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Biomedical subjects

J Israel

Publications and source records attributed to J Israel.

At least 19 recordsLinked to original sources
PubMed2001

Comparative effects of different doses of ribavirin plus interferon-alpha2b for therapy of chronic hepatitis C: results of a controlled, randomized trial.

Compared to either drug alone, therapy with the combination of ribavirin and interferon-alpha leads to improved rates of response in patients with chronic hepatitis C. Side effects often mandate downward dose adjustment or cessation of therapy, and the optimal dose of ribavirin has not been established. The aim of this study was to learn whether 600 mg ribavirin per day would prove as efficacious as 1,000-1,200 mg/day when combined with interferon (3 million units thrice weekly) for therapy of patients previously treated with standard interferon who had failed to respond or who had relapsed. We enrolled 69 patients with chronic hepatitis C and compensated liver disease: 45 were men, 65 were Caucasian, 48 were infected with genotype 1 hepatitis C virus. By random assignment, 35 received 600 mg ribavirin/day (group A), whereas the other 34 received 1,000 mg (< or = 75 kg body wt) or 1,200 mg/day (>75 kg body wt) (group B). At baseline, the two groups were well matched for demographic and laboratory features. In both groups, mean serum levels of alanine aminotransferase (ALT) and hepatitis C viral (HCV) RNA levels fell promptly and remained significantly lower than baseline throughout 24 weeks of therapy. There was no significant difference in mean levels of ALT or HCV RNA during therapy or at the end of follow-up (24 weeks after cessation of therapy). At the end of 24 weeks of posttherapy follow-up, 12 patients in each group had undetectable HCV RNA in serum, whereas 11 (31%) in group A and 9 (26.5%) in group B had normal serum ALT levels. The lower doses of ribavirin (group A) were tolerated better. In conclusion, in previous nonresponders or relapsers to interferon done, combination therapy with interferon-alpha2b (3 MU thrice weekly) + 600 mg ribavirin/day is tolerated better and is as effective as interferon plus higher (standard) doses of ribavirin (1,000-1,200 mg/day).

Adult↗
PubMed2000

Distinct missense mutations of the FGFR3 lys650 codon modulate receptor kinase activation and the severity of the skeletal dysplasia phenotype.

The fibroblast growth factor-receptor 3 (FGFR3) Lys650 codon is located within a critical region of the tyrosine kinase-domain activation loop. Two missense mutations in this codon are known to result in strong constitutive activation of the FGFR3 tyrosine kinase and cause three different skeletal dysplasia syndromes-thanatophoric dysplasia type II (TD2) (A1948G [Lys650Glu]) and SADDAN (severe achondroplasia with developmental delay and acanthosis nigricans) syndrome and thanatophoric dysplasia type I (TD1) (both due to A1949T [Lys650Met]). Other mutations within the FGFR3 tyrosine kinase domain (e.g., C1620A or C1620G [both resulting in Asn540Lys]) are known to cause hypochondroplasia, a relatively common but milder skeletal dysplasia. In 90 individuals with suspected clinical diagnoses of hypochondroplasia who do not have Asn540Lys mutations, we screened for mutations, in FGFR3 exon 15, that would disrupt a unique BbsI restriction site that includes the Lys650 codon. We report here the discovery of three novel mutations (G1950T and G1950C [both resulting in Lys650Asn] and A1948C [Lys650Gln]) occurring in six individuals from five families. Several physical and radiological features of these individuals were significantly milder than those in individuals with the Asn540Lys mutations. The Lys650Asn/Gln mutations result in constitutive activation of the FGFR3 tyrosine kinase but to a lesser degree than that observed with the Lys540Glu and Lys650Met mutations. These results demonstrate that different amino acid substitutions at the FGFR3 Lys650 codon can result in several different skeletal dysplasia phenotypes.

Adolescent↗
PubMed2000

Iron reduction before and during interferon therapy of chronic hepatitis C: results of a multicenter, randomized, controlled trial.

Patients with chronic hepatitis C and low serum and hepatic iron stores may have an improved response to interferon (IFN). We tested whether iron reduction before and during IFN therapy would lead to an improved sustained biochemical and virological response compared with IFN alone. Eighty-two previously untreated patients with chronic hepatitis C were randomized to either: group A IFN-alpha2b 3 MU 3 times per week for 6 months, or group B iron reduction before and during IFN-alpha2b 3 MU 3 times per week for 6 months. Group B patients had lower mean serum alanine transaminase (ALT) levels than group A patients during treatment and follow-up. Group B patients had significantly lower mean hepatitis C virus (HCV)-RNA levels at treatment weeks 4 and 12 (P <.05). Serum HCV RNA was undetectable at the end of treatment in 15 group B patients compared with 7 group A patients (P =.03); 7 group B patients and 3 group A patients had persistently undetectable serum HCV RNA 24 weeks after the end of therapy (P =.20). Paired pre- and posttreatment liver biopsies in 18 group B patients demonstrated significant improvements in 2 of the 3 inflammation scores of the Knodell histological activity index (P <. 05). No changes occurred in the paired biopsies from 15 group A patients. We conclude that iron reduction via therapeutic phlebotomy improves the end-of-treatment virological and histological response to short-term IFN therapy. Additional studies are needed to determine if iron reduction in combination with higher doses or longer duration of IFN may be of benefit.

Adult↗
PubMed1999

Significance of genetic testing for paternal uniparental disomy of chromosome 6 in neonatal diabetes mellitus.

Two patients who presented at birth with neonatal diabetes mellitus (NDM) are described: one with paternal uniparental disomy for chromosome 6 and one with normal, biparental inheritance. The first child presented with low birth weight, macroglossia, hypertelorism, and club foot in addition to NDM. In this patient hyperglycemia was transient, and insulin treatment was discontinued at 4 months of age. The second child also presented with low birth weight but was normal in appearance, and insulin dependence continues after 5 years. Genetic analysis with polymorphic DNA markers for chromosome 6 indicated the presence of paternal uniparental disomy (UPD) in the first case and normal, biparental inheritance in the second case. Paternal UPD 6 has been reported in 8 previous cases of which 6 showed NDM. Three cases with paternal UPD 6 also included additional anomalies, such as macroglossia, not usually associated with NDM. Therefore the simultaneous finding of NDM and macroglossia should be a strong indicator for genetic testing. The genetic finding of paternal UPD 6 allows prediction of a transient, rather than permanent, form of diabetes mellitus and no increased recurrence risk of transient NDM in subsequent pregnancies.

Aneuploidy↗
PubMed1996

Phenotypic variation in Waardenburg syndrome: mutational heterogeneity, modifier genes or polygenic background?

We have identified 11 mutational changes in the PAX3 gene in patients with type 1 Waardenburg syndrome (WS1) including three in the paired domain, six within or immediately adjacent to the homeodomain and two previously described polymorphic variants in exons 2 and 6. The affected members of one family carried substitutions involving two base pairs separated by one unaltered codon. Two of the deleterious mutations were identical and three others were identical to previously reported mutations. A comparison of clinical findings in families carrying substitutions in the same codon failed to reveal conspicuous similarities. Although subtle mutation-specific effects may well exist, allelic heterogeneity clearly cannot account for within family variation. However, the striking concordance of a pair of monozygotic twins with Waardenburg syndrome (WS) and previous reports of similar pairs indicate that phenotypic variation in WS has a genetic basis. If the genetic effects are mediated by oligogenic epistasis, as studies in the mouse suggest, it may ultimately be possible to predict clinically relevant aspects of the Waardenburg phenotype.

Amino Acid Sequence↗
PubMed1995

Analysis of variability of clinical manifestations in Waardenburg syndrome.

Expression of clinical findings of Waardenburg syndrome type 1 (WS1) and type 2 (WS2) is extremely variable. Using our collection of 26 WS1 and 8 WS2 families, we analyzed the occurrence, severity, and symmetry of clinical manifestations associated with WS. We found significant differences between WS1 and WS2 in deafness, and in pigmentary and craniofacial anomalies. Factor analysis was used to identify manifestations which covaried, resulting in 2 orthogonal factors. Since mean factor scores were found to differ when compared between WS1 and WS2, we suggest that these factors could be useful in distinguishing WS types. We found that the WS gene was transmitted from mothers more often than from fathers. We also extensively examined the W-Index, a continuous measure of dystopia canthorum. Our data suggest that use of the W-Index to discriminate between affected WS1 and WS2 individuals may be problematic since 1) ranges of W-Index scores of affected and unaffected individuals overlapped considerably within both WS1 and WS2, and 2) a considerable number of both affected and unaffected WS2 individuals exhibited W-index scores consistent with dystopia canthorum. Misclassification of families may have implications for risk assessment of deafness, since WS2 families have been reported to have greater incidence of deafness, as confirmed in our study.

Age Factors↗
PubMed1995

Spectrum of X-linked hydrocephalus (HSAS), MASA syndrome, and complicated spastic paraplegia (SPG1): Clinical review with six additional families.

X-linked hydrocephalus (HSAS) (MIM *307000), MASA syndrome (MIM *303350), and complicated spastic paraplegia (SPG1) (MIM *312900) are closely related. Soon after delineation, SPG1 was incorporated into the spectrum of MASA syndrome. HSAS and MASA syndrome show great clinical overlap; DNA linkage analysis places the loci at Xq28. In an increasing number of families with MASA syndrome or HSAS, mutations in L1CAM, a gene located at Xq28, have been reported. In order to further delineate the clinical spectrum, we studied 6 families with male patients presenting with MASA syndrome, HSAS, or a mixed phenotype. We summarized data from previous reports and compared them with our data. Clinical variability appears to be great, even within families. Problems in genetic counseling and prenatal diagnosis, the possible overlap with X-linked corpus callosum agenesis and FG syndrome, and the different forms of X-linked complicated spastic paraplegia are discussed. Since adducted thumbs and spastic paraplegia are found in 90% of the patients, the condition may be present in males with nonspecific mental retardation. We propose to abandon the designation MASA syndrome and use the term HSAS/MASA spectrum, incorporating SPG1.

Agenesis of Corpus Callosum↗
PubMed1994

X-linked pachygyria and agenesis of the corpus callosum: evidence for an X chromosome lissencephaly locus.

A family of 5 affected male infants in 2 generations with an X-linked pattern of inheritance is described. All affected infants manifested intractable seizures, severe psychomotor retardation, growth failure, microphallus, and death during infancy. Three of the affected patients had radiological studies that demonstrated findings consistent with pachygyria-agyria and agenesis of the corpus callosum. We believe that this family represents a form of X-linked pachygyria-agyria (lissencephaly) that has not been described previously and suggests a locus for lissencephaly on the X chromosome.

Agenesis of Corpus Callosum↗
PubMed1994

The spectrum of "complicated spastic paraplegia, MASA syndrome and X-linked hydrocephalus". Contribution of DNA linkage analysis in genetic counseling of individual families.

X-linked hydrocephalus and the X-linked MASA syndrome (Mental retardation. Adducted thumbs, Shuffling gait and Aphasia) both have a variable clinical spectrum with great overlap. Data from DNA linkage analysis placed the locus for both conditions at Xq28. On clinical and molecular grounds it has been hypothesized that both MASA syndrome and X-linked hydrocephalus are caused by a mutation in the same gene at Xq28. There is no significant clinical marker in the obligate female carriers and prenatal diagnosis by ultrasound is not reliable; DNA analysis can offer an improved genetic counseling for the families and more reliable prenatal diagnosis. In the gene encoding for Ll, a neural cell adhesion molecule and located at Xq28, several different mutations have been reported in X-linked hydrocephalus families and in a MASA family. We report data on DNA linkage analysis in 6 families with X-linked hydrocephalus/MASA syndrome. These data illustrate the importance of DNA linkage analysis in the individual family; they also show, however, the problem of studying small families. Genetic heterogeneity cannot be excluded.

Abortion, Eugenic↗
PubMed1992

Innovative approach to genetic counseling services for the deaf population.

Genetic service providers have stressed the importance of genetic counseling that is nondirective and specific to the personal needs of consultants. Successful genetic counseling for deaf persons often requires special provisions for complex family histories, syndromic conditions, and diversity in communication methods and cultural orientation. The Gallaudet University Genetic Services Center (GSC) was established in 1984 to provide genetic education and counseling services to the deaf community. The GSC staff developed and implemented a standardized system of data collection (family and medical history), clinical evaluation by consultant clinical geneticists, and counseling in sign language. In addition to clinical services, an in-depth educational program for professionals and consumers was developed and carried out. During a 6-year period, over 220 educational presentations were made and 659 deaf persons were seen for genetic evaluation and counseling. Most of these persons were self-referred. Sign language was the preferred means of communication of more than 90% of these individuals. A genetic cause of deafness was diagnosed in over 50% of the deaf consultants and was confirmed by segregation analysis, which had results similar to those reported for other studies of students in schools for the deaf. Special materials and strategies were developed in order to provide genetic services that were sensitive to the cultural and linguistic differences of the deaf population. These included written and visual materials that contained culturally neutral terminology and training of all staff members in sign language and the culture of the deaf.

Adolescent↗
PubMed1992

Oculoauriculovertebral anomaly: segregation analysis.

Seventy-four families of probands with oculoauriculovertebral anomaly were evaluated, including 116 parents and 195 offspring. Relatives were examined to identify ear malformations, mandibular anomalies, and other craniofacial abnormalities. For segregation analysis using POINTER, selection of the sample was consistent with single ascertainment. Different population liabilities were used for probands and relatives, because affection was narrowly defined for probands and broadly defined for relatives. The hypothesis of no genetic transmission was rejected. The evidence favored autosomal dominant inheritance; recessive and polygenic models were not distinguishable.

Adult↗
PubMed1992

Genetic counseling for the deaf.

Genetic counseling is a process that emphasizes accurate diagnosis of hereditary conditions and communication of information to families. Genetic counseling involves systematic collection of family and medical history, a physical examination by a certified clinical geneticist, sharing of information with the family, and follow-up and support services. The issues that arise in genetic counseling can differ for every family and are often dependent on the degree of deafness present in the family, age of onset, and linguistic and cultural orientation. It is important for the genetic counselor to consider these factors in the provision of genetic services. With the increasing application of molecular genetics to the diagnosis and management of hereditary deafness and the increasing participation of families with deafness in research studies, the involvement of genetic counselors to provide information and education to consumers as well as medical professionals and researchers is becoming even more critical. The success of genetic counseling for the provision of information to families and the delineation of types of hereditary deafness through clinical and laboratory research is dependent on appropriate referrals by medical professionals, including otolaryngologists. A working relationship between otolaryngologists and clinical geneticists for the referral and evaluation of patients with hereditary deafness or deafness of "unknown" etiology is important.

Adult↗
PubMed1992

Elevated CA19-9 in a case of Mirizzi's syndrome.

At levels greater than 1000 U/ml, the tumor-associated antigen CA19-9 has a specificity approaching 100% for malignant disease. A 67-yr-old woman with known cholelithiasis presented with painless jaundice and a CA19-9 of 1320 U/ml. The diagnosis of Mirizzi's syndrome was made at laparotomy, and the postoperative level fell rapidly to normal. Mirizzi's syndrome should be included among the few benign disorders which can yield such elevations in the CA19-9.

Aged↗
PubMed1991

Replication-defective missense mutations within the terminal protein and spacer/intron regions of the polymerase gene of human hepatitis B virus.

We have analyzed 11 independent mutations located at various domains of the polymerase gene (pol) of human hepatitis B virus. Surprisingly, one of the two missense mutants within the spacer/intron region appears to be lethal. This result further defines the N-terminal limit of the reverse transcriptase domain. Alternatively, it suggests the potential existence of a novel domain with an unknown function. Two missense mutations within the terminal protein (TP) domain appear to be replication-defective as well, suggesting a functionally essential role of the TP domain in DNA replication.

Blotting, Northern↗