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Biomedical subjects

M Fischbach

Publications and source records attributed to M Fischbach.

At least 19 recordsLinked to original sources
PubMed2001

[Tetralogy of Fallot in monozygotic twins].

UNLABELLED: The causative mechanisms of congenital heart defects remain unclear and little is known about the respective implication of chance, genetics and environment, though recent findings in molecular biology may provide further insight into understanding the pathophysiologic basis of congenital heart diseases. CASE REPORT: We report the exceptional but significant case of monozygotic twins both affected by tetralogy of Fallot, for whom prenatal diagnosis ruled out 22q11 microdeletion. CONCLUSION: We discuss how far this observation is consistent with the latest hypothesis, which emphasizes the leading role of genetic factors. Several genes indeed, either separately or in combination, could be responsible for those defects, even if other influences may still come into play.

Chromosomes, Human, Pair 22↗
PubMed2001

Glutathione S-transferase genotypes in systemic sclerosis and their association with clinical manifestations in early disease.

The glutathione S-transferases (GSTs) are a family of enzymes involved in limiting oxidative damage to tissues. Null alleles for one or more of the GST enzymes, especially GSTM1, reportedly occur more frequently in patients with Sjögren's syndrome and systemic lupus erythematosus who possess certain autoantibodies. Because systemic sclerosis (SSc) is a disease in which oxidative damage has been hypothesized to contribute both to immune dysfunction and tissue damage, we sought to determine if patients from a multi-ethnic cohort of SSc patients with early disease (< or =5 years) were more likely than ethnically-matched normal controls to have null alleles for GSTM1 (M1) and/or GSTT1 (T1), and if the null allele status correlated with any major disease features. The data show that while M1 and T1 null genotypes were not significantly increased in SSc compared to ethnically matched controls, their frequencies (especially T1 nulls) were significantly higher among SSc patients with hypertension and pulmonary involvement. This suggests that GST genotype may be a genetic factor that contributes to clinical disease expression in SSc.

Genotype↗
PubMed2001

Lack of association of a functionally relevant single nucleotide polymorphism of matrix metalloproteinase-1 promoter with systemic sclerosis (scleroderma).

Matrix metalloproteinase 1 (MMP-1) is necessary for degradation of interstitial collagen types I, II, and III, which are the major constituents of the extracellular matrix (ECM). Increased expression of MMP-1 has been correlated with invasiveness of certain malignancies and cartilage degradation in rheumatoid arthritis. Increased transcriptional activity of MMP-1 has been reported with a single nucleotide polymorphism (SNP) of the MMP-1 promoter. Systemic sclerosis (SSc) is characterized by increased accumulation and turnover of collagen and other components of ECM. Previous studies have reported increased expression of MMP-1 transcripts in SSc fibroblasts. Therefore, we sought to determine if SSc patients with early disease (< or =5 years) from a multi-ethnic cohort were more or less likely than ethnically-matched normal controls to have an increased frequency of the high promoter activity MMP-1 genotype and whether MMP-1 promoter genotypes correlated with any of the major clinical manifestations of SSc. The results show that the frequency of the high activity promoter genotype in either the heterozygous or homozygous state did not differ significantly between SSc patients and ethnically-matched controls, or between SSc patients with either diffuse or limited scleroderma. Furthermore, MMP-1 promoter genotypes did not significantly correlate with any of the major clinical manifestations of SSc.

Humans↗
PubMed2001

Systemic sclerosis in 3 US ethnic groups: a comparison of clinical, sociodemographic, serologic, and immunogenetic determinants.

OBJECTIVE: To determine whether ethnic factors influence the presentation, serologic expression and immunogenetics of systemic sclerosis (SSc), patients from 3 ethnic groups were compared for clinical features, SSc-associated autoantibodies, and human leukocyte antigen (HLA) class II alleles. METHODS: Fifty-four Hispanics, 28 African Americans, and 79 whites from Texas with recent-onset (less than 5 years) SSc enrolled in a prospective longitudinal study were assessed for sociodemographic, clinical, immunologic, immunogenetic, behavioral, and psychologic parameters using validated instruments and standard laboratory techniques. Serologic and immunogenetic characteristics from these patients and larger retrospective SSc cohorts of the same ethnic groups also were examined. RESULTS: Hispanics and African Americans in the prospective cohort were more likely to have diffuse skin involvement, skin pigmentary changes, digital ulcers, pulmonary hypertension (African Americans), and an overall lower sociodemographic status than whites, who had more facial telangiectasia and hypothyroidism. In the larger combined prospective and retrospective groups of SSc patients, whites were likely to have more anticentromere antibodies (ACA) and African Americans more anti-U1-ribonucleoprotein (RNP) and anti-U3-RNP (fibrillarin) autoantibodies. HLA-DQB1*0301 was significantly associated with SSc per se in all 3 ethnic groups; HLA-DRB1*11 correlated with the anti-topoisomerase I antibody response, and HLA-DRB1*01, DRB1*04, and DQB1*0501 with ACA. CONCLUSIONS: Important sociodemographic, clinical, and serologic differences exist between whites, African Americans, and Hispanics, despite shared genetic (HLA class II) predisposing factors. The impact of these differences on prognosis remain to be determined.

Adult↗
PubMed2001

Hemodialysis in children: principles and practice.

Hemodialysis has benefited from major progress over the last decade, improvements in technology and in clinical management. The morbidity over the sessions have decreased, seizures being exceptional, hypotensive episodes or headaches rare and pain related to the fistula puncture is effectively prevented by xylocaine ointment. The development of urea kinetic modeling allows the calculation of the dialysis dose Kt/V, and an indirect assessment of the protein intake. Even if the validity of these parameters are questioned their analyse provides an assessment and therefore is a "good thing." The patient also benefited from the technological revolution. The newer machines provide for precise control of ultrafiltration volumetrically assessed, buffered bicarbonate became a standard technique, biocompatible and highly efficient membranes and specific material available for infants have been developed. More recently the concept of ultrapure dialysate, ie, free of microbiological contamination, germs and endotoxins was developed, as was the availability of continuous blood volume monitoring during the session. The hemodiafiltration modality especially with the on line concept, because of all the advantages, should not be limited only to patients at risk.

Catheters, Indwelling↗
PubMed2001

Effects of automated peritoneal dialysis on residual daily urinary volume in children.

Preservation of residual renal function (RRF) is an important goal. In children, a more rapid decline in RRF has been observed under hemodialysis (HD) therapy as compared with peritoneal dialysis (PD) therapy. In adults, however, automated peritoneal dialysis (APD) may cause a more rapid decline of RRF than continuous ambulatory peritoneal dialysis (CAPD) does. The objective of the present study, a survey in a single center over the last 15 years, was to assess the impact of APD versus hemodiafiltration (HDF) on daily urinary volume (dUV) outcome. We included 97 children who were dialyzed for at least a 12-month period between January 1985 and December 1999, using either HDF (n = 60; 62%) or PD [n = 37; 38% (86% of those on APD)]. The endpoint was anuria occurrence, defined as a dUV below 50 mL/m2 body surface area (BSA) at three consecutive monthly determinations. Despite the use of HDF as hemodialysis therapy (that is, biocompatible membranes and a very low incidence of vascular instability during ultrafiltration), PD--even predominantly prescribed as APD--was associated with better preservation of residual dUV. At dialysis end, anuria occurred in 65% of the children undergoing HD as compared with 23% of those undergoing PD. The mean age of the children at dialysis start was lower in the PD group. No other significant differences were noted between the groups, either for the rate of uropathies or for the RRF at initiation of dialysis.

Adolescent↗
PubMed2000

Delineation of the human systemic lupus erythematosus anti-Smith antibody response using phage-display combinatorial libraries.

The anti-Smith (Sm) autoantibody response is highly specific for systemic lupus erythematosus and is predominantly targeted to the Sm-B/B' and -D1 polypeptides. In all animal species thus far studied, anti-Sm Abs initially recognize proline-rich epitopes in the carboxyl terminus of the Sm-B/B' protein and subsequently to multiple other epitopes in B/B' and D. The absence of appropriate mAbs has limited our understanding of the genetic and structural basis of this autoimmune response. Using phage-display technology and lymphocytes from a systemic lupus erythematosus patient we have generated the first and only panel of human IgG anti-Sm mAbs thus far available. These Abs reproduced to a remarkable extent the serological reactivity of the patient. Epitope mapping and genetic studies revealed that the anti-Sm response is produced by distinct B cell clones with restricted epitope reactivity. All of the Abs in our study were exclusively encoded by different members of the V(H)4 gene family. On the aggregate, our results demonstrate that combinatorial libraries can recapitulate the immune repertoire of peripheral blood B memory cells and that epitope spreading appears to occur through the sequential recruitment of nonclonally related autoreactive B cell clones.

Amino Acid Sequence↗
PubMed2000

Characterization of human anti-acetylcholine receptor monoclonal autoantibodies from the peripheral blood of a myasthenia gravis patient using combinatorial libraries.

Myasthenia gravis (MG) is an autoimmune disease caused by autoantibodies against the nicotinic acetylcholine receptor (AChR). Using phage-display technology we have characterized the largest panel of anti-AChR monoclonal antibodies thus far isolated from a single patient. Despite having been isolated with either Torpedo AChR or a human peptide, the recombinant antibodies shared with the donor's serum the ability to recognize human AChR expressed in its native configuration on the surface of TE671 cells. Their specificity for the main immunogenic region (MIR) of the AChR was demonstrated using a synthetic peptide corresponding to the region 67-76 of the human AChR alpha subunit and by inhibition of a highly pathogenic rat anti-MIR monoclonal antibody (mAb35). This work demonstrates the value of combinatorial libraries in isolating pathogenic autoantibodies from peripheral blood lymphocytes. Future genetic, structural, and functional analyses of the monoclonal antibodies reported herein should enhance our understanding of the pathogenesis of MG.

Animals↗
PubMed2000

Impact of fill volume changes on peritoneal dialysis tolerance and effectiveness in children.

In the last decade, it has became apparent that the prescribed fill volume (IPV) in children on peritoneal dialysis (PD) should be expressed per body surface area (BSA in square meters) to avoid a false perception of peritoneal hyperpermeability as determined during a peritoneal equilibration test [PET, dialysate-to-plasma (D/P) ratio]. Nevertheless, the optimal IPV in terms of both tolerance and effectiveness remains under discussion. An individual approach to IPV prescription might balance the measurement of the intraperitoneal pressure, the use of the mass transfer coefficient despite the D/P ratio, and a determination of the effective peritoneal area available for exchanges. Considering these parameters, we usually found the individual optimal fill volume to be less than 1400 mL/m2.

Body Surface Area↗
PubMed1999

The optimal approach to peritoneal dialysis prescription in children.

OBJECTIVE: To describe the optimal approach to peritoneal dialysis (PD) prescription in children. DESIGN: Review of the available literature. RESULTS: Unlike the situation in adults, the main method used for PD in children is automated peritoneal dialysis (APD). The prone position, while resting, permits the dialysis prescription to use a higher fill volume (IPV), as in continuous ambulatory peritoneal dialysis (CAPD), and is also probably more effective than PD in an upright position. However, because APD is limited to 10 hours, the dialytic effectiveness of nocturnal APD should avoid two potential risks: (1) use of too high an IPV per exchange, inducing lymphatic reabsorption, a factor in unsuitable water and sodium balance [Fischbach M. Peritoneal dialysis prescription for neonates. Perit Dial Int. 1996; 16(Suppl):S52-4]; and (2) use of too short a dwell time per exchange, limiting the purification of creatinine and phosphate despite an apparently adequate urea purification (Malhotra C, Murota GH, Tzamaloukas AH. Creatinine clearance and urea clearance in PD: What to do in case of discrepancy. Perit Dial Int. 1997; 17:532-5).

Biological Transport↗
PubMed1999

A three generations family with blepharo-naso-facial malformations suggestive of Pashayan syndrome.

Blepharo-naso-facial syndrome, described by Pashayan et al. (10), is characterized by telecanthus, lateral displacement and stenosis of lacrimal puncta, bulky nose, mask-like facies, trapezoïdal upper lip, torsion dystonia and mental retardation. We report on a family with this rare malformation syndrome, confirming the existence of this syndrome and its dominant inheritance. The proband had a fleshy nose, a prominant nose bridge, an hypoplastic midface, telecanthus with temporal displacement of puncta, lacrimal excretory obstruction. CNS torsion dystonia, increased deep tendon reflexes, Babinski reflexes, poor coordination and joint laxity. The proband's mother, brother and maternal grandfather also showed manifestations of the syndrome. The proband and his brother had delayed developmental milestones. Hearing impairment was present in the proband, his mother and his grandfather but was absent in the proband's brother. The blepharonasofacial syndrome was described by Pashayan et al. (10) in four members of one family, two male and one female sib and their mother. Two other sibs were unaffected. Many of the features of the blepharo-facio-nasal syndrome also occur in other well known syndromes i.e. Waardenburg syndrome. The pedigrees of the family of Pashayan et al. (10) and of our family are compatible with Mendelian dominant inheritance, either autosomal or X-linked. X-linked dominant inheritance cannot be ruled out except by male-to-male transmission, which does not occur in these families. Pashayan et al. (10) suggested that an autosomal gene with variable expressivity appears more likely. More families are needed for defining the transmission of the condition and for mapping the gene involved in the blepharo-naso-facial syndrome.

Abnormalities, Multiple↗
PubMed1998

Glucose-charged dialysate for children on hemodialysis: acute dialytic changes.

Glucose has been omitted from hemodialysates in the recent past. Currently, there is a tendency to include glucose in dialysates at physiological concentrations between 100 and 200 mg/dl (5.56-11.12 mmol/l). In adult patients, this induces, over the dialysis session, a significant uptake of glucose, with some benefits, i.e., avoidance of caloric loss, but also with some metabolic risks, i.e. decreased dialytic potassium removal secondary to an insulin-dependent intracellular potassium shift. We have performed a crossover study in five stable children (mean age 11.7 years) with normal fasting glucose on chronic bicarbonate hemodialysis. The dialysis prescription of 3-h sessions was changed only in terms of the glucose dialysate concentration, being either glucose free or containing 9.17 mmol/l (165 mg/dl) glucose; dialysates were potassium free. Twenty sessions were analyzed for each group by whole dialysate collection (glucose, potassium, phosphate) and serum concentration analysis during and post dialysis (glucose, potassium, phosphate, insulin). Glucose-free dialysis was associated with a patient net glucose loss of 113 +/- 12 mmol/session (nearly 20 g). Conversely, with the glucose-charged dialysate a small uptake of glucose was noted [13.8 +/- 2.1 mmol/session (nearly 2 g)]. At the end of the session, serum glucose was lower with the glucose-free dialysate (4.64 +/- 0.52 mmol/l) than the glucose-charged dialysate (6.11 +/- 0.92 mmol/l). Conversely, serum insulin was higher with the glucose-charged dialysate (38 +/- 17 mU/l) than the glucose-free dialysate (19 +/- 9 mU/l). There were no significant differences either for dialytic removal of potassium (70 vs. 73 mmol/session) or phosphate (20 vs. 22 mmol/session), with and without glucose dialysates. Our study, contrary to previously published data in adults, demonstrated that in children the use of a physiological concentration of glucose in the dialysate (165 mg/dl) avoids dialytic glucose loss without a significant decrease in dialytic potassium removal.

Bicarbonates↗
PubMed1998

Effect of posture on intraperitoneal pressure and peritoneal permeability in children.

The posture of the patient influences both the intraperitoneal pressure (IPP) and the peritoneal permeability. We have studied the effects of the supine and the upright position in six children. Two peritoneal equilibration tests (PET) of 90-min dwell time each were performed consecutively, firstly in the supine position and then in the upright position. The same amount of dialysate was instilled (1,000 ml/m2; isotonic 1.36% dextrose) for each PET. Using the same filling volume, the IPP was significantly higher in the upright position (18.4 +/- 4.8 cm H2O) than in the supine position (8 +/- 2.4 cm H2O). The mean percentage IPP increase was 130% +/- 35%. The decline in glucose resorption rate from the dialysate during the PET was significantly lower in the upright position. Despite this greater relative loss of osmotic gradient in the upright than the supine position, no significant difference in net ultrafiltration was noted after 90 min of dwell. The peritoneal equilibration ratio during the PET was lower in the upright than the supine position for urea, creatinine, and phosphate. These results favor performing peritoneal dialysis in a supine position, both to increase dialysis efficiency and to reduce patient discomfort.

Adolescent↗