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PubMedDate not supplied

Growth retardation in children with IgA deficiency.

We evaluated the clinical and immunological manifestations of 14 children with IgA deficiency. Four of the patients were asymptomatic, and ten were symptomatic, with recurrent sinopulmonary infections, allergic disease, recurrent intestinal giardiasis or celiac disease. Growth retardation was the second important feature in our patients. One of the seven patients with growth retardation had partial growth hormone deficiency. The levels of serum IgG and IgM were high in five and three patients, respectively. Cellular immunity was normal.

Child↗
PubMed1984

[A case of macroamylasemia].

An observed case of macroamylasaemia is presented with a description of the identification technique employed. As in cases reported in the literature, antiglobulin sera did not precipitate the complexes. This would appear to exclude the possibility of the immunity-related aetiopathogenesis the patient's immunological and electrophoretic patterns suggested.

Adult↗
PubMed1993

Bone marrow transplantation.

BMT has been successfully utilized in clinical medicine for nearly 25 years. Successful accomplishment of BMT has severely taxed the research and clinical capabilities of medical scientists, but the attainment of a cure for fatal disease has amply justified the efforts expended. The major problems still to be solved include better conditioning regimens, better control of GVHD, and enlargement of donor pools. The control of problems created by this therapy demands a thorough understanding of the immune system. As this knowledge increases, useful manipulation of immunity to control the hundreds of other diseases caused by aberrant immune processes should become possible. Soon, genetically engineered marrow transplants should be possible.

Acute Disease↗
PubMed1987

Increase of protein synthesis by uridine supplement in lectin-stimulated peripheral blood lymphocytes and EB virus-transformed B cell line of hereditary orotic aciduria type I.

A 2 month-old Japanese girl with hereditary orotic aciduria type I was treated with oral uridine supplement. The activities of orotate phosphoribosyltransferase (OPRT) and orotidine-5'-phosphate decarboxylase (ODC) in erythrocytes were 2.7 and 0.4%, respectively, of those in the controls. Megaloblastic anemia, excessive urinary excretion of orotic acid, lymphopenia and decreased number of OKT3 positive lymphocytes on admission were corrected after the uridine supplement. Peripheral blood lymphocytes (PBL) were cultured for 24 hr in RPMI 1640 medium with 10% heat-inactivated fetal calf serum and further stimulated with PHA-P, ConA or PWM in the presence of 10 to 1000 microM uridine. EB virus-transformed B cell line (LCL) maintained with an optimal concentration of uridine was cultured for 48 hr in uridine free medium and cultured for an additional 48 hr with 1 to 1000 microM uridine. The incorporations of leucine in to PHA-, ConA- and PWM-stimulated PBL and into LCL of the patient increased in the presence of uridine over 10 microM, although they did not increase in controls. These data suggest that low protein synthesis might correlate with an immune deficiency in hereditary orotic aciduria type I.

Antigens, Surface↗
PubMed2002

Mixed bone marrow or mixed stem cell transplantation for prevention or treatment of lupus-like diseases in mice.

Scientific analyses fortified by interpretations of immunodeficiency diseases as 'experiments of nature' have revealed the specific immune systems to be comprised of T cells subserving cell-mediated immunities plus B cells and plasma cells which produce and secrete antibodies. These two separate cellular systems regularly interact with each other to produce a coordinated defense which permits mammals to live within a sea of microorganisms that threaten the integrity and the survival of individuals. We have shown that bone marrow transplantation (BMT) can be used as a form of cellular engineering to construct or reconstruct the immune systems and cure otherwise fatal severe combined immunodeficiency. When severe aplastic anemia complicated the first BMT which was performed to cure a fatal severe combined immunodeficiency, a second BMT cured for the first time a complicating severe aplastic anemia. Subsequently, BMT has been used effectively to treat some 75 otherwise fatal diseases such as resistant leukemias, lymphomas, inborn errors of metabolism, and genetic anomalies of the hematopoietic development such as sickle cell anemia, thalassemia, congenital neutropenias, and many other diseases. More recently, we have employed BMT in mice both to cure and cause autoimmunities, and, together, these experiments showed that autoimmunities actually reside in the hematopoietic stem cells. We have also found that mixed BMT or mixed hematopoietic stem cell transplantation (HSCT) can be used to prevent and cure the most complex autoimmunities such as those occurring in BXSB mice and in (NZW x BXSB)F1 W/BF1 mice. Untreated, the former develop fulminating lethal glomerulonephritis plus numerous humoral autoimmunities. Mice of the (W/B)F1 strain develop autoimmune thrombocytopenic purpura, coronary vascular disease with myocardial infarction, glomerulonephritis, and numerous autoantibodies. All of these abnormalities are prevented or cured by mixed syngeneic (autoimmune) plus allogeneic (normal healthy) BMT or mixed peripheral blood HSCT. Thus, the most complex autoimmune diseases can be prevented or cured in experimental animals by mixed syngeneic plus allogeneic BMT or HSCT which produce stable mixed chimerism as a form of cellular engineering.

Animals↗
PubMed1998

Intravenous immune globulin in lysinuric protein intolerance.

In addition to systemic manifestations with skeletal, pulmonary, renal, and haematological signs, lysinuric protein intolerance (LPI), a membrane transport defect of cationic amino acids, is often complicated by severe life-threatening immunological manifestations. A 10-year-old boy with LPI who exhibited a severe systemic immunohaematological disease is described here. This patient showed cutaneous lesions similar to the subacute form of systemic lupus erythematosus, severe anaemia and dysproteinaemia, and a marked reduction of circulating T lymphocytes, mainly the CD4+ cells. In vitro bone marrow cell culture studies showed that addition of patient's serum induced macrophage proliferation and inhibited erythroid progenitor cell growth. Treatment with high-dose intravenous immune globulin resolved most of the clinical and laboratory abnormalities.

Amino Acid Metabolism, Inborn Errors↗
PubMed1985

Liver transplantation in pediatric patients.

Since the introduction of cyclosporine and a multidisciplinary surgical/medical approach, survival has improved in children undergoing orthotopic liver transplantation. In many areas, liver replacement is being considered a genuine treatment option for progressive liver disease. Before this procedure is routinely accepted, however, it will be important to follow long-term outcome and to compare results with those of conventional treatment when there are more patients in each disease category. In addition to continued experimentation with immunosuppressive regimens, methods for monitoring immunosuppression and detecting rejection at early stages are needed. Finally, the changes in bodily processes accompanying liver replacement should be used to learn more about the function of the liver, its role in immunity and its pathobiologic involvement by specific disorders.

Antilymphocyte Serum↗
PubMed1995

Principles of inborn errors of metabolism: an exercise.

Many inborn errors of intermediary metabolism present during periods of poor oral intake or intercurrent illness. Under these conditions, the body switches to a predominantly catabolic state, when glycogen, fat, and protein are mobilized as alternative energy sources. If a genetic defect already exists in any of these catabolic pathways, the problem is accentuated because the catabolic state demands a high flux of metabolite through these pathways. Therefore, a cardinal principle in the management of children who have IEM is to prevent them from lapsing into a catabolic state. This can be done through: 1) aggressive nutrition management to promote positive nitrogen balance and decrease accumulation of toxic metabolites, and 2) immunizations to minimize the possibility of viral or bacterial illness. When catabolism does occur, high-dose glucose infusion is a potent method for turning off the catabolic state. This simplistic view of the catabolic pathways neglects many details in each of the metabolic pathways and diseases cited in the article and questions. Nevertheless, it should provide a useful framework for explaining some of the clinical findings encountered in caring for this special group of patients. A partial list of more commonly encountered IEMs is contained in the Table. The different parts of the biochemical pathways discussed previously are combined into Figure 6. Hopefully, for some readers, the Figure also will lead to the affirmation that biochemistry is not so bad after all!

Energy Metabolism↗
PubMed1994

Unusual presentations of propionic acidemia.

The files of 25 patients with propionic acidemia (PA), followed by the Inborn Errors of Metabolism Service (IEMS) at King Faisal Specialist Hospital and Research Centre (KFSH & RC) from 1990 to 1993, were studied retrospectively. In 14 patients PA presented acutely with acidosis, hyperammonemia and thrombocytopenia, while in 11 patients the presentation of the disease was unusual. In the latter group, two neonates with PA initially appeared as a primarily hyperammonemic metabolic disease. In two other neonates the vomiting was so severe that they were diagnosed as intestinal obstruction in referral hospitals. The presentation in three infants was primarily as an immune disorder. In four infants, PA appeared as an acute or chronic encephalopathy, i.e. as a silent organic acidemia, with few other findings of the disease. The clinical picture of PA includes facial and nipple dysmorphia, severe hypotonia and vomiting. Severe thrombocytopenia is the hallmark of the metabolic crisis. In one patient it was noticed late and caused intracranial hemorrhage, while in three others intracranial bleeding caused death. The prognosis in PA remained grave despite rigorous treatment. Only seven of the 25 PA patients remained to have a normal life-style, while eight patients expired. The diagnosis is readily achieved by urine gas chromatography/mass spectrometry (GC/MS), by tandem mass spectrometry (MS/MS), or by enzyme analysis of fibroblasts. While there may be both examiner- and patient-related reasons for the variations in the presentation of PA, one other reason may be the heterogeneity of the molecular defect in propionyl-CoA carboxylase.

Abnormalities, Multiple↗
PubMed1999

Hepatology in the 21st century. Gene transfer, hepatocyte transplantation, DNA chips, cyberspace and ... a friendly hospital.

What to expect for hepatology in the 21st century? If science is allowed to proceed at its current rate, expectations can hardly be underestimated. Bound by the present day's limitations we are only able to see a glimpse of what could be available 100 years from now. For the next few decades, the global eradication of viral hepatitis will be on the agenda. For the treatment of inherited and acquired metabolic, toxic and immune liver disease, targeted drugs, genes and antisense oligonucleotides will be added to our therapeutic repertoire. The completion of the human genome project in 2003 will have far-reaching consequences: the widespread use of prenatal diagnosis, using DNA chip technology, may be expected to cause a dramatic decrease in the incidence of inherited diseases. Liver cirrhosis, hepatocellular carcinoma and inborn errors of metabolism may be treated by gene transfer or gene repair therapy. Although eventually these developments may decrease the need for organ transplantation, this by no means is the case yet and no solution is available for an increased demand and a decreased supply of organs. In the long run, diseases caused by multi-drug-resistant infectious agents and diseases associated with the abuse of alcohol and drugs are expected to become major problems. The future of university-based research is uncertain. The staggering costs of research and limited career possibilities may force universities to the limited task of higher education, with as a result biotech companies, shareholders and corporate finance ruling the scientific waves in the next century. The 21st century patient will know the way in cyberspace and will go shopping for the best doctor, for the best treatment and for the best, or friendliest, hospital.

Cell Transplantation↗
PubMed1998

Anonymous unlinked testing as a sentinel approach: experience in Germany.

STUDY OBJECTIVE: To establish a laboratory sentinel as a supplementary instrument for monitoring the seroprevalence of HIV among childbearing women as a proxy to the heterosexually active population. DESIGN/SETTING: Anonymous unlinked testing of neonatal dried blood spots has been performed in central laboratories of three federal states since 1993. The survey uses residual dried blood spots collected on Guthrie cards for screening of infants for metabolic disorders. These are eluted and tested for HIV antibodies. Data retained with the specimen are only district of residence along with year and month of birth. PARTICIPANTS: Because maternal IgG crosses the placenta before birth, the presence of antibodies in newborns reflects the infection status of the mother. Childbearing women are fairly representative for the heterosexually active general population. MAIN RESULTS: The observed HIV prevalence in childbearing women of less than 1 per thousand confirms the assumption of a low rate of HIV infection in the general population. Significant time trends could not be detected, but HIV prevalence was higher in metropolitan compared with rural areas. CONCLUSIONS: Laboratory sentinels in general and the anonymous unlinked testing of neonatal dried blood spots in particular can supply additional information on HIV seroprevalence. This surveillance system could be expanded to utilise residual samples of other sources as well as to monitor the immunity against specific vaccine preventable diseases and other infectious diseases of public health relevance.

Adolescent↗
PubMed1972

C1r deficiency: an inborn error associated with cutaneous and renal disease.

The studies of sera from two siblings with C1r deficiency are described. The brother (18 yr old) has shown clinical manifestations resembling lupus erythematosus for 5 yr, and the sister (24 yr old) has had arthralgia and recurrent episodes of rhinobronchitis since early childhood. Three siblings have died: one brother died at age 12 with symptoms similar to the disease of the male patient studied here, and two other siblings died in infancy, probably from infection. The low hemolytic C1 activity of the patients could be restored by the addition of purified C1r to their sera. Bactericidal activity and immune adherence were found to be impaired. When alternate pathways of the complement system were studied, both sera permitted activation of terminal components with endotoxin and cobra venom factor. These findings support the view that an alternate pathway for activation of the terminal portion of the complement cascade exists which does not utilize the conventional pathway operating through the usual early components.

Adolescent↗
PubMed1996

Infant formula, past and future: opportunities for improvement.

Infant formulas provide nutritional support to health infants that promotes growth and development equivalent to that in healthy infants fed human milk. Formula-fed infants are not as well protected against infections, and there remain infants whose health, growth, and development may not be supported optimally by either the formulas currently available or human milk. Some infants may be better supported by genetically engineered formulas that contain immunity-enhancing antibodies or antigens. Formulas that contain cytokines promoting epithelial cell growth and integrity may be protective against necrotizing enterocolitis. Formulas containing proteins with genetically excluded allergenic epitopes or formulas with tolerogenic peptides may be useful in treating allergic diseases of suppressing the development of autoimmune disorders later in life. Formulas with genetically engineered biologically active substances might increase the absorption of nutrients in infants with compromised absorption or digestion, enhance host immunity and mucosal integrity, and, potentially militate or protect against the risk of disease.

Animals↗
PubMed2005

Abnormal proinsulin congeners as autoantigens that initiate the pathogenesis of Type 1 diabetes.

Exposure of concentrated and purified monomeric insulin solutions to inorganic oxidants as iodine and chlorine lead to the appearance of a minor peak on gel chromatography that was disulfide cross-linked. It exhibited a 20-fold reduction in bioactivity, a markedly decreased immunoreactivity and a different electrophoretic pattern as compared to the starting material. The covalent dimer was formed by way of aggregation. These findings were reproduced by incubating monomeric insulin in normal blood spiked to hyperglycemic levels. In contrast, normoglycemic blood used as incubating medium failed to induce dimerization. Since the conformation of proinsulin is similar to that of insulin, involving the exposure of the anterior A7-B7 disulfide bridge, the authors hypothesize that proinsulin dimers rather than insulin dimers might be formed in Type 1 diabetes (TD1), leading to the autoimmune destruction of pancreatic B-cells. Proinsulin is present in a soluble aggregate state in the coated granule and may further accumulate allowing disulfide exchange due to abnormalities of the processing enzymes. This might be caused by inborn errors in genetically susceptible children or perhaps secondary to viral infection, whereas crystallization of insulin in mature granules is unlikely to be conducive to dimerization. Dimeric proinsulin would then migrate to pancreatic B-cell membranes to be taken up by surface immunoglobulins on B-lymphocytes that would in turn present it to cytotoxic T lymphocytes. The abnormal configuration of this congener would not be recognized as self by the immune system, triggering a selective destruction of pancreatic B-cells in the early pre-clinical development of TD1, resulting eventually in clinical disease. Since proinsulin is continuously converted to insulin in the coated granules of Type 2 diabetics, dimerization is unlikely in this condition. As pointed out by earlier investigators, TD1 is not a homogeneous disease, since several of its clinical features are different in children up to 6 years of age as compared to older patients. It is thus conceivable that there are subsets of TD1 triggered by dissimilar autoantigens and we propose in the present hypothesis that a conformationally altered congener of native proinsulin might play such a role.

Animals↗
PubMed2005

Altered glycan structures: the molecular basis of congenital disorders of glycosylation.

Congenital disorders of glycosylation (CDG) are a group of diseases that affect glycoprotein biogenesis. Eighteen different types of CDG have been defined genetically. They result from deficiencies in either the biosynthesis of oligosaccharide precursors or specific steps of N-glycan assembly, resulting in the absence or structural alteration of N-glycan chains. These diseases have a broad range of clinical phenotypes and affect nearly every organ system, with special emphasis on normal brain development and the multiple functions of the nervous, hepatic, gastrointestinal and immune systems. Although most of the deficiencies observed in CDG patients are only partial, the severity of the clinical manifestations signifies the relevance of protein N-glycosylation and shows the importance of defined glycan structures.

Carbohydrate Metabolism, Inborn Errors↗
PubMed2002

Growth-factor gene therapy for neurodegenerative disorders.

Preclinical neuroscience has advanced rapidly over the past two decades. New approaches for treating neurological disease, including gene-based therapies, nervous-system growth factors, stem cells, novel vaccines, and modulation of the immune system, offer the potential to prevent cell loss and degeneration in the brain, rather than attempting to compensate for loss after it has occurred. I will review one of these prospective therapies: growth-factor gene therapy for Alzheimer's disease, an approach that is currently the subject of a phase I clinical trial. Other disease targets for gene therapy will also be discussed, including Parkinson's disease, Huntington's disease, inborn errors of metabolism, and cancer. The progress of gene-therapy clinical trials is aiding the transition to molecular and gene-targeted therapeutic approaches which have the potential to improve dramatically the prognosis of neurological disease.

Animals↗