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Biomedical subjects

T R Welch

Publications and source records attributed to T R Welch.

At least 37 records · Page 2Linked to original sources
PubMed1997

The nonspecificity of focal segmental glomerulosclerosis. The defining characteristics of primary focal glomerulosclerosis, mesangial proliferation, and minimal change.

We performed a detailed clinical review and pathologic analysis of the kidney biopsies of 134 children with nephrotic syndrome or asymptomatic proteinuria. This analysis challenges some of our concepts about the classification of conditions associated with these disorders. The presence of focal segmental sclerotic lesions does not define a unique disorder in childhood. Some children with such lesions will have unaffected glomeruli that are ultrastructurally completely normal. These patients, predominately black adolescents, present either with nephrotic syndrome or asymptomatic proteinuria. We classify this disorder as primary focal segmental glomerulosclerosis (FSGS) and have never found it to recur after transplantation. Most other children with FSGS have 1 of 2 specific glomerulopathies. Those with minimal change have generalized fusion of podocyte foot processes. Those with mesangial proliferation have similar foot process changes combined with mesangial expansion and proliferation and, frequently, thinning of the lamina densa and tubuloreticular inclusions. The presence of segmental lesions in these glomerulopathies appears to be nothing more than a marker of severity. Children with these glomerulopathies are generally younger white children, virtually all of whom have nephrotic syndrome. These disorders have a strong propensity to recur after transplantation. The presence of mesangial labeling of IgM or C1q has no significance in any of these 3 disorders. The classification of disorders associated with nephrotic syndrome or asymptomatic proteinuria must concentrate less on the presence or absence of focal sclerosis and more on the histologic appearance of the rest of the glomeruli.

Adolescent↗
PubMed1996

Maternal-specific methylation of the human IGF2R gene is not accompanied by allele-specific transcription.

The human insulin-like growth factor type 2 receptor gene (IGF2R) is biallelically expressed in a variety of fetal and adult tissues. In contrast, the imprinted mouse Igf2r gene is expressed exclusively from the maternally inherited chromosome. The mouse gene contains two CpG islands that are methylated in a parent-specific manner. Methylation of the CpG island in the promoter region occurs on the repressed paternal gene copy. Methylation of the CpG island in intron 2 is specific for the active maternal allele and may represent the primary imprint. Here, we have analyzed the human IGF2R gene to investigate whether these motifs and their parent-of-origin-specific epigenetic modification have been conserved. As in the mouse, the human IGF2R gene was found to contain two CpG islands, one encompassing the transcription start site (CpG 1) and the other in the second intron (CpG 2). CpG 2 is hypermethylated on the maternal IGF2R allele. In contrast to the situation in the mouse, however, the human CpG 1 is completely unmethylated on both parental chromosomes. The human and mouse intronic CpG islands lack significant sequence homology, which suggests that DNA conformation plays a role in allele-specific methylation.

Alleles↗
PubMed1996

Antibody to C1-inhibitor in a patient receiving C1-inhibitor infusions for treatment of hereditary angioneurotic edema with systemic lupus erythematosus reacts with a normal allotype of residue 458 of C1-inhibitor.

Patients with hereditary C4 deficiency are likely to have severe lupus erythematosus. A patient with hereditary angioneurotic edema (HANE) and systemic lupus erythematosus (SLE) had a chronic deficiency in C4 because the hereditary deficiency in C1-inhibitor allowed the C1 in her serum to become activated and then inactivate C4. An attempt was made to repair the C4 deficiency as well as the deficiency in C1-inhibitor by giving infusions of human C1-inhibitor in the hope of inducing remissions of both HANE and SLE. During treatment, antibody to C1-inhibitor developed in the patient; this cleared when the infusions were stopped. During subsequent treatment with danazol alone, measurable C1-inhibitor developed in the patient's serum, but levels of C4 were never significantly increased. Antibody to normal C1-inhibitor was not expected to develop in the patient because she is heterozygous for this autosomal dominant trait. A normal allotype (VAL or MET 458), which would have been in the preparation used but which the patient does not synthesize because she can produce only one allotype (MET 458), appears to have been immunogenic. The antibody isolated from the patient's serum reacted with C1-inhibitor from a normal individual known to be homozygous for 458-VAL but not with one from a homozygote for MET-458.

Adult↗
PubMed1996

Regulated expression of complement factor B in the human kidney.

We have previously demonstrated regulated expression of C3 in the proximal renal tubular epithelial cells of humans. To test the hypothesis that local alternative pathway complement activation could contribute to the tubulointerstitial component of chronic renal disease, we examined factor B gene expression in human kidneys. 35S riboprobes were generated from a human factor B cDNA. By in situ hybridization, proximal tubular factor B message was seen in 17 kidneys with various nephropathies. The expression was most intense in organs with evidence of interstitial inflammation, and its localization paralleled the inflammation. As was the case with C3 and C4, there was never any evidence of glomerular factor B message, nor was any seen in infiltrating inflammatory cells. In eight normal kidney tissues, factor B expression was either absent or restricted to rare foci of interstitial infiltration. The proximal renal tubular epithelium of humans appears to express the genes for both components of the alternative pathway convertase, C3 and factor B. These locally produced components may be important mediators of the interstitial inflammation that is common to all progressive nephritides.

Base Sequence↗
PubMed1996

Variables related to urinary calcium excretion in young girls.

The relations among dietary and calcium kinetic factors and 24-h urinary mineral excretion were evaluated in a group of 89 healthy girls (51 white and 38 black) aged 4.9-16.7 years. Nutrient intakes were calculated for each participant using a weighed intake of all food and beverage on the day of the 24-h urine collection study and two subsequent 24-h food records. A significant relation was noted between urinary calcium and sodium excretion (r = 0.55; p < 0.0001). No significant relations were found between urinary calcium and (a) calcium intake (r = 0.08), (b) protein intake (r = 0.14), or (c) phosphorus intake (r = 0.11). Urinary calcium was not significantly related to fractional calcium absorption (r = 0.03) or net calcium absorption (r = 0.11), but was significantly associated with the bone calcium deposition rate (r = 0.24; p < 0.03). Using a multiple regression model, both urinary sodium and the bone calcium deposition rate were independent predictors of urinary calcium excretion in this population (r = 0.57; p = 0.0001). A substantial number of the children in this population had urinary calcium excretion > 4 mg/kg/day (12%). The incidence of hypercalciuria differed between the racial groups and was markedly higher in the white than in the black children (17.6 vs. 5.3%). Over a range of usual calcium intakes, during the rapid-bone-growth period in childhood and early adolescence, urinary calcium appears relatively unaffected by calcium intake and is most strongly associated with urinary sodium levels.

Absorption↗
PubMed1996

Short-term experimental hypercalciuria does not produce hematuria in normal subjects.

Hypercalciuria in the absence of urolithiasis has been considered to be a cause of asymptomatic hematuria. No mechanism for this association has been demonstrated. In an effort to establish the specificity of this association, we induced hypercalciuria in 10 healthy subjects by oral administration of 1,25(OH)2 vitamin D for 10 days. This protocol reproducibly produced markedly increased urinary calcium excretion (mean calcium:creatinine ratio 0.5). Despite this, no subject developed hematuria as seen by dipstick urinalysis or by alteration in erythrocyte Addis counts (mean counts 1.02 x 10(6)/12 h before vitamin D and 0.84 x 10(6)/12 h after 10 days of therapy). This study provides no evidence that short-term hypercalciuria alone produces hematuria in otherwise healthy individuals.

Adult↗
PubMed1995

Glomerulonephritis associated with complete deficiency of the fourth component of complement. Response to intravenous immunoglobulin.

A 15-year-old girl with complete C4 deficiency and a lupus-like disorder developed evidence of nephritis after 4 years of followup. Renal biopsy demonstrated an immune complex glomerulonephritis, with deposits in the capillary loops, the paramesangium, and the mesangial matrix. Renal function was normal. The patient was treated with monthly infusions of intravenous immunoglobulin for 6 months. The treatment was well tolerated, and resulted in resolution of the rash and hematuria. Followup biopsy showed less proliferation and fewer loop deposits. In light of the serious risk of infections that is associated with complement deficiency, approaches to glomerulonephritis that do not include immunosuppression should be considered.

Adolescent↗
PubMed1995

C3-independent glomerulonephritis in guinea pigs: dependence upon primary humoral response.

We used C3-deficient (C3D) guinea pigs to evaluate the role of C3 in an active model of experimental nephritis. Normal strain 2 (C3N, n = 13) and C3D (n = 6) guinea pigs were immunized with cationized bovine gamma-globulin (CBGG). Fourteen days later (Day 0), daily intravenous injections of CBGG were given for 3 to 7 days and the animals were sacrificed on Day 10 or 21. Immunofluorescence (IF) microscopy of renal tissue revealed two patterns of glomerular IgG deposition: granular loop (11/13 C3N, 3/6 C3D), and predominantly mesangial (2/13 C3N, 3/6 C3D). Codeposited C3 was seen in all C3N and in no C3D animals. Electron microscopy showed subepithelial deposits in all. A significant correlation (P < 0.005) was seen between an animal's IF pattern and its level of serum antibodies to CBGG; those with lower antibody levels exhibited the mesangial pattern. C3D animals had lower mean antibody levels than C3N (P < 0.01), but both IF patterns were represented. Urine protein concentration, which was increased relative to controls, did not differ between C3N and C3D groups, but was significantly greater in those with loop IF. Serum albumin was significantly reduced in animals with loop IF. C3N animals showed a significant reduction in mean serum C3. In this model, immune deposit location and degree of proteinuria are independent of C3 deposition and dependent upon the level of antibody response to CBGG. Induction of antibody to CBGG is impaired in the absence of C3.

Animals↗
PubMed1995

Absence of hepatitis B and C viruses in pediatric idiopathic membranoproliferative glomerulonephritis.

The blood-borne hepatitis viruses, hepatitis B virus (HBV) and hepatitis C virus (HCV), have similar epidemiological features. The association of chronic HBV infection and glomerulonephritis is well established, particularly in children. Recent reports have shown an association between HCV infection and glomerulonephritis in adults. In order to assess the role of these hepatotropic viruses in membranoproliferative glomerulonephritis (MPGN) we screened 34 children with idiopathic MPGN for the presence of HBV and HCV infection using highly sensitive polymerase chain reaction techniques for the detection of HBV DNA and HCV RNA. Also, enzyme-linked immunosorbent assays were used to detect the presence of antibody to hepatitis B surface antigen and antibody to HCV. No evidence of HBV or HCV infection was demonstrated in any of the patients. We conclude that HBV and HCV are not significant causes of idiopathic MPGN in children in the United States.

Adolescent↗
PubMed1995

Precise determination of the absorptive component of urinary calcium excretion using stable isotopes.

Some patients with hypercalciuria are thought to have enhanced enteric calcium absorption, with a major component of recent diet contributing to urinary calcium. This mechanism has been difficult to test with the usual calcium loading procedures. We employed dual stable calcium isotope tracers to quantitate the components of urinary calcium excretion in 38 healthy female children. The mean urinary calcium excretion in these girls was 2.4 mg/kg per day. The contribution of recent diet to this total was a mean of 0.2 mg/kg per day. The maximum dietary contribution to urinary calcium excretion was 0.86 mg/kg per day. Recent diet contributes a mean of 8% to total dietary calcium excretion. This novel method permits precise quantitation of the contributions of recent diet and tissue stores to urinary calcium excretion. In these healthy girls, the fraction of urinary calcium derived from diet is trivial.

Absorption↗
PubMed1995

Giardiasis as a threat to backpackers in the United States: a survey of state health departments.

Forty-eight of the 50 state health departments in the United States responded to a questionnaire about giardiasis in their jurisdictions. The agencies had reports of 34348 cases during 1991 and studied 80 outbreaks in the same period. Nineteen of these outbreaks were attributed to consumption of contaminated drinking water; only two outbreaks were reported among individuals identified as campers or backpackers. Only two departments considered water-associated giardiasis to be a problem for backpackers in their jurisdiction, and neither had any data to support this concern. The surveillance data of health departments indicate that giardiasis is a common communicable disease in the United States. They do not, however, provide any evidence that wilderness water is an important cause of the disease in this country.

Camping↗
PubMed1994

Glomerulonephritis in Henoch-Schöenlein purpura without mesangial IgA deposition.

Ten patients with Henoch-Schöenlein purpura (HSP) were selected for study because their early renal biopsies showed focal and segmental hypercellularity, with IgA present only in deposits at the periphery of the lobules. Mesangial deposits of IgA were absent. All had laboratory evidence of nephrotic syndrome and/or renal compromise. The glomerular hypercellularity was largely the result of the infiltration of monocytes whose cytoplasm often contained tubular lysosomes and wrapping lysosomal membranes, evidence of monocyte activation. Mean levels of C3 were normal but those of C4 and properdin significantly depressed. This complement profile, as well as a glomerular monocytic infiltrate, are also seen in essential cryoglobulinemia in the adult. Of follow-up biopsies in six patients, the glomeruli were normal in three, with no IgA deposition. In the other three, mesangial deposits of IgA typical of HSP were present. The initial focal-segmental glomerulitis of these patients appeared to be the benign first phase of a disease which had the potential to culminate in mesangial IgA deposition. Patients like the three who escaped mesangial IgA would be among those responsible for the observed dissociation between severity of the initial illness and ultimate prognosis.

Adolescent↗
PubMed1994

Hypercalciuria in premature infants receiving high mineral-containing diets.

We evaluated urinary calcium excretion in 21 premature infants fed either a formula containing high concentrations of calcium (Ca) and phosphorus (P) or human milk fortified with a commercially available human milk fortifier. Dual-tracer stable-isotope Ca absorption studies were performed on all infants. Urinary Ca excretion was not significantly related to Ca or P intake or true Ca absorption. The recovery of the orally administered tracer in the urine was used to evaluate the source of calciuria in study subjects. In almost all subjects, tissue-derived (Vbu), rather than diet-derived (Vou), Ca was the principal source of urinary Ca. Hypercalciuric subjects demonstrated greater Vbu and Vou than nonhypercalciuric subjects. Our data demonstrate that moderate hypercalciuria is common in premature infants whose diets are high in mineral content and that hypercalciuria is not related to inadequate mineral intake or Ca absorption but is related, instead, to losses of both tissue and dietary Ca.

Birth Weight↗
PubMed1993

DP polymorphism in HLA-A1,-B8,-DR3 extended haplotypes associated with membranoproliferative glomerulonephritis and systemic lupus erythematosus.

We and others have shown an association between autoimmune disorders and the major histocompatibility complex extended haplotype HLA-A1,-B8,-SCO1,-DR3. The primary gene or genes within this haplotype conferring such susceptibility, however, have not been defined. In this study, we tested the hypothesis that linkage disequilibrium in this haplotype extends through the DP locus, and that DP type may be linked to membranoproliferative glomerulonephritis (MPGN) and systemic lupus erythematosus (SLE). DP and DQ typing was performed by restriction fragment length polymorphism analysis for 43 chromosomes (19 healthy controls, 9 SLE, 15 MPGN) bearing the -A1,-B8,-SCO1,-DR3 extended haplotype. Although all were DQw2, a variety of DP types were identified (DPw1, 0.26; DPw2, 0.09; DPw3, 0.14; DPw4, 0.44). Although DPw1 was represented on extended haplotypes with greater frequency than on 113 non-A1,-B8,-SCO1,-DR3 haplotypes (0.26 vs. 0.03; P < 0.001), there were no significant differences between healthy individuals with this haplotype and those with autoimmune disease. We conclude that the strong linkage disequilibrium of this haplotype breaks down between the DQ and DP loci. Loci important to disease susceptibility, therefore, are more likely to occur telomeric to DP.

Blotting, Southern↗
PubMed1993

Differential expression of complement C3 and C4 in the human kidney.

Complement activation is associated with a variety of immunologically-mediated renal diseases. Proximal tubular epithelial cells in situ constitutively express messenger RNA for C4 of the complement system. These same epithelial cells in culture have been reported to contain message for C3 and to secrete this protein when stimulated by IL-2. The present study compared the in situ localization of C3 and C4 message in parallel in a variety of renal biopsy and nephrectomy specimens. All adequate tissue samples (n = 23) had C4 mRNA throughout in the cortical tubular epithelium. Although C3 message was also expressed in tubular epithelial cells, there was much greater variation in its distribution. mRNA for C3 was not detected in histologically normal specimens (n = 4) either by in situ or Northern hybridization. Focal C3 message correlated with focal histologic abnormalities (e.g., focal glomerulosclerosis), while more generalized C3 signal occurred in specimens with more diffuse inflammatory processes (e.g., SLE). Infiltrating inflammatory cells and cells of the glomeruli were uniformly negative for C3 (and C4) message. Tubular C3 and C4 mRNA appeared to be translated, since selected specimens showed cytoplasmic staining by monoclonal antibodies to C3c and C4c. These observations are consistent with the hypothesis that local production of inflammatory mediators could induce C3 synthesis in the renal interstitium, with the possibility that subsequent complement activation could enhance the pathogenic process.

Complement C3↗