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Biomedical subjects

J M Friedman

Publications and source records attributed to J M Friedman.

At least 163 records · Page 9Linked to original sources
PubMed1993

Recommendations on the use of folic acid supplementation to prevent the recurrence of neural tube defects. Clinical Teratology Committee, Canadian College of Medical Geneticists.

OBJECTIVE: To prevent the recurrence of neural tube defects (NTDs) in families at increased risk of having offspring with NTDs with the use of periconceptional folic acid supplementation. OPTIONS: Genetic counselling and prenatal diagnosis of NTDs. OUTCOMES: NTDs cause stillbirth, neonatal death and severe disabilities. The cost for medical care and rehabilitation in the first 10 years of life of a child with spina bifida cystica was estimated to be $42,507 in 1987. EVIDENCE: The authors reviewed the medical literature, communicated with investigators from key studies, reviewed policy recommendations from other organizations and drew on their own expertise. A recent multicentre randomized controlled trial showed that among women at high risk of having a child with an NTD those who received 4 mg/d of folic acid had 72% fewer cases of NTD-affected offspring than nonsupplemented women. Two previous intervention studies also demonstrated that folic acid supplementation was effective in reducing the rate of NTD recurrence. Several retrospective studies support this conclusion. VALUES: Recommendations are the consensus of the Clinical Teratology Committee of the Canadian College of Medical Geneticists (CCMG) and have been approved by the CCMG Board. The committee believes that primary prevention of NTDs is preferable to treatment or to prenatal detection and abortion. BENEFITS, HARMS AND COSTS: Folic acid supplementation should result in fewer NTDs among infants in Canada and ancillary savings in medical costs. The recommended dosage of folic acid is not known to be associated with adverse effects. Higher dosages of folic acid may make vitamin B12 deficiency difficult to diagnose and may alter seizure frequency in patients with epilepsy due to drug interactions with anticonvulsants. RECOMMENDATIONS: A minimum dosage of folic acid of 0.8 mg/d, not to exceed 5.0 mg/d, is recommended along with a well-balanced, nutritious diet for all women who are at increased risk of having offspring with NTDs and who are planning a pregnancy or may become pregnant. Supplementation should begin before conception and continue for at least 10 to 12 weeks of pregnancy. VALIDATION: These guidelines are similar to those of the Society of Obstetricians and Gynaecologists of Canada, the US Centers for Disease Control and Prevention and the Department of Health in Britain. SPONSORS: These guidelines were developed by the CCMG Clinical Teratology Committee and endorsed by the Board of the CCMG. No funding for the development of these guidelines was obtained from any other sources.

Female↗
PubMed1993

Pattern of cardiac malformation in oculoauriculovertebral spectrum.

The reported prevalence of congenital heart defects (CHD) in the oculoauriculovertebral "spectrum" (OAVS) is 5-58%. This variability is mainly due to differences in the diagnostic criteria used, and to ascertainment bias introduced by selection of patients from different specialty databases. Two-thirds of the cardiac anomalies reported are either tetralogy of Fallot (TOF) or ventricular septal defect (VSD). We found a CHD frequency of 19% in a series of 32 patients identified either through a genetic or autopsy database. The cardiac lesions were much more varied and complex than previously reported and included asplenia syndrome, ventricular inversion associated with double outlet right ventricle, pulmonary atresia with VSD, double outlet right ventricle, and infradiaphragmatic total anomalous pulmonary venous connection. Pulmonary and renal abnormalities were more common in OAVS patients with CHD than in those where the heart was normal.

Canada↗
PubMed1993

Heme-heme interactions in a homodimeric cooperative hemoglobin. Evidence from transient Raman scattering.

The comparison of the resonance Raman spectrum of the deoxy dimeric hemoglobin (HbI) from the Arcid clam, Scapharca inaequivalvis, to its CO photoproduct at 10 ns reveals several significant differences in the low frequency vibrational modes including those involving motions of the peripheral substituents on the heme such as the propionates. This finding reflects the involvement of the propionates in a hydrogen bonding network which connects the two heme groups across the subunit interface and is sensitive to ligand binding. A frequency difference in the iron-histidine stretching mode of 6 cm-1 in this invertebrate hemoglobin is substantially smaller than that detected in tetrameric vertebrate hemoglobins under similar conditions. Time evolution studies of the vibrational modes from the photoproduct demonstrate that the transient form relaxes to the deoxy structure concertedly with a half-life of 1 microseconds, the time scale in which tertiary relaxations of tetrameric hemoglobins occur. These data establish that the tertiary and quaternary structural changes take place on the same time scale and confirm a mechanism of cooperativity involving direct interaction between the two heme groups through the peripheral substituents. This direct structural communication provides a very tight linkage between the heme groups prohibiting modulation of the oxygen affinity by factors in the physiological milieu.

Animals↗
PubMed1993

Heme-CO religation in photolyzed hemoglobin: a time-resolved Raman study of the Fe-CO stretching mode.

Time-resolved resonance Raman spectroscopy has been employed to monitor geminate heme-CO rebinding in photolyzed HbCO. The excitation frequency was tuned to enhance the scattering from rebound heme sites 20-500 ns subsequent to CO photolysis. The behavior of vFe-C during ligand rebinding has important ramifications concerning heme pocket dynamics of the distinct equilibrium configurations of the six-coordinate heme sites. During the geminate phase of recombination, the Fe-CO bond strengths and configurations of the rebound sites (inferred from the positions and line widths of vFe-C) were found to be the same as those of equilibrium configurations of HbCO within 500 ns of CO photolysis for all samples. No evidence was found for the existence of transient metastable configurations during geminate recombination. Spectra obtained at earlier times (100 ns) revealed small differences in the geminate rebinding rates of the two equilibrium configurations. Since there is little or no further CO rebinding between 100 and 500 ns after photolysis, some interconversion must occur between the dominant HbCO configurations on a submicrosecond time scale.

Carboxyhemoglobin↗
PubMed1993

National Neurofibromatosis Foundation International Database.

The National Neurofibromatosis Foundation International Database is a system for collecting comprehensive information on the clinical manifestations and natural history of neurofibromatosis. Data are entered into personal computers at participating centres and are pooled at the Central Database and coordinating centre in Vancouver, Canada. The system includes special mechanisms to assure consistency among centres and to maintain patient confidentiality. The database is designed to foster collaborative clinical and molecular genetic research in many aspects of neurofibromatosis.

Canada↗
PubMed1993

Microdissection and microcloning of mid-chromosome 4: genetic mapping of 41 microdissection clones.

Available genetic information places the mouse db gene approximately 5 cM distal to Ifa on mid/distal mouse chromosome 4. These data have indicated that there is a relevant paucity of genetic markers that map to this region of chromosome 4. To increase the density of the genetic map on mid-chromosome 4, we have applied the techniques of microdissection and microcloning of the mid-portion of mouse chromosome 4. A total of 47 RFLPs from the microdissection library were used to type the progeny of three C57BL/6J Mus spretus backcrosses. The resulting composite genetic map positions seven known genes, 41 microclones, and three other anonymous markers to a region of approximately 21 cM on mid-chromosome 4 extending from b to Lck. The density of markers in this region of chromosome 4 should be sufficient to initiate the physical mapping of this subchromosomal segment, facilitating efforts to clone the db gene, as well as other uncloned mutant loci in this region of chromosome 4.

Animals↗
PubMed1993

Microdissection of proximal mouse chromosome 6: identification of RFLPs tightly linked to the ob mutation.

In a previous report, the ob mutation was mapped to a position 5 cM distal to Met on murine Chromosome (Chr) 6 in tight linkage to Cpa. In order to identify additional RFLPs in the region of ob, we have made use of chromosome microdissection of a 6:16 Robertsonian chromosome. In total, 19 RFLPs were used to type 131 progency of a B6D2 ob/ + x B6 spretus ob/ + intercross. Fifteen of the RFLPs mapped to Chr 6, one of which, D6Rck13, was tightly linked to ob. For refinement of the genetic map around ob, 350 obese progency of a B6 Mus castaneus ob/ + intercross were characterized. DNAs from these animals were typed for microsatellite markers from Chr 6 that flank ob. Recombinants were then typed for D6Rck13. D6Rck13 was nonrecombinant among all the progency of both crosses corresponding to 831 meioses. This probe will be of use as an entry point for physical mapping of the ob mutation.

Animals↗
PubMed1993

The medical status of methadone maintenance patients in treatment for 11-18 years.

To assess the safety and potential health consequences of long-term methadone maintenance treatment, we identified 111 male patients admitted to methadone maintenance treatment between 1965 and 1968, still enrolled in 1980 and in continuous treatment for at least 10 years. We were able, between 1980 and 1985, to examine patients or review records of 110 patients (99%). Most medical diagnoses, symptomatic complaints, physical examination findings and laboratory test results occurred with similar frequency in the long-term methadone maintenance patients and in a group of 56 long-term heroin addicts. These data suggest that prolonged methadone maintenance treatment is safe and is not associated with unexpected adverse effects.

Adult↗
PubMed1993

Strategies for the molecular genetic analysis of obesity in humans.

Studies of twins, adopted children, and some human populations indicate that body composition is significantly influenced by genetic factors. However, in no specific instance in either man or animals is the precise etiology of obesity known at the molecular level. Attempts to identify the molecular basis of obesity in humans have been hampered by difficulties in measuring food intake and energy expenditure with sufficient accuracy, as well as the apparent polygenic control of body composition in man. These constraints have stimulated interest in inbred animal strains, particularly mice, that have a genetic predisposition to obesity. Using the techniques of positional cloning, molecular markers flanking two autosomal recessive mouse obesity mutants (ob and db), which demonstrate a metabolic/behavioral phenotype similar to that observed in obese humans, have been identified. These markers are being used: (1) as starting points for chromosome walks to identify these genes, (2) as an aid in identifying genetically obese rodents prior to the development of the experimentally confounding obese phenotype, and (3) to investigate the possible contribution of the ob and db gene products to obesity in families segregating an obese phenotype. Additionally, genetic crosses segregating these obesity mutations are being used to identify "polygenes" that influence the severity of obesity and type II diabetes. Such studies may ultimately lead to the characterization of genes that influence the development and severity of obesity and non-insulin-dependent diabetes (NIDDM) in humans.

Animals↗
PubMed1992

Williams syndrome in adults.

There are few published reports of adults with Williams syndrome (WS). We have evaluated ten adult WS patients. The patients in our study were very variable in clinical presentation, ranging from severely affected patients with complicated medical histories to mildly affected patients who are generally in good health. Cardiovascular anomalies and hypertension were frequent. Supravalvular aortic stenosis was seen in four patients, mitral valve prolapse in three, bicuspid aortic valve in one, valvular aortic stenosis in one, and pulmonary stenosis with right ventricular hypertrophy in one. Typical facial features included stellate irides, prominent cheeks, full lips, and micrognathia. Mental retardation was seen in all patients. Verbal skills were better developed than motor skills. All patients in our study lead active lives, and most are involved in sports. Some hold supervised jobs. Eight of our patients live with their parents and two in group homes. Independent living is restricted by their mental and adaptive limitations.

Abnormalities, Multiple↗
PubMed1992

Complementary duplication and deletion of 17 (pcen----p11.2): a family with a supernumerary chromosome comprised of an interstitially deleted segment.

A sister and brother were investigated because both were developmentally delayed although they had somewhat different physical anomalies. The girl was found to have an interstitial deletion of chromosome 17. Her karyotype was 46,XX,del(17) (pter----p11.2::cen----qter). Her brother had normal chromosomes in peripheral lymphocytes. Cytogenetic investigation of the mother showed the presence of the same deletion as in her daughter and a small supernumerary chromosome. The supernumerary chromosome appeared to contain the material deleted from the short arm of 17 since the mother's phenotype was normal. Study of skin fibroblasts in her son showed that he was mosaic for a normal cell line and one that contained the extra small chromosome; thus, he had mosaic partial trisomy 17(cen----p11.2). The origin of the centromere and telomere(s) of the small supernumerary chromosome in this family presents an interesting problem.

Centromere↗
PubMed1992

Expression of the cholecystokinin gene in pediatric tumors.

We have examined a wide range of cultured human tumor cell lines and found that a specific subset of tumors expresses the cholecystokinin (CCK) gene. All neuroepitheliomas (eight) and Ewing sarcoma (eight) cell lines that were tested express CCK RNA. In addition, two of six rhabdomyosarcoma cell lines also express the CCK gene, suggesting that rhabdomyosarcomas are probably heterogenous and that a subset may be similar to Ewing sarcoma and neuroepithelioma. Very few of the positive tumors express completely processed immunoreactive CCK. However, we have used a radioimmunoassay that detects the CCK precursor to demonstrate synthesis of CCK precursor-like peptides by all of the Ewing sarcoma and neuroepithelioma lines that were tested and by the rhabdomyosarcoma cell line that expresses CCK mRNA. These data demonstrate a consistent association of CCK gene expression with a specific group of human neoplasms. The data also add credence to the theory that Ewing sarcoma and neuroepithelioma are derived from the same transformed cell type. Finally, our results suggest that CCK gene expression may serve as a marker to distinguish these tumors, which are considered to be small-round-cell tumors of childhood, from other pediatric tumors.

Cholecystokinin↗
PubMed1992

Crystal structure at 3.5 A resolution of HIV-1 reverse transcriptase complexed with an inhibitor.

A 3.5 angstrom resolution electron density map of the HIV-1 reverse transcriptase heterodimer complexed with nevirapine, a drug with potential for treatment of AIDS, reveals an asymmetric dimer. The polymerase (pol) domain of the 66-kilodalton subunit has a large cleft analogous to that of the Klenow fragment of Escherichia coli DNA polymerase I. However, the 51-kilodalton subunit of identical sequence has no such cleft because the four subdomains of the pol domain occupy completely different relative positions. Two of the four pol subdomains appear to be structurally related to subdomains of the Klenow fragment, including one containing the catalytic site. The subdomain that appears likely to bind the template strand at the pol active site has a different structure in the two polymerases. Duplex A-form RNA-DNA hybrid can be model-built into the cleft that runs between the ribonuclease H and pol active sites. Nevirapine is almost completely buried in a pocket near but not overlapping with the pol active site. Residues whose mutation results in drug resistance have been approximately located.

Azepines↗