.07 and +36%, P = 0.02) compared to baseline levels. These data support the notion that low‐dose rhGH regimens may increase expediently total and bioactive IGF‐I and improve T‐cell restoration in patients infected with HIV on HAART. J. Med. Virol. 82:197–205, 2010. © 2009 Wiley‐Liss, Inc.     

Phenotypic expression of integrin membrane receptors on spontaneously proliferating CD8 cells in human T-lymphotropic virus type II (HTLV-II)-infected individuals

Spontaneous lymphocyte proliferation in the absence of exogenous stimulators was examined in asymptomatic HTLV-II-seropositive (n=12) and seronegative individuals (n=16). Mean spontaneous lymphocytic proliferation significantly increased on day 8 postculture in HTLV-II-infected individuals (5762±899 cpm) compared with normal controls (2034±925 cpm,P<0.01). The proliferating cells in infected individuals were predominantly T cells; neither B cells nor monocytes demonstrated any proliferation. Phenotypic analysis of cultured cells from individuals with HTLV-II infection demonstrated differential expression of integrin molecules as defined by anti-CD29 and anti-S6F1 (42.8±4.2 and 39.6±5.9%, respectively) on CD8 cells, as compared with day 0 peripheral blood mononuclear cells (PBMC) from infected individuals (19.7±3.5 and 19.9±1.9%, respectively) or normal controls (12.9±3.1 and 11.5±2.5%, respectively;P<0.001 for both comparisons). These CD8⁺ cells did not express CD16 or CD11b. The culture supernatants derived from the spontaneously proliferating cells had significantly increased levels of sCD8 and sCD25 (765±180 and 1805±320 U/ml, respectively) compared with those from normal controls (222±120 and 305±90 U/ml, respectively;P<0.01). Furthermore, culture supernatants derived from spontaneously proliferating PBMC from HTLV-II-infected individuals had no detectable levels of HTLV antigen and did not stimulate proliferation of PBMC from normal donors. These results suggest that the spontaneous proliferation in HTLV-II asymptomatic carriers is due to expansion of CD8 cells expressing integrin receptors which may serve as costimulatory molecules for their activation.     

Immunological responses and long-term treatment interruption after human immunodeficiency virus type 1 (HIV-1) lipopeptide immunization of HIV-1-infected patients: the LIPTHERA study

We studied the time course of immunological and virological markers after highly active antiretroviral therapy (HAART) interruption in chronically human immunodeficiency virus type 1 (HIV-1)-infected patients immunized with an HIV lipopeptide preparation. In a prospective open pilot study, 24 HIV-1-infected HAART-treated patients with undetectable plasma viral loads (pVLs) and CD4⁺ T-cell counts above 350/mm³ were immunized at weeks 0, 3, and 6 with a candidate vaccine consisting of six HIV lipopeptides. At week 24, patients with pVLs of <1.7 log₁₀ copies/ml were invited to stop taking HAART. Antiretroviral therapy was resumed if the pVL rose above 4.47 log₁₀ copies/ml and/or if the CD4⁺ cell count fell below 250/mm³. Immunological and virologic parameters were studied before and after HAART interruption. The median baseline and nadir CD4⁺ cell counts were 482 (interquartile range [IQR], 195 to 826) and 313 (IQR, 1 to 481)/mm³, respectively. New specific CD8⁺ cell responses to HIV-1 epitopes were detected after immunization in 13 (57%) of 23 assessable patients. Twenty-one patients were evaluated 96 weeks after HAART interruption. The median time to pVL rebound was 4 weeks (IQR, 2 to 6), and the median peak pVL was 4.26 (IQR, 3 to 5) log₁₀ copies/ml. Thirteen of these 21 patients resumed HAART a median of 60 weeks after immunization (IQR, 9.2 to 68.4 weeks), when the median pVL was 4.8 (IQR, 2.9 to 5.7) log₁₀ copies/ml and the median CD4⁺ cell count was 551 (IQR, 156 to 778)/mm³. Eight patients were still off therapy at 96 weeks, with a median pVL of 4 (IQR, 1.7 to 4.6) log₁₀ copies/ml and a median CD4⁺ cell count of 412 (IQR, 299 to 832)/mm³. No clinical disease progression had occurred. Despite the lack of a control arm, these findings warrant a randomized study of therapeutic vaccination with HIV lipopeptides followed by long-term HAART interruption in AIDS-free chronically infected patients.     

Einflu\ von Absto\ungskrisen und immunsuppressiver Therapie auf die Lymphozytensubpopulationen von Patienten nach Nierentransplantation

Summary The lymphocyte subsets in the peripheral blood were examined 3 times a week in 17 patients receiving a cadaveric renal allograft using 2-color flow cytometry and several combinations of monoclonal antibodies. Patients who experienced a rejection crisis (n=12) had a significantly higher CD4/CD8-ratio (2.72±1.26 mean±SD) than patients with stable graft function (1.76±1.33, p<0.05). 9/12 patients showed 0–3 days prior to the rejection episode an increase of the CD4/CD8-ratio (0.5) and/or a high ratio (2.5) with a decrease following antirejection therapy. The activation markers HLA-DR and IL-2 receptor on T cells were increased only during 3/12 rejection episodes. Patients with rejections resistant to prednisone pulse therapy (n=6) had significantly more lymphocytes/mm³ in the peripheral blood (1111.7±597.5) than successfully treated patients (n=6, 336.7±196.0, p<0.02). Antirejection therapy with prednisone pulses and/or antithymocyte globuline resulted in a significant decrease of T lymphocytes (CD3+) with a selective reduction of T helper/inducer cells (CD4+). 6 months after renal transplantation the patients had a higher percentage of suppressor/cytotoxic cells (CD8+) compared to the pretransplant values (26.3±10.9% vs 17.7±6.2%, p<0.02) and blood donors (16.3±6.2%, p<0.01). Furthermore the percentage of T helper cells (CD4+/CD28–) was significantly higher and the T suppressor-inducer cells (CD4+/CD28+) were significantly lower compared to the controls. Serial flow cytometric determinations of lymphocyte subsets in renal allograft recipients may be helpful in some cases although rejection episodes could not be predicted in the individual patient.

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Abkürzungsverzeichnis MAK Monoklonale Antikörper - Ly Lymphozyten - NTPL Nierentransplantation - CD Cluster Designation - NK-Zellen Natürliche Killerzellen - CyA Cyclosporin A - Aza Azathioprin - Pred Prednison - ATG Antithymozytenglobulin - FITC Fluorescein-isothiozyanat - PE Phycoerythrin - CMV Zytomegalievirus     

Selective depletion of CD14+ CD16+ monocytes by glucocorticoid therapy

Glucocorticoids (GC) are potent anti-inflammatory and immunosuppressive agents that act on many cells of the body, including monocytes. Here we show that a 5-day course of high dose GC therapy differentially affected the CD14⁺⁺ and the CD14⁺ CD16⁺ monocyte subpopulations in 10 patients treated for multiple sclerosis. While the classical (CD14⁺⁺) monocytes exhibited a substantial increase from 495 ± 132 to 755 ± 337 cells/μl, the CD14⁺ CD16⁺ monocytes responded with a pronounced decrease from 36 ± 15 to 2 ± 3 cells/μl (P < 0.001). In 4/10 patients the CD14⁺ CD16⁺ monocytes fell below detection limits (< 0.2 cells/μl). This observation was confirmed when the CD14⁺ CD16⁺ monocytes were identified by virtue of their low CD33 expression as these cells decreased as well. After discontinuation of GC therapy the CD14⁺ CD16⁺ monocytes reappeared and reached normal levels after 1 week. The profound depletion of CD14⁺ CD16⁺ monocytes by GC as described here is a novel effect of GC action in vivo and may contribute to GC-mediated immunosuppression. Determination of the number of this monocyte subset may also serve to monitor the effectiveness of GC therapy in patients requiring immunosuppressive treatment.