A case of primary erythermalgia, wintry hypothermia and encephalopathy.

Primary erythermalgia is a rare neuropathy characterized by attacks of burning pain and redness in the extremities in response to warm stimuli. We describe here a boy with erythermalgia whose painful attacks began in infancy. We found a novel mutation of SCN9A, which is a responsible gene for primary erythermalgia in this case. In his teens, he developed wintry hypothermia with resultant neurological dysfunction and recurrent pneumonia. During the course of pneumonia, he had transient encephalopaty with a reversible lesion in the splenium of the corpus callosum. In addition to excessive cooling, a defect in central thermoregulation may have caused hypothermia in this patient.

Peripheral blood dendritic cells, but not monocyte-derived dendritic cells, can augment human NK cell function.

Dendritic cells (DCs) are essential antigen-presenting cells with a wide variety of functions relating to both adaptive and innate immunity. Recently, interactions of DCs with natural killer (NK) cells and NK1.1-positive T cells have been reported in mice. However, in humans, this interaction is not well understood. Here we report the use of a coculture method to analyze the modulation of NK cell function in antitumor immunity by DCs. We found that peripheral blood DCs (PDCs) enhanced NK cell activity in cytotoxicity assay, even without direct contact between DC and NK cells. In contrast, neither monocyte-derived DCs (MoDCs), nor TNF-alpha-treated MoDCs, stimulated NK lytic activity. Secretion of IL-12 and TNF-alpha into the PDC-NK coculture supernatant was increased. However, blocking antibodies against these cytokines could not completely abolish the upregulation of NK activity, suggesting the presence of other soluble factor(s) that affect DC-NK cell interaction. To summarize, this study demonstrates for the first time the direct activation of human NK cells by DC-NK cell interaction in vitro, suggesting that DCs may have a central role linking the innate and adaptive immune responses. Moreover, in stimulating NK cell function, PDCs appear to have a different potential from MoDCs.

Dendritic cells activate antitumor immunity for malignant intracranial germ cell tumor: a case report.

We report a 22-year-old male patient with a history of intracranial malignant germ cell tumor (GCT) who had undergone tumor resection twice, followed by radiation and chemotherapy. The tumor had rapidly recurred along the entire ventricular wall with extensive invasion into the brain parenchyma. The serum level of human beta-chorionic gonadotropin (beta-hCG) was 232.3 ng/ml on admission. Although tissue samples of the recurrent tumor could not be obtained, the previous histological diagnosis of germinoma and elevated serum beta-hCG levels suggested recurrence of malignant GCT. The patient declined chemotherapy but accepted dendritic cell (DC)-based immunotherapy. DC inoculation five times resulted in rapid tumor shrinkage and a significant decrease in the serum level of beta-hCG. Here we discuss the effectiveness of immunotherapy using DCs for recurrent intracranial malignant GCTs.

Failure of pre-diarrheal antibiotics to prevent hemolytic uremic syndrome in serologically proven Escherichia coli O157:H7 gastrointestinal infection.

A girl had hemolytic uremic syndrome after Escherichia coli O157:H7 infection, despite pre-diarrheal administration of an antibiotic that prevented detectable intestinal colonization. This report casts doubt on the advisability of antibiotic therapy for E coli O157:H7 infections and has implications for our understanding of the mechanism of this disorder.

Enhanced theophylline metabolism in patients with bronchial asthma at age 4 and under.

The plasma levels of theophylline (TP) and its metabolites were measured in patients with bronchial asthma who were treated with a slow-release preparation of TP. The ratios of the plasma levels of these metabolites to TP levels in the group aged 1-4 years were larger than those in the group aged 5 years and older, suggesting enhanced activity of drug-metabolizing enzymes during infancy.

Stimulation with thromboxane A2 (TXA2) receptor agonist enhances ICAM-1, VCAM-1 or ELAM-1 expression by human vascular endothelial cells.

A previous study reported that intercellular adhesion molecule-1 (ICAM-1) expression by human vascular endothelial cells (HUVEC) is augmented by intracellular signal transmission mainly through the protein kinase C (PKC) system stimulated by TXA2 receptors. In the present study, we show that a TXA2 receptor agonist, U46619, augments the expression of not only ICAM-1, but also vascular cell adhesion molecule-1 (VCAM-1) or endothelial leucocyte adhesion molecule-1 (ELAM-1) in HUVEC both at protein and mRNA levels. Pretreatment with SQ29,548 (a TXA2 receptor antagonist) or PKC inhibitors greatly diminished the extent of U46619-induced mRNA accumulation and surface expression of the adhesion molecules. An inhibitor of nuclear factor kappaB (NF-kappaB) activation, PDTC, diminishes U46619-induced VCAM-1 mRNA accumulation. NAC, which inhibits NF-kappaB and activation protein 1 (AP-1) binding activity, inhibits the expression of ICAM-1 or ELAM-1 at protein and mRNA levels. These findings suggest that ICAM-1 or ELAM-1 expression of HUVEC stimulated via TXA2 receptors is augmented by induction of NF-kappaB and AP-1 binding activity through the PKC system, and that VCAM-1 expression is augmented by induction of NF-kappaB binding activity.

Rapidly progressive interstitial lung disease associated with dermatomyositis responding to intravenous cyclophosphamide pulse therapy.

Interstitial lung disease, especially the rapidly progressive type, carries a grave prognosis when associated with polymyositis (PM)/dermatomyositis (DM). We describe a case of rapidly progressive interstitial lung disease associated with DM. Pathological findings included bronchiolitis obliterans organizing pneumonia (BOOP) pattern in the right upper lung lobe and interstitial fibrosis with microscopic honeycomb lesions in the right lower lung lobe. The patient's respiratory distress was severe and persistent, and oral intubation with mechanical ventilation was transitionally introduced. The respiratory distress condition responded to intravenous cyclophosphamide pulse therapy.

Dendritic cells that process and present nominal antigens to naive T lymphocytes are derived from CD2+ precursors.

Dendritic cells (DC) are potent APC that, in mature form, can be distinguished from other mononuclear cells on the basis of their distinct morphology, absence of lineage markers, and dense expression of MHC and costimulatory molecules. While comparing different DC preparation methods, we observed that DC derived from cultured PBMC that had been depleted of CD2+ cells before culture were functionally distinct from DC derived from PBMC that had not been depleted of CD2+ cells. Thus, both types of DC stimulated allogeneic T cells to proliferate in the MLR, but only DC derived from CD2+ precursors could sensitize naive T cells to soluble Ags such as keyhole limpet hemocyanin and HIV gp160 glycoprotein. Subsequent studies confirmed the existence of CD2+ and CD2- DC precursor populations among HLA-DRbright, lineage-negative PBMC. Immediately after their isolation, these populations were morphologically similar to one another by light and electron microscopy, and neither had substantial Ag-presenting activity. After culture for 24 to 48 h with supernatant from PHA-activated PBMC, both populations developed dendrites, formed clusters with T cells, and stimulated allogeneic T cell responses in the MLR as well as autologous T cell responses to tetanus toxoid, a recall Ag. However, CD2+ DC precursors alone gave rise to APC that presented soluble Ags to naive CD4+ T cells, a property that could be inhibited by Abs to CD4, CD11a, and CD28 on T cells or CD86 on DC. The expression of CD54 and CD86 on CD2+ DC precursors was increased markedly after their culture and differentiation, while the expression of these molecules on CD2- DC precursors was not remarkably changed. These findings reveal the existence of two functionally distinct populations of DC, each derived from a phenotypically distinct precursor present in monocyte-depleted peripheral blood.

Role of B70/B7-2 in CD4+ T-cell immune responses induced by dendritic cells.

Dendritic cells (DC) are potent antigen-presenting cells (APC). However, the molecular basis underlying this activity remains incompletely understood. To address this question, we generated murine monoclonal antibodies (mAb) against human peripheral blood-derived DC. One such antibody, designated IT209, stained differentiated DC and adherent monocytes, but failed to stain freshly isolated peripheral blood mononuclear cells (PBMC). The antigen recognized by IT209 was identified as B70 (B7-2; also recently identified as CD86). Using this mAb we studied the role of B70 in CD4+ T-cell activation by DC in vitro. IT209 partly inhibited the proliferative response of CD4+ T cells to allogeneic DC and to recall antigens, such as tetanus toxoid (TT) and purified protein derivative (PPD) of tuberculin, presented by autologous DC. More importantly, the mAb had a potent inhibitory effect on the primary response of CD4+ T cells to autologous DC pulsed with human immunodeficiency virus (HIV) gp160 or keyhole limpet haemocyanin (KLH). Adherent monocytes, despite their expression of B70, failed to induce T-cell responses to these antigens. IT209-mediated inhibition of CD4+ T-cell responses was equivalent to that produced by anti-CD25 mAb, whereas an anti-CD80 mAb was only marginally inhibitory and did not augment the effect of IT209. These findings indicate that the B70 antigen plays an important role in DC-dependent CD4+ T-cell activation, particularly in the induction of primary CD4+ T-cell responses to soluble antigens. However, since activated monocytes, despite their expression of B70, failed to prime naive T cells to these antigens, our results suggest that additional molecules contribute to the functions of DC in CD4+ T-cell activation.

Cellular and molecular basis of human gamma delta T cell activation. Role of accessory molecules in alloactivation.

Although gamma delta T cell receptor-bearing lymphocytes (gamma delta T cells) constitute a significant minority of circulating and tissue-associated T lymphocytes, the mechanism responsible for the activation of these cells is unknown. To address this question, resting gamma delta TCR+, CD3+, CD4-, CD8- cells isolated from the blood of healthy volunteers were cultured with allogeneic dendritic cells (DC) or monocytes, and their proliferative response measured. DC alone induced gamma delta T cells to proliferate, with a peak response on the sixth day of culture. Pretreatment of DC with an anti-HLA-DR mAb, but not anti-HLA class I or anti-CD1 mAbs, inhibited the response of gamma delta T cells. Antibodies to gamma delta T cell receptor, CD2, CD3, or CD11a were also inhibitory, whereas antibodies to alpha beta T cell receptor, CD4, CD5, and CD8 had no effect. Although only 40-60% of freshly isolated gamma delta T cells expressed CD28, mAbs directed against CD28 or its ligand, CD80, were markedly inhibitory. Moreover, removal of CD28+ cells from the gamma delta T cell population nearly abrogated the response to DC. These results demonstrate that resting gamma delta T cells recognize and respond to MHC class II determinants on allogeneic DC in a manner that is highly dependent on the CD28 activation pathway as well as molecules such as CD2 and CD11a that mediate cell-to-cell adhesion.

HLA antigens in Japanese patients with myasthenia gravis.

HLA antigens in 104 Japanese patients and 41 families with myasthenia gravis (MG) were investigated. The frequencies of DR9 and DRw13 were significantly increased in the patients who developed MG before 3 yr of age. The DQw3 antigen was positive for all the patients that developed MG before 15 yr with only one exception. All the examined cases that developed MG before 3 yr (including this DQw3 negative patient) had the same DQA and DQB DNA restriction fragments. These HLA frequencies decreased as the age of onset increased, and no significant association was observed in adult-onset MG. No patients had B8, DR3, and DQw2. The relative risk was higher for the DR9/DRw13 heterozygotes (37.4) than for DR9 (16.4) or DRw13 (7.1) in the childhood-onset MG. Statistical analysis suggested that DR9 and DRw13 (or DQw1 and DQw3) act synergistically in the disease development. Family study revealed diverse DR9 haplotypes. The most frequent DRw13 haplotype was Bw44-BFF-C4A3B1-DRw13-DQw1, which may be evolutionarily related to the caucasian B8-DR3-DQw2 haplotype. These results showed that MG in early childhood in Japanese individuals is genetically different from that in adulthood and that in caucasians.

[Clinical diagnoses of pediatric patients without detectable auditory brainstem response (ABR)].

One hundred and forty-seven out of 1,600 infants and children showed no detectable ABR. ABRs were evoked by clicks. As to hearing acuity, 121 out of 147 patients had sensorineural hearing loss and 19 had no hearing impairment of high frequency (3-4 kHz) and high sound intensity (85-90 dBnHL). Eight patients could not be diagnosed whether they had hearing impairment or not. Among 19 patients who did not have sensorineural hearing loss in those ranges described above, 5 patients had cerebral palsy with severe mental retardation, 4 had mitochondrial encephalomyopathy, 3 had degenerative disease of unknown etiology, 2 patients had Down syndrome, 1 was a low birth weight infant with respiratory distress syndrome, 1 was a neonate born to a diabetic mother, 1 experienced severe neonatal asphyxia, 1 patient had acute lymphoblastic leukemia and 1 infant was later confirmed as a healthy girl. Of these, four patients showed transiently negative response in ABR. Nine patients remained undiagnosed as to hearing because they were in deep coma, had profound brain damage, or died in early neonatal period. They had major neurological diseases: severe neonatal asphyxia, holoprocencephaly, microcephaly, degenerative diseases of the central nervous system of unknown origin, metachromatic leukodystrophy, trisomy of chromosome 18, anoxic encephalopathy, small for gestational age newborn with intracranial bleeding and posthemorrhagic hydrocephalus. When ABR cannot be recorded using high sound intensity clicks, it usually suggests presence of hearing impairment of high frequency range. However, there are patients who have no hearing impairment in those sounds.(ABSTRACT TRUNCATED AT 250 WORDS)

[Studies of the treatment of recurrent abortion with husband's lymphocytes].

Thirty-two primary habitual aborters who had more than 3 abortions during the early stages of pregnancies without any known causes of habitual abortions were studied. The degree of HLA-DR compatibility of the patient couples was similar to that of 70 control couples. The patients were treated with intra-dermal injections of their husbands' lymphocytes 4 times every 2 weeks. The skin reactions at the sites of the injection were estimated 24 hours and 48 hours after the first and fourth injections. The mixed lymphocyte reaction (MLR) after the last injection decreased in the patients whose skin reaction was weaker following the last injection than the first (p = 0.007), and these patients had a good prognosis for subsequent pregnancies (p = 0.010). On the other hand, the MLR after the last injection did not weaken in the patients whose skin reaction did not become weaker (p = 0.007), and in these patients abortion resulted in subsequent pregnancies (p = 0.010). The HLA-DR compatibility of the patient couple and anti-HLA-DR antibody induced by the treatment did not affect the prognosis for subsequent pregnancies.

[Immunohistochemical localization of estradiol in malignant epithelial tumors of the ovary].

Granulosa cell tumors derived from sexcord-stromal cells are thought to be generally estrogen producing neoplasms. However recent reports show that these common epithelial tumors, adenocarcinomas and Brenner tumors, are capable of estrogen activity. We have studied the production of estrogen in common epithelial malignant tumors of the ovary. Two cases of serous cystadeno-carcinomas, five cases of mucinous cystadeno-carcinomas and two cases of endometrioid carcinomas were examined for the presence of estradiol using an indirect immunoperoxidase method. The results were as follows: In all tumors, one case of serous cystadeno-carcinoma, four cases of mucinous cystadeno-carcinomas and one case of endometrioid carcinoma had a positive immunoperoxidase reaction. The incidence of positive reaction showed that mucinous cystadeno-carcinomas were more numerous than others. In positive cases, estradiol localization was recognized in the epithelial cell of mucinous tumors to various degrees, but there was no estradiol localization in admixed goblet like cells. In serous tumors and endometrioid carcinomas also estradiol localization was seen in the cytoplasm. Stromal cells tended to be more weakly positive than epithelial cells. No estradiol localization was detected in any of the spindle cells or fibrinous connective tissues. These results suggest that some common epithelial malignant tumors of the ovary have estrogen activity and estradiol is produced not only in stromal cells but also in epithelial cells.