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A rare overlap syndrome between CREST (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia) syndrome and primary biliary cholangitis (PBC) is described as PACK syndrome, an acronym for primary biliary cholangitis, anticentromere antibodies, CREST syndrome, and keratoconjunctivitis sicca. In this retrospective cohort analysis and review, we present fourteen patients who meet diagnostic criteria for PACK syndrome in one of the largest case series of this group. All patients were female, 86% of whom were White with an average age of 66.7 years (range 39-78 years). The prevalence was 5.08% in our PBC cohort (n=256) similar to previous findings. CREST syndrome was diagnosed prior to PBC in 58% of our patients and limited pulmonary and renal involvement were observed. This syndrome is rare, but given its insidious development, clinicians should be aware of this potential overlap in CREST-only and PBC-only patients.

Objective: To determine, by expert consensus through a modified Delphi process, the role of standardized and new ultrasound signs in the prenatal evaluation of patients at high risk of placenta accreta spectrum (PAS). Methods: A systematic review of articles providing information on ultrasound imaging signs or markers associated with PAS was performed before the development of questionnaires for the first round of the Delphi process. Only peer-reviewed original research studies in the English language describing one or more new ultrasound sign(s) for the prenatal evaluation of PAS were included. A three-round consensus-building Delphi method was then conducted under the guidance of a steering group, which included nine experts who invited an international panel of experts in obstetric ultrasound imaging in the evaluation of patients at high risk for PAS. Consensus was defined as agreement of ≥ 70% between participants. Results: The systematic review identified 15 articles describing eight new ultrasound signs for the prenatal evaluation of PAS. A total of 35 external experts were approached, of whom 31 agreed and participated in the first round. Thirty external experts (97%) and seven experts from the steering group completed all three Delphi rounds. A consensus was reached that a prior history of at least one Cesarean delivery, myomectomy or PAS should be an indication for detailed PAS ultrasound assessment. The panelists also reached a consensus that seven of the 11 conventional signs of PAS should be included in the examination of high-risk patients and the routine mid-gestation scan report: (1) loss of the ‘clear zone’, (2) myometrial thinning, (3) bladder-wall interruption, (4) placental bulge, (5) uterovesical hypervascularity, (6) placental lacunae and (7) bridging vessels. A consensus was not reached for any of the eight new signs identified by the systematic review. With respect to other ultrasound features that are not specific to PAS but increase the probability of PAS at birth, the panelists reached a consensus for the finding of anterior placenta previa or placenta previa with cervical involvement. The experts were also asked to determine which PAS signs should be quantified and consensus was reached only for the quantification of placental lacunae using an existing score. For predicting surgical outcome in patients with a high probability of PAS at delivery, a consensus was obtained for loss of the clear zone, bladder-wall interruption, presence of placental lacunae and presence of placenta previa involving the cervix. Conclusions: We have confirmed the continued importance of seven established standardized ultrasound signs of PAS, highlighted the role of transvaginal ultrasound in evaluating the placental position and anatomy of the cervix, and identified new ultrasound signs that may become useful in the future prenatal evaluation and management of patients at high risk for PAS at birth.

OBJECTIVE To investigate the relationship between Krebs von den Lungen 6 (KL-6) and CCL18 levels and the severity and progression of systemic sclerosis (SSc)-related interstitial lung disease (ILD). METHODS Patients enrolled in the Scleroderma Lung Study II (cyclophosphamide [CYC] versus mycophenolate mofetil [MMF]) were included. Baseline and 12-month plasma samples were analyzed by enzyme-linked immunosorbent assay to assess CCL18 and KL-6 levels. The forced vital capacity (FVC) and the diffusing capacity for carbon monoxide (DLco) were measured every 3 months. Joint models were created to investigate the relationship between baseline CCL18 and KL-6 levels and the course of the FVC and DLco over 1 year according to treatment arm. RESULTS Baseline KL-6 and CCL18 levels each correlated with the extent of radiographic fibrosis. Levels of both CCL18 and KL-6 declined significantly at 1 year. In both treatment arms (n = 71 for CYC, n = 62 for MMF), a higher baseline KL-6 level predicted progression of ILD based on the course of FVC (P = 0.024 for CYC; P = 0.005 for MMF) and DLco (P < 0.001 for CYC; P = 0.004 for MMF) over 1 year. A higher baseline CCL18 level predicted progression of ILD based on the course of the FVC (P < 0.001 for CYC; P = 0.007 for MMF) and DLco (P = 0.001 for CYC; P < 0.001 for MMF) over 1 year, as well as mortality (P = 0.0008 for CYC arm only). CONCLUSION In a rigorously conducted clinical trial for SSc-related ILD, KL-6 and CCL18 levels correlated with ILD severity and declined with immunosuppression. Patients with higher baseline KL-6 and CCL18 levels were more likely to experience disease progression despite treatment. KL-6 and CCL18 levels could be used to identify patients with a progressive ILD phenotype who may benefit from a more aggressive initial treatment approach.

To determine, by expert consensus, a definition for early and late fetal growth restriction (FGR) through a Delphi procedure.A Delphi survey was conducted among an international panel of experts on FGR. Panel members were provided with 18 literature-based parameters for defining FGR and were asked to rate the importance of these parameters for the diagnosis of both early and late FGR on a 5-point Likert scale. Parameters were described as solitary parameters (parameters that are sufficient to diagnose FGR, even if all other parameters are normal) and contributory parameters (parameters that require other abnormal parameter(s) to be present for the diagnosis of FGR). Consensus was sought to determine the cut-off values for accepted parameters.A total of 106 experts were approached, of whom 56 agreed to participate and entered the first round, and 45 (80%) completed all four rounds. For early FGR ( 32 weeks), three solitary parameters (abdominal circumference (AC) 3(rd) centile, estimated fetal weight (EFW) 3(rd) centile and absent end-diastolic flow in the umbilical artery (UA)) and four contributory parameters (AC or EFW 10(th) centile combined with a pulsatility index (PI) 95(th) centile in either the UA or uterine artery) were agreed upon. For late FGR (≥ 32 weeks), two solitary parameters (AC or EFW 3(rd) centile) and four contributory parameters (EFW or AC 10(th) centile, AC or EFW crossing centiles by two quartiles on growth charts and cerebroplacental ratio 5(th) centile or UA-PI 95(th) centile) were defined.Consensus-based definitions for early and late FGR, as well as cut-off values for parameters involved, were agreed upon by a panel of experts. Copyright © 2016 ISUOG. Published by John WileySons Ltd.

The aim of this study was to utilise the Quality Enhancement Research Initiative in Systemic Sclerosis (QuERI-SSc) to measure and reduce a perceived gap in the diagnosis of pulmonary arterial hypertension (PAH) associated with systemic sclerosis (SSc).Rheumatologists enrolled patients with SSc (aged ≥ 18 years) and provided data on a panel of diagnostic tests over 3 years. Pulmonary function testing, echocardiography, 6-minute walk distance, N-terminal pro-brain natriuretic peptide assays, high-resolution computed tomography of the lungs, and ventilation/perfusion scan plus right heart catheterisation (RHC; when appropriate) were emphasised. Exclusion criteria included previously documented PAH, interstitial lung disease, and SSc overlapping with other connective tissue disease.Participating rheumatologists enrolled 207 patients with SSc (90% female; 80% white), with a median age of 57 years and median disease duration of 5 years. A total of 82% of patients were classified as New York Heart Association functional class I and II; of these patients, 177 had an echocardiogram at enrolment and 191 at any time during the study. Of those who met study-specified criteria for RHC at enrolment, only 3 of 7 patients underwent RHC.The screening algorithm was successful in identifying patients with mild impairment. Although specific tools were recommended for screening PAH in patients with SSc, results indicate that significant diagnostic care gaps still exist in the general rheumatology community. Better understanding and adherence to guidelines could improve the care and, ideally, outcomes of these high-risk patients.

Lateral dopant profiling of cleaved, passivated abrupt GaAs pn junctions using scanning tunneling microscopy/spectroscopy is demonstrated both in ultrahigh vacuum and air. A combination of forward‐ and reverse‐bias imaging and position‐dependent tunneling spectroscopy makes it possible to delineate the metallurgical junction location of abrupt asymmetric n+p and symmetric n+p+ junctions. The experimental results are shown to be consistent with simulations based on the metal–insulator–semiconductor band‐bending model when surface states and bulk transport through the pn junction are properly taken into account in the calculations.

Scatterfield microscopy is a technique that combines the best attributes of scatterometry and high‐magnification imaging using a bright‐field microscope. In our work, we have traditionally moved an aperture in a conjugate back focal plane (CBFP) of the objective lens to control the angle of incidence. We have incorporated a new source into an existing microscope in order to scan the illumination wavelength, which has necessitated a new set of tool characterization requirements. We present experimental data and preliminary quantitative modeling results for metrology of sub‐wavelength features using this new method of illumination engineering.

Scleroderma (SSc) is an autoimmune connective tissue disorder characterized by progressive fibrosis of the skin and internal organs. The leading cause of death in SSc patients is pulmonary dysfunction as a result of interstitial fibrosis and pulmonary vasculopathy. Our objective was to evaluate histopathological abnormalities associated with the development of pulmonary fibrosis in SSc.Postmortem SSc lung tissue from various stages of fibrosis and tissue from normal lung were analyzed by Masson's trichrome staining and immunohistochemistry. Monoclonal antibodies against smooth muscle-alpha actin (myofibroblast marker), von Willebrand Factor, platelet endothelial cell adhesion molecule-1 (endothelial cell markers), or caldesmon (smooth muscle cell marker) were employed.We found that in the early active stages of SSc lung fibrosis two major types of cellular abnormalities occur. One is the induction of a large number of smooth muscle alpha-actin-positive myofibroblasts in interstitia. The other is the excessive formation of alveolar capillaries (hypervascularity) accompanied by an increase in the number of microvascular endothelial cells. The vascular abnormality also involves the development of microvessels that are irregular in size and shape. However, the population of myofibroblasts and capillary endothelial cells decline as the fibrosis progresses to its most marked, later stages.We conclude that the induction of myofibroblasts and the overdevelopment of capillary microvessels characterize the progression of lung fibrosis in SSc. Using these histological alterations as criteria, therefore we have divided the fibrosis formed in the SSc lungs into four pathological stages. These results suggest that both fibroblast overproliferation and vascular abnormality play an important role in the pathogenesis of lung fibrosis in SSc.

The vascular hypothesis for the pathogenesis of systemic sclerosis was perhaps Professor LeRoy's most important scientific contribution. One early and important consequence of vascular injury is the release of activated thrombin. In this manuscript we present our data and review the current understanding of the role played by thrombin in the process of fibrosis, particularly as it relates to scleroderma lung disease. Thrombin's cellular effects are intimately involved in promoting myofibroblast differentiation, endothelial cell activation, extracellular matrix protein deposition, and the induction of important profibrotic factors. Such studies confirm that thrombin is one of the major mediators in the development and progression of pulmonary fibrosis. Therefore, targeting the major receptor of thrombin, PAR-I, and its downstream signaling molecules may lead to novel therapeutic approaches for the management of scleroderma lung fibrosis. We are indebted to Dr LeRoy for his many contributions to the field of scleroderma, and for all that he did to stimulate our interest in these studies.

To investigate population hospitalization rates to community hospitals for systemic sclerosis (SSc, scleroderma) and examine whether age, sex, race, and insurance status independently predict length of stay (LOS), hospital charges, and in-hospital death.The 1995 Healthcare Cost and Utilization Project national inpatient sample was used to identify 3,621 SSc hospitalizations. Weighted age, sex, and race-specific frequencies were divided by population estimates to calculate hospitalizations per million people. Regression models were used to model LOS, charges, and in-hospital death with age, sex, race, and insurance serving as the primary independent variables. Covariates included numbers of diagnoses and procedures, whether or not the admission was a transfer from another hospital, and the presence of comorbid conditions.Population hospitalization rates were higher for non-whites compared to whites among those65, while rates were higher for whites compared to non-whites for thoseor =65 years old. On average, non-whites were at least 10 years younger than whites. The mean LOS was 7.5 days, with whites' average LOS being 10% shorter than non-whites', and patients with public health insurance having approximately 9% longer LOS than those with private insurance. Charges averaged almost US$15,000 per hospitalization (median = $8,441), amounting to $280 million in community hospital charges in the U.S. in 1995. The overall in-hospital death rate was 7.1%.These patterns are consistent with a greater burden and increased severity of disease among non-whites under age 65 with Ssc.

Treatment with heparin and low-dose aspirin improves fetal survival among women with antiphospholipid syndrome. Despite treatment, however, these pregnancies are frequently complicated by preeclampsia, fetal growth restriction, and placental insufficiency, often with the result of preterm birth. Small case series suggest that intravenous immune globulin may reduce the rates of these obstetric complications, but the efficacy of this treatment remains unproven. This pilot study was undertaken to determine the feasibility of a multicenter trial of intravenous immune globulin and to assess the impact on obstetric and neonatal outcomes among women with antiphospholipid syndrome of the addition of intravenous immune globulin to a heparin and low-dose aspirin regimen.This multicenter, randomized, double-blind pilot study compared treatment with heparin and low-dose aspirin plus intravenous immune globulin with heparin and low-dose aspirin plus placebo in a group of women who met strict criteria for antiphospholipid syndrome. All patients had lupus anticoagulant, medium to high levels of immunoglobulin G anticardiolipin antibodies, or both. Patients with a single live intrauterine fetus at/=12 weeks' gestation were randomly assigned to receive either intravenous immune globulin (1 g/kg body weight) or an identical-appearing placebo for 2 consecutive days each month until 36 weeks' gestation in addition to a heparin and low-dose aspirin regimen. Maternal characteristics, obstetric complications, and neonatal outcomes were compared with the Student t test and the Fisher exact test as appropriate.Sixteen women were enrolled during a 2-year period; 7 received intravenous immune globulin and 9 were given placebo. The groups were similar with respect to age, gravidity, number of previous pregnancy losses, and gestational age at the initiation of treatment. Obstetric outcomes were excellent in both groups, with all women being delivered of live-born infants after 32 weeks' gestation. The rates of antepartum complications such as preeclampsia, fetal growth restriction, and placental insufficiency (as manifested by fetal growth restriction or fetal distress) were similar between the 2 groups. Gestational age at delivery (intravenous immune globulin group, 34.6 +/- 1.1 weeks; placebo group, 36.7 +/- 2.1 weeks) and birth weights (intravenous immune globulin group, 2249.7 +/- 186.1 g; placebo group; 2604.4 +/- 868.9 g) were similar between the 2 groups. There were fewer cases of fetal growth restriction (intravenous immune globulin group, 0%; placebo group, 33%) and neonatal intensive care unit admission (intravenous immune globulin group, 20%; placebo group, 44%) among the infants in the intravenous immune globulin group than those in the placebo group, but these differences were not significant.A multicenter treatment trial of intravenous immune globulin is feasible. In this pilot study intravenous immune globulin did not improve obstetric or neonatal outcomes beyond those achieved with a heparin and low-dose aspirin regimen. Although not statistically significant, the findings of fewer cases of fetal growth restriction and neonatal intensive care unit admissions among the intravenous immune globulin-treated pregnancies may warrant expansion of the study.

To examine whether those participating in solvent oriented hobbies (SOH) are at greater risk of developing systemic sclerosis (SSc), and if the association is modified by the presence of the anti-Scl70 antibody.Patients with SSc and controls were recruited from a university hospital rheumatology clinic. Recreational hobby and occupational histories were obtained along with blood samples. Cumulative scores were created for participation in SOH. Logistic regression was used to calculate odds ratios associated with SOH exposure after adjustment for sex, age at diagnosis, and occupational solvent exposure, and to examine the association between SOH exposure and the presence of anti-Scl70.Solvent exposure based on hobbies and occupations was determined for 178 cases (141 women, 37 men) and 200 controls (138 women, 62 men). Overall participation in SOH was not associated with SSc. However, odds of high cumulative SOH exposure was 3 times greater in those patients with SSc testing positive for the anti-Scl70 antibody compared to patients testing negative (OR 2.9, 95% CI 1.1, 7.9), and twice as great as controls (OR 2.5, 95% CI 1.1, 5.9).While patients with SSc did not participate more often in SOH than controls over all, odds of high cumulative SOH exposure was greater among patients with SSc testing positive for anti-Scl70 compared to those testing negative and compared to controls. These results provide further evidence that environmental agents may play a role in the development of Ssc.

Lung disease is a major cause of morbidity and is the leading cause of mortality in patients with systemic sclerosis, most commonly occurring as interstitial lung disease or as pulmonary hypertension. Cyclophosphamide has been used to treat the interstitial lung disease and a placebo-controlled trial is planned. Potent pulmonary vasodilators, many of which have been studied in primary pulmonary hypertension, are now undergoing study in patients with systemic sclerosis.

A duplication in the fibrillin-1 gene has been implicated as the cause of the tight skin 1 (tsk1) phenotype, an animal model of scleroderma or systemic sclerosis (SSc). In addition to the production of abnormal fibrillin-1 protein, the tsk1 mouse also produces autoantibodies to fibrillin-1. Among a population of Choctaw Native Americans with the highest prevalence of SSc yet described, a chromosome 15q haplotype containing the fibrillin-1 gene has been strongly associated with SSc. With a recombinant human fibrillin-1 protein, autoantibodies to fibrillin-1 were detected in the sera of Native American SSc patients that correlated significantly with disease. Abs to fibrillin-1 also were detected in sera from Japanese, Caucasian, and African-American SSc patients. Compared with other ethnic groups, Japanese and Native American SSc patients had significantly higher frequencies of anti-fibrillin-1 Abs. Sera from patients with diffuse SSc, calcinosis, Raynaud's, esophageal dysmotility, sclerodactyly, and telangiectasias syndrome and mixed connective tissue disease also had significantly higher frequencies of anti-fibrillin-1 Abs than sera from controls or patients with other non-SSc connective tissue diseases (lupus, rheumatoid arthritis, and Sjögren's syndrome). Ab specificity for fibrillin-1 was demonstrated by the lack of binding to a panel of other purified autoantigens. The results presented demonstrate for the first time the presence of high levels of anti-fibrillin-1 Abs in a significant portion of patients with SSc.

The primary objective was to determine whether occupational exposure to organic solvents is related to an increased risk of systemic sclerosis (SSc; scleroderma).Occupational histories were obtained from 178 SSc patients and 200 controls. Exposure scores were computed for each individual using job exposure matrices, which were validated by an industrial expert.Among men, those with SSc were more likely than controls to have a high cumulative intensity score (odds ratio [OR] 2.9, 95% confidence interval [95% CI] 1.1-7.6) and a high maximum intensity score (OR 2.9, 95% CI 1.2-7.1) for any solvent exposure. They were also more likely than controls to have a high maximum intensity score for trichloroethylene exposure (OR 3.3, 95% CI 1.0-10.3). Among men and women, significant solvent-disease associations were observed among SSc patients who tested positive for the anti-Scl-70 autoantibody; these trends were not observed among the men and women who tested negative for anti-Scl-70.These results provide evidence that occupational solvent exposure may be associated with an increased risk of SSc.

Beta(2)glycoprotein I (beta(2)GPI) physiologically binds to negatively charged phospholipids (PLs) and is a natural regulator of the coagulation cascade. Thrombotic clinical complications and recurrent fetal loss associated with autoimmune antiphospholipid (aPL) antibodies are thought to be related to their binding to Beta(2)GPI-PL complex and interference with the physiological function of Beta(2)GPI.To investigate the effect of aPL on beta(2)GPI-PL interaction, we studied the binding of biotinylated Beta(2)GPI to cardiolipin (CL) by enzyme-linked immunosorbent assay (ELISA) in the presence and absence of purified aPL immunoglobulin G (IgG) antibodies.Adding five different aPL IgG antibodies with different levels of aPL activity isolated from the sera of five patients with aPL-associated recurrent fetal death greatly increased the binding of biotinylated beta(2)GPI to CL-coated plates. The optical densities (ODs) were 0.635, 0.890, and 1.265 in the presence of three aPL IgG antibodies, compared to 0.425 in the absence of aPL IgG. In contrast, normal human IgG had no enhancing effect. The OD was 0.480 and 0.425, respectively. The enhancement of beta(2)GPI binding to CL by aPL IgG correlated with the titers of aPL antibodies. The use of phosphate-buffered saline with increasing salt concentrations as a washing buffer for the ELISA resulted in more stable binding of beta(2)GPI to PL in the presence of aPL IgG.These findings suggest that the binding of autoimmune aPL antibodies to beta(2)GPI-PL complex results in abnormally tighter interaction between beta(2)GPI and PLs, which may lead to physiological dysfunction of beta(2)GPI as a regulator of coagulation.

To determine whether ceramide regulates prostaglandin (PG) production by cultured human amnion cells and decidual cells independently of interleukin-1 beta (IL-1 beta).Cells were grown in monolayer culture and then incubated with varying concentrations of ceramide, IL-1 beta, ceramide in the presence and absence of IL-1, and control media. Production of PGE2 was determined using a specific radioimmunoassay.Ceramide induced a significant concentration-dependent increase in PGE2 production by amnion cells and decidual cells. However, PGE2 production induced by IL-1 beta was significantly more than with ceramide alone, and there was no potentiation of PGE2 production with coincubation of ceramide and IL-1 beta.We suggest that term human amnion cells and decidual cells are responsive to ceramide independent of IL-1 beta and that generation of these substances in response to an infection in the uterus may lead to increased PG production by human gestational tissues, indicating that there are several mechanisms leading to PG production by these cells.

Autoimmune diseases occur most commonly in women of childbearing age. Over 70% of individuals with autoimmune diseases are women, though some conditions (e.g., ankylosing spondylitis) are more common in men. Many authorities have focused on sex hormones as an explanation for the relatively high proportion of females affected by autoimmune diseases. This article covers systemic lupus erythematosus, the prototypical autoimmune disease, and antiphospholipid syndrome, which is associated particularly with pregnancy loss.

To explore whether antiphospholipid antibodies (aPL) are markers of vascular related damage or merely evidence of toxic related autoimmunity, we investigated the presence of different aPL in patients with toxic oil syndrome (TOS) and compared the profile with patients with eosinophilia myalgia syndrome (EMS).Reactivity against cardiolipin, P-serine, P-inositol, and P-choline was investigated by ELISA in the blood of 266 patients with acute and chronic TOS, 25 healthy relatives of TOS patients, and 48 patients with EMS.32% of TOS and 13% of EMS patients had IgG antibodies against cardiolipin and other polyanions. 20% of both TOS and EMS patients presented IgM antibodies against anionic and zwitterionic phospholipids. 36% of TOS healthy relatives had IgM antibodies against differently charged phospholipids. Among 200 patients with chronic TOS, there was no significant association between antibodies and clinical manifestations.aPL with different specificity are present in a high percentage of patients with TOS and EMS. The significance of these antibodies remains unclear.

A recent follow-up study found that patients with pulmonary involvement (with no renal or cardiac involvement) survived a median of 78 +/- 17 months. Another study found death from SSc was most frequently due to pulmonary hypertension. Improved diagnostic modalities and better understanding of the pathophysiology of SSc lung disease are essential, because mortality from this SSc lung disease remains high. During the past decade, advances have been made in the understanding of the alveolitis of SSc lung disease. Although the inciting injury remains uncertain, a cascade of inflammatory and fibrosing mediators culminates in a chronic state of interstitial lung disease. There is increasing evidence that the fibrogenic cytokines PDGF and TGF-beta are major contributors to the pathophysiology of interstitial lung disease, including that of SSc. Future research aimed at modifying the biologic response to such cytokines may yield novel therapeutic approaches to the management of this type of lung disease. Similarly, improved understanding of mediators of vascular tone, such as endothelin and nitric oxide, may yield much-needed treatments for pulmonary hypertension.

Significant morbidity and mortality occur during the acute phase of the eosinophilia-myalgia syndrome (EMS), and many patients still have chronic manifestations of the disease. Although the precise etiologic agent or agents within implicated batches of L-tryptophan remain uncertain, histopathologic studies support a role for a cell mediated immune response underlying the pathophysiology of EMS. The cellular immune response seems to lead to a microangiopathy and release of cytokines that can induce eosinophilia and fibrosis. Such responses are most marked within the dermis, subcutis, fascia, and connective tissue in and around muscles, nerves, and other tissues. The pathophysiology of the chronic symptoms is poorly understood but may involve ischemia, neuropathy, and metabolic abnormalities.

Systemic sclerosis (scleroderma, SSc) frequently affects the lungs, and interstitial pulmonary fibrosis is one of its major complications. The pathophysiology of SSc lung disease s poorly understood, but recent studies document an inflammatory process resembling that of idiopathic pulmonary fibrosis with increased numbers of activated alveolar macrophages and granulocytes in bronchoalveolar lavage (BAL) fluid). We determined levels of 2 potentially important mediators of fibroproliferative repair in BAL fluid from patients with SSc.Using Western blot and ELISA techniques we measured levels of platelet derived growth factor (PDGF) and transforming growth factor-beta (TGF-beta in BAL fluid from patients with SSc and healthy controls. The mitogenic effect of these cytokines on SSc lung myofibroblasts was determined by [3H]thymidine incorporation.SSc BAL fluid contains significantly elevated levels of PDGF-AA and PDGF-BB. Where TGF-beta 1 was significantly elevated in SSc lavage fluid, the amount of TGF-beta 2 was significantly less than that observed in normal lavage fluid. Myofibroblasts cultured from SSc lavage fluid exhibited enhanced [3H]thymidine incorporation upon exposure to the growth factors present in SSc BAL fluid: PDGF and TGF-beta 1. SSc lung myofibroblasts pretreated with TGF-beta 1 exhibited an enhanced mitogenic effect upon stimulation by PDGF, due in part to the induction of the PDGF alpha receptor.Our studies support a role for PDGF and TGF-beta 1 in the pathogenesis of SSc lung disease.

Systemic sclerosis (scleroderma) is a disease of unknown cause whose pathogenesis involves interaction between the vasculature, the immune system, and connective tissue cells. Although specific therapy awaits a better understanding of its pathogenesis, proper management may enhance not only the duration, but the quality of life for most scleroderma patients. Presently, controlled prospective trials of therapeutic agents are lacking. Published reports of drug therapy for skin, kidney, cardiac, pulmonary, and gastrointestinal complications, as well as management of Raynaud's phenomenon, are critically reviewed in this article, and the authors' approach to management of difficult clinical problems is presented.

We describe 2 cases of diffuse fasciitis with eosinophilia (DFE) associated with prolonged exposure to the industrial solvent trichloroethylene (TCE). The medical and personal histories, examinations, and laboratory and pathological investigations were reviewed and summarized. The 2 case reports, representing the first and 2nd cases of DFE associated with TCE, were compared with 8 reported cases of systemic sclerosis associated with TCE and suggest a direct association between TCE exposure and the development of fasciitis (DFE).

Lipopolysaccharide (LPS) administration has been known to cause murine fetal death for over 50 years, but the responsible mechanism(s) remains unclear. We used the LPS-hyporesponsive murine strain, C3H/HeJ, to 1) establish whether LPS-induced fetal death is due to a maternal or fetal response to LPS and 2) to investigate the involvement of tumor necrosis factor alpha (TNF alpha) in fetal death caused by LPS. C3H/HeJ (LPS-hyporesponsive) or C3H/HeN (LPS-responsive) females were mated with C57B1/6 or C3H/HeN males (both LPS-responsive). Administration of 10 micrograms LPS caused fetal death in C3H/HeN mothers. However, up to 1000 micrograms LPS did not result in the death of LPS-responsive fetuses when administered to C3H/HeJ mothers. Systemic administration of TNF alpha was able to cause fetal death in both C3H/HeN and C3H/HeJ strains of mice. Pretreatment of pregnant C3H/HeN mice with anti-TNF alpha antibodies significantly reduced fetal death caused by LPS administration. The administration of a sublethal dose of TNF alpha plus 10 micrograms LPS to pregnant C3H/HeJ mice restored abortifacient activity. These results indicate that LPS-induced fetal death is due to a maternal response as opposed to a direct fetal response to LPS and that TNF alpha appears to be an important mediator of fetal death caused by LPS.

To determine the risk of antiphospholipid antibody-related disorders in women with elevated levels of these antibodies.We used an historic cohort study design. Surveys of medical and obstetric histories for the interval from initial antibody testing to the time of patient interview were used to calculate age-adjusted rates for the development of medical disorders associated with antiphospholipid antibodies. The cohort included 130 women with lupus anticoagulant, medium to high levels of immunoglobulin G anticardiolipin antibodies, or both.The median interval of study was 3.2 years (range 0.7-9.5, mean 3.7). Sixty-three subjects (48%) developed at least one new disorder during the study interval. The age-adjusted rates (per 1000 patient-years; +/- standard error) for the development of the disorders studied were as follows: thrombosis (156.8 +/- 30.0), cerebrovascular accident (93.8 +/- 25.1), amaurosis fugax (57.1 +/- 23.2), transient ischemic attack (170.4 +/- 27.6), systemic lupus erythematosus (9.8 +/- 3.8), and autoimmune thrombocytopenia (56.0 +/- 22.2). Of the 34 thrombotic events that occurred during the study interval, eight were associated with pregnancy and eight occurred while the patients were taking anticoagulant medications.Our subjects developed complications associated with antiphospholipid antibodies at a substantial rate, and almost half suffered at least one new event during the study interval. The high rate of thrombosis in individuals with antiphospholipid antibodies, especially associated with pregnancy, underscores the need to evaluate long-term anticoagulation in these patients.

To determine whether unexplained elevations of maternal serum alpha-fetoprotein (MSAFP) in women with antiphospholipid antibodies are associated with adverse pregnancy outcomes.A retrospective cohort study was used to compare pregnancy outcomes between women with second-trimester MSAFP values equal to or greater than 2.5 multiples of the median (MoM) and less than 2.5 MoM. The cohort included 60 pregnancies in 47 women with medium to high positive levels of immunoglobulin (Ig) G anticardiolipin antibodies, lupus anticoagulant, or both.Thirteen pregnancies (22%) had elevated MSAFP values (median 3.6 MoM, range 2.5-12.6). Of these, amniotic fluid AFP was normal in seven and elevated in one. None of the elevated MSAFP levels were explained by fetal anomalies, current fetal death, multiple gestation, incorrect dates, or vaginal bleeding. Pregnancies with elevated MSAFP values had a significantly higher incidence of fetal death (eight of 13, 62%, versus three of 47, 6%) and perinatal loss (ten of 13, 77%, versus seven of 47, 15%) than those with normal MSAFP (P.001, Fisher exact test). In these women, the sensitivity and specificity of an unexplained elevated MSAFP level in ascertaining fetal death were 73 and 90%, respectively. For perinatal loss, the sensitivity was 59% and the specificity was 93%. Of the placentas studied, infarction occurred in eight of nine (89%) among the women with elevated MSAFP.Unexplained second-trimester elevations of MSAFP are common in women with antiphospholipid antibodies and are significantly associated with fetal loss. Abnormalities in the fetoplacental barrier are implicated as part of the pathophysiology of antiphospholipid antibody-mediated pregnancy loss.

Fourteen patients with systemic sclerosis (SSc, scleroderma) and interstitial lung disease were treated with oral cyclophosphamide (1-2 mg/kg/day) and low dose prednisone (10 mg/day). There was a significant improvement in FVC after 6 months compared to entry values (2.21 +/- 0.19 l vs. 2.03 +/- 0.15 l, p0.02). Improvement was maintained at 12 months (2.27 +/- 0.27 l, p0.05) and 18-24 months (2.60 +/- 0.28 l, p0.001). In 12 cases followed for 18-24 months, FVC was stable or improved. No significant improvement or decline was noted for the DLCO. Side effects included cytopenia (2), infection (1), and hemorrhagic cystitis (2), and one possible related malignancy. A controlled prospective trial of cyclophosphamide is warranted in patients with SSc and active interstitial lung disease.

Eosinophilia-myalgia syndrome reached epidemic proportions in 1989. Its precise etiology remains uncertain, yet virtually all cases were associated with the ingestion of L-tryptophan containing trace amounts of several chemicals. Clinical and pathologic features of eosinophilia-myalgia syndrome are similar to those of the toxic-oil syndrome, which occurred in Spain in 1981 in association with the ingestion of adulterated rapeseed oil. During the past year, the epidemiology of eosinophilia-myalgia syndrome has been better defined, with a second trace contaminant linked to this condition. Knowledge of the clinical and histopathologic features of eosinophilia-myalgia syndrome has also expanded. These and other important advances in the understanding of eosinophilia-myalgia syndrome, toxic-oil syndrome, and diffuse fasciitis with eosinophilia are presented.

We describe the detection and the growth of fibroblasts with human smooth muscle cell differentiation features from bronchoalveolar lavage (BAL) fluid of 53% of patients with scleroderma, but not from healthy controls. The binding of alpha-actin, vimentin and desmin antibodies by scleroderma lung fibroblasts exceeded that of normal adult lung fibroblasts, indicating that scleroderma lung fibroblasts express some markers of human smooth muscle cell differentiation (myofibroblasts), which may account for differences in biological behavior. A mesenchymal cell phenotype was documented by mRNA analysis, showing high expression of collagen type I and fibronectin in these cells. Fibronectin is also released in significantly higher amounts by scleroderma alveolar macrophages than by macrophages from healthy donors.

To determine the outcome of treated pregnancies in women with well-characterized antiphospholipid syndrome.We reviewed 82 consecutive pregnancies in 54 women with antiphospholipid syndrome who were treated during pregnancy with the following: 1) prednisone and low-dose aspirin; 2) heparin and low-dose aspirin; 3) prednisone, heparin, and low-dose aspirin; or 4) other combinations of these medications or immunoglobulin.The overall neonatal survival rate was 73%, excluding spontaneous abortions, but treatment failures (fetal and neonatal deaths) occurred in all treatment groups. Patients with successful treated pregnancies had fewer previous fetal deaths than those with unsuccessful treated pregnancies. There were no significant differences in outcome among the four treatment groups. Preeclampsia and fetal distress occurred in half of all pregnancies, and fetal growth impairment occurred in nearly one-third. Preterm delivery due to maternal or fetal indications was required in 37% of the pregnancies. Four pregnancies were also complicated by postpartum thrombosis during treatment.Pregnancy in women with antiphospholipid syndrome appears to be improved by treatment, but fetal loss may occur despite treatment. Preeclampsia, fetal distress, fetal growth impairment, and premature delivery are common. Because of the clinically significant risk of thrombotic episodes, thrombosis prophylaxis should be considered in these patients.

We describe two patients with life-threatening puerperal infection due to group A beta-hemolytic streptococcus. Each patient had bacteremia, shock, and multi-organ involvement. Both cases were compatible with a recently described streptococcal toxic shock-like illness. Both women failed to improve despite vigorous medical and antibiotic therapies, and each required hysterectomy. Obstetricians should be alert to the importance of early diagnosis and treatment of this potentially lethal infection.

The eosinophilia-myalgia syndrome (EMS) was associated with ingestion of L-tryptophan containing products and was accompanied by altered metabolism of L-tryptophan during the active phase. Many patients with EMS exhibited clinical and histopathological features similar to another epidemic, the toxic oil syndrome (TOS), associated with ingestion of adulterated rapeseed oil. We hypothesized that patients with TOS, like patients with EMS, may have had altered metabolism of L-tryptophan during the acute phase of the illness. Therefore, we quantitated the tryptophan metabolites, L-kynurenine and quinolinic acid, and we measured neopterin, a marker of interferon-gamma (IFN-gamma), in blood obtained during the acute phase of each syndrome. Patients with TOS or EMS had significantly higher L-kynurenine and quinolinic acid than healthy control subjects or rheumatic disease control subjects. Neopterin was also elevated in patients with untreated TOS and EMS, and correlated strongly with L-kynurenine and quinolinic acid. Our data suggest that indoleamine-2,3-dioxygenase (IDO), the rate limiting enzyme of the kynurenine pathway of L-tryptophan metabolism, was activated in both syndromes by cytokines including IFN-gamma, and that perhaps products of tryptophan metabolism played a role in the pathogenesis of EMS and TOS.

Seventeen patients with early systemic sclerosis (SSc) underwent high resolution computed tomography (HRCT) of the chest to evaluate dyspnea and/or abnormal pulmonary function tests (PFT). All patients were assigned a dyspnea score and each had routine chest radiography (CXR). Bronchoalveolar lavage (BAL) was performed on 10 patients. HRCT was abnormal in 15 patients (88%), while CXR was abnormal in only 10 patients (59%). Mediastinal lymphadenopathy was detected in 7 patients (41%). Disease duration, dyspnea score, and forced vital capacity (FVC) did not correlate with HRCT score. However, trends toward higher total BAL cell counts and higher BAL neutrophil counts were noted in patients with ground glass opacities on HRCT, and BAL lymphocyte counts were significantly higher in such cases. HRCT is superior to CXR for detecting early interstitial lung disease in SSc, but patient history and FVC correlate poorly with HRCT findings. Ground glass opacities on HRCT may reflect active alveolitis, and mediastinal lymphadenopathy associated with SSc lung disease may be a consequence of pulmonary inflammation.

Lymphokine activated killer (LAK) cells, which arise from interleukin-2 (IL-2) activation of natural killer (NK) cells, are capable of lysing NK-resistant cell targets, including endothelial cells (EC). Since EC cytotoxicity is postulated to play a role in the pathogenesis of systemic sclerosis (SSc), experiments were performed to measure LAK activity in the peripheral blood lymphocytes (PBL) of 10 SSc patients and 10 normal controls. SSc patients had no significant spontaneous cytotoxicity against NK-resistant cell targets, including EC. After IL-2 stimulation in vitro, SSc patients and normal controls demonstrated cytotoxicity toward NK-resistant cell targets, including EC. This LAK-mediated EC cytotoxicity was actually lower for SSc patients than for normal controls. These studies do not preclude a role for LAK-mediated EC cytotoxicity in the pathogenesis of SSc, but demonstrate that LAK cells are not spontaneously present in circulating PBL.

The lungs are frequently affected in systemic sclerosis, and pulmonary disease may significantly influence morbidity and mortality. The clinical, radiographic, and physiologic features of scleroderma lung disease are discussed in this article, as are new approaches to the detection and study of interstitial pneumonitis. The pathogenesis of pulmonary fibrosis is discussed in the context of data derived from bronchoalveolar lavage studies. Pulmonary vascular disease and less common pulmonary features of systemic sclerosis are also discussed.

Clinically, Electron Probe X-ray Microanalysis (EPMA) studies have detected elemental silicon (Si) in remote sites of chronic inflammation (skin, finger, knee and elbow) in patients who were previously implanted with a silicone polymer-filled breast augmentation prostheses. Subsequent biopsy material obtained from the fibrous tissue capsule surrounding the implant was found to contain abundant silicon in foamy macrophages. In the remote biopsies, the elemental silicon is believed to be derived from macrophages that originated in the connective tissue capsule.In order to study the possible cellular distribution of silicone in an animal model, 120gm female SD rats were injected subcutaneously at the nape of the neck with 2ml of breast prothesis silicone gel (1.7% of total body weight). The injection correlates to a 0.9kg silicone prostheses implanted in a 55kg human recipient. Adjuvant arthritis was produced after 8 weeks in Si injected and control animals by the subdermal injection of 0.75 mg of heat killed Mycobacterium butyrium (MB) over the left rear knee. Si injected only, Si plus MB, MB only and untreated control animals were sacrificed by Metofane inhalation at 16, 24 and 32 week intervals and tissues were processed for routine light microscopy and TEM. Decalcified knee joints were sectioned longitudinally and sent to JEOL USA, Inc. for blind, collaborative SEM x-ray microanalysis studies.