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Background The prevalence of burnout and depressive symptoms is high among physician trainees. Research Question What is the burden of burnout and depressive symptoms among fellows training in pulmonary and critical care medicine (PCCM) and what are associated individual fellow, program, and institutional characteristics? Study Design and Methods We conducted a cross-sectional electronic survey of fellows enrolled in pulmonary, PCCM, and critical care medicine training programs in the United States to assess burnout and depressive symptoms. Burnout symptoms were measured using the Maslach Burnout Index two-item measure. The two-item Primary Care Evaluation of Mental Disorders Procedure was used to screen for depressive symptoms. For each of the two outcomes (burnout and depressive symptoms), we constructed three multivariate logistic regression models to assess individual fellow characteristics, program structure, and institutional polices associated with either burnout or depressive symptoms. Results Five hundred two of the 976 fellows who received the survey completed it—including both outcome measures—giving a response rate of 51%. Fifty percent of fellows showed positive results for either burnout or depressive symptoms, with 41% showing positive results for depressive symptoms, 32% showing positive results for burnout, and 23% showing positive results for both. Reporting a coverage system in the case of personal illness or emergency (adjusted OR [aOR], 0.44; 95% CI, 0.26-0.73) and access to mental health services (aOR, 0.14; 95% CI, 0.04-0.47) were associated with lower odds of burnout. Financial concern was associated with higher odds of depressive symptoms (aOR, 1.13; 95% CI, 1.05-1.22). Working more than 70 hours in an average clinical week and the burdens of electronic health record (EHR) documentation were associated with a higher odds of both burnout and depressive symptoms. Interpretation Given the high prevalence of burnout and depressive symptoms among fellows training in PCCM, an urgent need exists to identify solutions that address this public health crisis. Strategies such as providing an easily accessible coverage system, access to mental health resources, reducing EHR burden, addressing work hours, and addressing financial concerns among trainees may help to reduce burnout or depressive symptoms and should be studied further by the graduate medical education community.

Symptoms of Sjogren’s syndrome (SS) are chronic and can sometimes be devastating, compromising patients’ quality of life to a major degree. Despite the advances in our understanding of the pathogenesis of SS, its therapy remains largely empiric, symptomatic, and focused on alleviating sicca symptoms. Eye lubricants, saliva substitutes, and stimulators of the glandular secretion are the cornerstones of therapy in SS. Despite the autoimmune nature of the disorder, evidence for the use of immunosuppressive agents, the mainstay of therapy of diseases of autoimmune origin, is scarce. In an attempt to alleviate the symptoms of SS by altering the natural disease process, a number of immunosuppressive agents have been tested in clinical studies, mostly with unsatisfactory or questionable results (Table 38.1).

Sjogren syndrome (SS) is a common autoimmune disease evidenced by broad organ-specific and systemic manifestations, the most prevalent being diminished lacrimal and salivary gland function, xerostomia, keratoconjunctivitis sicca, and parotid gland enlargement. Primary SS presents alone, and secondary SS occurs in connection with autoimmune rheumatic diseases. In addition, symptoms do not always present concurrently. This diversity of symptomatic expression adds to the difficulty in initial diagnosis. Armed with the recently refined criteria for diagnosis, specialists, such as rheumatologists, primary care physicians, ophthalmologists, and dentists, who would otherwise focus only on those symptoms that encompass their areas of expertise, can get a comprehensive image of the presenting patient, leading to earlier identification and treatment of SS.

Classification criteria for Sjogren's syndrome (SS) were developed and validated between 1989 and 1996 by the European Study Group on Classification Criteria for SS, and broadly accepted. These have been re-examined by consensus group members, who have introduced some modifications, more clearly defined the rules for classifying patients with primary or secondary SS, and provided more precise exclusion criteria.

We have developed a highly specific and sensitive “two-site” immunoradiometric assay for murine IgM in which antigen bound to immobilized antibody reacts with affinity-purified radiolabeled antibody. We utilized the sensitivity of this assay to study the rate of IgM secretion in short-term cultures by spleen cells from the autoimmune strains, New Zealand Black (NZB) and New Zealand Black by New Zealand White F1 hybrid (BW), and from normal (C57BL/6, DBA/2, NZW) mice. The temperature dependence of IgM secretion in short-term cultures, its pentameric structure, and the similar viability of NZB and normal strain spleen cells indicate that active IgM synthesis is being measured. We observed that the splenic B lymphocytes of NZB and BW mice, in contrast to normal strains, produce IgM in vitro at birth. By 6 to 8 weeks of age NZB and BW spleen cells produce 40 times more IgM than spleen cells from normal strains of mice. The IgM produced in vitro by splenic lymphocytes from NZB and BW mice is not absorbed by syngeneic or allogeneic thymocytes or erythrocytes.

New Zealand Black (NZB) and NZB by New Zealand White (NZW) F 1 hybrid ( B W ) mice develop clinical signs of autoimmune disease between 6 and 10 months of age but spleen cells from these strains have a greatly reduced in vitro response to sheep erythrocytes (SRBC) as early as 5–6 weeks of age. This hyporesponsiveness can be only partially restored with 2-mercaptoethanol, allogeneic macrophages or spleen cells, or allogeneic factor. The response of NZB and B W spleen cells to the thymic independent antigen DNP-Ficoll is nearly normal. The reduced in vitro SRBC response was found to be attributable to splenic T and B cells rather than macrophages. Macrophages from NZB mice were found to function normally. The in vitro behavior of NZB lymphocytes is very similar to non-autoimmune mice infected with common murine viral pathogens. NZB and B W mice may be making an active immune response as early as 5 weeks of age.

The presence of a precipitating antibody to an extractable nuclear antigen, termed Ha, was examined by immunodiffusion in gel in three subpopulations of patients with Sjogren's syndrome (SS): (1) those with sicca complex alone, (2) those with SS and rheumatoid arthritis (SS-RA) and (3) those with SS and systemic lupus erythematosus (SS-SLE). Control populations included patients with rheumatoid arthritis (RA) alone and systemic lupus erythematosus (SLE) alone, and normal age-matched blood donors without a history of SS or other connective tissue disease. The results demonstrate the high incidence of anti-Ha antibody in sicca complex (68 per cent) versus the low incidence of the antibody in SS-RA (5 per cent) (p No correlations were found between anti-Ha antibody positivity and clinical parameters, such as serum immunoglobulin concentration, degree of abnormality of parotid scan, titer of rheumatoid factor or focal score of labial biopsy in the patients with SS. However, a correlation between anti-Ha antibody titer and clinical disease activity was noted in two patients examined. The appearance of the anti-Ha antibody was correlated with the development of pseudolymphoma in a third patient. The presence of the anti-Ha antibody may identify a subpopulation of patients with SS at greater risk of rapid progression of the disease and/or the development of pseudolymphoma.

Cerebrospinal fluid samples from patients with systemic lupus erythematosus (SLE) and neurologic involvement were evaluated for guanosine 3',5'-cyclic monophosphate (C-GMP) and cyclic adenosine monophosphate (C-GMP) content by radioimmunoassay and radioassay, respectively. Twenty-five samples from 15 patients with SLE had an average C-GMP level of 2.4 nM +/- 0.44 (average +/- SE) compared with 0.68 nM +/- 0.14 in a control group with lumbosacral pain (p less than 0.0002). No significant difference was noted in C-AMP content between patients with SLE and control subjects. C-GMP levels in cerebrospinal fluid samples from patients with SLE who had changing neurologic disease were higher than in those with stable neurologic disease. Elevated C-GMP levels in cerebrospinal fluid correlated with the leukocyte number in cerebrospinal fluid (r = 0.53 p less than 0.01), but not with the initial pressure, protein concentration or daily prednisone dosage. Experimental results suggested that leukocytes in the cerebrospinal fluid were not the source of elevated C-GMP levels. Thus, elevated C-GMP levels in cerebrospinal fluid of patients with SLE appeared to reflect neurologic involvement. C-GMP levels were alos found to be elevated in five patients with other active neurologic diseases; thus, measurement of C-GMP in cerebrospinal fluid may have more general diagnostic value.

Cyclic-GMP (C-GMP), a normal constituent of the central nervous system, was found to be present in increased amounts in the cerebrospinal fluid (CSF) of systemic lupus erythematosus (SLE) patients with active neurologic disease. Twenty-four CSF samples from 17 patients with SLE were evaluated for C-GMP concentration by radioimmunoassay. This study extends our initial observations and examines three groups of SLE patients based on their clinical status at the time of each lumbar puncture: those with active neurologic and psychologic abnormalities (group I), active neurologic abnormalities (group II), and psychologic abnormalities without active neurologic involvement (group III). Groups I and II had mean CSF C-GMP values of 3.1 nM ± 0.64 (SE) and 4.1 nM ± 0.10 respectively, which were both significantly higher than the mean for group III (1.2 nM ± 0.43) (P < 0.05). Other CSF findings did not display this close correlation with activity of neurologic disease. In 4 SLE patients, significantly higher levels of CSF C-GMP were found on serial sampling during times when neurologic abnormalities were active. Thus elevated CSF C-GMP concentration may be a marker of active neurologic disease in SLE.

Ha, a soluble nuclear protein, was purified from calf thymus nuclear extract by successive application of fractional ammonium sulfate precipitation (60 to 80% saturation), DEAE-Sephadex chromatography (eluted between 0.26 and 0.38 M NaCl in 0.05 M Tris HCl buffer, pH 7.2), and affinity chromatography utilizing an immunoabsorbent column of Sepharose coupled to IgG from a patient with a high titer of antibody to Ha. The Ha antigen could be iodinated by the method of Bolton and Hunter but not by the chloramine-T or lactoperoxidase methods indicating the absence of tyrosine and histidine. The iodinated material was passed through a Sephadex G-100 column to remove minor contaminants. The final product migrated as a single band in polyacrylamide gel electrophoresis. The 125I-Ha antigen was utilized to measure specific antibody by the ammonium sulfate method. Elevated serum-binding capacity was observed in 73% of patients with sicca syndrome in the absence of another connective tissue disease and 85% of patients with sicca syndrome associated with systemic lupus erythematosus. It was infrequent in sicca syndrome associated with rheumatoid arthritis (6%) and in systemic lupus erythematosus without sicca syndrome (3%). Anti-Ha antibodies were not found in patients with other connective tissue diseases or normal controls. Antibody to Ha characterizes a subset of patients with sicca syndrome.

Antibodies to Toxoplasrna gondii were measured in sera from 69 patients with polymyositis, dermatomyositis, and myositis associated with other connective tissue diseases and compared to 69 age-, race-, and sex matched controls with unrelated diseases. Complement fixation toxoplasma antibodies were significantly more frequent in polymyositis and correlated with high IgM levels. Other distinguishing clinical or laboratory fea tures of these patients were not found. The high tox oplasma antibodies were not associated with generally hyperactive humoral immunity. The serologic data sug gested that inflammatory muscle disease was associated with recent active toxoplasma infection in certain patients. The pathogenetic role of the microorganism remains uncertain.

The in vitro antibody-forming cell response of mouse spleen cells to the thymic independent synthetic polymer, TNP-Ficoll, was found to require the presence of either macrophages or 2-mercaptoethanol. The TNP-Ficoll response and that to the thymic dependent antigen, sheep erythrocytes, demonstrated the same degree of macrophage dependence. However, macrophage-depleted spleen cells which did not produce plaque-forming cells responded normally to T and B cell mitogens. Comparison of the antibody-forming cell response of macrophage-depleted spleen cells in the presence and absence of 2-mercaptoethanol indicated that either macrophages function 10 to 100 times more efficiently in its presence or that 2-mercaptoethanol partially replaces the function of macrophages.

Sjögren's syndrome is associated with a serologically defined histocompatibility antigen of the HLA-B locus, HLA-B8. Another closely linked locus, HLA-D, determines lymphocyte-defined cell-surface antigens. In laboratory animals such antigens are closely linked to immune response genes. To determine whether Sjögren's syndrome is primarily associated with an HLA-D antigent or with HLA-A and HLA-B antigens as well as HLA-Dw3, which is known to be in linkage disequilibrium with HLA-B8. We found the primary association of association of Sjögren's syndrome to be with HLA-Dw3, which we observed in 84 percent of patients with Sjögren's syndrome in the absence of rheumatoid arthritis as compared to 24 percent in controls (P less than 0.00001). The frequency of HLA-B8 and HLA-Dw3 in patients with both Sjögren's syndrome and rheumatoid arthritis did not differ from that in controls. Patients with Sjögren's syndrome and rheumatoid arthritis comprise genetically distinct groups.

Two male patients with pulmonary manifestations of Wegener's granulomatosis are presented. One had an elevated rheumatoid factor, and both had elevated levels of immunoglobulin E. Both demonstrated characteristic necrotizing granulomatous lesions on light microscopy of lung tissue. Immunohistologic analysis of lung tissue demonstrated a granular deposition of immunoglobulin G and complement. Raji cell assay of sera demonstrated elevated levels of circulating immune complexes in the sera of the one patient tested prior to any therapy. These findings support the hypothesis that immune complex deposition contributes to the pathogenesis of Wegener's granulomatosis.

LYMPH-node enlargement occurs in approximately half of all patients with systemic lupus erythematosus.1 Although the histologic characteristics were described by Short2 in 1907, until 1943, lymphad...

The risk of cancer was ascertained in 136 women with sicca syndrome followed at the National Institutes of Health (NIH). Seven patients developed non-Hodgkin's lymphoma from 6 months to 13 years after their first admission to NIH. This was 43.8 times (P less than 0.01) the incidence expected from the rates of cancer prevailing among women of the same age range in the general population during this time. In addition, three cases of Waldenstrom's macroglobulinemia occurred in this study group. Eight patients developed cancers other than lymphoma, similar to the number expected based on the rates prevailing in the general population. Patients with a history of parotid enlargement, splenomegaly, and lymphadenopahy had an increased risk of lymphoma. These clinical conditions did not appear to be early manifestations of undiagnosed lymphoma but rather seemed to identify a subgroup of patients with sicca syndrome with marked lymphoid reactivity, who had a particularly high risk of subsequently developing lymphoma.