Systematic review: worldwide variation in the frequency of coeliac disease and changes over time.

BACKGROUND: Coeliac disease (CD), originally thought to be largely confined to Northern Europe and Australasia and uncommon in North America and the Middle East, is now recognised to be equally common in all these countries. It is still thought to be rare in the Orient and Sub-Saharan Africa. AIM: To assess geographical differences and time trends in the frequency of CD. METHODS: Medline and Embase searches were conducted on 10 November 2012, from 1946 and 1980 respectively, using the key words: coeliac disease or celiac disease + prevalence or incidence or frequency. RESULTS: There were significant intra- and inter-country differences in the prevalence and incidence of CD. Only 24 ethnic Chinese and Japanese patients have been reported in the English literature. Of CD-associated HLA DQ antigens, DQ2 occurs in 5-10% of Chinese and sub-Saharan Africans, compared to 5-20% in Western Europe. DQ8 occurs in 5-10% of English, Tunisians and Iranians, but in <5% of Eastern Europeans, Americans and Asians. The prevalence and incidence of both clinically and serologically diagnosed CD increased in recent years. These geographical and temporal differences seem genuine, although variable indices of suspicion and availability of diagnostic facilities are confounding factors. CONCLUSIONS: Coeliac disease is increasing in frequency, with significant geographical differences. Although few cases have been described to date in the Orient and Sub-Saharan Africa, there is a significant prevalence of HLA DQ2 and wheat consumption is of the same order as that in Western Europe. CD may therefore become more common in the future in these countries.

The effects of interleukin-18 on rat articular chondrocytes: a study of mRNA expression and protein synthesis of proinflammatory substances.

Interleukin (IL)-18 is a potent stimulator of immunity and augments the severity of type II collagen-induced arthritis (CIA) in rats and mice by enhancing T helper 1 (Th1) cell activation, which increases the production of proinflammatory cytokines and arthritogenic antibodies. In this study, we show that recombinant IL-18 (rIL-18) also has a direct effect on normal rat chondrocytes maintained in vitro inducing them to produce proinflammatory factors including IL-6, regulated upon activation normal T cell expressed and secreted (RANTES), prostaglandin E(2) (PGE(2)) and prostaglandin F(2alpha) (PGF(2alpha)) in a dose- and time-dependent manner. The production of matrix metalloproteinase (MMP)-13, nitric oxide (NO), tumour necrosis factor (TNF)-alpha and IL-1beta were also enhanced, although less intensely. Neutralizing polyclonal anti-rIL-18 antibodies effectively blocked the production of IL-6, PGE(2) and RANTES, as well as mRNA expression for the same products in addition to IL-18 and TNF-alpha. In contrast, neutralizing antibodies to IL-1beta, TNF-alpha and IL-6 were ineffective in suppressing any of these products. Together, these findings suggest that IL-18 may play an important, possibly direct, role in mediating cartilage injury, which might not be amenable to treatment with currently utilized anti-cytokine agents. These findings suggest further that IL-18 antagonists might prove beneficial as anti-inflammatory and chondroprotective agents in the treatment of arthritis, and that the development of such agents for human use is worth consideration.

The isozyme-specific effects of cyclooxygenase-deficiency on bone in mice.

Prostaglandin E(2) (PGE(2)) plays a critical role in skeletal physiology and bone loss. PGE(2) production is regulated in vivo by at least two cyclooxygenase (COX) isozymes, COX-1 and COX-2. The purpose of this study was to investigate the in vivo effects of the selective deletion of COX-1 or COX-2 on bone mineral density (BMD), bone microarchitecture and bone strength in wild type (WT), COX-1(-/-) and COX-2(-/-) mice. Using a LUNAR PIXImus, BMD was measured in 18 (WT), 18 COX-1(-/-) and 16 COX-2(-/-) mice. COX-1(-/-) mice exhibited significantly higher BMD (0.0506 g/cm(2) +/- 0.0014 g/cm(2)) than either WT (0.0493 g/cm(2) +/- 0.0019, P < or = 0.05) or COX-2(-/-) (0.0473 g/cm(2) +/- 0.0034, P < or = 0.01) mice. COX-2(-/-) mice had significantly lower BMD than WT (P < or = 0.01) or COX-1(-/-) (P < or = 0.01). Flexure stress of the femurs, determined by breaking the bones with three-point bending, correlated with bone density. Although plasma levels of both Ca(2+) and PTH were comparable in wild type and COX-1(-/-) mice, both were elevated in COX-2(-/-) mice consistent with primary hyperparathyroidism. These studies suggest that COX enzymes are important regulators of BMD and bone strength in mice. The beneficial effect of absence of the COX-1 enzyme on skeletal parameters may be secondary to decreases in PGE(2). On the other hand, primary hyperparathyroidism and lower bone magnesium content may account for the lower BMD and impairments in bone strength of COX-2(-/-) mice. Further elucidation of the effects of the COX pathway on bone remodeling may provide important information on potential therapeutic targets for preventing and/or treating osteoporosis.

Efficacy of modified recombinant type II collagen in modulating autoimmune arthritis.

OBJECTIVE: Previous studies have shown that an analog peptide of the immunodominant T cell determinant of type II collagen (CII), i.e., CII(256-276)(N(263), D(266)), was able to suppress the immune response to CII and the development of arthritis in DR1-transgenic mice. The present study tested the hypothesis that introduction of the same amino acid substitutions into full-length CII might improve the efficacy of the mutant collagen in achieving suppression of autoimmune arthritis. METHODS: Using recombinant technology, full-length CII was modified, while the native conformation was retained. Two point mutations were introduced within the immunodominant T cell determinant to convert the F(263) to N and E(266) to D, using a baculovirus expression system that has previously been utilized in the production of recombinant CII (rCII). RESULTS: The mutant rCII(N(263), D(266)) was capable of reducing the incidence and severity of arthritis as well as the antibody response to CII when administered to DR1-transgenic mice that display susceptibility to collagen-induced arthritis. More importantly, it was significantly more effective than the synthetic analog peptide, CII(256-276)(N(263), D(266)). Its mechanism of suppression may be explained by the secretion of predominantly Th2 cytokines by the T cells immunized with rCII(N(263), D(266)). Administration of rCII(N(263), D(266)) was ineffective in suppressing arthritis in IL4(-/-) mice, suggesting that the profound suppressive effects of rCII(N(263), D(266)) were mediated through the production of interleukin-4. CONCLUSION: These findings describe a promising specific immunotherapy for patients with DR1-mediated autoimmunity to CII.

Generation of glycosylated remnant epitopes from human collagen type II by gelatinase B.

Gelatinase B/matrix metalloproteinase-9 (MMP-9) is an inflammatory mediator and effector. Considerable amounts of gelatinase B are released by neutrophils in the synovial cavity of patients with rheumatoid arthritis, and gelatinase B-deficient mice are resistant against antibody-induced arthritis. Native human collagen type II is susceptible to cleavage by various collagenases (MMP-1, MMP-8, and MMP-13), which cleave at a single position in the triple helix. Although the triple-helical structure may persist after this single cleavage, we show that gelatinase B degrades the resulting fragments into small remnant peptides. These were identified by mass spectrometry and Edman degradation. Localization of 31 cleavage sites shows that the immunodominant epitopes remain intact after cleavage and may become available, processed as antigens and presented in MHC-II molecules. Furthermore, most post-translational modifications were identified on the fragments, including nine glycosylation sites. In particular, it is shown for the first time by structural analysis that in natural human collagen II, lysines in the main immunodominant epitope are modified by partial hydroxylation and partial glycosylation. Determination of T-cell reactivity against such fragments indicates that, besides the two known main immunodominant epitopes, other glyco-epitopes may be present in collagen II. This reinforces the role of glycopeptide antigens in autoimmunity.

The roles of interleukin-18 in collagen-induced arthritis in the BB rat.

Interleukin (IL)-18 is a member of the IL-1 cytokine family. Its expression is increased in rheumatoid arthritis synovium, and its proinflammatory effects have been demonstrated in experimental models of murine arthritis. Here, we investigate the actions of varying doses of recombinant rat IL-18 (rIL-18) on the course of type II collagen-induced arthritis (CIA) in BB rats, including clinical and immune events, plus splenic cytokine production. Small doses of rIL-18 (10 and 50 microg/rat) administered intraperitoneally (i.p.) increased arthritis incidence and severity (P < 0.01) when a low-potency CII preparation was used for immunization. IgG1 and IgG2a anti-CII antibody levels were significantly greater in rats given 10 and 50 microg rIL-18 doses than controls. rIL-18 significantly increased levels of proinflammatory cytokines [interferon (IFN)-gamma, IL-2, tumour necrosis factor (TNF)-alpha and IL-6] produced by splenocyte cultures. Larger doses of rIL-18 (300 microg/rat) suppressed arthritis and immunity. To ascertain whether the pro-arthritic effects of IL-18 could be attenuated, rats were treated with neutralizing rabbit anti-rIL-18 IgG before immunization with a high-potency CII preparation. When given serially for 3 weeks, the incidence and severity of CIA, in addition to anti-CII IgG2a and splenic IL-6 and IFN-gamma production, were all significantly reduced. Similar results were noted when antibody was given twice, just before arthritis onset. These results demonstrate that IL-18 plays an important proinflammatory role in the pathogenesis of CIA which is achieved, in part, by an immunostimulatory action. Neutralizing endogenous IL-18 with antibodies attenuated CIA, CII immunity and cytokine responses. These studies support the use of IL-18 antagonists as treatments for inflammatory arthritis.

Immunogenicity of recombinant type IX collagen in murine collagen-induced arthritis.

OBJECTIVE: Past attempts to isolate type IX collagen (CIX) from cartilage using limited proteolysis yielded partially degraded material. Recent application of recombinant technology, however, has allowed the preparation of intact native CIX. We used the murine collagen-induced arthritis model to characterize the immunologic properties of recombinant human CIX (rCIX) produced using a baculovirus expression system. METHODS: A panel of B10 congenic mice was immunized with rCIX emulsified with Freund's complete adjuvant (CFA). The ability of the rCIX to induce tolerance and suppress arthritis was determined by administration intravenously or orally before challenge with CII/CFA. RESULTS: None of the mice immunized with rCIX developed overt arthritis, although 2 of 5 HLA-DR1 transgenic mice developed limited digital erythema and swelling. Recombinant CIX administered by either route effectively induced suppression of arthritis, although the suppression was less pronounced than that induced with CII. Immune responses to CIX and CII were specific, suggesting that bystander suppression, rather than cross-reactivity with CII, was instrumental in suppressing arthritis. CONCLUSION: These data show that CIX down-regulates arthritis in mice while having no associated risk of inducing arthritis.

The role of IL-4 in regulation of murine collagen-induced arthritis.

Collagen-induced arthritis (CIA) is a murine model of autoimmune-mediated polyarthritis. CIA can be prevented by the administration (intravenously) of CII, inducing regulatory CD4+ T cells which produce Th2 cytokines. However, the relative importance of IL-4 in suppressing arthritis remains unclear. To address this question, a neutralizing monoclonal antibody to IL-4 was given to mice treated with tolerized, CII-specific cells. The antibody significantly reversed the expected suppression of arthritis. Moreover, CII administered intravenously to DBA/1 IL4-/- mice (developed by backcrossing C57B1/6 IL4-/- to wild-type DBA/1 mice) was completely ineffective in suppressing disease. These data support the importance of IL-4 in the regulation of autoimmune arthritis. Compensatory increases in mRNA message for other Th2 cytokines were observed, but they did not restore suppression of arthritis. Antibodies to CII, mostly IgG2a, were increased in IL4-/- mice. These studies represent a unique opportunity to analyze the role of IL-4 and its absence on an autoimmune murine model of arthritis.

Implications for the role of endogenous nitric oxide inhibitors in hemodialysis hypotension.

Hypotensive episodes during hemodialysis in patients with end-stage renal disease in the absence of inadequate maintenance of the plasma volume, pre-existence of cardiovascular disease, or autonomic nervous system dysfunction is accompanied by increase in the plasma concentrations of the end-products of nitric oxide metabolism, above the levels expected based on the reduction of urea. Factors that can influence the synthesis of nitric oxide or the regulation of the effects of this free radical in patients with chronic renal failure are reviewed. Convergence of these factors and their interactions during the hemodialysis procedure are discussed as the basis for the generation of excessive amounts of nitric oxide that serves as an important contributing factor in the development of symptomatic hypotension.

Anti-Human type II collagen CD19+ B cells are present in patients with rheumatoid arthritis and healthy individuals.

OBJECTIVE: To determine the frequency and repertoire of CD19+ B cells capable of producing antibodies reactive to type II collagen (CII) in synovial fluid (SF) and peripheral blood (PB) of patients with rheumatoid arthritis (RA) and PB of healthy control individuals. METHODS: CD19+ B cells were isolated and activated to secrete immunoglobulins (Ig) by CD4+ T cells. Frequencies of anti-CII B cells were determined by limiting dilution analysis. The isotype and cross-reactivity of the antibodies produced were determined by ELISA. RESULTS: SF and PB from 5 patients and PB from 4 healthy controls were analyzed. Anti-CII CD19+ B cells were identified in all samples tested. In the RA SF, the percentage of activated B cells reactive to human CII was significantly higher than in the PB of patients with RA (p < 0.05) or controls (p < 0.01). A majority of anti-human CII B cells from patients' SF secreted IgG isotype, whereas most anti-human CII B cells in PB of patients and controls secreted IgM. The anti-CII B cells, regardless of source, are usually reactive to both native and denatured human CII, to different types of human collagens, and to type II collagens from different species. CONCLUSION: Anti-CII CD19+ B cells responsive to activated helper T cells are present in both patients with RA and healthy individuals. However, these B cells, especially those secreting the IgG isotype, accumulate in the inflamed joints of RA patients.

Juvenile arthritis and autoimmunity to type II collagen.

OBJECTIVE: Joint inflammation in juvenile rheumatoid arthritis (JRA) is sometimes associated with an autoimmune response to type II collagen (CII), a cartilage-specific protein. To test the hypothesis that down-regulation of autoimmunity to CII can be accomplished in JRA by oral administration of CII, an open-label study of CII was performed in 9 patients with JRA. METHODS: Seven rheumatoid factor-negative JRA patients with polyarticular disease and 2 JRA patients with pauciarticular disease (1 with early onset and 1 with late onset) were treated for 3 months with oral bovine CII. Patients were examined for disease activity and underwent routine laboratory testing at monthly intervals. Two of the patients had flares of disease when treatment was discontinued, and these patients were re-treated for an additional 3 months. To test the hypothesis that oral tolerance induces an immune deviation of T cells, peripheral blood mononuclear cells from patients were collected before and after treatment and cultured with CII. Supernatants and RNA were collected and analyzed for the presence of various cytokines. RESULTS: Eight patient trials met the criteria for clinical improvement outlined by Giannini and coworkers in 1997. None of the patients had any side effects from the treatment. In 6 of the 8 patients who improved, interferon-gamma production decreased after oral CII therapy, correlating with clinical improvement, while 6 patients had increases in levels of transforming growth factor beta3. CONCLUSION: These results are encouraging. The possible beneficial effect of oral CII in JRA merits further investigation.

Induction of immune tolerance to human type I collagen in patients with systemic sclerosis by oral administration of bovine type I collagen.

OBJECTIVE: To determine whether oral tolerance to type I collagen (CI) could be induced in patients with systemic sclerosis (SSc). METHODS: Twenty adult patients with limited or diffuse SSc were enrolled in a study to receive 0.1 mg of solubilized native bovine CI daily for 1 month, followed by 0.5 mg daily for 11 months. Peripheral blood mononuclear cells (PBMC) were obtained from the patients and cultured with human alpha1(I) and alpha2(I) chains, before and after CI treatment. Culture supernatants were analyzed for levels of interferon-gamma (IFNgamma) and interleukin-10 (IL-10). Sera obtained before and after treatment were analyzed for levels of soluble IL-2 receptor (sIL-2R). Although this study was not intended to assess the clinical efficacy of oral CI administration in SSc, selected measures of disease severity and organ involvement were evaluated. RESULTS: Oral administration of CI to SSc patients induced significant reductions in levels of IFNgamma and IL-10 in alpha1(I)- and alpha2(I)-stimulated PBMC culture supernatants, indicating that T cell immunity to CI was decreased by this treatment. Serum levels of sIL-2R also decreased significantly after oral CI treatment, suggesting a reduction in T cell activation. Significant improvements occurred in the modified Rodnan skin thickness score and the modified Health Assessment Questionnaire after 12 months of oral CI in this open trial. The lung carbon monoxide diffusing capacity improved statistically and showed a trend toward clinically significant improvement. CONCLUSION: Oral administration of bovine CI to patients with diffuse or limited SSc induces a reduction in T cell reactivity to human CI, appears to be well tolerated, and does not worsen the disease. Further evaluation of oral tolerance to CI in patients with SSc is justified to determine whether it has therapeutic efficacy.

Accumulation of T cells reactive to type II collagen in synovial fluid of patients with rheumatoid arthritis.

OBJECTIVE: To determine if type II collagen (CII) reactive T lymphocytes selectively accumulate in the inflamed joint of patients with rheumatoid arthritis (RA) and to study the specificity of the CII reactive cells. METHODS: Synovial fluid (SF) cells or peripheral blood lymphocytes were cultured with interleukin 2 (IL-2) for 24 h and then cultured at limiting dilution concentrations in the presence of filler cells and IL-2. The outgrowing cell lines were screened for their responses to CII. The percentages of the CII reactive T cells from SF were compared with those from peripheral blood of patients with RA. The CII reactive T cell lines were tested for their responses to different types of collagen. RESULTS: CII reactive T cell lines were identified in the SF of 3 RA patients; the frequencies were 5.0% (11/219), 3.7% (5/134), and 3.5% (3/86), respectively. In contrast, none of CII-specific T cell lines were identified in peripheral blood of the patients. The T cell lines recognized both human and bovine CII and, to a lesser extent, type I collagen. CONCLUSION: CII reactive T cells are present in high frequency in the inflamed joint of patients with RA, where they may play an important role in the pathogenesis of RA.

Immunogenicity and arthritogenicity of recombinant CB10 in B10.RIII mice.

Two major T cell determinants are recognized by I-Ar-specific T cells in CII, the immunodominant CII610-618 (GPAGT AGA R) within CB10 and the subdominant CII445-453 (GPAGP AGE R) within CB8. Although the determinants differ by only two residues, CB8 is capable of inducing collagen-induced arthritis (CIA), while CB10 is not. We, therefore, investigated the structural differences between the two determinants that are critical to inducing arthritis. When the CB10 determinant was mutated to that of CB8 using recombinant techniques, the resulting mutant rCB10T614P,A617E product became arthritogenic. Conversely, when the CB8 determinant was mutated to that of CB10, the resulting mutant CB8P449T,E452A was no longer arthritogenic. Comparison of the epitope specificity of the autoantibodies induced by wild-type CB10 and mutant rCB10T614P, A617E revealed no qualitative differences. T cells from mice immunized with either CB10 or mutant rCB10 produced predominantly Th1 cytokines when cultured with the immunizing Ag. In contrast, when cultured with mouse CII, T cells from mice immunized with the nonarthritogenic CB10 produced predominantly Th2 (IL-4 and IL-10) cytokines whereas the arthritogenic mutant rCB10 induced predominantly Th1 (IFN-gamma) cytokines. We conclude that the T cell cytokine response most critical for the induction of CIA is that induced against the corresponding homologous murine T cell determinant and, further, that the structural differences between the T cell determinants in CB8 and -10 are important in breaking self tolerance and inducing autoimmune response.

The genetic ablation of cyclooxygenase 2 prevents the development of autoimmune arthritis.

OBJECTIVE: To determine the effects of cyclooxygenase 1 (COX-1) and COX-2 gene deletion on collagen-induced arthritis (CIA). METHODS: Mice that were susceptible to CIA but lacked either the COX-1 or the COX-2 gene were immunized with type II collagen (CII), and the incidence and severity of arthritis were compared with findings in wild-type animals, by clinical and histologic examination. The immune response was assessed by measuring total CII IgG, IgG1, and IgG2 antibody production in sera from immunized mice. The passive transfer of arthritis, accomplished using anti-CII monoclonal antibodies, was tested in wild-type and COX-deficient (-/-) mice. Splenocytes cultured from CII-immunized wild-type and COX-/- mice were challenged with bovine alpha1(II), and cytokine production was assessed. RESULTS: COX-2 gene deletion reduced the incidence and severity of CIA compared with findings in wild-type and COX-1-/- mice. Histologic examination of joints after the onset of clinical arthritis revealed cartilage erosions, proliferation of the synovial lining, and inflammatory cell infiltration in wild-type and COX-1-/- mice, but not in COX-2-/- mice. COX-2-/- mice exhibited reduced anti-CII IgG antibody levels, indicating a decreased immune response. However, cytokine production by spleen cells from immunized mice indicated no cytokine deficiencies in COX-2-/- mice compared with wild-type or COX-1-/- mice. More important, arthritis could not be passively transferred to naive COX-2-/- mice, indicating a requirement for COX-2 in the pathogenesis of arthritis, independent of the immune response. CONCLUSION: COX-2-/- mice exhibit at least 2 defects resulting in down-modulation of the development of CIA: a reduced immune response to CII demonstrated by a markedly reduced antibody titer, and an "inflammatory" defect reflected by the inability to passively transfer arthritis to COX-2-/- mice.

Molecular definition and characterization of recombinant bovine CB8 and CB10: immunogenicity and arthritogenicity.

Theoretically, the ability to produce recombinant type II collagen (CII) peptide fragments in a prokaryotic expression system would be extremely useful for preparing adequate amounts of CII peptides suitable for therapeutic uses. Bacteria do not contain the enzymes involved in the extensive posttranslational modifications that occur during the biosynthesis of CII, such as the hydroxylation of prolyl and lysyl residues and glycosylation of hydroxylysyl residues. As these posttranslational modifications may play a role in the immune and arthritogenic response to CII, it was unclear whether collagen expressed in Escherichia coli would be immunologically comparable to tissue-derived CII. Therefore, we prepared recombinant proteins for CB8 and CB10 by cloning CB8 (CII 403-551) and CB10 (CII 552-897) genes from bovine chondrocytes by RT-PCR technique and expressing them in an E. coli expression system. Characterization of these recombinant proteins revealed that both rCB8 and rCB10 stimulated T cell proliferation in a T cell determinant-specific manner. The T cells from mice immunized with rCB8 respond specifically to a synthetic peptide, CII 445-453, the CB8 T cell determinant. Conversely, rCB10-primed T cells respond strongly to CII 610-618, the CB10 T cell determinant. Recombinant CB8-induced autoantibodies that bound to mouse CB8 as effectively and in the same topographic distribution as tissue-derived CB8. Finally, when rCB8 and rCB10 proteins were used to immunize B10.RIII (H-2(r)) mice, rCB8 induced arthritis in 33% of the mice, very similar to the incidence induced by tissue-derived CB8 peptide. As was found to be the case with tissue-derived CB10, rCB10 was completely ineffective in inducing arthritis. Pathological changes of arthritic joints in the mice immunized with rCB8 were similar to those observed in mice immunized with tissue-derived CB8. Thus, these recombinant CII peptides expressed in E. coli can induce an effective immunologic response and suggest that functionally useful CII peptides can be generated by the prokaryotic expression system.

Intravenous tolerization with type II collagen induces interleukin-4-and interleukin-10-producing CD4+ T cells.

Intravenous (i.v.) administration of type II collagen (CII) is an effective way to induce tolerance and suppress disease in the collagen-induced arthritis (CIA) model. In this study, we demonstrated that a single i.v. dose of CII (as low as 0.1 mg/mouse) completely prevented the development of CIA. This suppression was accompanied by decreases in levels of antibody specific for the immunogen, bovine CII and autoantigen, mouse CII. Splenocytes obtained from CII-tolerized mice and stimulated with CII in vitro produced predominantly the T helper 2 (Th2)-type cytokines interleukin-4 (IL-4) and interleukin-10 (IL-10). In contrast, cells obtained from mice immunized with CII produced predominantly interferon-gamma (IFN-gamma). Two-colour flow cytometric analysis of cytokine expression and T-cell phenotype demonstrated that CD4+ cells and not CD8+ or gammadelta+ cells were the predominant regulatory cells producing IL-4 and IL-10. Transgenic mice bearing a T-cell receptor (TCR) specific for CII had a greater increase in the number of IL-4-secreting CD4+ cells, as well as a marked increase of IL-4 in culture supernatants. This cytokine was produced by transgene-bearing T cells. Elucidation of mechanisms for the induction of tolerance in mature T cells is an important line of study in autoimmune models because of the potential application for treating organ-specific autoimmune disease.

Herpes simplex hepatitis in pregnancy: a case report and review of the literature.

Fulminant hepatic dysfunction in the third trimester of pregnancy accompanied by fever may result from disseminated herpes simplex virus. Since 1969, 24 cases of herpes simplex hepatitis, including the current case, have been reported. Mucocutaneous lesions are present in only half of cases; therefore, suspicion for diagnosis of this disease is low. Twenty-five percent of cases were not diagnosed until autopsy. Maternal and perinatal mortality are high, approaching 39 percent for both mother and fetus. Early recognition with initiation of antiviral therapy appears to be most important in maximizing survival.

Lack of efficacy of oral bovine type II collagen added to existing therapy in rheumatoid arthritis.

OBJECTIVE: To investigate the efficacy of oral type II collagen (CII) in the treatment of rheumatoid arthritis (RA), when added to existing therapy. METHODS: Patients with active RA (n = 190) were randomized into a 6-month, double-blind, placebo-controlled trial. Patients continued to take their current arthritis medications. Patients received either placebo or bovine CII, 0.1 mg/day for 1 month, then 0.5 mg/day for 5 months. RESULTS: There were no significant differences between the baseline characteristics of either group. The primary response parameter was the American College of Rheumatology (ACR) preliminary definition of improvement in RA (ACR 20). There was no statistically significant difference in the ACR 20 after 6 months (20.0% of placebo patients; 16.84% of bovine CII patients). There were significant differences in several clinical variables after treatment, all favoring the placebo group. CONCLUSION: Oral solubilized bovine CII, added to existing therapy, did not improve disease activity in patients with RA.

The clinical significance of intermittent sinusoidal fetal heart rate.

Sinusoidal fetal heart rate may have a spectrum of occurrence that indicates degree of fetal morbidity. Twelve cases of intermittent sinusoidal fetal heart rate were reviewed for fetal outcome. Findings of anemia, low umbilical cord pH, and large base excess support that intermittent sinusoidal fetal heart rate may be an early indicator of impending fetal compromise.