Long-term effects of combination treatment with fludarabine and low-dose pulse cyclophosphamide in patients with lupus nephritis.

OBJECTIVES: To determine the safety and efficacy of a short course of fludarabine combined with cyclophoshamide in lupus nephritis. METHODS: A phase I/II open label pilot study. Thirteen patients with active proliferative lupus nephritis received monthly oral boluses of low-dose cyclophoshamide (0.5 gm/m(2) on day 1) and subcutaneous fludarabine (30 mg/m(2) on days 1-3) for 3-6 cycles. Concomitant prednisone was aggressively tapered from 0.5 mg/kg/day to a low-dose, alternate-day schedule. Patients were followed for at least 24 months after therapy. The primary outcome was the number of patients achieving renal remission defined as stable creatinine, proteinuria <1 gm/day and inactive urine sediment for at least 6 months. RESULTS: The study was terminated early because of bone marrow toxicity. Eleven patients who received at least three cycles were evaluated for efficacy. Ten patients improved markedly with seven patients achieving complete remission and three patients achieving partial remission. There were three serious haematological adverse events during the treatment with one death due to transfusion-associated graft vs host disease. Profound and prolonged CD4 (mean CD4: 98/microl at 7 months and 251/microl at 12 months) and CD20 lymphocytopenia was noted in most patients. Three patients developed Herpes zoster infections. CONCLUSIONS: A short course of low-dose fludarabine and cyclophoshamide can induce long-lasting remissions in patients with proliferative lupus nephritis, but severe myelosuppression limits its widespread use.

[The importance of an endexspiratory plateau in respirators (author's transl)]. / Die Bedeutung des endinspiratorischen Beatmungs-plateaus von Respiratoren.

A two-compartment lung model with a bronchial obstruction was ventilated with different respirators: Engström E 200, ER 300, ECS 2000, Bennett MA 1 B, Sandoz M 250 and Dräger Servoventilator 900 under same conditions. Redistribution of air, the socalled "pendelluft", was found in all respirators. The amount of "pendelluft" produced by E 200 and M 250 was much more lower than that produced by respirators with low internal compliance, ECS 2000 and Servo 900. Endinspiratory plateau means more even distribution of ventilation volume despite airway obstruction.

[Narcorex 19 - a new anaesthetic apparatus (author's transl)]. / Narcorex 19 - ein neues Narkosegerät.

The Dräger "Narcorex 19" anaesthetic apparatus incorporates a closed anaesthetic circuit (7a) and the Pulmomat 19 K1. There is a possibility to connect Water's- or Kuhn's-System. This perspicuous and flexible apparatus is designed for induction as well as maintenance of anaesthesia with or without artificial ventilation.

[Controlled hypotension anaesthesia in ENT surgery (author's transl)]. / Die kontrollierte Blutdrucksenkung in der HNO-Chirurgie.

Based on an experience over two years with 316 cases the principles of general anaesthesia with controlled hypotension in ENT surgery are described and discussed. Indications, contraindications and methods of application are outlined. The method reduces bleeding considerabley and proved to be useful for rhinoplasties, major sinus surgery as well as parotid gland and necksurgery.

[Megamed 0.5.2.2D--a ventilation analyser (author's transl)]. / Megamed 0.5.2.2.D--ein Analyser atemmechanischer Grössen.

Megamed 05.2.2.D is a ventilation analyser. Pressure and flow is measured pneumotachographically; tidal volume, compliance, resistance, work and power are calculated. This values are given on a digital display, besides being printed continuously or in given intervals. Analog recording of graphics is possible as well as storing the values in a data processing system.

[The effect of fentanyl on spontaneous respiration]. / Der Einfluss von Fentanyl auf die Spontanatmung.

UNLABELLED: AIM OF THE INVESTIGATION: The effects of fentanyl on spontaneous respiration have been investigated in both animals and humans. The investigations in humans have been performed under circumstances and using methods that do not relate the results to clinical practice, e.g., predicting the effects of opioids used for postoperative pain relief on the ward. We investigated the effects of fentanyl on mechanical parameters, oxygen saturation (SAT), and end-expiratory CO2 (exCO2) in humans. METHODS: Fifteen male volunteers took part in this study, which was approved by the local ethics committee. Each received 3 micrograms/kg fentanyl intravenously after 5 min measurement of base-line values and were observed for 30 min. We continuously registered thoracic (A1) and abdominal (A2) extension and respiratory rate (RR) using piezoceramic elements. SAT, heart rate (HR), and exCO2 were measured with a pulse oximeter and infrared absorption (OSCAR, Datex). All data were transferred to a high-performance microcomputer (Multitalent, ZAK). The statistical analysis included descriptive and correlation statistics. RESULTS: After the injection of fentanyl A1, A2, RR, HR, and SAT were reduced; exCO2 increased. After a few minutes A1 increased, occasionally exceeding the base-line value. A2, RR, HR, and SAT increased without reaching base-line values. ExCO2 remained increased. The best overall correlation was found between A2 and SAT (r = 0.87). DISCUSSION: As far as comparable, our results are in accordance with those of the majority of other investigators. The difference between thoracic and abdominal extension, the latter being closely correlated with tidal volume, has not previously been described quantitatively. We attribute this result to the different innervation of the phrenic and intercostal nerves. Whereas the influence of fentanyl on SAT and exCO2 during the first 8 min can easily be explained, the varying behavior in the following minutes has not previously been described and may be due to the different binding characteristics of O2 and CO2. Alteration of the CNS setting for pCO2 may also contribute to this result. The time course of the measured parameters seems to be of clinical importance for the detection of respiratory problems in spontaneously breathing patients.

[Anaesthetic problems with glomus tumors of the head and neck (author's transl)]. / Anästhesiologische Probleme bei Glomustumoren des Kopf-Hals-Gebietes.

Anaesthesia and Postanaesthetic Course of Three Cases of Glomus Jugulare Tumor Were Studied. Pathophysiology and clinical features of this very rare tumor is discussed on a brief review of literature. After all localisation and dimension of this tumor can cause serious complications during operation and postoperative period. It must be considered that a safe operative and postoperative period is implied by carefull preoperative diagnostic management, special anaesthetic technics like controlled hypotension as well as postoperative intensive care.

Distinct T cell/renal tubular epithelial cell interactions define differential chemokine production: implications for tubulointerstitial injury in chronic glomerulonephritides.

Chemokines can promote interstitial fibrosis that is, in turn, a strong predictor of renal failure in chronic glomerulonephritides (GN). Resident renal cells, including renal tubular epithelial cells (RTEC), represent a prominent source of chemokine expression. Evaluating those factors responsible for sustained chemokine production by RTEC during GN is therefore crucial. The contribution of interstitial T cells to such expression, and in particular the precise nature of their interactions with RTEC, are poorly understood. Activated T cell/RTEC coculture induced production of high levels of monocyte chemoattractant protein-1 (MCP-1), RANTES, and IFN-inducible protein-10 from RTEC. Using double-chamber cultures and activated T cell plasma membrane preparations we demonstrated that both cell contact and soluble factors contributed to RTEC chemokine production. Importantly, different chemokines exhibited distinct activation requirements. Thus, for RANTES cell contact was essential, but not sufficient. In contrast, either soluble factors or cell contact induced MCP-1 and IFN-inducible protein-10 production, although both pathways were required for a maximal response. Neutralization experiments identified critical roles in this process for proinflammatory cytokines such as TNF-alpha, IL-1beta, and IFN-gamma as well as membrane molecules such as LFA-1, CD40 ligand, and membrane bound TNF-alpha. Finally, chemotactic bioassays of T cell/RTEC coculture supernatants demonstrated 80% reduction of monocyte migration following MCP-1 neutralization, indicating a dominant role for this chemokine. In summary, activation of renal tubular cells by infiltrating T cells can amplify and perpetuate local inflammatory responses through chemokine production differentially mediated by soluble and cell contact-dependent factors. Recognition of this regulatory diversity has important implications in the choice of potential therapeutic targets in GN.

A prototype pathogen bound ex vivo to human erythrocyte complement receptor 1 via bispecific monoclonal antibody complexes is cleared to the liver in a mouse model.

Immune complexes (IC) bound to the primate erythrocyte (E) complement receptor (CR1) are cleared from the circulation of primates and localized to the liver. IC can be bound to E CR1 either via C3b opsonization or with cross-linked mAb complexes (heteropolymers, HP) which contain an mAb specific for CR1 and a mAb specific for a prototype pathogen. The long-term goal of our work is to apply the HP to the treatment of human diseases associated with blood-borne pathogens. Therefore we have investigated the feasibility of a non-primate model by studying clearance in mice of bacteriophage phiX174 bound via HP to primate E. E-HP-phiX174 complexes were prepared in vitro and infused into the circulation of mice under conditions allowing short term survival of E in the circulation. By radioimmunoassays and flow cytometry, we found that phiX174 is removed from E and cleared from the circulation coincident with loss of HP and CR1, and that the majority of cleared phiX174 is localized to the liver. Through the use of HP constructed with Fab' fragments, we verified the requirement for the Fc portion of the mAb in clearance; inhibition of C3 activation delayed clearance, suggesting a role for complement. The present findings in the mouse confirm previous observations in the non-human primate model.

Infusion of bispecific monoclonal antibody complexes into monkeys provides immunologic protection against later challenge with a model pathogen.

Heteropolymers (HP), bispecific mAbs which bind target pathogens to primate erythrocytes via complement receptor 1, facilitate clearance of pathogens from the bloodstream by targeting them for destruction in the liver without causing lysis or clearance of the erythrocytes. We show that when HP prepared with mouse IgG are intravenously infused into monkeys one or more times prior to exposure to a prototype pathogen, they bind to erythrocytes and remain in the circulation long enough to act as "sentinels," preventing pathogen invasion of the bloodstream. The effectiveness of HP as sentinels is limited both by the monkey's immune response to the HP and, prior to the immune response, by a gradual loss of the HP from monkey erythrocytes over a period of 1 week, and we have investigated possible causes of this HP loss. In overview, our results suggest that HP prepared with mouse IgG are able to effectively function as sentinels for a minimum of 4 days and, after repeat infusion, possibly for up to 2 weeks.

Bispecific monoclonal antibody complexes facilitate erythrocyte binding and liver clearance of a prototype particulate pathogen in a monkey model.

We used Anger camera imaging in a monkey model to investigate the organ localization of a prototype particulate pathogen, 131I-labeled bacteriophage phi X174, after it was bound to the primate erythrocyte complement receptor and then cleared from the circulation. This 131I-labeled phi X174 was infused into the circulation of an immunized monkey, and the nascently formed immune complexes showed rapid and quantitative binding to erythrocytes via the immune adherence reaction (complement-mediated binding). Alternatively, phi X174 was infused into the circulation of a naive animal, and then cross-linked bispecific mAb complexes (heteropolymers, anti-CR1 x anti-phi X174) were infused into the circulation. The infused heteropolymers also facilitated rapid and quantitative binding of phi X174 to erythrocytes. In both cases, after a short lag period, the erythrocyte-bound phi X174 was rapidly cleared from the circulation, and the vast majority of the radiolabel was cleared to the liver, with a small amount clearing to the spleen. Further liver imaging confirmed that within 24 h most of the bacteriophage previously cleared to the liver via the heteropolymer system was phagocytosed and destroyed. The findings in this model system provide additional evidence for the potential utility of heteropolymers to facilitate the safe and rapid clearance of blood-borne pathogens as a potential treatment for infectious diseases.

Lymphocyte depletion with fludarabine in patients with psoriatic arthritis: clinical and immunological effects.

OBJECTIVE: To obtain preliminary information on the safety and efficacy of fludarabine in PsA and analyse its immunomodulatory effects in peripheral blood and synovial tissue. METHODS: 15 patients with active PsA who did not respond to DMARDs were randomly allocated to receive fludarabine every four weeks or placebo. Primary outcomes were the proportion of patients who met the ACR20 and the psoriatic arthritis response criteria (PsARC) at 16 weeks. Secondary outcomes were changes in tender or swollen joint counts and scores of the psoriasis area and severity index (PASI). Phenotypic analysis of peripheral blood mononuclear cells (PBMC), synovial immunohistochemistry, and functional analysis of PBMC were used to determine the immunomodulatory effects of fludarabine. RESULTS: At 16 weeks the ACR20 criteria were met by 3/7 (43%) fludarabine treated v 0/8 placebo treated patients (p=0.08); the PsARC was achieved by 4/7 (57%) fludarabine treated v 2/8 (25%) placebo treated patients; and 3/7 (43%) fludarabine treated v 0/7 placebo treated patients had > or =20% improvement in the PASI. Marked peripheral lymphopenia involving naive (CD4(+) CD45RA(+)) and memory (CD4(+) CD45RO(+)) T cells, CD8(+) T cells, and B cells was seen in fludarabine treated patients. CONCLUSIONS: In PsA fludarabine induces significant peripheral, but modest, synovial lymphopenia, and a trend towards improved clinical response.

IL-10 improves skin disease and modulates endothelial activation and leukocyte effector function in patients with psoriatic arthritis.

Psoriatic arthritis (PsA) provides an ideal disease model in which to investigate the bioactivities of potentially therapeutic cytokines at multiple sites of tissue inflammation. We investigated the effects of IL-10, an antiinflammatory cytokine, given s.c. for 28 days in a double-blind, placebo-controlled study in PsA patients. Synovial/skin biopsies, peripheral blood leukocytes, articular magnetic resonance images, and clinical disease activity scores were obtained sequentially. Modest, but significant clinical improvement in skin, but not articular disease activity scores with only minor adverse effects was observed. Type 1, but not type 2 T cell cytokine production in vitro was suppressed in human rIL-10 compared with placebo recipients. Similarly, monokine production in vitro was reduced, whereas serum soluble TNFRII levels were elevated, indicating suppression of monocyte function. Decreased T cell and macrophage infiltration in synovial tissues was accompanied by reduced P-selectin expression. Moreover, suppressed synovial enhancement on magnetic resonance imaging and reduced alpha(v)beta(3) integrin expression on von Willebrand factor(+) vessels were observed. Together these data demonstrate that a short course of IL-10 modulates immune responses in vivo via diverse effects on endothelial activation, and leukocyte recruitment and effector function. Such biological changes may result in clinically meaningful improvement in disease activity.

Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes.

Autosomal dominant periodic fever syndromes are characterized by unexplained episodes of fever and severe localized inflammation. In seven affected families, we found six different missense mutations of the 55 kDa tumor necrosis factor receptor (TNFR1), five of which disrupt conserved extracellular disulfide bonds. Soluble plasma TNFR1 levels in patients were approximately half normal. Leukocytes bearing a C52F mutation showed increased membrane TNFR1 and reduced receptor cleavage following stimulation. We propose that the autoinflammatory phenotype results from impaired downregulation of membrane TNFR1 and diminished shedding of potentially antagonistic soluble receptor. TNFR1-associated periodic syndromes (TRAPS) establish an important class of mutations in TNF receptors. Detailed analysis of one such mutation suggests impaired cytokine receptor clearance as a novel mechanism of disease.