Direct comparison of optical lattice clocks with an intercontinental baseline of 9000 km.

We have demonstrated a direct frequency comparison between two 87Sr lattice clocks operated in intercontinentally separated laboratories in real time. Two-way satellite time and frequency transfer technique, based on the carrier-phase, was employed for a direct comparison, with a baseline of 9000 km between Japan and Germany. A frequency comparison was achieved for 83,640 s, resulting in a fractional difference of (1.1±1.6)×10⁻¹5, where the statistical part is the largest contributor to the uncertainty. This measurement directly confirms the agreement of the two optical frequency standards on an intercontinental scale.

Epstein-Barr virus load for early detection of lymphoproliferative disorder in pediatric renal transplant recipients.

AIM: The aims of this study were to establish a protocol for monitoring Epstein-Barr virus (EBV) infection for identification of pediatric renal transplant recipients with a high risk of developing posttransplant lymphoproliferative disorder (PTLD) and to predict the development of PTLD. SUBJECTS AND METHODS: Peripheral blood mononuclear cells (PBMCs) and plasma EBV loads were measured by nested PCR (n-PCR) and real-time PCR (r-PCR) every 1 - 3 months after grafting in 17 pediatric recipients who were seronegative for EBV before grafting (4 with EBV-associated symptoms, including 2 with PTLD (Group A); 6 with asymptomatic persistent high EBV loads in PBMCs of > 1,000 copies/µgDNA for over 6 months (Group B); and 7 with neither EBV-associated symptoms nor persistent high EBV loads in PBMCs (Group C)). RESULTS: n-PCR revealed EBV-DNA in PBMCs from all patients. The EBV genome was present in plasma in 3 (75%), 1 (17%), and 0 (0%) in Groups A, B and C (p < 0.01 for A vs. B and A vs. C). EBV loads detected by r-PCR in PBMCs were significantly higher in Groups A (p < 0.05) and B (p < 0.01) compared to Group C. EBV genomes in plasma were detected by n- and r-PCR in only the 2 cases with PTLD. One patient with lymphadenitis in Group A and 1 patient in Group B had EBV-DNA in plasma based on n-PCR, but the viral loads using r-PCR were < 250 copies/ml. CONCLUSION: EBV loads in PBMCs alone are insufficient for predicting EBV-associated symptoms including PTLD. Plasma EBV loads (over 250 copies/ml) estimated by r-PCR may be useful to distinguish PTLD from other EBV-associated diseases or asymptomatic viremia.

Four cases of postrenal renal failure induced by renal stone associated with rotavirus infection.

Rotavirus (RV) is a common pathogen that causes acute gastroenteritis in childhood. Some cases with RV infection also have prerenal renal failure induced by dehydration associated with vomiting and diarrhea. Here, we report 4 patients with RV infection who developed postrenal renal failure induced by urinary tract obstruction with uroammoniac calculi or crystals. The patients did not have metabolic disorders or abnormalities of the urinary tract, and increased urinary excretion of uric acid was not recognized at discharge. In addition, no abnormalities in the uric acid transporter (URAT1) were found in any of the patients. Uric acid stone formation was considered to have originated from the low pH caused by dehydration and the increase of urinary uric acid excretion from damaged cells.

Association between maternal active smoking during pregnancy and placental weight: The Japan environment and Children's study.

INTRODUCTION: Maternal smoking during pregnancy is a well-known risk factor for reduced birthweight. However, research investigating the association between maternal smoking and placental weight is scarce and inconsistent. Our study was conducted to evaluate the association between maternal smoking and placental weight and placental weight/birthweight ratio (PW/BW ratio). METHODS: We used data from a birth cohort study, the Japan Environment and Children's Study (JECS). Main outcome measures were placental weight, PW/BW ratio, and the risk of high PW/BW ratio. High PW/BW ratio was defined as PW/BW ratio above the 90th percentile for gestational age and sex of offspring. The association between maternal smoking and placental weight was estimated as crude and as adjusted beta coefficients by applying linear regression analyses. Logistic regression analyses were also performed to estimate the association between maternal smoking and the risk of high PW/BW ratio. RESULTS: Of the 91,951 pregnant women, the mean placental weight and the mean PW/BW ratio were lowest for the group of women who had never smoked. Smokers had higher odds ratio for high PW/BW ratio compared with non-smokers. Furthermore, among smokers, the mean placental weight and mean PW/BW ratio were lowest in women who smoked less than 5 daily cigarettes, and highest in women who smoked 20 or more daily cigarettes during pregnancy. DISCUSSION: Placental weight was greater and PW/BW ratio was higher among smokers compared with non-smokers. Moreover, the number of daily cigarettes was positively associated with heavy placental weight.

Effect of oral mizoribine pulse therapy for frequently relapsing steroid-dependent nephrotic syndrome.

AIM: To evaluate the efficacy of oral mizoribine (MZB) pulse therapy given twice a week for frequently relapsing steroid-dependent nephrotic syndrome (FR-SDNS). SUBJECTS: 16 patients with FR-SDNS with a median age of 11.6 years (range 5.1 â 17.8 years) were enrolled in the study. This study was a Phase II trial. METHODS: The dose of MZB was adjusted to achieve a peak blood level of about 3 microg/ml (10.0-19.7 mg/kg/d, maximum total dose 750 mg) in two divided doses given 2 days a week before a meal. The therapeutic benefits of MZB pulse therapy were assessed based on a comparison of the incidence of relapse (times/year) and the required daily dosage of prednisolone (PSL) before and after therapy. RESULTS: The incidence of relapse after therapy was significantly lower than that before therapy (2.4 A+/- 1.6 vs. 3.4 A+/- 1.1 times/year, p < 0.05), and the required daily dosage of PSL after therapy was lower than that before therapy (0.39 A+/- 0.26 vs. 0.47 A+/- 0.24 mg/kg/d; not significant). During the follow-up period, discontinuation of PSL was possible in 6 of 12 patients who showed a decreased rate of relapse after therapy. The age at entry into the study and the peak blood concentration of MZB of these patients were significantly higher than in four patients who did not show a decreased rate of relapse (12.3 A+/- 4.3 vs. 7.9 A+/- 2.6 years, p < 0.05; 3.00 A+/- 0.93 vs. 1.97 A+/- 0.36 microg/ml, p < 0.005, respectively). No adverse effects were observed in any patients. CONCLUSION: Our results show that MZB pulse therapy is effective in decreasing the frequency of relapse and reducing the required PSL dosage in older pediatric patients with FR-SDNS.

Monitoring of Epstein-Barr virus load and killer T cells in pediatric renal transplant recipients.

AIM: The aim of this study is to establish a monitoring method to prevent Epstein-Barr virus (EBV)-associated symptoms including post-transplant lymphoproliferative disorder (PTLD) that occur after pediatric renal transplantation. SUBJECTS AND METHODS: Circulating EBV loads were quantified by real-time PCR every 1 - 3 months after grafting in 22 pediatric recipients (13 EBV-seronegative [R(-)] and 9 EBV-seropositive [R(+)] recipients before grafting). The peripheral blood cell populations of non-specific activated killer cells (CD8+HLA-DR+ phenotype) in 13 R(-) recipients and EBV-specific cytotoxic T cells (CTLs) reactive with a tetramer expressing HLA-A24-restricted EBV-specific antigens in 8 of 13 R(-) recipients were determined by flow cytometry. RESULTS: EBV-associated symptoms including PTLD (2 cases) were found in 4 R(-) and none of the R(+) recipients. The maximum of EBV load in the R(-) group was significantly higher that in the R(+) group. In R(-) recipients, 4 symptomatic cases had significantly more EBV genome than asymptomatic cases. EBV-specific CTLs were detected in 6 of the 8 R(-) recipients, but these CTLs could not be detected in 1 of the 2 cases at onset of PTLD. The percentage of CD8+HLA-DR+ cells was significantly higher in asymptomatic recipients than in recipients with EBV-associated symptoms whose EBV loads were over 400 copies/microg DNA. CONCLUSION: Monitoring of killer T cells and EBV loads may allow assessment of the risk of EBV-associated symptoms, and high EBV loads and low EBV-specific and/or non-specific CTL responses may be predictive for development of EBV-associated symptoms such as PTLD.

A potential role of activated NF-kappa B in the pathogenesis of euthyroid sick syndrome.

Euthyroid sick syndrome, characterized by low serum 3,5, 3'-triiodothyronine (T(3)) with normal L-thyroxine levels, is associated with a wide variety of disorders including sepsis, malignancy, and AIDS. The degree of low T(3) in circulation has been shown to correlate with the severity of the underlying disorders and with the prognosis. Elevated TNF-alpha levels, which accompany severe illness, are associated with decreased activity of type I 5'-deiodinase (5'-DI) in liver, leading us to speculate that high levels of this factor contribute to euthyroid sick syndrome. Here we demonstrate that the activation of NF-kappa B by TNF-alpha interferes with thyroid-hormone action as demonstrated by impairment of T(3)-dependent induction of 5'-DI gene expression in HepG2 cells. Inhibition of NF-kappa B action by a dominant-negative NF-kappa B reversed this effect and allowed T(3) induction of 5'-DI. Furthermore, we show that an inhibitor of NF-kappa B activation, clarithromycin (CAM), can inhibit TNF-alpha-induced activation of NF-kappa B and restore T(3)-dependent induction of 5'-DI mRNA and enzyme activity. These results suggest that NF-kappa B activation by TNF-alpha is involved in the pathogenesis of euthyroid sick syndrome and that CAM could help prevent a decrease in serum T(3) levels and thus ameliorate euthyroid sick syndrome.

Renal complications in two patients with dentatorubral-pallidoluysian atrophy.

Dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenerative disorder characterized by various combinations of myoclonus epilepsy, ataxia, choreoathetosis and dementia. No specific therapy has been established and renal complication is rare. We report two cases of DRPLA with renal complications. Hematuria and proteinuria had gradually progressed for 2 and 13 years in these patients. Renal biopsy findings revealed focal glomerulosclerosis in one case and end-stage kidney disease in the other case. Angiotensin-converting enzyme inhibitor and angiotensin receptor II antagonist were administered to both patients, resulting in improved proteinuria and preserved renal function in one patient, while renal function continued to deteriorate in the other patient. Although renal complication is rare in patients with DRPLA, the presence of renal disease has to be suspected in patients with persistent proteinuria.

Analysis of MPO-ANCA subtypes in a patient with propylthiouracil-induced vasculitis with multiple complications.

BACKGROUND: We report a 16 year-old girl with propylthiouracil (PTU)-induced antineutrophil cytoplasmic antibody (ANCA)-positive glomerulonephritis combined with Henoch-Schönlein purpura nephritis (HSPN) and antiphospholipid syndrome (APS). CASE AND METHODS: The patient had Graves' disease and had been treated with PTU for about 6 years. She complained of arthralgia, epigastralgia, purpura of the lower extremities, anemia, and abnormal urinalysis. Lupus anticoagulant was positive. Additionally, a high level of anti-myeloperoxidase (MPO) antibodies (IgG) and a low level of coagulation factor XIII were recognized. She had several complications including lung bleeding, lacuna infarctions of the right frontal and parietal brain lobes, and deep vein thrombosis of the left lower extremity. We studied tissue histology and carried out MPO-ANCA subtype analysis by immunofluorescence and flow cytometry and MPO-ANCA epitope analysis. RESULTS: Histologically, purpura showed leukocytoclastic vasculitis with perivascular depositions of IgA and complement C3. Renal biopsy showed necrotizing glomerulonephritis with crescents and mesangial IgA deposits. Notably, IgG, IgM, and IgA ANCA were detected in the patient's serum by flow cytometry and immunofluorescence. We diagnosed an overlap syndrome of ANCA-positive vasculitis, HSPN, and APS. A change in the reactivity of MPO-ANCA from recognition of only the Hg epitope in the C-terminal region to recognition of multiple MPO epitopes was accompanied by a remission of symptoms. CONCLUSIONS: This report may provide a very rare description of an overlap syndrome of PTU-induced ANCA vasculitis, HSPN, and APS in which not only IgG ANCA but also IgA and IgM ANCA were found. Epitope analysis may be a useful marker for disease-monitoring of PTU-induced ANCA-positive vasculitis. This case may provide insight into the pathological mechanism underlying each of these diseases.

Epitope analysis of myeloperoxidase-specific antineutrophil cytoplasmic autoantibodies (MPO-ANCA) in childhood onset Graves' disease treated with propylthiouracil.

AIM: This study aimed to elucidate the relationship between epitope profiles and clinical manifestations of patients with myeloperoxidase antineutrophil cytoplasmic autoantibodies-(MPO-ANCA) positive childhood onset Graves' disease treated with propylthiouracil (PTU). METHODS: Sixteen patients were studied. The patients were grouped into ten without clinical vasculitis and nephritis (non-vasculitis group) and six with biopsy-proven pauci-immune necrotizing crescentic glomerulonephritis (vasculitis group). Epitope analysis was performed on serum samples by an enzyme-linked immunosorbent assay (ELISA) using a panel of recombinant deletion mutants of MPO. RESULTS: The high frequency sites were region upstream of Met341 (Ha region) near the N-terminus of the heavy chain, and regions downstream of Gly598 (Hf and Hg regions) near the C-terminus. Most patients in the non-vasculitis group had polyclonal MPO-ANCA recognizing both the above linear sites and other epitope sites of the heavy chain of MPO. Only one of ten patients in the non-vasculitis group, and four of six patients in the vasculitis group had MPO-ANCA recognizing only the linear sites of the heavy chain of the MPO molecule (Ha, Hf and/or Hg). Of the four patients in the vasculitis group, two had nephritis, like rapidly progressive glomerulonephritis and one had alveolar hemorrhage. CONCLUSION: These findings suggest that most patients with childhood onset Graves' disease treated with PTU who manifest no vasculitis have polyclonal MPO-ANCA recognizing both the linear and other epitope sites of the heavy chain of MPO. However, some patients who develop nephritis have MPO-ANCA recognizing only the linear sites of the heavy chain of MPO. This clonality of MPO-ANCA may be a risk factor that induces clinical vasculitis and nephritis in patients treated with PTU. Therefore, patients exposed to PTU should be monitored for MPO-ANCA level and epitopes.

Effect of thyroid hormone on epidermal growth factor gene expression in mouse submandibular gland.

Epidermal growth factor (EGF) in mouse submandibular gland (SMG) is synthesized in the granular convoluted tubular (GCT) cells. The synthesis of EGF in SMG has been shown to be increased by thyroid hormone. This increase was attributed to the increase in EGF mRNA. Not known is how thyroid hormone increases the mRNA level. In the present study the effect of thyroid hormone administration on EGF gene expression in SMG was studied in hypothyroid mice. Hypothyroidism was induced by treating the mice with propylthiouracil. The amount of SMG EGF mRNA was markedly decreased in hypothyroid mice. Administration of T3 increased the mRNA in a dose-dependent manner. The increase in EGF mRNA by T3 was evident as early as 6 h after T3 administration. A nuclear run-off assay indicated that the induction of EGF gene expression by T3 is at a transcriptional level. Bromodeoxyuridine incorporation into GCT cells was not affected by T3 administration, suggesting that T3 does not cause the proliferation of these cells. In situ hybridization revealed that T3 increases EGF mRNA in GCT cells at a single cell level. These results suggest that thyroid hormone increases EGF gene transcription without affecting cellular proliferation.

High prevalence of antineutrophil cytoplasmic antibody positivity in childhood onset Graves' disease treated with propylthiouracil.

Propylthiouracil (PTU)-induced antineutrophil cytoplasmic antibody (ANCA)-related vasculitis and nephritis were recently reported in about 30 patients with hyperthyroidism. The objective of this study was to clarify the prevalence of ANCA and the relationship between ANCA and thyroid antibodies in children with Graves' disease. Titers of myeloperoxidase (MPO)-ANCA in sera of 51 patients with childhood onset Graves' disease (16 before treatment, 25 and 10 treated with PTU and methimazole, respectively) were measured by enzyme-linked immunosolvent assay. Antithyroglobulin antibodies (TGAbs) and antithyroperoxidase antibodies (TPOAbs) were also measured by RIA in 25 PTU-treated patients. No patients had clinical manifestations of vasculitis and nephritis. MPO-ANCA was positive in 6.7% of patients before treatment and in 64.0% of those treated with PTU and in none of those treated with methimazole. MPO-ANCA had a significantly positive correlation with TGAbs (P < 0.05) and no significant correlation with TPOAbs. These findings show the high prevalence of the MPO-ANCA positivity in PTU-treated childhood onset Graves' disease, suggesting that PTU may not be preferred as the first line for the treatment of children with Graves' disease. The significant correlation between MPO-ANCA and TGAbs indicates that the severity of Graves' disease may be a factor responsible for the MPO-ANCA positivity. The cross-reactivity between MPO-ANCA and TPOAbs may not play a role in the high prevalence of MPO-ANCA in the patients exposed to PTU.

Phorbol ester-induced production of prostaglandin E2 from phosphatidylcholine through the activation of phospholipase D in UMR-106 cells.

To determine the effects of 12-O-tetradecanoylphorbol-13-acetate (TPA) on phospholipase D (PLD) activity in osteoblast-like UMR-106 cells, we used cells prelabeled with [3H] myristic acid or [3H] arachidonic acid, which were preferentially incorporated to phosphatidylcholine. The treatment of [3H] myristate-labeled cells with TPA in the presence of 1% ethanol caused a dose-dependent formation of [3H] phosphatidylethanol (PEt), a product specific to PLD, suggesting an activation of this enzyme. Pretreatment of the cells with protein kinase C (PKC) inhibitors (GF109203X, staurosporine or H-7) abolished the TPA-dependent formation of PEt. The PEt formation in response to TPA treatment was not observed after the pretreatment of the cells with TPA to downregulate PKC. These results suggest the involvement of PKC in the TPA-induced activation of PLD. With [3H] arachidonate-labeled cells, TPA treatment in the absence of ethanol resulted in the liberation of [3H] arachidonic acid, which was gradually converted to prostaglandin E2 (PGE2), but the accumulations of [3H] phosphatidic acid (PA) and [3H] diacylglycerol (DAG) were very small and temporary. In contrast, PA was linearly accumulated following TPA treatment, when the cells were pretreated with an inhibitor of phosphatidate phosphohydrolase (PAP), propranolol, with no accumulation of either DAG or arachidonic acid. The TPA treatment of the cells pretreated with a DAG lipase inhibitor, RHC-80267, caused the generation of DAG after a lag period of approximately 5 min, with a very small and temporary accumulation of PA. The TPA treatment of cells pretreated with a cyclooxygenase (COX) inhibitor, indomethacin, blocked the PGE2 production. The TPA-induced PGE2 production was not affected by the pretreatment of cells with a phospholipase A2 inhibitor, p-bromophenacylbromide, or with a phospholipase C inhibitor, D-609. TPA also stimulated PGE2 production in osteoblastic cells that were enzymatically isolated from adult rat calvaria, and the experiments with lipid metabolizing enzyme inhibitors gave the same profile of inhibition of TPA-induced PGE2 production as was observed in UMR-106 cells. These results suggest that PA formed as a consequence of the activation of PLD by TPA is rapidly converted to arachidonic acid via a PAP/DAG lipase pathway, followed by a gradual conversion of arachidonic acid to PGE2 by COX in both UMR-106 cells and isolated adult osteoblastic cells, and that neither phospholipase A2 nor phospholipase C is involved in the TPA-induced PGE2 production. To the best of our knowledge, this is the first report that shows that the activation of PKC in osteoblastic cells leads to the production of PGE2 via a PLD/PAP/DAG lipase/COX pathway.

Lysosomal glycogen storage disease with normal acid maltase with early fatal outcome.

In a male infant who had cardiomyopathy, generalized muscle weakness and increased serum creatine kinase levels, his muscle biopsy revealed myopathic changes with tiny intracytoplasmic vacuoles containing PAS-positive material and high acid phosphatase activity, but had normal acid maltase activity biochemically. These findings were consistent with those seen in lysosomal glycogen storage disease with normal acid maltase (Danon disease). Sarcolemmal indentations commonly seen in this disease were missing, but a complement membrane attack complex, C5b-9 was positive along the surface membrane of the muscle fibers as seen in X-linked vacuolar myopathy. The patient was on a respirator and died at 27 months of age from pneumonia and hypertrophic cardiomyopathy. Lysosomal glycogen storage disease with normal acid maltase may be manifested at birth with marked skeletal and cardiac involvement leading to death in early infancy.

Slit skiascopic-guided ablation using the Nidek laser.

PURPOSE: To present the approach of using a scanning slit refractometer (the ARK 10000) in conjunction with a corneal topography system to guide customized corneal ablation. This diagnostic system is coupled with the Nidek EC-5000 system which combines scanning slit and a scanning small area ablation (1.0 mm) to perform a customized ablation. METHODS: The ARK 10000 diagnostic system which contains a scanning slit refractometer is described. Information generated from the ARK 10000 wavefront sensor and corneal topography system can be coupled to the new Nidek EC-5000 excimer laser system, which combines the larger area of scanning slit ablation with the small area (1.0 mm) ablation. RESULTS: The Nidek ARK 10000 diagnostic system captures wavefront information using a retinoscopic system which is converted into a refractive power map. This is different from other autorefraction systems in that it has four sensors at different diameters of the cornea and captures 1440 points in 0.4 seconds. This map is used in conjunction with corneal topography-captured simultaneously. This information is then combined to perform a customized ablation using the new Nidek EC-5000 system. CONCLUSIONS: The ARK 10000 diagnostic system represents a different approach to customized ablation in that it combines a corneal topography system with a wavefront system and a larger treatment area of the traditional scanning slit ablation with a new small area ablation treatment for greater efficiency.

Elevated IgA antibodies to Epstein-Barr virus in children with chronic active Epstein-Barr virus infection.

Anti-Epstein-Barr virus (EBV) antibodies were tested in 11 children with chronic active EBV infection. Anti-virus capsid antigen (VCA)-IgG antibody titers ranged from 1:640 to 1:10,240. Anti-VCA-IgM antibody was consistently positive in 5 of the 11 patients; anti-VCA-IgA antibody was consistently positive in 6 of the 10 patients; anti-early antigen (EA)-IgG antibody was consistently positive in 10 of the 11 patients and anti-EA-IgA antibody was consistently positive in 4 out of the 7 patients. Anti-EBV nuclear antigen (EBNA) antibody was not detected in two patients. Consistently positive anti-VCA-IgA- and anti-EA-IgA- antibody may be a characteristic feature of abnormal antibody responses in severe chronic active EBV-infection in childhood.

Defective killer cell activity in patients with chronic active Epstein-Barr virus infection.

Natural killer (NK) cell activity, lymphokine activated killer (LAK) activity and Epstein-Barr virus specific cytotoxic T lymphocyte (EBV-CTL) activity were examined in 10 children with chronic active EB-virus infection and an adult with persistently positive early antigen-antibody to EB-virus. NK cell activity against erythroleukemia cell line K-562 was significantly (p less than 0.005) lower in the patients (22.3 +/- 8.5%, mean +/- SD) than in normal controls (40.4 +/- 15.9%). Spontaneous cytotoxicity against an EB-virus transformed autologous lymphoblastoid cell line was 15.0 +/- 7.6% in the patients, and was comparable to spontaneous cytotoxicity activity in normal controls (11.7 +/- 4.3%). LAK activity against Raji cells was significantly (p less than 0.02) lower in the patients (14.6 +/- 11.4%) than in normal controls (29.2 +/- 15.9%). EBV-CTL activity against an EB-virus transformed autologous lymphoblastoid cell line was significantly (p less than 0.005) lower in the patients (11.8 +/- 5.5%) than in seropositive normal controls (33.7 +/- 14.7%). No regression of the lymphoblastoid cell line was observed when EBV-CTL activity of the patients was tested by regression assay. It is conceivable that defects in both EB-virus specific and nonspecific killer cell activities play important roles in the pathogenetic abnormalities which allow EB-virus infection to progress to a chronic active state.

Hyperreactivity of lymphocytes to streptolysin O and lack of plasma inhibitory factor (s) in patients with mucocutaneous lymphnode syndrome.

Lymphocyte activation by streptolysin O (SLO) and factors in the plasma which inhibit the response to SLO were examined in 19 patients with mucocutaneous lymphnode syndrome (MCLS), 54 age-matched (6 months-6 years) normal children, 41 normal children older than 6 years and 10 normal adults. In normal children younger than 6 years, the response to SLO was weak and in many cases no response was seen. On the other hand, in the patients with MCLS, the response of lymphocytes to SLO was high and comparable to the response in adults and children older than 6 years. The DNA synthesis of lymphocytes stimulated by SLO was inhibited almost completely by autologous or allogeneic plasma of many of the normal children and adults. The plasma of patients with MCLS did not inhibit, but rather enhanced the response to SLO. These results suggest that the increased response of lymphocytes to SLO and the lack of plasma inhibitory factors in patients with MCLS may be due to the immune response to the pathogen of MCLS, as yet undiscovered.