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Biomedical subjects

R H McLean

Publications and source records attributed to R H McLean.

At least 19 recordsLinked to original sources
PubMed1992

Segmental renal artery embolization for treatment of pediatric renovascular hypertension.

Selective intrarenal arterial embolization was used to treat three children with documented renovascular hypertension. Embolization resulted in complete cure (ie, elimination of all antihypertensive medicines) in all three patients and caused only minimal loss of renal parenchyma. Renal vein renin sampling, including sampling after furosemide administration, correlated well with the location of identified vascular lesions and helped direct selective angiography when lesions were not found initially. Intrarenal arterial embolization is a safe, effective alternative to surgical resection in the treatment of renovascular hypertension in children who have identifiable intrarenal arterial lesions not amenable to balloon angioplasty.

Child↗
PubMed1992

A unique recombination event resulting in a C4A*Q0,C4B*Q0 double null haplotype.

The fourth component of complement (C4) is encoded by two closely linked genes (C4A and C4B) within the MHC. Null alleles at either locus (C4AQ0 or C4BQ0) are relatively common, occurring at the C4A locus in approximately 10% of normal individuals and at the C4B locus in approximately 16% of normal individuals. However, the presence of the double null haplotype (C4A*Q0,B*Q0) on the same chromosome is extremely rare. We recently studied a 7-yr-old patient with recurrent sinopulmonary infections in whom we documented the mechanism by which the C4A*Q0,B*Q0 double null haplotype arose. Evaluation revealed significantly reduced levels of both C4 antigen and C4 hemolytic activity. Analysis of extended haplotypes in the family was performed using MHC typing and genomic DNA analysis. The patient was found to have a C4A*3,B*Q0 haplotype and a C4A*Q0,B*Q0 haplotype. The C4A*3,B*Q0 haplotype was contributed by the father. The mother possessed a C4A*Q0,B*1 haplotype and a C4A*3,B*1 haplotype. The first maternal haplotype was involved in a recombination event within the C4B locus on her other chromosome and resulted in a new C4B*Q0 null allele and the patient's C4A*Q0,B*Q0 haplotype. Segregation analysis mapped the recombination to a region 3' to the unique 6.4-kb TaqI restriction fragment of the maternal C4B locus. This is the first demonstration of a recombination event producing a C4 double null haplotype.

Blotting, Southern↗
PubMed1992

Neonatal lupus erythematosus syndrome: analysis of C4 allotypes and C4 genes in 18 families.

We examined 18 families with infants who had neonatal lupus erythematosus (NLE) syndrome to determine whether abnormalities in C4 phenotypes and genotypes were an additional risk factor for this syndrome. Fifteen of 18 mothers of infants with NLE (83%) had C4 null allotypes compared with 36% of population controls (p = less than .001). This increased frequency was due mainly to the presence of C4A null allotypes (11/18, 61%). C4 gene abnormalities, i.e., deletion or probable duplication, were present in 100% (16/16) of mothers of infants with NLE. The most common molecular genetic abnormality in mothers of infants with NLE in this study was deletion of C4A genes. Duplication of C4A and C4B loci was also commonly seen. Duplication of C4A genes was detected only in mothers of infants with complete congenital heart block (CCHB), and duplication of C4B was detected only in mothers of infants with dermatitis. No significant increase in C4A or C4B null allotypes or protein deficiencies was noted in mothers of infants with neonatal lupus when compared with anti-Ro(SS-A)-positive mothers delivered of clinically normal infants. Fathers of infants with NLE showed a trend toward increase in C4B null allotypes when compared with population controls (75%, 3/4, p = .06). The two infants with CCHB examined were C4B protein-deficient, in contrast to infants with lupus dermatitis, who had frequent C4B null allotypes but no C4B protein deficiency. C4B null allotypes were not seen in unaffected siblings of infants with NLE and in only 1 of 7 anti-Ro(SS-A)-positive mothers who delivered clinically normal infants. We conclude that inheritance of C4A null allotypes is not predictive of increased risk of neonatal lupus when present in anti-Ro(SS-A)-positive women. Examination of paternal and maternal C4 genes of additional infants with NLE, in particular those with CCHB, and of normal infants born to anti-Ro(SS-A)-positive mothers--and of the normal infants' parents--is required to determine if abnormal C4B genes are a critical factor rendering susceptibility to the NLE syndrome.

Antibodies, Antinuclear↗
PubMed1991

C4A deficiency and poor prognosis in patients with IgA nephropathy.

IgA nephropathy (Berger's disease) is an important cause of end-stage renal failure in persons of Asian and European descent. We performed C4 phenotyping on plasma from 123 patients with IgA nephropathy who resided in several different parts of the United States. All of these patients underwent diagnostic renal biopsy in adulthood. Six patients had a total deficiency for the C4A protein and all six had chronic renal insufficiency (serum creatinine concentration higher than 1.4 mg/dl at last follow-up). In contrast, 47% of the patients without C4A deficiency had chronic renal insufficiency (p = 0.001). The C4 gene defect was due to deletion of both C4A genes in only two individuals, whereas three patients were heterozygous for the C4A gene deletion. We speculate that the functional alteration of the complement system related to C4A deficiency might lead to expression of clinically severe disease in an individual with a genetic susceptibility to IgA nephropathy.

Chromosome Deletion↗
PubMed1990

Hypomorphic C4B* 15 variant of the fourth component of complement.

We report a rare 'hypomorphic' C4 allotype detected during routine screening in controls for the Rogers:1 epitope. C4B* 15 was distinguished by having only faint staining when using polyclonal anti-C4 antibody on agarose immunoelectrophoresis (e.g. hypomorphic), having relatively weak hemolytic activity but being strongly reactive with monoclonal antibody to Rodgers 1. TaqI restriction fragment length polymorphism (RFLP) demonstrated that C4B* 15 segregated with 7 kb and 5.4 kb C4 gene fragments and with the haplotype HLA-A2,C-, B50,BW6,DR7,DQ2,DR52,SO7C2(1,15). The 5.4-kb fragment was more intense than the 7.0-kb fragment, suggesting duplication of the 5.4-kb fragment. This hypomorphic C4 allotype (genotype frequency = 0.0088) has diminished expression of C4 epitopes commonly recognized by polyclonal anti-C4 and may be missed by standard phenotyping methods.

Adult↗
PubMed1990

Intravenous immunoglobulin in minimal change nephrotic syndrome: a crossover trial.

To determine whether intravenous immunoglobulin (IVGG) would be an efficacious adjunct in the treatment of childhood minimal change nephrotic syndrome (MCNS), we enrolled ten patients with frequently relapsing or steroid-dependent MCNS in a double-blind crossover clinical trial. At the time of relapse of the nephrotic syndrome, patients were assigned to treatment with a single outpatient infusion of IVGG (800 mg/kg) or intravenous albumin as a control. The relapse was treated concurrently with standard doses of oral prednisone. At the time of the next relapse, patients who had first received IVGG were treated with albumin, and vice versa. There were no significant differences in the length of remission between the IVGG and albumin treatments. The study had a power of 0.72 to detect a true difference of 45 days between the two therapies. We conclude that in the dose of drug used in this trial, administered at the time of relapse in conjunction with prednisone therapy to children with frequently relapsing or steroid-dependent MCNS, IVGG does not lead to a clinically important extension of the period of remission.

Adolescent↗
PubMed1990

Recurrent haemolytic uraemic syndrome and acquired hypomorphic variant of the third component of complement.

In a girl with recurrent haemolytic uraemic syndrome (HUS), persistently low serum levels of C3 were found. Analysis of complement phenotype revealed a hypomorphic variant of C3 Fast in the patient (C3fS) and a normal heterozygous pattern in both parents and the brother (C3FS). Other complement aberrations in the patient were: the presence of a null gene for C4A and C4B and low serum levels of factor H. The father also had partial factor H deficiency. It is hypothesized that the hypomorphic C3 variant may predispose to recurrent HUS. In the acquired forms the role of uraemia in alteration of C3F should be considered.

Complement C3↗
PubMed1990

Characterization of two hybrid C4 allotypes (C4A*12 and C4B*3) by electrophoretic, serological and restriction fragment length polymorphism analyses.

Informative pedigree analysis of two rare C4 allotypes is reported. One proband was C4A deficient as a consequence of having one haplotype with a deleted C4A gene, and the second haplotype with two C4B genes--one encoding the common C4B*1 and one encoding a unique hybrid gene product C4B*3. C4B*3 had approximately normal C4B hemolytic activity, a single alpha-chain of MR 94,000 by SDS-PAGE but was positive for Rg:1,2 by hemagglutination inhibition (HAI) and for Rg:1 by Western blotting. The hybrid nature was confirmed by RFLP analysis with a Rg:1-associated fragment by Eco0109 digestion but no C4A-associated fragments by N1aIV digestion were identified. A gene conversion at Locus I which included just the C4 isotype region could explain the structure of C4B*3. The second pedigree had a Rodgers negative C4A*12 allotype. This C4A gene, which segregated with a single 7.0 kb TaqI fragment, encoded a C4A alpha-chain, which was negative for Rg:1 epitope. The affected haplotype lacked the Rg:1-associated fragment by Eco0109 digestion yet had the C4A specific N1aIV digestion fragment. These studies successfully employed RFLP analyses to confirm serologic and electrophoretic observations.

Adolescent↗
PubMed1990

Connective tissue disease in southeast Georgia. A community based study of immunogenetic markers and autoantibodies.

HLA antigens, C4 allotypes and T cell antigen receptor (TcR)beta DNA polymorphisms were determined in a community based study of connective tissue diseases (CTD). HLA-B8, DR3 and C4A null phenotypes occurred frequently in Caucasian patients with CTD, especially those with systemic lupus erythematosus (SLE), but were also more commonly found among healthy white controls of this southeast Georgia community. TcR beta gene polymorphisms also showed differential segregation patterns between patients with SLE and scleroderma. High frequencies of ANA and anti-ssDNA antibodies occurred among apparently healthy family members and local controls. Genetic factors predisposing to CTD in a community setting appear to be similar to those reported from referral centers.

Alleles↗
PubMed1989

Association of homozygous C4B deficiency with bacterial meningitis.

The fourth component of complement (C4) is encoded by two separate but linked loci (C4A and C4B), each of which produces functionally active C4. Although C4A and C4B share certain antigenic and functional characteristics that identify them as C4, they differ with respect to other structural and functional properties. For example, C4B possesses four times the functional hemolytic activity of C4A. This suggests that homozygous deficiency of C4B might be associated with an increased susceptibility to infection. Forty-six children with bacterial meningitis were examined. Of these, 5 (10.9%) were homozygous deficient for C4B versus 7 (3.1%) of 223 controls (P = 0.038). There was no relation between the prevalence of heterozygous C4B deficiency and meningitis or between the prevalence of either homozygous or heterozygous C4A deficiency and meningitis. These results suggest that homozygous C4B deficiency is a relatively common immunodeficiency disorder that is clinically significant and predisposes children to bacterial meningitis.

Adolescent↗
PubMed1988

Molecular heterogeneity of complement component C4-null and 21-hydroxylase genes in systemic lupus erythematosus.

C4A-null alleles (C4A*Q0) and hereditary complete C4 deficiency (homozygous C4A*Q0,C4B*Q0) are associated with systemic lupus erythematosus (SLE). Using Southern blot analysis with C4 and 21-hydroxylase (21-OH) DNA probes, we studied SLE patients and normal control subjects with or without C4A*Q0, and 2 C4-deficient SLE patients. A previously reported large C4A,21-OHA gene deletion associated in normal subjects with the HLA-A1;B8;DR3;C4AQ0 haplotype was detected by the appearance of a new C4 Hind III 8.5-kb fragment and disappearance of a 3.2-kb 21-OH Taq I fragment. In 3 SLE patients with homozygous C4A*Q0 and 15 with heterozygous C4A*Q0, this deletion pattern occurred almost exclusively in association with the HLA-B8;DR3;C4A*Q0 phenotype; the one exception was a black SLE patient. Other C4A*Q0-bearing HLA phenotypes in white patients and black patients with SLE, and the 2 completely C4-deficient SLE patients, had normal DNA hybridization to both C4 and 21-OH probes. The genetic basis for C4-null alleles in SLE is heterogeneous. A large C4A,21-OHA deletion occurs mainly on the HLA-B8;DR3;C4AQ0 haplotype in SLE and controls. Other HLA haplotypes bearing C4A*Q0 have normal C4 and 21-OH genes, as demonstrated by Southern blot analysis.

Alleles↗
PubMed1988

Neonatal obstructive uropathy.

Neonatal obstructive uropathy is the leading cause of renal failure during infancy. A variety of upper and lower genito-urinary (GU) tract disorders may cause obstructive uropathy. The prompt diagnosis and evaluation of obstructive uropathy is imperative since appropriate intervention and follow-up can lead to excellent early recovery of function. The role of in utero diagnosis is primarily to alert physicians to the presence of obstructive uropathy and permit rapid initiation of care at birth or earlier in certain instances. The GU tract must be evaluated for evidence of dilatation, for reflux and for renal function using radionuclide studies, voiding cystourethrograms, cystoscopy and pyelography. The early course of neonatal obstructive uropathy has been improved by institution of GU diversion and primary repair, yet the effect of early surgical intervention and medical therapy in preventing renal failure remains unclear. Further studies are needed to identify prognostic features heralding progression to renal failure and how such progression can be prevented.

Female↗
PubMed1988

Restriction fragment analysis of duplication of the fourth component of complement (C4A).

The two genes encoding the fourth component of complement (C4A and C4B) reside between HLA-B and HLA-DR on human chromosome 6. Two kilobases downstream from each C4 gene lies a 21-hydroxylase gene (CA21HA and CA21HB, respectively). Utilizing the method of Southern blotting and a 5'-end 2.4-kb BamHI/KpnI fragment of the C4 cDNA, we have analyzed TaqI-digested DNA from four pedigrees with one or more extended haplotypes containing a C4A duplication, as demonstrated by protein electrophoresis and segregation analysis. Two C4A protein duplications (C4A*2,A*3,C4B*QO and C4A*3,A*5,C4B*QO) segregated with two large TaqI DNA restriction fragments (7.0 and 6.0). In pedigree Fi, one individual homozygous for HLA-A3,B35,C4,DR1,DQ1,BFF,C2C,-C4A2,3,C4BQO had TaqI 7.0- and 6.0-kb restriction fragments with equal hybridization intensities as measured by two-dimensional densitometry (7.0/6.0 kb = 0.83, SD = 0.12, N = 7). A hybridization probe for the 21-hydroxylase gene also demonstrated equal gene dosage (CA21HA/CA21HB = 1.01). DNA from another individual (Ma I-2) with a different C4A gene duplication (C4A*3,A*5,C4B*QO) also had equal densitometry measurements (7.0/6.0 kb = 1.07). We conclude that two extended haplotypes from unrelated pedigrees have two C4 genes and both C4 genes encode separate C4A alleles. These findings are compatible with a gene conversion event of C4B to C4A.

Adrenal Hyperplasia, Congenital↗