The mosaic of autoimmunity.

Autoimmunity is a normal event, while autoimmune diseases result from an aberration of this normal phenomenon. The etiology of this switch is considered multifactorial with the final common pathway being the loss of normal self-tolerance in a particular organ or group of organs. Genetic, environmental, hormonal and immunologic factors (along with probably other yet unrecognised factors) are considered important in the development of these disorders. The particular autoimmune disease which any patient develops is most likely a result of which combination of factors the patient has accumulated. We begin with a brief review of immunobiology in order to arrive at a suitable definition of autoimmunity. This is followed by a concise description of the current theories regarding the development of autoimmune disease and the factors known to be associated with these illnesses. Concluding remarks address the factors that normally prevent the progression of autoimmunity to autoimmune disease and the application of current knowledge to future therapeutic approaches.

Evaluation of the Jones jig appliance for distal molar movement.

The purpose of this study was to determine the effects of the Jones jig appliance on distal movement of maxillary molars and reciprocal effects on premolars and maxillary incisors. Cephalometric radiographs before and after orthodontic treatment of 72 consecutively treated patients, 46 females and 26 males, were measured to define treatment changes attributed to the Jones jig. Comparative measurements were made on a matched sample of 35 patients (20 females and 15 males) treated with cervical headgear by the same clinician. Both series of patients were treated to correct an Angle Class II molar relationship. The molar correction in the Jones jig patients consisted primarily of molar distal movement. Dental, soft tissue, and skeletal changes were evaluated and compared for significant differences between techniques. The results from the Jones jig sample showed the mean maxillary first molar distal movement was 2.51 mm, with distal tipping of 7.53 degrees. The mean reciprocal mesial movement of the maxillary premolar was 2.0 mm, with mesial tipping of 4.76 degrees. The maxillary first molar extruded 0.14 mm; the maxillary premolar extruded 1.88 mm. The maxillary second molars were also moved distally 2.02 mm and tipped distally 7.89 degrees. The longitudinal assessment (initial to completion of orthodontic treatment) showed significant differences between the Jones jig sample and the cervical headgear sample for lower lip to E-line and SNA. The Jones jig sample showed a mean decrease in lower lip to E-line of 0.25 mm versus 1.20 mm (P < .0212) for the headgear sample. SNA decreased 0.40 degrees for the Jones jig sample versus 1.20 degrees (P < .0093) for the headgear sample. However, the Jones jig sample and cervical headgear sample did not show significant differences of the final position in either linear or angular measurements of the maxillary first molars and corresponding premolar-incisor anchor units. The Jones jig appliance demonstrated treatment results comparable with those of the sample treated with cervical headgear. The Jones jig sample demonstrated effective distal molar movement and maintenance of the Class I molar relationship. Advantages of the Jones jig include minimal dependence on patient compliance, ease of fabrication, and ease of buccal force application.

Hypersensitivity reaction to carboplatin. Results of skin tests.

Four patients with hypersensitivity reaction to carboplatin of variable severity, after previous uneventful cisplatin and carboplatin treatment, are described. Skin testing performed in two of the patients suggests a cross-reaction with cisplatin but was negative with carboplatin in one of them. The mechanism of hypersensitivity reaction to carboplatin is poorly understood and the issue of retreatment with carboplatin is controversial. Physicians should be aware of the possible hypersensitivity reaction to carboplatin and appropriate precautions should be taken.

Fit-testing for firefighters.

When fit-testing firefighters who may be required to wear an SCBA unit in the positive pressure mode for IDLH or structural firefighting applications, use these guidelines. 1. The firefighter shall be allowed to pick the most acceptable respirator from a sufficient number of respirator models and sizes so the respirator is acceptable to, and correctly fits, the firefighter. 2. Before a firefighter may be required to use the SCBA, he/she must be fit-tested with the same make, model, style, and size of respirator that will be used. If different makes, models, styles, and sizes of facepieces are used, the firefighter must be fit-tested for each. 3. Based on current interpretations and guidance, OSHA requires firefighters to be quantitatively or qualitatively fit-tested while in the negative pressure mode. 4. Quantitative fit-testing of these respirators shall be accomplished by modifying the facepiece to allow sampling inside the facepiece and breathing zone of the user, midway between the nose and mouth. This requirement shall be accomplished by installing a permanent sampling probe onto a surrogate facepiece or by using a sampling adapter designed to temporarily provide a means of sampling air from inside the facepiece. 5. Qualitative fit-testing can be accomplished by converting the user's actual facepiece into a negative pressure respirator with appropriate filters or by using an identical negative pressure air-purifying respirator facepiece with the same sealing surfaces as a surrogate for the SCBA facepiece. 6. If after passing the fit-test the firefighter subsequently determines the fit of the respirator is unacceptable, he/she shall be given a reasonable opportunity to select a different respirator facepiece and be retested. 7. The new standard requires initial and at least annual fit-testing using quantitative or qualitative fit-testing protocols. 8. Additional fit-testing may be required whenever physical changes to the employee occur that may affect respirator fit, such as facial scarring, dental changes, cosmetic surgery, or an obvious change in body weight.

Nimesulide-induced hepatitis and acute liver failure.

BACKGROUND: Nimesulide is a relatively new non-steroidal anti-inflammatory drug that is gaining popularity in many countries because it is a selective cyclooxygenase 2 inhibitor. Occasionally, treatment is associated with mild elevation of liver enzymes, which return to normal upon discontinuation of the drug. Several cases of nimesulide-induced symptomatic hepatitis were also recently reported, but these patients all recovered. OBJECTIVES: To report the characteristics of liver injury induced by nimesulide. PATIENTS AND METHODS: We report retrospectively six patients, five of them females with a median age of 59 years, whose aminotransferase levels rose after they took nimesulide for joint pains. In all patients nimesulide was discontinued, laboratory tests for viral and autoimmune causes of hepatitis were performed, and sufficient follow-up was available. RESULTS: One patient remained asymptomatic. Four patients presented with symptoms, including fatigue, nausea and vomiting, which had developed several weeks after they began taking nimesulide (median 10 weeks, range 2-13). Hepatocellular injury was observed with median peak serum alanine aminotransferase 15 times the upper limit of normal (range 4-35), reversing to normal 2-4 months after discontinuation of the drug. The remaining patient developed symptoms, but continued taking the drug for another 2 weeks. She subsequently developed acute hepatic failure with encephalopathy and hepatorenal syndrome and died 6 weeks after hospitalization. In none of the cases did serological tests for hepatitis A, B and C, Epstein-Barr virus and cytomegalovirus, as well as autoimmune hepatitis reveal findings. CONCLUSIONS: Nimesulide may cause liver damage. The clinical presentation may vary from abnormal liver enzyme levels with no symptoms, to fatal hepatic failure. Therefore, monitoring liver enzymes after initiating therapy with nimesulide seems prudent.

Room temperature sterilization of surfaces and fabrics with a one atmosphere uniform glow discharge plasma.

We report the results of an interdisciplinary collaboration formed to assess the sterilizing capabilities of the One Atmosphere Uniform Glow Discharge Plasma (OAUGDP). This newly-invented source of glow discharge plasma (the fourth state of matter) is capable of operating at atmospheric pressure in air and other gases, and of providing antimicrobial active species to surfaces and workpieces at room temperature as judged by viable plate counts. OAUGDP exposures have reduced log numbers of bacteria, Staphylococcus aureus and Escherichia coli, and endospores from Bacillus stearothermophilus and Bacillus subtilis on seeded solid surfaces, fabrics, filter paper, and powdered culture media at room temperature. Initial experimental data showed a two-log10 CFU reduction of bacteria when 2 x 10(2) cells were seeded on filter paper. Results showed > or = 3 log10 CFU reduction when polypropylene samples seeded with E. coli (5 x 10(4)) were exposed, while a 30 s exposure time was required for similar killing with S. aureus-seeded polypropylene samples. The exposure times required to effect > or = 6 log10 CFU reduction of E. coli and S. aureus on polypropylene samples were no longer than 30 s. Experiments with seeded samples in sealed commercial sterilization bags showed little or no differences in exposure times compared to unwrapped samples. Plasma exposure times of less than 5 min generated > or = 5 log10 CFU reduction of commercially prepared Bacillus subtilis spores (1 x 10(5)); 7 min OAUGDP exposures were required to generate a > or = 3 log10 CFU reduction for Bacillus stearothermophilus spores. For all microorganisms tested, a biphasic curve was generated when the number of survivors vs time was plotted in dose-response cures. Several proposed mechanisms of killing at room temperature by the OAUGDP are discussed.

The phenotype of SLE associated with complete deficiency of complement isotype C4A.

Complete deficiency of the complement C4A isotype is a known genetic risk factor for systemic lupus erythematosus (SLE). The disease phenotype of C4A-deficient patients has never been defined. Among 200 patients with SLE from five centers, 18 (9%) with C4A deficiency were identified. These individuals were compared to those who were C4A replete with regard to a series of clinical and serologic features. The only significant differences between the two groups were in the presence of renal disease (C4A deficient, 11%; C4A replete, 46%; P < 0.006) and a decrease in the serum concentrations of C3 (C4A deficient, 11%; C4A replete, 35%; P < 0.04). There was also a trend for the C4A-deficient individuals to have milder disease. In light of the tendency for C4A-deficient individuals to have lower serum concentrations of C4, it is important that such patients not be subjected to overly aggressive efforts to "normalize" their C4 levels.

Cerebrospinal fluid C3a increases with age, but does not increase further in Alzheimer's disease.

Complement activation is present in the brain in Alzheimer's disease (AD), and C1q concentrations are decreased in AD cerebrospinal fluid (CSF). To determine whether concentrations of other complement proteins are also altered in AD CSF, we measured concentrations of C3a and SC5b-9 in CSF from patients with probable AD (n = 19), normal aged controls (n = 11), and normal younger controls (n = 15). C3a concentrations were similar between AD and aged controls, but threefold higher than in younger controls (p < 0.05 vs. both groups). A similar pattern was found with SC5b-9, though the increase was only twofold and statistically significant only for AD vs. younger controls. These results suggest that an increased generation of complement proteins in localized areas of the AD brain does not result in elevated concentrations of these proteins in CSF, compared with age-matched controls. Increased C3a (and, to a lesser extent, SC5b-9) in aged controls may be due to increased complement activation, increased central nervous system production, and/or blood-brain barrier leakage of these proteins.

Increased regional brain concentrations of ceruloplasmin in neurodegenerative disorders.

Ceruloplasmin (CP), the major plasma anti-oxidant and copper transport protein, is synthesized in several tissues, including the brain. We compared regional brain concentrations of CP and copper between subjects with Alzheimer's disease (AD, n = 12), Parkinson's disease (PD, n = 14), Huntington's disease (HD, n = 11), progressive supranuclear palsy (PSP, n = 11), young adult normal controls (YC, n = 6) and elderly normal controls (EC, n = 7). Mean CP concentrations were significantly increased vs. EC (P < 0.05) in AD hippocampus, entorhinal cortex, frontal cortex, and putamen. PD hippocampus, frontal, temporal, and parietal cortices, and HD hippocampus, parietal cortex, and substantia nigra. Immunocytochemical staining for CP in AD hippocampus revealed marked staining within neurons, astrocytes, and neuritic plaques. Increased CP concentrations in brain in these disorders may indicate a localized acute phase-type response and/or a compensatory increase to oxidative stress.

Interlayer formation and its effect on debonding polycrystalline alumina orthodontic brackets.

During the debonding of ceramic orthodontic brackets, there is a risk of causing fractures, cracks, or flaking of enamel or of the bracket itself. Preliminary work on the resin-enamel interface under bonded brackets with the indirect (modified Thomas) or the thermal-cured indirect bonding techniques revealed an interlayer of unfilled resin formed between the filled resin and the enamel surface. The direct bonding technique, on the other hand, showed no such layer. This study was designed to determine the effect of the interlayer on conventional debonding techniques for polycrystalline ceramic orthodontic brackets. Variables examined were bracket failure or fracture (BF), amount of remnant adhesive (ARI), and enamel damage. Brackets were bonded to 90 fresh bovine teeth. These were divided into three groups of 30 each, based on three methods of bonding, i.e., direct, indirect (modified Thomas), and an indirect technique that used a thermal-cured resin. Each bonding group was further divided into three groups of 10 each, based on the type of debonding technique used, i.e., lift off, delamination, and twisting. Brackets bonded by the indirect (modified Thomas, BF mean = 0.27, ARI mean = 0.93) and the indirect technique that used a thermal-cured resin (BF mean = 0.03, ARI mean = 0.43) resulted in an overall significantly lower failure (p < 0.01) and ARI score on debonding (p < 0.0001) compared with those bonded by the direct technique (BF mean = 1.03, ARI mean = 1.97). Specimens evaluated under the stereomicroscope revealed that the brackets bonded with the indirect techniques debonded at the filled-unfilled resin interface or within the interlayer of unfilled resin.(ABSTRACT TRUNCATED AT 250 WORDS)

Transferrin and iron in normal, Alzheimer's disease, and Parkinson's disease brain regions.

Oxidant-mediated damage is suspected to be involved in the pathogenesis of several neurodegenerative disorders. Iron promotes conversion of hydrogen peroxide to hydroxyl radical and, thus, may contribute to oxidant stress. We measured iron and its transport protein transferrin in caudate, putamen, globus pallidus, substantia nigra, and frontal cortex of subjects with Alzheimer's disease (n = 14) and Parkinson's disease (n = 14), and in younger adult (n = 8) and elderly (n = 8) normal controls. Although there were no differences between control groups with regard to concentrations of iron and transferrin, iron was significantly increased (p < 0.05) in Alzheimer's disease globus pallidus and frontal cortex and Parkinson's disease globus pallidus, and transferrin was significantly increased in Alzheimer's disease frontal cortex, compared with elderly controls. The transferrin/iron ratio, a measure of iron mobilization capacity, was decreased in globus pallidus and caudate in both disorders. Regional transferrin and iron concentrations were generally more highly correlated (Pearson's correlation coefficient) in elderly controls than in Alzheimer's and Parkinson's disease. The altered relationship between iron and transferrin provides further evidence that a disturbance in iron metabolism may be involved in both disorders.

Ceruloplasmin is increased in cerebrospinal fluid in Alzheimer's disease but not Parkinson's disease.

Although the pathophysiology of Alzheimer's disease (AD) and Parkinson's disease (PD) is unknown, altered brain antioxidative mechanisms have been found in both disorders. Ceruloplasmin (CP) and transferrin (TF) interact to limit concentrations of free ferrous iron (Fe2+), and thus play an important role in antioxidant defense in serum; both proteins are also produced in brain, where their significance as antioxidants is unknown. We quantified concentrations of CP and TF by immunoassay in AD (n = 17) and PD (n = 12) cerebrospinal fluid (CSF) to determine whether these proteins could serve as disease markers. CP was increased versus aged normal subjects (n = 11) in AD (p < 0.05) but not PD CSF, whereas TF concentrations did not differ between groups. CP levels have been reported to be elevated in some brain regions in AD, and increased CP in AD CSF may reflect this finding. Systemic inflammation and oxidative stress are major factors stimulating hepatic CP synthesis, and it remains to be determined whether increased CP concentrations in AD CSF and brain follow from similar mechanisms.

Non-specific binding of normal human IgG, including F(ab')2 and Fc fragments, to embryonic rat brain neurons and human cortex synaptosomes.

Binding of normal human IgG to embryonic rat brain neurons was quantitated by flow cytometry. IgG binding was linear between 0.05 and 1.5 mg/ml; slight binding was detectable even at normal cerebrospinal fluid concentrations. Similar binding curves were obtained for purified Fc and F(ab')2 fragments from normal human IgG. Normal human IgG also bound to synaptosomes (resealed nerve terminals) from human cerebral cortex. However, competition assays utilizing 125I-IgG showed no evidence for specific binding. This study indicates that the specificity of putative anti-neuronal antibodies should be confirmed by competition assays as for other receptor-ligand binding.

A new, simplified method for oxidation of human complement component C2.

Oxy C2 is a valuable immunologic reagent, particularly for investigators whose research or clinical assays require a stable classical pathway C3 and/or C5 convertase or a highly active plasma complement source. To date only one method for the conversion of serum C2 or purified C2 to their respective oxy C2 forms has been published. However, this method has several disadvantages. For example, handling and dissolving the iodine crystals required in this process are difficult and time consuming. Also, the enhancement procedure results in a significant dilution of the original C2 sample. We have, therefore, developed a new, simplified method for oxidation of plasma, serum, or pure C2 which circumvents the difficulties associated with the earlier method. Moreover, this method offers additional flexibility with regard to oxidative conditions (i.e., buffer pH, temperature, and C2 concentrations) and reagent handling and final C2 product stability.

Abdominal pain in hereditary angioedema: the role of acid hypersecretion.

Hereditary angioedema is a familial disorder characterized by recurrent episodes of soft tissue swelling and abdominal pain. Whereas most patients are successfully treated with androgenic steroids, some have abdominal pain unresponsive to therapy. To determine whether acid-peptic disease could account for the abdominal pain unresponsive to androgen therapy, we performed upper gastrointestinal endoscopy and determined basal acid output in 21 consecutive patients with hereditary angioedema and abdominal pain. Mean basal acid output of this group was 6.0 +/- 5.9 mEq/h, with five patients having gastric acid hypersecretion (defined as a basal acid output of greater than 10.0 mEq/h). The abdominal pain in 18 responded to stanozolol, whereas the pain in three patients did not change. Acid-peptic mucosal disease (esophagitis or duodenal ulcer) was present in these three patients with abdominal pain unresponsive to androgen therapy, all of whom had gastric acid hypersecretion (basal acid outputs of 13.7, 19.1, and 21.5 mEq/h, respectively). These three patients were treated with ranitidine but required increased doses to control their gastric acid hypersecretion, and to promote complete relief of abdominal pain and healing of their esophagitis or ulcer disease. These results indicate that there is a subset of patients with hereditary angioedema whose abdominal pain may be secondary to acid-peptic disease and gastric acid hypersecretion. Such individuals may require increased therapeutic doses of antisecretory medication to promote complete healing of esophagitis or ulcer disease. Basal acid output and upper gastrointestinal endoscopy are important determinants when evaluating abdominal pain in patients with hereditary angioedema that fails to respond to standard therapy.

Urine-histamine levels in patients with hereditary angioedema (HAE).

Hereditary angioedema (HAE) is defined clinically by recurrent, self-limited episodes of angioedema. The disease is defined biochemically by a deficiency in the functional activity of C1 esterase inhibitor. To date, the actual serum or tissue mediator(s) responsible for the angioedematous lesion remains controversial. Although antihistaminics have been clearly demonstrated to have no efficacy in the long-term treatment of this disorder, instances of elevated urine-histamine levels in patients with HAE raises the possibility of a role for histamine in the pathophysiology of this disease. Urine samples were collected from 28 asymptomatic and from 11 symptomatic patients with HAE. The urine-histamine levels were compared with levels of 41 normal control subjects. With the exception of one asymptomatic patient with HAE whose diagnoses also included rheumatoid arthritis and secondary Sjögren's syndrome, the urine-histamine levels from asymptomatic patients with HAE were similar to values obtained from normal control subjects. Except for data from two patients with HAE, urine-histamine levels from symptomatic patients with HAE were also indistinguishable from levels of normal volunteers. These data suggest that the vast majority of patients with HAE have normal urine-histamine levels both during and between attacks. Consequently, histamine is unlikely to play a pathophysiologic role in HAE.

Immunoregulatory disorders associated with hereditary angioedema. II. Serologic and cellular abnormalities.

Hereditary angioedema is defined biochemically by a deficiency in the functional activity of the inhibitor of Cl, Cl esterase inhibitor (Cl INH). Deficiency of this regulator of the early classic pathway of complement results in chronic activation of this cascade with a resultant deficiency of C4 and C2. Ninety-seven patients with either complicated (associated with autoimmune disorders) or uncomplicated hereditary angioedema were evaluated for laboratory evidence of immunoregulatory defects. Specific cellular and humoral abnormalities were found and included increased mean total lymphocyte counts, increased mean Leu 4+ (total) and Leu 3+ (helper) T cells, an increased mean Leu 3/Leu 2 (helper/suppressor T cell) ratio, polyclonal B cell activation, and evidence of circulating immune complexes. C4 functional titers were negatively correlated with percent Leu 3+ cells and absolute Leu 3+ cell numbers. We failed to detect any evidence of immune deficiency in this population, and yet a statistically significant number of patients demonstrated elevated levels of antibodies to Epstein-Barr virus antigens when patients were compared to a control group. Thus, early classic complement pathway activation and/or partial complement component deficiency may effect T cell subpopulations and B cell activation. However, additional predisposing factors (e.g., genetic or viral) appear necessary for the development of a particular autoimmune disease in hypocomplementemic patients.

Immunoregulatory disorders associated with hereditary angioedema. I. Clinical manifestations of autoimmune disease.

Occasional reports have appeared linking hereditary angioedema (HAE) with autoimmune diseases. We have systematically evaluated 157 patients for manifestations of autoimmunity. Nineteen of these patients (12%) had clinical immunoregulatory diseases including glomerulonephritis (five patients), Sjögren's syndrome (three), inflammatory bowel disease (three), thyroiditis (two), systemic lupus erythematosus (one), drug-induced lupus (one), rheumatoid arthritis (one), juvenile rheumatoid arthritis with IgA deficiency (one), incipient pernicious anemia (one), and sicca syndrome (one). All eight patients with HAE who developed an autoimmune disease with a known human histocompatibility antigen association developed a disease associated with their histocompatibility antigen haplotype (p = 0.014). Although only four patients developed Sjögren's syndrome or sicca syndrome, an additional nine manifested part of the sicca complex. We also found patients with HAE with features suggestive of an immune-based abnormality. These features included idiopathic pancreatitis (three patients), Raynaud's disease (two), partial lipodystrophy (one), chronic chorioretinitis (one), and alopecia universalis (one).

Danazol-induced cystitis: an undescribed source of hematuria in patients with hereditary angioneurotic edema.

From 1975 through 1983, 69 patients with hereditary angioneurotic edema were treated with danazol, a semisynthetic anabolic steroid. Hematuria developed in 13 of these patients (19 per cent). Careful evaluation of the genitourinary tract showed the presence of a distinct form of hemorrhagic cystitis in 10 patients. Clinically, 9 patients presented with microscopic and 1 with intermittent gross hematuria. Irritative bladder symptoms were reported by 2 patients. Neither the dose nor duration of danazol therapy correlated with the severity of the cystoscopic or pathological findings. Cystoscopically, a rather nonspecific pattern of erythema, submucosal telangiectasia and neovascularity was observed. Histopathologically, bladder biopsy typically showed numerous dilated submucosal vessels with hemorrhage, mucosal ulceration and occasional inflammatory cells. These changes regressed in all but 1 patient when danazol therapy was discontinued. Further studies are needed to elucidate the role of danazol itself or of the danazol-hereditary angioneurotic edema interaction in the pathogenesis of these abnormalities.