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Objective: To develop evidence based recommendations for the management of ankylosing spondylitis (AS) as a combined effort of the 'ASsessment in AS' international working group and the European League Against Rheumatism., Methods: Each of the 22 participants was asked to contribute up to 15 propositions describing key clinical aspects of AS management. A Delphi process was used to select 10 final propositions. A systematic literature search was then performed to obtain scientific evidence for each proposition. Outcome data for efficacy, adverse effects, and cost effectiveness were abstracted. The effect size, relative risk, number needed to treat, and incremental cost effectiveness ratio were calculated. On the basis of the search results, 10 major recommendations for the management of AS were constructed. The strength of recommendation was assessed based on the strength of the literature evidence, risk-benefit trade-off, and clinical expertise., Results: The final recommendations considered the use of non-steroidal anti-inflammatory drugs (NSAIDs) (conventional NSAIDs, coxibs, and co-prescription of gastroprotective agents), disease modifying antirheumatic drugs, treatments with biological agents, simple analgesics, local and systemic steroids, non-pharmacological treatment (including education, exercise, and physiotherapy), and surgical interventions. Three general recommendations were also included. Research evidence (categories I-IV) supported 11 interventions in the treatment of AS. Strength of recommendation varied, depending on the category of evidence and expert opinion., Conclusion: Ten key recommendations for the treatment of AS were developed and assessed using a combination of research based evidence and expert consensus. Regular updating will be carried out to keep abreast of new developments in the management of AS.

Background: Systemic lupus erythematosus (SLE) is an autoimmune disease affecting multiple organ systems triggered by the production of autoantibodies. Previous clinical studies in humans and murine models suggest that type I interferons (IFNs) are important for the initiation and potentiation of SLE activity., Methods: 65 consecutive patients with SLE were identified from the University of California, San Francisco Lupus Clinic with moderate-severe disease activity. 94 serological samples were collected. Type I IFN levels and the ability of plasma to induce expression of several surface markers of dendritic cell maturation were measured., Results: Type I IFN levels correlated with the presence of cutaneous manifestations, and there was a trend towards correlation with renal disease. No correlation was found between type I IFN levels and neurological disease. Type I IFN levels correlated positively with the SLEDAI score and anti-dsDNA levels and inversely with C3 levels. Interestingly, type I IFN levels were highest in African American patients. SLE plasma also induced the expression of MHC class I, CD38, and CD123 on monocytes, and was blocked by the addition of a monoclonal antibody to IFNAR1., Conclusions: The pathogenic role of type I IFN is suggested by the induction of cell surface markers for dendritic cell maturation. The potential therapeutic utility of antibodies directed to either type I IFN or IFNAR1/IFNAR2 may be of interest in further studies.

Objective: Anti-tumor necrosis factor-alpha (TNF-alpha) therapies are not only beneficial for reducing symptoms in rheumatoid arthritis (RA) but also for structural damage visible on plain radiographs and serological biomarkers of articular cartilage damage. It is not known if these therapies also prevent structural damage in ankylosing spondylitis (AS). The low sensitivity to change over time of plain radiographic instruments mandates a search for the effects of these therapies on possible biomarkers of cartilage damage., Methods: We studied 2 populations of patients with AS: (1) patients recruited to a placebo controlled trial of etanercept in AS for 16 weeks; (2) an observational cohort receiving infliximab for disease refractory to conventional therapy. Clinical (morning stiffness, nocturnal pain, Bath AS Disease Activity Index) and laboratory [erythrocyte sedimentation rate (ESR), C-reactive protein (CRP)] assessments of disease activity were performed at baseline and at either 16 weeks (clinical trial cohort) or at 14 weeks (observational cohort). We measured serum matrix metalloproteinase-1 (MMP-1), MMP-3, human cartilage glycoprotein-39 (YKL-40), and cartilage oligomeric matrix protein by ELISA at the same timepoints. We also measured serum concentrations of 2 novel biomarker epitopes, C2C and 846, by competitive ELISA. The C2C assay detects a neoepitope at the carboxy terminus of the long three-quarter amino-terminal fragment generated following cleavage of type II collagen by collagenases. Aggrecan 846 epitope is a chondroitin sulfate epitope present on intact aggrecan molecules. Both these assays would detect products originating from both hyaline cartilages and intervertebral discs., Results: There was a significant reduction in levels of C2C (p = 0.005) and a significant increase in the 846 epitope (p = 0.01) in patients who received etanercept compared to placebo controls. Changes in C2C correlated significantly with changes in ESR (r = 0.51, p = 0.04) and CRP (r = 0.48, p = 0.048). Significant changes in C2C were not evident in the infliximab observational cohort, although significant reductions were noted in levels of MMP-3 (p = 0.04) and MMP-1 (p = 0.02) at 14 weeks that were not observed in the etanercept group. Analysis of all baseline samples showed a significant correlation between levels of MMP-3 with CRP (r = 0.73, p < 0.0001), and YKL-40 (r = 0.71, p < 0.0001). No correlation was evident at baseline between levels of C2C or 846 epitope and either acute phase reactants or other biomarkers., Conclusion: Our data suggest that an anti-TNF-alpha agent, etanercept, may modify cartilage turnover. These include decreased degradation of type II collagen and increased turnover of aggrecan. Additional therapeutic properties of some anti-TNF-alpha agents in AS, such as infliximab, may be related to decreased expression of MMP. Additional studies in larger populations are therefore warranted.

Background: Retroviral infection has been implicated in the pathogenesis of primary Sjögren's syndrome., Objective: To examine the efficacy of the reverse transcriptase inhibitor lamivudine in patients with this syndrome., Methods: 16 patients with primary Sjögren's syndrome were randomised to receive either lamivudine 150 mg twice daily or placebo for three months. Measures of lacrimal and salivary function, including minor salivary gland biopsies, were obtained before and after treatment., Results: Treatment with lamivudine did not result in significant improvement in the primary outcome measure of unstimulated whole salivary flow or other secondary measures, including minor salivary gland biopsy focus scores., Conclusion: Lamivudine is not effective in patients with primary Sjögren's syndrome, suggesting either that a retroviral aetiology is not present or that it may be important only in early disease.

Objective: To examine the baseline demographic and disease characteristics that might influence improvement as measured by the Assessment in Ankylosing Spondylitis Response Criteria (ASAS 20) in patients with ankylosing spondylitis (AS)., Methods: A multicenter Phase 3 study was performed to compare the safety and efficacy of 24 weeks of etanercept 25 mg subcutaneous injection twice weekly (n = 138) and placebo (n = 139) in patients with AS. The ASAS 20 was measured at multiple time points. Using a significance level of 0.05, a repeated measures logistic regression model was used to determine which baseline factors influenced response in the etanercept-treated patients during the 24-week double blind portion of the trial. The following baseline factors were used in the model: demographic and disease severity variables, concomitant medications, extra-articular manifestations, and HLA-B27 status. The predictive capability of the model was then tested on the patients receiving placebo after they had received open-label etanercept treatment., Results: Baseline factors that were significant predictors of an ASAS 20 response in etanercept-treated patients were C-reactive protein (CRP), back pain score, and Bath Ankylosing Spondylitis Functional Index (BASFI) score. Although clinical response to etanercept was seen at all levels of baseline disease activity, responses were consistently more likely with higher CRP levels or back pain scores and less likely with increased BASFI scores at baseline., Conclusions: Higher CRP values and back pain scores and lower BASFI scores at baseline were significant predictors of a higher ASAS 20 response in patients with AS receiving etanercept but predictive value was of insufficient magnitude to determine treatment in individual patients.

Background: Venous thrombotic events (VTEs) have been observed in Wegener granulomatosis, but the incidence rate is not known., Objective: To measure the incidence of VTEs in patients with Wegener granulomatosis., Design: Prospective, observational cohort study., Setting: A multicenter, randomized, double-blind, placebo-controlled treatment trial for Wegener granulomatosis., Patients: 180 patients with Wegener granulomatosis enrolled during periods of active disease., Measurements: Venous thrombotic events (deep venous thromboses or pulmonary emboli) were documented and confirmed prospectively. Incidence rates were calculated on the basis of time to first VTE., Results: Thirteen patients had VTEs before enrollment. During 228 person-years of prospective follow-up, 16 VTEs occurred in 167 patients with no history of VTE. Median time from enrollment to VTE for patients with an event was 2.1 months. The incidence of VTE among patients with Wegener granulomatosis was 7.0 per 100 person-years (95% CI, 4.0 to 11.4)., Limitations: Although prospectively recorded, screening for VTEs did not occur., Conclusions: The incidence rate of VTEs in Wegener granulomatosis is high when compared with available rates in the general population, patients with lupus, and patients with rheumatoid arthritis. These results have important implications for clinical care of patients with Wegener granulomatosis.

Background: Ankylosing spondylitis (AS) is a chronic inflammatory disorder that affects approximately 350,000 patients in the United States. Over time, the spinal and peripheral joint involvement of AS may cause severe disability and functional limitations. Research in the molecular and cellular events of AS has uncovered a distinct role for the proinflammatory cytokine, tumor necrosis factor (TNF), in the pathogenesis of this disease., Objectives: This article reviews the role of TNF in the pathogenesis of AS and evaluates new therapeutic options for the disease., Methods: Literature searches were conducted and various studies were reviewed and evaluated from the perspective of study design and validity of conclusions. Data are presented from animal studies and human clinical trials designed to test the efficacy of TNF inhibition in AS., Results: The TNF inhibitors etanercept and infliximab not only demonstrate a significant reduction in the signs and symptoms of AS but also improve quality of life while reducing serious toxicities. Etanercept is the first TNF inhibitor to be approved by the United States Food and Drug Administration (FDA) for use in the treatment of AS and has recently been approved in the European Union. Infliximab has also been approved for use in the European Union., Conclusions: Early treatment with TNF inhibitors in patients with RA has been shown to result in significant improvements in disability, pain, and joint scores compared with delayed treatment. Ongoing trials are currently investigating whether these agents can halt or delay disease progression in patients with AS., Relevance: Understanding the role of TNF inhibition in AS has led to new therapies that offer improved function and less disability for many patients suffering from this disease.

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.

Ankylosing spondylitis (AS) is the most common of a group of diseases called seronegative spondyloarthropathies. This group of diseases shares common demographic, clinical, and genetic features. This article reviews the rationale, clinical efficacy, and safety reports of etanercept, thalidomide, and pamidronate in the treatment of patients who have AS.

Ankylosing spondylitis is an inflammatory disorder affecting the axial skeleton and periphery. Symptoms can often be debilitating. Current therapy for the disease include physical therapy, non-steroidal anti-inflammatory drugs (NSAIDS, anti-rheumatic disease modifying drugs (DMARDS), and the newly developed biologic agents targeting tumor necrosis factor alpha (TNF-alpha). This paper will provide a comprehensive review of these treatments which focusing on evidence based medicine for the daily clinical practice of rheumatology.

Objective: To evaluate the safety and efficacy of a humanized monoclonal antibody against CD154 (IDEC-131) in patients with active systemic lupus erythematosus (SLE)., Methods: In this phase II, double-blind, placebo-controlled, multiple-center, multiple-dose study, 85 patients with mild-to-moderately active SLE were randomized to receive 6 infusions of IDEC-131, ranging from 2.5 mg/kg to 10.0 mg/kg, or placebo over 16 weeks. Efficacy was assessed at week 20, primarily by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and secondarily, by multiple measures of disease activity. Safety was assessed through week 28 by clinical and laboratory evaluation. Immunogenicity studies were also performed., Results: SLEDAI scores improved from the baseline levels of disease activity in all groups, including the placebo group. However, these scores were not statistically different among the IDEC-131 treatment and placebo groups at week 20. Evaluations of secondary variables did not indicate significant differences between the IDEC-131 treatment and placebo groups. The type and frequency of adverse events were similar between the IDEC-131 and placebo groups., Conclusion: IDEC-131 administered at doses ranging 2.5-10.0 mg/kg over 16 weeks was safe and well tolerated in patients with SLE. Efficacy of the drug compared with placebo was not demonstrated. There were statistically significant improvements from baseline in all groups, including the placebo group.

Ankylosing spondylitis is a chronic inflammatory disease that leads to significant loss of function and disability in patients. Current conventional therapies have not demonstrated improvement in axial symptoms and progressive ankylosis of the spine. The use of new biologic agents that block the actions of tumor necrosis factor-alpha have, for the first time, reported significant improvement in axial symptoms and reduction in spinal inflammation in short-term studies. Future studies with larger numbers of patients over long periods of time will eventually determine the long-term success and safety of these agents.

The last significant breakthrough in the treatment of systemic lupus erythematosus (SLE) was the use of cyclophosphamide and methylprednisolone in the treatment of lupus nephritis. Recent advances in immunology, oncology, and endocrinology have resulted in many potential therapies for SLE. These therapies include new immunosuppressants, biologic medications, tolerizing agents, immunoablation techniques, and hormonal medications. Each of these approaches will be discussed in this review. Some therapies are currently in use in clinical rheumatology practice (mycophenolate mofetil) and others are entering phase I trials (anti-BLyS monoclonal antibody). While some of these new therapies target specific inflammatory mechanisms in SLE (anti-CD40L monoclonal antibody), others work by nonspecific inhibition of the immune system (immunoablation).

Objective: To investigate the safety and pharmacology of a humanized monoclonal antibody against CD40-ligand (IDEC-131) in patients with systemic lupus erythematosus (SLE)., Methods: Cohorts of 3 to 5 patients with symptomatic lupus each received 0.05, 0.25, 1.0, 5.0, or 15.0 mg/kg of IDEC-131 as a single intravenous infusion. Patients were followed for 3 months to evaluate toxicity and pharmacokinetics., Results: This phase I, single dose, dose-escalating study was conducted in 23 patients at a single institution. All patients experienced at least 1 adverse event (AE) during a 3 month followup period, although 58 AE in 17 patients were considered possibly or probably related or of unknown relationship to treatment. No dose relationship in the distribution of AE was apparent. No infusion related cytokine-release syndrome was observed; no infusions were interrupted, and all patients completed treatment. Eight mild (grade 1 or 2) infections were reported in 8 patients. All infections were considered unrelated to drug administration and all resolved uneventfully. No patient developed detectable antibodies to IDEC-131. Flow cytometry revealed no apparent treatment related depletion of lymphocyte subsets. Pharmacokinetic analysis indicated that the maximum serum concentration and the area under the concentration curve of IDEC-131 were proportional to the dose administered. At doses between 1.0 and 15.0 mg/kg, the serum half-life ranged from 299 to 320 h. Efficacy was not formally evaluated in this single dose study., Conclusion: IDEC-131 (humanized Mab against CD40L) administered in a single intravenous infusion at doses of 0.05-15.0 mg/kg is safe and well tolerated in patients with SLE.

This report describes the case of a patient with multicentric reticulohistiocytosis. Immunohistochemical analysis revealed prominent markers of monocyte/macrophage origin, as well as the presence of tumor necrosis factor alpha, interleukin-1beta (IL-1beta), and IL-12; the occurrence of the latter in this disease has not previously been reported. Clinical, laboratory, radiographic, and histologic findings in multicentric reticulohistiocytosis are reviewed. In addition, all published cases of multicentric reticulohistiocytosis which included reports of cytokine and immunohistochemical analysis are reviewed, and evidence for a monocyte/macrophage origin and role in disease pathogenesis is provided.

Gouty arthritis is the culmination of a number of physiologic mechanisms that ultimately result in deposition of uric acid within joints and soft tissues. Decreased uric acid clearance through the kidney is the most common cause of gout. Tophaceous gout occurs in less than 10% of patients. Acute episodes are treated with NSAIDs or colchicine. Low-dose therapy with these agents can also prevent recurrent attacks. Most patients with gout need long-term treatment with either uricosuric agents or xanthine oxidase inhibitors.

Systemic lupus erythematosus (SLE) is characterized by the production of pathogenic autoantibodies to nucleoprotein antigens, including double-stranded DNA (dsDNA). The deposition of IgG dsDNA immune complexes in glomeruli is thought to be crucial for disease pathogenesis and complement activation. rhDNase catalyzes the hydrolysis of extracellular DNA and has been shown to delay the development of dsDNA antibodies, reduce proteinuria, and delay mortality in a lupus-prone murine model. We conducted a 40d, phase Ib, randomized, double-masked, placebo-controlled trial to determine the safety and pharmacokinetics of rhDNase, and to measure any changes in markers of disease activity in 17 patients with lupus nephritis. Patients were assigned to receive either: (1) 25 microg/kg rhDNase (n = 8); (2) 125 microg/kg rhDNase (n=6); or (3) placebo (n = 3) initial single intravenous (IV) dose followed by 10 subcutaneous (SC) doses. Skin biopsies performed on nine patients pre- and post-treatment were studied for immune complex deposition by immunofluorescence. Serum cytokine levels (sIL2-R, IL-6, IL-10, and TNF-alpha) were analyzed by ELISA. Cytokine secretion and antibody production were measured by ELISPOT analysis and ELISA. Serum hydrolytic activity of rhDNase was achieved after IV administration at 25 and 125 microg/kg, but not after SC administration at either dose. A t 1/2 of 3-4h was estimated from serum concentration profiles following IV administration. Serum dsDNA antibodies were unchanged (mean values: 33 IU/mL vs 39 IU/mL [pre- and post-treatment] for the 25 microg/kg group, and 74 IU/mL vs 74 IU/mL for the 125 microg/kg group, and 14 IU/mL vs 20 IU/mL for the placebo group). Complement levels (C3 and C4) and circulating immune complexes did not change appreciably during the treatment period for any of the groups. Serum cytokine profiles by ELISA revealed no changes in sIL-2 receptor, IL-6, IL-10, or TNF-alpha. There was no change in the number of cells secreting either Th1 or Th2 specific cytokines, nor in the number of cells secreting dsDNA antibodies. Neutralizing antibodies to rhDNase were not detected in serum at any time during the study. Immune complex deposition was unchanged in pre- and post-treatment in skin biopsies in both dose groups. rhDnase was well tolerated without significant adverse events following administration, and treatment was not associated with the development of neutralizing antibodies to rhDNase. Serum rhDNase concentrations capable of hydrolytic activity of rhDNase were achieved for a few hours following IV, but not SC administration. Serum markers of disease activity were unchanged during the study period.

Study Objective: To describe the pharmacokinetics and pharmacodynamics of fludarabine in patients with rheumatoid arthritis (RA)., Design: Open-label, staggered trial conducted in conjunction with a phase I-II clinical trial., Setting: Government research hospital., Patients: Twenty-six patients with refractory RA., Intervention: Fludarabine 20 or 30 mg/m2/day was administered as a 0.5-hour infusion for 3 consecutive days (1 cycle) for 6 months (1 cycle/mo)., Measurements and Main Results: Serial plasma samples were collected for pharmacokinetic analysis on day 2 of the first cycle of therapy. Relationships between pharmacokinetic parameters and hematologic and efficacy parameters were examined. The disposition of fludarabine was characterized by a two-compartment model. There were no differences in pharmacokinetics between the low- and high-dose groups. The mean+/-SD total clearance, volume of distribution at steady state, and beta-half-life were 13.68+/-5.1 L/hour, 170.08+/-86.5 L, and 10.9+/-3.1 hours, respectively. The volume of the peripheral compartment was approximately twice as large as the volume of the central compartment, indicating a significant amount of tissue distribution. No significant pharmacodynamic relationships were observed between pharmacokinetic parameters and hematologic and efficacy parameters., Conclusion: Fludarabine pharmacokinetics in patients with RA are characterized by an intermediate-length distribution phase (approximately 40 min), terminal half-life of 10.9 hours, and significant amount of tissue distribution.

Objective: Fludarabine, a nucleoside analog that targets both resting and proliferating lymphocytes, is a promising drug for the treatment of autoimmune diseases. We conducted a 2 dose, open label clinical trial to evaluate the toxicity/safety of the fludarabine treatment and its clinical and immunological effects., Methods: Twenty-six patients with severe rheumatoid arthritis (RA) refractory to treatment with at least one slow acting antirheumatic drug were treated with intravenous fludarabine [20 mg/m2 body surface area (n=12) or 30 mg/m2 body surface area (n=14) per day for 3 consecutive days] given monthly for 6 months. Second line agents with the exception of glucocorticoids were discontinued at least 4 weeks before study entry. Measurements included toxicity and tolerability monitored at monthly intervals: efficacy, by both a 50% reduction in tender or swollen joint count and American College of Rheumatology (ACR) criteria for 20% response; and phenotypic analysis of peripheral blood mononuclear cells and T cell functional assays., Results: Using intention-to-treat analysis, 2 of 12 (17%) patients in the low dose and 7 of 14 (50%) in the high dose groups had 50% or greater reduction in tender and/or swollen joint count after 6 months of therapy compared to baseline (p=0.09). Two of 12 (17%) in the low dose group and 5 of 14 (36%) in the high dose group met ACR criteria for 20% improvement (p=0.28). No immediate toxicity was observed. Several infections occurred, including 4 episodes of limited Herpes zoster, which responded to standard therapy. Significant lymphopenia involving T and B cells was observed in all patients. Both naive (CD4+CD45RA+) and memory CD4+ T cells (CD4+CD45RO+) were reduced (naive > memory). No significant regeneration of naive T cells was observed, which may suggest limited thymic regenerative capacity. Fludarabine decreased the proliferative response of peripheral blood lymphocytes to mitogens, as well as the production of T cell (interleukin 2 and interferon-gamma) and monocyte derived (tumor necrosis factor-alpha and IL-10) cytokines., Conclusion: Fludarabine treatment of patients with severe, refractory RA resulted in significant lymphopenia, suppression of lymphocyte function, and clinical improvement in the high dose group. There was no immediate toxicity; however, several infections occurred. Controlled trials are needed to substantiate the clinical improvement observed in this open label trial.

Objective: To determine the safety and tolerability, as well as the clinical and immunologic effects, of 2-chloro-2'-deoxyadenosine (2-CdA) in patients with systemic lupus erythematosus-associated glomerulonephritis., Methods: In a phase I study, 12 patients with proliferative lupus nephritis received 2-CdA either in weekly escalating intravenous treatments (0.15 mg/kg/week x 4, 0.1875 mg/kg/week x 4, 0.225 mg/kg/week x 4; n = 5) or in a continuous 7-day infusion (0.05 mg/kg/day; n = 7). Safety, renal improvement, and immunologic effects were evaluated for 12 months., Results: Patients treated with 2-CdA showed peripheral lymphocyte depletion without a significant reduction in neutrophil, monocyte, or platelet numbers or hematocrit levels. Naive and memory T cells were decreased, as were lymphocytes with markers of early and late activation. Peripheral B cell depletion was not associated with significant decreases in serum immunoglobulin levels. Continuous infusion induced better clinical responses than weekly infusions, as evidenced by 1) the percentage of patients showing complete response (43% versus 0%), 2) the percentage with at least 50% reduction in proteinuria (43% versus 20%), 3) the percentage with at least a 50% reduction in urinary dysmorphic red cells (57% versus 0%), and 4) the percentage in whom cellular casts disappeared (43% versus 0%). Several infections occurred; these responded to standard antibiotic therapy., Conclusion: In this pilot study, 2-CdA was safely administered to 12 patients with lupus nephritis. It induced prolonged reductions in lymphocyte populations and may be efficacious in selected patients with lupus nephritis when administered as a continuous infusion.

Unlabelled: OBJECTIVE--To describe the identification of human immunodeficiency virus (HIV)-infected infants born to women who were seronegative or indeterminate during pregnancy. RESEARCH DESIGN--Longitudinal cohort study. SETTING--Inner-city medical center., Participants: A series of children born to women with histories of risk factors for HIV infection were followed up for studies of the natural history of HIV-infected infants. These children were identified through risk factor assessment of pregnant women presenting for obstetric care. INTERVENTIONS--Counseling and testing to detect HIV. RESULTS--Three women were retrospectively identified who were infected with HIV during pregnancy but whose test results showed them to be either seronegative or indeterminate. Two of these women transmitted HIV infection to their children. Subsequently, all three women were confirmed to be infected. CONCLUSIONS--Standard serologic testing to detect HIV infection will not identify all infected pregnant women. Perinatal transmission of HIV can occur in women with negative results of enzyme-linked immunosorbent assay or indeterminate results of Western blot analysis during pregnancy.

1. The intrarenal pressure of dogs anesthetized with pentobarbital averages 26 mm. Hg, and ranges from 10 to 58 mm.; that of decerebrate dogs is 25 mm., and that of unanesthetized dogs with explanted kidneys is 25 mm. Tests of a few cats and rabbits indicate that their intrarenal pressure has about the same magnitude. 2. There is a slight positive correlation between intrarenal pressure and both body weight and kidney weight, but intrarenal pressure is not related to sex, blood pressure, or age.

A rapid method for measuring tissue pressures has been designed. A pressure of 250 mm. Hg is imposed on a manometer. Then the system is allowed to discharge into a needle cannula inserted in the tissue. The manometer forces out fluid (about 10 c.mm.) until the pressure within it is the same as that within the tissue. Records of the pressure changes are made. Each observation takes about a minute. The method gives results that are closely comparable with other reports of tissue pressures. With this method, the pressure in the following organs of dogs was found to be: kidney, 26 mm. Hg, cerebral cortex, 0 to 5 mm., muscle, 1 to 10 mm., spleen, S to 16 mm., subcutaneous tissue, 0 to 3 mm., and liver -2 to 14 mm. The reliability of the method was tested on the kidneys of decerebrate dogs. Measurements were found to be the same within narrow limits over a period of an hour; they were the same when taken simultaneously in different regions of the same kidney or in opposite kidneys. They were independent of the volume of fluid forced into the tissue. Similar pressures were observed with 1 or 5 or 10 holes bored in the shaft of the cannulating needle. The intrarenal pressure was also measured by inserting a needle cannula into the tissue and then allowing the pressure to reach equilibrium passively with a manometer. This method gave similar results. The intrarenal pressure has now found to be the same when measured by three different technics.