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OBJECTIVE: This cross-sectional study investigated the relationship among obesity, depressive symptoms, eating attitudes and behaviors, and dietary intake. It compared women at risk for recurrence of breast cancer and women who had not been diagnosed with breast cancer and were recruited from the same community and age group (middle-aged and older). METHOD: Body mass index (BMI), dietary intake, self-reported depressive symptoms, and eating disorder psychopathology (assessed with the Eating Disorder Examination - Questionnaire [EDE-Q]) were examined in women who had been diagnosed with breast cancer (n = 56) and the comparison group of women with no breast cancer history (n = 52). Multivariate regression analysis was used to identify factors independently associated with global and subscale EDE-Q scores and BMI. RESULTS: BMI and depressive symptoms were significantly and independently associated with global and subscale EDE-Q scores in women at risk for breast cancer recurrence and women with no breast cancer history. Dietary restriction was also significantly associated with EDE-Q scores in the group with no breast cancer history. CONCLUSIONS: An association among obesity, depressive symptomatology, and abnormal eating attitudes and behavior may affect response to standard nutritional interventions in women at risk for breast cancer recurrence. Copyright 2000 by John Wiley Sons, Inc. [ABSTRACT FROM AUTHOR]

Patients with head and neck squamous cell cancer with N2 and N3 neck disease have a poor prognosis and are at risk to fail regionally despite combined surgery and radiation. Twenty-two patients with N2 and N3 neck disease (and T3-4 primaries) were treated with intra-arterial, high-dose cisplatin (CDDP), 150 mg/m2 per week for 4 weeks, and concurrent radiation. All patients were followed for at least 2 years or until death from any cause. Twenty patients had a complete response at the primary site. Two of the 20 with a complete response later had a neck recurrence and died. Five patients with palpable nodes after treatment underwent fine-needle aspiration (FNA), one of which was positive and two suggestive of cancer. Six neck dissections were performed in this group, only two of which had positive nodes. This chemoradiation protocol may offer reasonable control of N2 and N3 neck disease in advanced head and neck squamous cell cancer. Neck dissection appeared to be necessary in only those patients with nodes 8 weeks after treatment in whom FNA was positive or suggestive of cancer. Because of the relatively small size of this series, additional accrual and monitoring of such patients is planned. [ABSTRACT FROM AUTHOR]

Background: Mammalian target of rapamycin (mTOR) inhibitor-associated stomatitis (mIAS) is a frequent adverse event (AE) associated with mTOR inhibitor therapy and can impact treatment adherence. The objectives are to evaluate two steroid-based mouthrinses for preventing/ameliorating mIAS in patients with metastatic breast cancer (MBC) treated with everolimus., Materials and Methods: This prospective, randomized phase II study enrolled 100 postmenopausal patients with hormone receptor-positive MBC within the US Oncology Network who were initiating therapy with an aromatase inhibitor + everolimus (AIE; 10 mg/day). Patients were randomized to prophylactic therapy with one of two oral rinses (Arm 1: Miracle Mouthwash [MMW] 480 mL recipe: 320 mL oral Benadryl [diphenhydramine; Johnson & Johnson, New Brunswick, NJ, USA], 2 g tetracycline, 80 mg hydrocortisone, 40 mL nystatin suspension, water; or Arm 2: prednisolone [P] 15 mg/5 mL oral solution, 1.8% alcohol). Patients were instructed to swish/expectorate 10 mL of the assigned rinse for 1-2 minutes four times daily starting with day 1 of AIE treatment, for the first 12 weeks., Results: A total of 100 patients received treatment (49 MMW; 51 P). The incidence of stomatitis/oral AEs during the first 12 weeks was 35% ( n  = 17/49) and 37% (19/51) in the MMW and P arms, respectively. The incidence of grade 2 oral AEs was 14% (7/49) and 12% (6/51) with MMW or P, respectively. There were two grade 3 oral AEs (MMW arm) and no grade 4 events. There was one everolimus dose reduction (MMW) and six dose delays (four MMW, two P) and one dose reduction + delay (MMW) during the first 12 weeks of treatment. No patients stopped steroid mouthwash therapy because of rinse-related toxicity., Conclusion: Prophylactic use of steroid-containing oral rinses can prevent/ameliorate mIAS in patients with MBC treated with AIE. MMW + hydrocortisone is an affordable option, as is dexamethasone oral rinse., Implications for Practice: This prospective phase-II study showed that two steroid-containing mouthrinses substantially reduced incidences of all-grade and grade ≥2 stomatitis and related oral adverse events (AEs), and the number of everolimus dose-delays and/or dose-reduction in metastatic breast cancer (MBC) patients receiving everolimus treatment plus an aromatase inhibitor. Both oral rinses were well tolerated and demonstrated similar efficacy. Prophylactic use of steroid mouth rinse provides a cost-effective option that substantially decreases the incidence and severity of mammalian target of rapamycin (mTOR) inhibitor-associated stomatitis and related oral AEs as well as the need for dose modification in MBC patients undergoing treatment with an mTOR inhibitor., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2019.)

Interprofessional and intraprofessional education (when students from two or more professions or within the same profession, respectively, learn about, from, and/or with each other) is crucial for effective interdisciplinary collaboration. The aims of this study were to assess the effectiveness of a clinical intraprofessional education program for dental and dental hygiene students, based on students' expectations and satisfaction with the program and patients' satisfaction with the team-based care. The pilot program was developed at the University of Tennessee Health Science Center College of Dentistry, where dental hygiene students were paired randomly with dental students scheduled for prophylaxis, scaling and root planing, or periodontal maintenance. Surveys with questions about the students' expectations and satisfaction were distributed to 89 senior dental students and 27 senior dental hygiene students before and after team-based procedures. Another survey was distributed to 17 patients asking about their satisfaction with the team-based care. All 27 dental hygiene students (100% response rate), 51 dental students (57.3% response rate), and all 17 patients (100% response rate) participated in the surveys. The results showed that both the dental and dental hygiene students had high expectations and were overall satisfied with the intraprofessional education. The students' expectations and perceived educational gap (difference between expectations and satisfaction) differed for the dental and dental hygiene students (p<0.001). The male dental students were also more satisfied than the female dental students (p<0.01). Overall, the program met or exceeded the students' expectations, and the patients were overwhelmingly satisfied with the team-based care. These results suggest that this intraprofessional practice model provided an effective educational experience for both dental and dental hygiene students and patients. The differences between the dental hygiene and dental students' expectations will help in the design of more effective training that promotes intraprofessional and interprofessional teamwork.

Background: The present phase II, open-label, multicenter study explored the feasibility, safety, and tolerability of eribulin, a novel non-taxane microtubule inhibitor, plus capecitabine as adjuvant therapy., Patients and Methods: Postmenopausal women with early-stage, human epidermal growth factor receptor 2 (HER2)-negative, estrogen-receptor (ER)-positive breast cancer received four 21-day cycles of treatment with eribulin mesylate (1.4 mg/m(2) intravenously on days 1 and 8 of each cycle) combined with capecitabine (900 mg/m(2) orally twice daily on days 1-14 of each cycle [standard schedule] or 1500 mg orally twice daily using a 7-days on/7-days off schedule [weekly schedule]). Feasibility was determined by the relative dose intensity (RDI) of the combination using prespecified criteria for 80% of patients achieving an RDI of ≥ 85%, with a lower 95% confidence boundary > 70%., Results: The mean RDI was 90.6%, and the feasibility rate was 81.3% among women (n = 67, mean age, 61.3 years) receiving the standard schedule and 95.6% and 100% among women (n = 10, mean age 62.3 years) receiving the weekly schedule. Dose reductions, missed doses, and withdrawals due to adverse events (most commonly hand-foot syndrome) ascribed to capecitabine led to a higher RDI (93.5% vs. 87.8%) and feasibility rate (82.8% vs. 71.9%) for eribulin than for capecitabine using the standard dosing schedule. The most common adverse events were alopecia and fatigue., Conclusion: Eribulin plus capecitabine with standard or weekly dosing schedules is feasible in patients with early-stage, HER2-negative, ER-positive breast cancer. Full-dose eribulin (1.4 mg/m(2) on days 1 and 8) with capecitabine (1500 mg orally twice daily, 7 days on/7 days off) is recommended as a regimen for further evaluation., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Recent studies suggest that tumor-infiltrating lymphocytes (TILs) are associated with disease-free (DFS) and overall survival (OS) in operable triple-negative breast cancer (TNBC). We seek to validate the prognostic impact of TILs in primary TNBCs in two adjuvant phase III trials conducted by the Eastern Cooperative Oncology Group (ECOG)., Patients and Methods: Full-face hematoxylin and eosin–stained sections of 506 tumors from ECOG trials E2197 and E1199 were evaluated for density of TILs in intraepithelial (iTILs) and stromal compartments (sTILs). Patient cases of TNBC from E2197 and E1199 were randomly selected based on availability of sections. For the primary end point of DFS, association with TIL scores was determined by fitting proportional hazards models stratified on study. Secondary end points were OS and distant recurrence–free interval (DRFI). Reporting recommendations for tumor marker prognostic studies criteria were followed, and all analyses were prespecified., Results: The majority of 481 evaluable cancers had TILs (sTILs, 80%; iTILs, 15%). With a median follow-up of 10.6 years, higher sTIL scores were associated with better prognosis; for every 10% increase in sTILs, a 14% reduction of risk of recurrence or death (P = .02), 18% reduction of risk of distant recurrence (P = .04), and 19% reduction of risk of death (P = .01) were observed. Multivariable analysis confirmed sTILs to be an independent prognostic marker of DFS, DRFI, and OS., Conclusion: In two national randomized clinical trials using contemporary adjuvant chemotherapy, we confirm that stromal lymphocytic infiltration constitutes a robust prognostic factor in TNBCs. Studies assessing outcomes and therapeutic efficacies should consider stratification for this parameter.

Wild-type green fluorescent protein (GFP) folds on a time scale of minutes. The slow step in folding is a cis-trans peptide bond isomerization. The only conserved cis-peptide bond in the native GFP structure, at P89, was remodeled by the insertion of two residues, followed by iterative energy minimization and side chain design. The engineered GFP was synthesized and found to fold faster and more efficiently than its template protein, recovering 50% more of its fluorescence upon refolding. The slow phase of folding is faster and smaller in amplitude, and hysteresis in refolding has been eliminated. The elimination of a previously reported kinetically trapped state in refolding suggests that X-P89 is trans in the trapped state. A 2.55 Å resolution crystal structure revealed that the new variant contains only trans-peptide bonds, as designed. This is the first instance of a computationally remodeled fluorescent protein that folds faster and more efficiently than wild type., (© 2014 The Protein Society.)

Purpose: The purpose of this research was to determine the toxicity and immunological activity of large multivalent immunogen (LMI), a preparation of tumor cell membranes affixed to amorphous silica microbeads, in patients with melanoma., Experimental Design: Nineteen patients with metastatic (stage IV) melanoma were entered into the study, of whom 15 received the full 3 months of treatment with LMI. LMI was administered without adjuvant, one-half intradermally (i.d.) and the other half s.c. Because we expected little toxicity, we first treated 2 patients at each dose level, 10-, 30-, or 100-million tumor cell equivalents on weeks 0, 4, and 8, and subsequently randomized the remaining 13 patients to receive treatment with one of those dosage schedules, for a total of 19 patients. Two patients who were registered were found to be ineligible because of brain metastases, and 2 others did not complete the course of treatment for reasons other than toxicity. Thus, 15 patients were fully evaluable. Patients with evidence of a clinical response (at least stable disease at the 12-week checkpoint) had the option of continuing treatment at 4-week intervals. Frequencies of cytolytic T cell precursors against HLA-A2 matched melanoma cells, and delayed-type hypersensitivity to a melanoma cell membrane preparation from a component melanoma cell line were performed to measure immunological efficacy, and serum chemistries and complete blood counts were performed every 2 weeks throughout the study to measure possible toxicity. Computed tomography scans were performed pretreatment and at week 12 to measure possible beneficial effects on known lesions., Results: Eight of the 15 evaluable patients had an increase in cytolytic T-cell precursors during the course of therapy, usually by day 42. No patient had demonstrable delayed-type hypersensitivity to a melanoma membrane preparation before or after treatment. No toxicity of any kind was observed. A degree of clinical effectiveness of LMI was suggested by the elicitation of stable disease in 5 patients at 12 weeks. One patient had >50% regression of a lung nodule but progression of disease to the brain, whereas a second patient had a bona fide partial remission of a 3-cm diameter solitary lung nodule., Conclusions: LMI was nontoxic, improved immunological reactivity to melanoma cells, and showed evidence of clinical effectiveness (shrinkage of tumor) in 1 patient. Additional studies with LMI with added adjuvant materials, in melanoma and other cancers, appear warranted.

Background: Clouston syndrome is an autosomal dominant disorder characterized by nail dystrophy, partial or total alopecia, and hyperkeratosis of the palms and soles., Objective: Although a variety of unusual cutaneous manifestations have been described, the incidence of melanoma in this population is unknown., Methods: This article reports a case of in-transit metastatic subungual melanoma in a patient with Clouston syndrome successfully treated with hyperthermic limb perfusion with melphalan., Results: Six months postperfusion, the patient is doing well, with resolution of the extremity erythema and edema. Followup ultrasonography revealed reduction in size of the eight subcutaneous nodules, with the largest measuring 3.3 cm in maximum diameter, representing nearly a 50% reduction in tumor volume postperfusion., Conclusion: Although melanoma has also been associated with some forms of ectodermal dysplasia, such as ectrodactyly--ectodermal dysplasia--clefting (EEC) syndrome, the incidence of melanoma in patients with Clouston syndrome is unknown. Thus far, to our knowledge, this is the first case report of melanoma arising in a patient with Clouston syndrome.

The Women's Healthy Eating and Living (WHEL) Study is a multisite randomized controlled trial of the effectiveness of a high-vegetable, low-fat diet, aimed at markedly raising circulating carotenoid concentrations from food sources, in reducing additional breast cancer events and early death in women with early-stage invasive breast cancer (within 4 years of diagnosis). The study randomly assigned 3088 such women to an intensive diet intervention or to a comparison group between 1995 and 2000 and is expected to follow them through 2006. Two thirds of these women were under 55 years of age at randomization. This research study has a coordinating center and seven clinical sites. Randomization was stratified by age, stage of tumor and clinical site. A comprehensive intervention program that includes intensive telephone counseling, cooking classes and print materials helps shift the dietary pattern of women in the intervention. Through an innovative telephone counseling program, dietary counselors encourage women in the intervention group to meet the following daily behavioral targets: five vegetable servings, 16 ounces of vegetable juice, three fruit servings, 30 g of fiber and 15-20% energy from fat. Adherence assessments occur at baseline, 6, 12, 24 or 36, 48 and 72 months. These assessments can include dietary intake (repeated 24-hour dietary recalls and food frequency questionnaire), circulating carotenoid concentrations, physical measures and questionnaires about health symptoms, quality of life, personal habits and lifestyle patterns. Outcome assessments are completed by telephone interview every 6 months with medical record verification. We will assess evidence of effectiveness by the length of the breast cancer event-free interval, as well as by overall survival separately in all the women in the study as well as specifically in women under and over the age of 55 years.

Melanoma vaccines, which have been under development for many years, are being refined as a result of the knowledge gained from practical testing. We now have a more complete understanding of their mode of action and the problems that remain to be solved. There are points to recommend both crude and pure vaccines-each have specific advantages, but both require further development. Isolation of relevant peptide epitopes, addition of co-stimulatory molecules, the development of novel vehicles for vaccine delivery and improved vaccine adjuvants, and the problem of tumor-induced immunosuppression are among the issues for future study.

Although expression of the haptoglobin (HP) as an acute phase reactant is evolutionarily conserved among mammals, there are differences among species with regard to the hormones required for stimulation. Using primary hepatocyte cultures, we show that in Mus caroli, as in rat, IL-1 and IL-6 are stimulatory, whereas in M. domesticus, as in humans, IL-1 response is diminished. In vivo, an acute inflammatory process increases hepatic HP expression in both mouse species up to 30-fold but minimally affects the low level HP expression in the lung. To define the species-specific differences in regulation, we isolated the hormone-responsive elements of the HP gene from the Mus species, M. domesticus, M. caroli, and M. saxicola. Functional studies in transfected hepatoma cells revealed an exceptionally strong dexamethasone response for all three murine HP gene elements. The IL-6 response was less prominent than in rat or human. A modest response to IL-1 was observed in M. caroli and M. saxicola. A mouse-specific insertion of a polypurine sequence led to a binding site for the PEA3 transcription factor in the HP gene promoter of M. domesticus and M. saxicola, but not M. caroli. The specific regulatory effects of glucocorticoid receptor, C/EBP beta, and Ets proteins were documented by co-transfection.

The hepatic action of cytokines has generally been analysed in terms of the acute-phase response of the liver. The qualitative and quantitative changes in the expression of plasma proteins serve as defining criteria for cytokine function. Interleukin 6 (IL-6) and leukaemia inhibitory factor (LIF) are representatives of a group of cytokines which display strikingly similar effects in both human and rodent liver cells. Hallmarks of the action of these cytokines are the stimulation of type 2 acute-phase plasma proteins and enhancement of the effect of interleukin 1 (IL-1) or tumour necrosis factor alpha (TNF-alpha) on type 1 acute-phase plasma proteins. The transcriptional activation of the various acute-phase plasma protein genes involves common cis-acting regulatory elements whose sequences and location relative to the transcription start site vary from gene to gene. The activity of the IL-6- and LIF-responsive genes depends in part on transcription factors including several members of the C/EBP family, JunB and the glucocorticoid receptor. The expression of these transcription factors is in turn under cytokine-specific control. In a few cases, expression is temporally correlated with the activation of 'late' acute-phase protein genes. The finding that structurally distinct cytokines interact with separate receptors but elicit an almost identical liver cell response demands a reassessment of the contribution of each factor to the in vivo acute-phase response.

Independent of de novo protein synthesis, interleukin-1, interleukin-6, and dexamethasone caused immediate stimulation of transcriptional activity of most major acute phase plasma protein genes in the rat hepatoma H-35 cells. However, activation of alpha 2-macroglobulin and alpha 1-acid glycoprotein genes were delayed by 2-4 h and required ongoing protein synthesis. The hormones also increased transiently the transcription of the junB gene and the amounts of JunB, C/EBP, and C/EBP-like mRNA. To identify whether JunB and C/EBP have the ability to control both the early and late acute phase reactants, expression vectors for mouse C/EBP and JunB together with reporter gene constructs containing recognized hormone-specific regulatory elements were introduced into hepatoma cells. C/EBP displayed prominent transactivation activity with the interleukin-1 and glucocorticoid regulatory elements of alpha 1-acid glycoprotein, the interleukin-1 regulatory element of haptoglobin gene, and the interleukin-6 regulatory element of beta-fibrinogen. The interleukin-6 regulatory elements of the first two genes and the glucocorticoid response element of the third gene were not affected by C/EBP. These data suggest that normal hormone activation of these three acute phase reactant genes might involve, in part, C/EBP-related factors which have a broad range of specificity. H-35 cells stably transformed with a mouse C/EBP expression vector showed an elevated basal level as well as cytokine inducible expression of some but not all acute phase reactants. Cotransfected JunB resulted in reduced activity of cytokine-responsive constructs and in lower transactivation by C/EBP. JunB appears to function as a modulator of plasma protein expression during the course of acute phase response.

Associations were sought between major histocompatibility complex (MHC) genes on chromosome 6 and the complement component C3 and immunoglobulin genes located on other chromosomes which might contribute to susceptibility to mild inflammatory arthritis (IA) or definite rheumatoid arthritis (RA). Frequencies of the complement C3F allele were raised in patients with IA but were normal in patients with RA and controls. When associations between C3F and MHC genes were sought frequencies of some MHC genes were greater in patients with C3F than in those without--for example, HLA-B8 and DR3 in patients with RA and DR2 in patients with IA. Conversely, DR4 frequency was lower in patients with IA with C3F than in those without. Thus the C3F allele may act independently or exert an epistatic effect on MHC genes to increase susceptibility or protect against disease. The frequency of the immunoglobulin heavy chain allotype Glm(2) on chromosome 14 was increased in patients with RA but only in those with the phenotype Gm1,2,3,17;21,5; no significant associations were found between MHC genes and Gm phenotypes. Further, no associations of MHC, C3F, and immunoglobulin genes were shared by patients with RA and those with IA, indicating a different genetic basis for the two clinical entities.

Patients with mild inflammatory arthritis (IA) were compared with patients with definite rheumatoid arthritis (RA) for abnormal frequencies of major histocompatibility complex (MHC) antigens and haplotypes to determine whether a genetic predisposition either to RA or to mild self-limiting arthritis/arthralgia was present in the patients with IA. In general the MHC antigens with abnormal frequencies found in patients with IA differed from those in patients with RA and were mainly at the A and B loci. In patients with IA the frequencies of HLA-A24, A25, B27, and B35 antigens were significantly higher than those of controls and HLA-DR5 and C4A4 were slightly raised. In contrast, in patients with RA abnormal frequencies of the MHC antigens DR4 and DR2 and the extended haplotypes associated with them [B62 BfS C4A3 C4B3 DR4 GLO2] and [B7 BfS C4A3 C4B1 DR2] confirmed the observations reported on other white populations. Thus MHC antigen associations with IA and RA differ sufficiently to suggest a different genetic basis for the two conditions.

Fourteen patients with multiple sclerosis were given two tolerizing doses of equinine gammaglobulin followed by equine antilymphocyte globulin. Twelve were sufficiently tolerant to have no clinical symptoms of hypersensitivity, no skin reactivity and normal plasma clearance rates. Some tolerance was lost in the following months revealed by immediate wheal and flare skin reactions. No correlation between success in tolerance induction and beneficial effects on the disease process could be established in the short term follow-up period of this pilot study.

Synovial fluids and paired sera taken from patients either before, after or at the time of diagnosis of definite rheumatoid arthritis (RA) were compared with samples from patients with unclassified inflammatory arthropathies (IA). Raised levels of immune complexes (IC) were detected in some RA patients by C1q binding activity but in the majority of both RA and IA patients by the platelet aggregation test; levels were usually higher in joint fluids than in sera. IgM rheumatoid factors (RF) and IgA RFs were lower in synovial fluids but IgF RF levels were similar in matched samples. Synovial fluid to serum albumin ratios were used to estimate synovial permeability (inflammation) and then to calculate which patients synthesized macromolecules locally in the synovium. Local synthesis of RFs was detected in a greater proportion of RA than IA patients and only two patients formed RFs locally in the first months of symptoms. Half the patients in both groups however appeared to synthesize or trap IC constituents and in many patients there was evidence of local synthesis within 6 months after their symptoms had started. We conclude that local synthesis of large amounts of RFs is uncommon in the early stages of RA but that IC of unknown composition are synthesized or localized in the affected joints of many patients with RA and inflammatory arthropathies shortly after their symptoms appear.

Fourteen patients with multiple sclerosis were given two tolerizing doses of equine gamma-globulin before treatment with anti-lymphocyte globulin. Twelve patients had no clinical symptoms of hypersensitivity and most of them had no detectable antibody to the equine globulin until several months later. Even then, antibody could only be shown by immediate type skin reactions but not by any in vitro assay. We conclude that a state of partial tolerance was established in these patients for the period of treatment but that later they may develop traces of hypersensitivity.

IgG with rheumatoid factor activity has been recovered from immune complexes containing IgM rheumatoid factor. This was done by passing serum from patients with rheumatoid arthritis through an immunoadsorbent column of the F(ab')2 fragment of rabbit anti-human mu chain. The recovered IgM was analysed by radioimmunoassays for IgM and IgG rheumatoid factors before and after sucrose density gradient centrifugation at neutral and acid pH. It is considered that the method may be generally applicable for the isolation of immune complexes containing IgM antibodies.

A new method has been developed to determine the specificities of polyclonal rheumatoid factors (naturally occurring antibodies which react with human Fc gamma) (RF) found in sera from patients with rheumatoid arthritis. In this method, monoclonal anti-Rh(D) antibodies of known IgG isotype and allotype are bound to erythrocytes and then act as the target IgG antigen for RF in a direct haemagglutination test. Using two monoclonal anti-D antibodies of the IgG3 isotype and G3m(21) allotype, which were cloned from different donors, we found that a large number of rheumatoid sera reacted with both these G3m(21) proteins. In contrast reactivity of rheumatoid sera with polyclonal anti-D of the G3m(21) allotype in the direct haemagglutination test was rare. A strong correlation was found between reactivities to both G3m(21) monoclonal anti-D antibodies but not with a monoclonal anti-D antibody carrying the alternative allele, namely G3m(5). Haemagglutination inhibition experiments using human paraproteins of known IgG isotype and allotype provided some additional evidence that this method can detect RF with specificity for the G3m(21) allotypic determinant or a related allotypic determinant in polyclonal rheumatoid sera. When each patient's autoantibody response was related to their Gm phenotype, we found that the frequency of reactivity for G3m(21) monoclonal anti-D antibodies was significantly greater in patients negative for G3m(21) than in patients positive for the G3m(21) allotype. IgM preparations from patients' sera were dissociated at acid pH but no 'hidden' antibodies were found. We suggest trans-placental sensitization as one of several possible interpretations of this finding.

Fifty-three patients with early arthritis were studied longitudinally for up to 3 years. During this time, 24 developed sufficient features for definite rheumatoid arthritis (RA) to be diagnosed. The other (arthralgia patients) differed from the RA patients as, in the majority, C-reactive protein and ESR were normal and anti-nuclear antibodies or rheumatoid factors were rarely found. Moreover, in time their signs and symptoms improved or disappeared. Circulating immune complexes were detected in both groups of patients by the platelet aggregation test whereas complexes detected by abnormal Clq-binding activity were found mainly in the RA patients. Platelet-aggregating complexes were usually present in the first samples studied and disappeared in the arthralgia patients with recovery from their symptoms. In the RA patients, Clq-binding complexes appeared simultaneously or later than platelet-aggregating complexes but both tests were positive several months before RA could be diagnosed. These results suggest that immune complexes are one of the first immunological abnormalities to appear in patients with arthritis. Although the constituent antigen and antibody of complexes detected by either test are unknown, their possible nature is discussed.

It is currently believed that the rate and direction of sodium transport in the small intestine may be regulated by the activity of Na,K-ATPase in the basolateral cell membrane. We tested this hypothesis by selectively infusing ouabain, a known inhibitor of Na,K-ATPase, into the mesenteric artery supplying a perfused loop of ileum in 18 dogs. Before ouabain infusion there were significant correlations between the activity of Na,K-ATPase and net and lumen to plasma fluxes of sodium and chloride. After ouabain, there was no significant change in sodium and chloride transport, unidirectional fluxes or transmucosal potential difference, despite a 50% reduction in Na,K-ATPase activity. Furthermore, there was no significant correlation between Na,K-ATPase activity and sodium or chloride transport after ouabain. The only statistically significant effect of ouabain infusion was a reduction in the rate of bicarbonate secretion. Thus, the results of our experiments suggest that mucosal Na,K-ATPase is not a rate-limiting step in the absorption of sodium and chloride in the dog ileum, though it may be an important facilitative factor.

The function of Class II molecules in proliferation was explored by treating human cell lines with three distinct anti-DR monoclonal antibodies (MABs). Dose-dependent, specific inhibition of eight DR+ cell lines of different origin and lineage was found. Inhibition was durable (i.e., cells did not become resistant to the anti-DR MABs despite prolonged treatment) yet reversible. The mechanism of inhibition was not due to differentiation or killing but was cytostatic. Inhibition was temporally associated with decreases in nuclear size and irregularity and appeared to be due to a non-phase-specific cell cycle arrest.

Evidence of recent infection with human parvovirus B19 (HPV) was found in two patients with early rheumatoid arthritis (RA) and in four patients with acute inflammatory arthritis (IA). Both of the patients with RA but only one of the four patients with IA carried RA associated haplotypes. No evidence of persistent infection with HPV was found, but evidence of past infection with HPV was significantly more common in patients with RA than in controls. The results confirm the arthritogenic potential of HPV and are consistent with the hypothesis that rheumatoid arthritis may develop in a genetically predisposed patient after an arthritogenic insult such as an HPV infection.

Human monoclonal anti-Rh(D) antibodies of known IgG isotype and Gm allotype were bound to erythrocytes and then used as the target IgG antigens for rheumatoid factors (RFs) in a direct haemagglutination test. When serum samples from patients with rheumatoid arthritis (RA) were tested for RF specificity towards these IgG monoclonal anti-D antibodies the incidence and titre of reactivity towards an IgG3 monoclonal anti-D antibody was considerably greater than for a polyclonal anti-D antibody of the same Gm allotype, G3m(5). This difference was not explained by the amount of each anti-D antibody which bound to erythrocytes. Furthermore, when patients with RA were divided into groups according to their Gm phenotype, sera from a greater proportion of patients negative for the phenotype G3m(5) reacted to the G3m(5) monoclonal anti-D antibodies than sera from those patients positive for this allotype. Analysis of RF reactivities towards two IgG3 and three IgG1 monoclonal anti-D antibodies, each with different Gm allotypic epitopes, indicated, however, that individual serum samples contained RFs with a spectrum of specificities; some sera appeared to react to a single set of Gm alleles, whereas others also reacted to isotypic or iso-allotypic epitopes, or both. Our data suggest that RFs with specificity for Gm allotypes do not arise in patients who carry that particular allotype owing to tolerance induced in fetal-neonatal life. Conversely, RFs with apparent specificity for a Gm allotype formed in patients negative for that allotype may be reacting to a closely related but different epitope. Final proof requires precise specificities for each RF formed, and IgG3 monoclonal anti-D antibodies would be useful reagents for this purpose.

A Fowl antiserum to human polyclonal F(ab')2 with specificities for variable region antigens of both light and heavy chains and for the constant portion of the Fd fragment bound to about 20 per cent of thymocytes from three children. Binding was completely inhibited by purified human polyclonal IgG and only partly by L chains. The fowl anti-F(ab')2 also bound to a subpopulation of peripheral blood lymphocytes which was somewhat larger than the B-cell population identified with other anti-immunoglobulin sera. Binding was detected by autoradiography and the amount of radiolabel seen on thymocytes was nearly as great as that on peripheral blood lymphocytes. As no binding to thymocytes was seen with other anti-immunoglobulin sera we propose that the fowl anti-F(ab')2 recognizes immunoglobulin or material with structural similarities which is synthesized by thymocytes but of which predominantly V region determinants are exposed on the membrane surface.

The effects of intra-articular methotrexate (MTX) were compared with saline in 20 patients with persistent knee effusions due to rheumatoid arthritis (15) and psoriasis (5) in a double-blind pilot study. Clinical improvement was seen in most patients given either MTX or saline and was attributed to joint irrigation during arthroscopy and the placebo effects. MTX had a local anti-inflammatory effect in the psoriatic arthropathies; the percentages of polymorphonuclear cells and pyroninophilic mononuclear cells in synovial fluids fell sharply. Intraarticular hydrocortisone acetate was not anti-inflammatory in 2 psoriatic patients treated subsequently. The anti-inflammatory action of MTX in joints may resemble its effectiveness in controlling the rash of psoriasis.

The MRSPAH (mixed reverse solid-phase passive antiglobulin haemadherence) test for antiglobulins (Agbs) of IgA, IgG and IgM classes has been quantified and also modified to measure their C3 fixing activity. An alternative ELISA technique is also described. Levels of all Agbs and their C3 fixing activity were significantly raised in established rheumatoid arthritis (RA) patients, early RA patients and established SLE patients. Ankylosing spondylitis (AS) patients had normal levels of Agbs and C3 fixation. Patients with infectious mononucleosis (IM) had high levels of all Agbs, but these did not fix complement. Thus, C3 fixing activity of Agbs is heterogeneous and raised levels are associated with the presence of joint disease. Isolated IgA, IgG and IgM fractions showed examples of Agbs which fixed C3. The proportion of C3 fixed per unit weight of Agbs was no greater in 'hidden' Agbs from serum and synovial fluids (SFs) than in untreated serum, and Agbs in SF do not fix more C3 than in serum. We conclude that the C3 fixing activity of Agbs is not directly related to affinity.

Hapten-specific delayed hypersensitivity was produced by immunization of guinea pigs with arsanilic acid conjugated to N-acetyltyrosine or other small aromatic molecules. Such hapten-specific delayed sensitivity could be passively transferred by peritoneal exudate cells. While a conjugate made from a polymer of D-amino acids was ineffective in producing sensitization, the conjugate made with D-tyrosine was effective, suggesting that the inability of D-amino acid polymers to be broken down by enzymes might be bypassed by use of the monomer. The effectiveness of such monomers in producing delayed sensitivity, but not antibody production, is consistent with a hypothesis that different types of antigenic determinants are involved in the production of each.