Hirschsprung disease (HSCR) is sometimes associated with a set of characteristics including mental retardation, microcephaly, and distinct facial features, but the gene mutated in this condition has not yet been identified. Here we report that mutations in SIP1, encoding Smad interacting protein-1, cause disease in a series of cases. SIP1 is located in the deleted segment at 2q22 from a patient with a de novo t(2;13)(q22;q22) translocation. SIP1 seems to have crucial roles in normal embryonic neural and neural crest development.
The proliferative responses and the immunoglobulin production of peripheral blood mononuclear cells to pokeweed mitogen were dose-dependently suppressed by sulfonated intravenous immunoglobulin (IVIG), polyethylene glycol-treated IVIG, pH 4-treated IVIG, or human gamma-globulin, but they were not or only slightly suppressed by human serum albumin or pepsin-treated IVIG. Moreover, the suppression of immunoglobulin production by sulfonated IVIG, polyethylene glycol-treated IVIG, or pH 4-treated IVIG was seen in the cases in which B cells preincubated with IVIGs were cocultured with T cells and monocytes preincubated with or without IVIGs and in the cases in which monocytes preincubated with IVIGs were cocultured with T cells and B cells preincubated with or without IVIGs. However, in the cases in which only T cells were preincubated with IVIGs, immunoglobulin production was not suppressed. The suppression of the monocyte function by IVIGs tended to be less than the suppression of the B-cell function by IVIGs. Moreover, the suppression by IVIGs was blocked by anti-human IgG Fc. Our results suggest that IVIGs suppress the immunoglobulin production of lymphocytes through suppression of the B-cell function and the antigen presenting-cell function by attachment of IVIGs to Fc receptors of B-cell membranes and antigen presenting-cell membranes.
Key wordsductal closure, heart failure, indomethacin.Indomethacin is a prostaglandin synthesis inhibitor and has been used in the treatment of premature labor since the mid-1970s. Experimental data indicates that maternal ingestion of indomethacin and other cyclo-oxygenase inhibitors can cause constriction of the fetal ductus arteriosus and persistent pulmonary hypertension of the newborn (PPHN). 1,2 Although an association between prostaglandin synthesis inhibitors and PPHN 3 or cardiac failure 4 has been described in case reports, studies of large series of neonates exposed in the antenatal period to indomethacin have failed to reveal severe cardiopulmonary effects. 5,6 It has been shown that ductal constriction induced by administration of indomethacin can cause right ventricular concentric hypertrophy and left ventricular dilatation in fetal rats. 7 Ductal constriction is assumed to cause pulmonary and right ventricular hypertension, decreased right ventricular output, rise in right atrial pressure, increased blood flow through the foramen ovale and increased volume load to the left ventricle. A patient, whose mother had been treated with indomethacin for premature labor from 26 to 34 weeks' gestation, had severe congestive heart failure at birth. We consider that maternal administration of indomethacin caused ductal constriction and subsequently congestive failure occurred in the patient. Case reportA 27-year-old woman was admitted to our hospital because of premature labor at 24 weeks' gestation. She had been well and did not have diabetes mellitus. Intravenous ritodrin hydrochloride therapy was administered at a rate of 100 µ g/min and was increased to 400 µ g/min, but the uterine contraction did not cease. From 26 weeks' gestation she was given 25 mg of indomethacin every 24 h in the form of rectal suppositories. The dosage was increased to 25 mg every 8 h at 27 weeks' gestation. Indomethacin therapy was discontinued at 34 weeks' gestation and ritodrin was continued until delivery.The patient was male and delivered at 35 weeks' gestation. His birthweight was 3846 g and Apgar score was 5 at 1 min. Fetal heart rate monitoring revealed no evidence of fetal distress. Cord blood gas analysis showed that the pH was 7.299, the partial pressure of carbon dioxide (PCO 2 ) 44.9 mmHg, the partial pressure of oxygen (PO 2 ) 38.0 mmHg and the base excess − 3.9 mmol/L. Respiration was labored and cyanosis was present in spite of the 40% oxygen environment of the incubator. The liver edge was dull and extended to 3.5 cm below the right costal margin. His serum glucose was 36 mg/dL, calcium 3.8 mEq/L and hemoglobin level 19.3 g/dL.The chest roentogenogram obtained 30 min after birth revealed marked cardiomegaly (Fig. 1). Echocardiography revealed an enlarged right atrium, right-to-left bulging of the atrial septum and thickening of the right ventricular wall and papillary muscles (Fig. 2). Congenital cardiac malformation was absent. Color flow Doppler echocardiography showed tricuspid regurgitation, mild pulmonary regurg...
Five patients with common variable immunodeficiency treated in our hospital between December 1979 and December 1990 were given six kinds of intravenous immunoglobulin preparations (pepsin treated, S-sulfonated, polyethylene glycol treated, pH4 treated, alkylated, and pH4.25 formulation preparation) for replacement therapy. Duration of the therapy ranged from 7.6 to 11 years. Incidences of fever and acute infections were variable among patients, but no significant differences were seen in the incidences among periods given each preparation. Three cases revealed abnormal pulmonary functions in tests. Adverse reactions were rarely seen in our study periods, and no severe reactions were observed. No significant differences were seen in incidences of adverse reactions. Postinfusion levels of serum complement slightly decreased from preinfusion levels. However, the decrease in complement was not related to any adverse reaction. No long-term complications such as transmission of hepatitis have been observed. Our data suggest that no obvious differences exist between the efficacy and safety of each IVIG preparation. Differences of efficacy of IVIG replacement therapy may be due to the variable pathophysiology of each patient.
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