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J M Friedman

Publications and source records attributed to J M Friedman.

At least 55 records · Page 3Linked to original sources
PubMed2002

Unidentified bright objects associated with features of neurofibromatosis 1.

Unidentified bright objects are commonly observed on magnetic resonance imaging in young neurofibromatosis 1 patients, but their clinical and pathologic significance is largely unknown. Diagnostic features of neurofibromatosis 1 include café-au-lait spots, intertriginous freckling, Lisch nodules, neurofibromas, bony lesions, and optic glioma. We investigated the relationship between unidentified bright objects and other features of neurofibromatosis 1. Data from the National Neurofibromatosis Foundation International Database included 523 neurofibromatosis 1 patients between 2 and 20 years of age who had cranial magnetic resonance imaging examinations. The presence or absence of unidentified bright objects, diagnostic features of neurofibromatosis 1, and central nervous system neoplasms was known in these patients. Logistic regressive models were used to measure associations between unidentified bright objects and the other features while controlling for age. The occurrence of unidentified bright objects was associated with the number of diagnostic features, but most significantly with central nervous system neoplasms other than optic gliomas [odds ratio (OR) = 9.0, 95% confidence interval (CI) = 1.2-70], optic gliomas (OR = 2.1, 95% CI = 1.2-3.6), subcutaneous neurofibromas (OR = 2.0, 95% CI = 1.3-3.1), and Lisch nodules (OR = 1.6, 95% CI = 1.1-2.3). These findings suggest a common causal mechanism between unidentified bright objects and these cardinal clinical features in children with neurofibromatosis 1.

Adolescent↗
PubMed2002

Pathogenesis of hereditary tumors: beyond the "two-hit" hypothesis.

Knudson's 'two-hit' hypothesis has provided extremely important insights into the pathogenesis of tumors in autosomal dominant tumor predisposition syndromes, but recent evidence suggests that some such tumors may occur without a 'second hit' or require more than two mutations. Inactivation of both RB1 alleles appears to be insufficient by itself to cause malignancy in the tumors that develop in patients with hereditary retinoblastoma. On the other hand, certain tumors in patients with tuberous sclerosis complex appear to develop in haploinsufficient tissues that do not have 'second hit' mutations of a tuberous sclerosis gene. The molecular pathogenesis of certain other tumors in patients with tuberous sclerosis complex or neurofibromatosis 1 may not be fully explained by the 'two-hit' hypothesis either. Hereditary tumors, like non-hereditary tumors, may arise by a variety of molecular mechanisms, with loss of both alleles of a particular tumor suppressor gene being a frequent, but not invariably necessary or sufficient, event. Four models are presented to explain how various tumors may arise in patients with inherited tumor predisposition syndromes such as hereditary retinoblastoma, tuberous sclerosis complex or neurofibromatosis 1. Even tumors of one particular type may develop by more than one mechanism.

Genetic Diseases, Inborn↗
PubMed2002

Neurofibromatosis 1: clinical manifestations and diagnostic criteria.

Neurofibromatosis 1 occurs in 2 to 3 people per 10,000. The most frequent clinical features are café-au-lait macules, neurofibromas, intertriginous freckling, Lisch nodules, and learning disabilities, but optic and other gliomas, malignant peripheral nerve sheath tumors, and characteristic osseous lesions also can be present. Two striking aspects of neurofibromatosis 1 are its progressive nature and its extreme variability. This article reviews the natural history and some important clinical manifestations of neurofibromatosis 1, with emphasis on features that constitute the standard diagnostic criteria. The pathogenic implications of these clinical manifestations are also considered.

Adolescent↗
PubMed2002

Vestibular schwannoma growth in patients with neurofibromatosis Type 2: a longitudinal study.

OBJECT: The factors that determine the growth rates of vestibular schwannomas (VSs) in patients with neurofibromatosis Type 2 (NF2) are unknown. The authors undertook this study to determine if clinical factors or type of constitutional NF2 mutation were associated with VS growth rates in cases of NF2. METHODS: The authors reviewed serial gadolinium-enhanced magnetic resonance (MR) images of the head and full spine of 37 patients with sporadic NF2 who had been observed over periods ranging from 0.2 to 8 years (median 3.9 years) at a specialized referral clinic for NF2. A box model was used to calculate VS volumes so that tumor growth rates could be estimated. Temperature-gradient gel electrophoresis was used to screen for constitutional NF2 mutations. The VS growth rates tended to decrease with increasing patient age at onset of signs or symptoms (r2 = 0.23, p = 0.003) and at the time the baseline gadolinium-enhanced MR image was obtained (r2 = 0.38, p < 0.001). The authors did not find significant associations between VS growth rates and the number of non-VS cerebral or spinal tumors or different types of constitutional NF2 mutations. CONCLUSIONS: There is considerable variability in growth rates of VSs in patients with NF2, but they tend to be higher in patients who are younger at onset of signs or symptoms.

Adolescent↗
PubMed2001

Distinct transcriptional profiles of adipogenesis in vivo and in vitro.

Obesity, defined as an increase in adipose tissue mass, is the most prevalent nutritional disorder in industrialized countries and is a growing problem in developing countries. An increase in adipose tissue mass can be the result of the production of new fat cells through the process of adipogenesis and/or the deposition of increased amounts of cytoplasmic triglyceride per cell. Although much has been learned about the differentiation of adipocytes in vitro, less is known about the molecular basis for the mechanisms regulating adipogenesis in vivo. Here oligonucleotide microarrays have been used to compare the patterns of gene expression in preadipocytes and adipocytes in vitro and in vivo. These data indicate that the cellular programs associated with adipocyte differentiation are considerably more complex than previously appreciated and that a greater number of heretofore uncharacterized gene regulatory events are activated during this process in vitro. In addition, the gene expression changes associated with adipocyte development in vivo and in vitro, while overlapping, are in some respects quite different. These data further suggest that one or more transcriptional programs are activated exclusively in vivo to generate the full adipocyte phenotype. This gene expression survey now sets the stage for further studies to dissect the molecular differences between in vivo and in vitro adipocytes.

3T3 Cells↗
PubMed2001

Beta 93 modified hemoglobin: kinetic and conformational consequences.

The reactive sulfhydryl on Cys beta93 in human adult hemoglobin (HbA) has been the focus of much attention. It has purported functional roles such as a transporter of nitric oxide and a detoxifier of super oxide. In addition, it has a proposed role in the allosteric mechanism. The present study addresses the functional and conformational consequences of modifying the beta93 sulfhydryl using either maleimide or disulfide-based reactions. The geminate and bimolecular recombination of CO derivatives of several different beta93-modified Hbs in both solution and sol-gel matrixes provide a window into functional modifications associated with both the R and T states of these proteins. Nanosecond time-resolved visible resonance Raman spectroscopy is used to probe conformational consequences associated with the proximal heme environment. The results show functional and conformational consequences that depend on the specific chemistry used to modify beta93. Maleimide-based modification show the most significant alterations of R-state properties including a consistent pattern of a reduced geminate yield and a loss of the favorable heme-proximal histidine interaction normally seen for liganded R-state HbA. A mechanism based on a displacement of the side chain of Tyr beta145 is explored as a basis for this effect as well as other situations where there is loss of the quaternary enhancement effect. The quaternary enhancement effect refers to the enhancement of ligand binding properties of the alphabeta dimers when they are associated into the R-state tetramer.

Carboxyhemoglobin↗
PubMed2001

Cardiac findings in an individual with neurofibromatosis 1 and sudden death.

Vascular lesions in neurofibromatosis 1 (NF1) are infrequently recognised as manifestations of the disease, yet they can produce serious complications. Most individuals with NF1 vasculopathy are asymptomatic, which may contribute to underestimation of its frequency. A recent study indicates that vascular changes in individuals with NF1 contribute to mortality at younger ages. We report the sudden death of a young man with NF1. On autopsy examination there was evidence of an intramyocardial vasculopathy characteristic of the vascular pathology previously described in NF1. Other cardiac findings included non-specific cardiomyopathic changes, myocardial fibrosis, and a "floppy" mitral valve.

Adult↗
PubMed2001

Virus-assisted mapping of neural inputs to a feeding center in the hypothalamus.

We report the development of a pseudorabies virus that can be used for retrograde tracing from selected neurons. This virus encodes a green fluorescent protein marker and replicates only in neurons that express the Cre recombinase and in neurons in synaptic contact with the originally infected cells. The virus was injected into the arcuate nucleus of mice that express Cre only in those neurons that express neuropeptide Y or the leptin receptor. Sectioning of the brains revealed that these neurons receive inputs from neurons in other regions of the hypothalamus, as well as the amygdala, cortex, and other brain regions. These data suggest that higher cortical centers modulate leptin signaling in the hypothalamus. This method of neural tracing may prove useful in studies of other complex neural circuits.

Afferent Pathways↗
PubMed2001

Mortality in neurofibromatosis 1: an analysis using U.S. death certificates.

Although neurofibromatosis 1 (NF1) is a relatively common autosomal dominant condition, information about its effect on mortality is limited. We used Multiple-Cause Mortality Files, compiled from U.S. death certificates by the National Center for Health Statistics, for 1983 through 1997. We identified 3,770 cases of presumed NF1 among 32,722,122 deaths in the United States, a frequency of 1/8,700, which is one-third to one-half the estimated prevalence. Mean and median ages at death for persons with NF1 were 54.4 and 59 years, respectively, compared with 70.1 and 74 years in the general population. Results of proportionate mortality ratio (PMR) analyses showed that persons with NF1 were 34 times more likely (PMR=34.3, 95% confidence interval [CI] 30.8-38.0) to have a malignant connective or other soft-tissue neoplasm listed on their death certificates than were persons without NF1. Overall, persons with NF1 were 1.2 times more likely than expected (PMR=1.21, 95% CI 1.14-1.28) to have a malignant neoplasm listed on their death certificates, but the PMR was 6.07 (95% CI 4.88-7.45) for persons who died at 10-19 years of age and was 4.93 (95% CI 4.14-5.82) for those who died at 20-29 years of age. Similarly, vascular disease was recorded more often than expected on death certificates of persons with NF1 who died at <30 years of age (PMR=3.26, 95% CI 1.31-6.71 at age <10 years; PMR=2.68, 95% CI 1.38-4.68 at age 10-19 years; and PMR=2.25, 95% CI 1.46-3.32 at 20-29 years) but not in older persons. This study supports previous findings of decreased life expectancy for persons with NF1 and, within the limitations of death certificates, provides population-based data about NF1 morbidity and mortality that are useful to clinicians caring for patients with NF1.

Adolescent↗
PubMed2001

Renal-coloboma syndrome: prenatal detection and clinical spectrum in a large family.

Renal-coloboma syndrome includes abnormalities in the urogenital and ocular systems as its primary manifestations, although it can be associated with abnormalities in other systems as well. This syndrome is caused by mutations in the PAX2 gene and is transmitted as an autosomal dominant trait. We report a family in which at least 7 members have manifestations of renal-coloboma syndrome, including two in whom renal disease was diagnosed prenatally by ultrasound examination. A pathogenic frame-shift mutation (619insG) was found in the PAX2 gene in affected family members, who show remarkable variability in both the ocular and renal manifestations of the syndrome.

Adolescent↗
PubMed2001

Activation of the low oxygen affinity-inducing potential of the Asn108(beta)-->Lys mutation of Hb-Presbyterian on intramolecular alpha alpha-fumaryl cross-bridging.

The Asn108 beta-->Lys mutation in hemoglobin (HbPresbyterian mutation) endows a low O(2) affinity-inducing propensity to the protein. Introduction of a fumaryl cross-bridge between its two alpha 99 lysine residues also induces a low O(2) affinity into HbA. We have now engineered an alpha alpha-fumaryl cross-bridge into Hb-Presbyterian to determine the synergy or additivity, if any, that can be achieved between these two low O(2) affinity-inducing structural perturbations. Despite the presence of the additional epsilon-amino group of Lys108(beta) within the central cavity, the epsilon-amino group of Lys99(alpha alpha) of deoxy Hb-Presbyterian retained high selectivity for alpha alpha-fumaryl cross-bridging, with an overall efficiency comparable to that with HbA. The alpha alpha-fumaryl cross-linking of Hb-Presbyterian reduced its O(2) affinity much more significantly than that observed with HbA, indicating a synergy between the two low O(2) affinity-inducing structural perturbations. Apparently, the alpha alpha-fumaryl cross-bridge in Hb-Presbyterian activates part of the latent low O(2) affinity-inducing potential of Lys108(beta) that is generally activated in the presence of chloride. The synergy between the Asn108(beta)-->Lys mutation and the alpha alpha-fumaryl cross-bridging was conserved in the presence of chloride, but not in the presence of DPG. Furthermore, in the presence of chloride and DPG, alpha alpha-fumaryl Hb-Presbyterian accessed a low O(2) affinity T-state that is accessed by HbA, alpha alpha-HbA and Hb-Presbyterian only in the presence of IHP. Isoelectric focusing analysis suggested that the alpha alpha-fumaryl cross-linking of Hb-Presbyterian induces changes in the ionization behavior of one or more of the functional groups neighboring Lys99(alpha) and Lys108(beta) [presumably His103(alpha) and/or Glu101(beta)] to compensate for the extra positive charge of Lys108(beta). Molecular modeling studies identified two potential chloride binding sites per alpha beta dimer within the middle of the central cavity of alphaalpha-fumaryl HbA involving residues His103(alpha), Arg104(beta) and Asn108(beta). The affinity of these sites is increased in alpha alpha-fumaryl Hb-Presbyterian as a result of the Asn108(beta)-->Lys mutation. Thus, the results of the present study suggest that the enhanced neutralization of the positive charges in the middle of the central cavity of Hb achieved by these two electrostatic modifications, one (the alpha alpha-fumaryl cross-bridge) acting directly and the other (the Presbyterian mutation) acting indirectly through the mediation of chloride ion binding, facilitates the alpha alpha- fumaryl-Hb Presbyterian to access a low O(2) affinity T-state structure much more readily than either Hb-Presbyterian or alpha alpha-fumaryl HbA.

Allosteric Regulation↗
PubMed2001

Epidemiology and factor analysis of obesity, type II diabetes, hypertension, and dyslipidemia (syndrome X) on the Island of Kosrae, Federated States of Micronesia.

OBJECTIVES: Obesity, type II diabetes, hypertension, and dyslipidemia are major causes of morbidity and mortality throughout the world. Though these disorders often cluster in individuals and families and are collectively known as syndrome X, the basis for this aggregation is not well understood. To further understand the pathogenesis of syndrome X, a comprehensive epidemiological study was undertaken on the Pacific Island of Kosrae, Federated States of Micronesia (FSM). METHODS: The entire adult (>20 years of age) population of Kosrae underwent a clinical evaluation that included a questionnaire that noted the participants' sex, family data including listing of biological parents, siblings, and children, smoking status, village of residence, age and health status. The medical evaluation included: anthropometric measures (weight, height, waist, hip), serum chemistries (leptin, fasting blood sugar (FBS), insulin, total cholesterol (TC), triglycerides (TG), and apolipoproteins B and A-I (apo B and apo A-I) and blood pressure (BP) measurements. RESULTS: Obesity (BMI >/=35) was found in 24%, diabetes (FBS >/=126 or 2-hour oral glucose tolerance test >/=200) in 12%, hypertension (SBP >/=140 or DBP >/=90) in 17%, and dyslipidemia (TC >/=240 or TG >/=200 or apo B >/=120 or apo A-I </=88) in 20% of the population. Significant covariate effects after multivariate analysis were as follows: sex affected the frequency of all four disorders, parity affected the frequency of dyslipidemia, smoking affected the frequency of obesity and diabetes, village of residence affected the frequency of obesity, hypertension, and dyslipidemia, and age affected the frequency of all four disorders. Factor analysis identified four independent factors that explained 73% of the total variance of the entire data set: factor 1 (weight, waist, leptin, insulin, and TG), factor 2 (TC, TG, apo B, apo A-I, and insulin), factor 3 (systolic and diastolic BP, FBS, waist and weight), and factor 4 (apo A-I, TG, leptin, and weight). CONCLUSIONS: This population-based study on the Island of Kosrae suggests that syndrome X is a composite of 4 independent factors: obesity with diabetes and hypertriglyceridemia, combined hyperlipidemia with diabetes, hypertension with obesity and diabetes, and increased HDL-low TG with thinness and high leptin. Further studies to identify the genetic components of these factors as well as the individual traits are under way.

Adult↗
PubMed2001

Selective deletion of leptin receptor in neurons leads to obesity.

Animals with mutations in the leptin receptor (ObR) exhibit an obese phenotype that is indistinguishable from that of leptin deficient ob/ob mice. ObR is expressed in many tissues, including brain, and the relative importance of leptin's effects on central versus peripheral sites has not been resolved. To address this, we generated mice with neuron-specific (ObR(SynI)KO) and hepatocyte-specific (ObR(Alb)KO) disruption of ObR. Among the ObR(SynI)KO mice, the extent of obesity was negatively correlated with the level of ObR in hypothalamus and those animals with the lowest levels of ObR exhibited an obese phenotype. The obese mice with low levels of hypothalamic ObR also show elevated plasma levels of leptin, glucose, insulin, and corticosterone. The hypothalamic levels of agouti-related protein and neuropeptide Y RNA are increased in these mice. These data indicate that leptin has direct effects on neurons and that a significant proportion, or perhaps the majority, of its weight-reducing effects are the result of its actions on brain. To explore possible direct effects of leptin on a peripheral tissue, we also characterized ObR(Alb)KO mice. These mice weigh the same as controls and have no alterations in body composition. Moreover, while db/db mice and ObR(SynI)KO mice have enlarged fatty livers, ObR(Alb)KO mice do not. In summary, these data suggest that the brain is a direct target for the weight-reducing and neuroendocrine effects of leptin and that the liver abnormalities of db/db mice are secondary to defective leptin signaling in the brain.

Animals↗
PubMed2000

Sol-gel trapping of functional intermediates of hemoglobin: geminate and bimolecular recombination studies.

The encapsulation of proteins in porous sol-gels is a promising technique for generating, trapping, and probing functionally significant nonequilibrium protein species. An essential step needed in the pursuit of that goal is establishing the degree to which the sol-gel limits conformational change upon adding or removing substrates. In the present study, geminate recombination and solvent phase bimolecular recombination of CO to human adult hemoglobin (HbA) are used as sensitive probes of the degree of conformational constraint within the sol-gel. Two forms of CO saturated encapsulated HbA are generated. In one case, designated [COHbA], the equilibrium form of COHbA is directly encapsulated. In the second case, designated as [deoxyHbA] + CO, the equilibrium form of deoxyHbA is encapsulated and only after the sample has aged is CO introduced to the HbA through the porous sol-gel matrix. Three different preparative protocols are used to generate the sol-gels for each of the two forms of encapsulated COHbA. The kinetic traces obtained from these encapsulated samples allow for an easy evaluation of the extent to which the sol-gel is locking in the initial tertiary/quaternary structure. The results show that the sol-gel encapsulated samples can be used with pulsed laser sources and that one of the tested encapsulation protocols is far superior with respect to conformational locking. This protocol is used to trap and probe nonequilibrium forms such as the liganded T state of HbA, a species whose properties are needed to fully explore allostery in HbA.

Buffers↗
PubMed2000

Cardiovascular malformations and other cardiovascular abnormalities in neurofibromatosis 1.

Although it is well recognized that a peripheral vasculopathy may occur in patients with neurofibromatosis 1 (NF1), it is unclear whether cardiovascular abnormalities are more common. We reviewed the frequency of cardiovascular abnormalities, in particular, cardiovascular malformations (CVMs), among 2322 patients with definite NF1 in the National Neurofibromatosis Foundation International Database from 1991-98. Cardiovascular malformations were reported in 54/2322 (2.3%) of the NF1 patients, only 4 of whom had Watson syndrome or NF1-Noonan syndrome. There was a predominance of Class II "flow" defects [Clark, 1995: Moss and Adams' Heart Disease in Infants, Children, and Adolescents Including the Fetus and Young Adult. p 60-70] (43/54, 80%) among the NF1 patients with CVMs. Pulmonic stenosis, that was present in 25 NF1 patients, and aortic coarctation, that occurred in 5, constitute much larger proportions of all CVMs than expected. Of interest was the paucity of Class I conotruncal defects (2 patients with tetralogy of Fallot), and the absence of atrioventricular canal, anomalous pulmonary venous return, complex single ventricle and laterality defects. Besides the 54 patients with CVMs, there were 27 patients with other cardiac abnormalities (16 with murmur, 5 with mitral valve prolapse, 1 with intracardiac tumor, and 5 with electrocardiogram abnormalities). No patient in this study had hypertrophic cardiomyopathy. There were 16 patients who had a peripheral vascular abnormality without an intracardiac CVM, plus an additional 4 patients among those with a CVM who also had a peripheral vascular abnormality.

Aortic Coarctation↗
PubMed2000

Vanilloid receptor-related osmotically activated channel (VR-OAC), a candidate vertebrate osmoreceptor.

The detection of osmotic stimuli is essential for all organisms, yet few osmoreceptive proteins are known, none of them in vertebrates. By employing a candidate-gene approach based on genes encoding members of the TRP superfamily of ion channels, we cloned cDNAs encoding the vanilloid receptor-related osmotically activated channel (VR-OAC) from the rat, mouse, human, and chicken. This novel cation-selective channel is gated by exposure to hypotonicity within the physiological range. In the central nervous system, the channel is expressed in neurons of the circumventricular organs, neurosensory cells responsive to systemic osmotic pressure. The channel also occurs in other neurosensory cells, including inner-ear hair cells, sensory neurons, and Merkel cells.

Amino Acid Sequence↗
PubMed2000

Recurrent trisomy 21 in a couple with a child presenting trisomy 21 mosaicism and maternal uniparental disomy for chromosome 21 in the euploid cell line.

Recurrence of trisomy 21 was observed in a family in which both parents had a normal chromosome complement. Mosaic trisomy 21 was found in a blood karyotype of the first child, a second pregnancy ended in spontaneous abortion, and a full trisomy 21 was found at prenatal diagnosis of the third pregnancy of this same couple. Although recurrent trisomy 21 may be due to chance, the possibility of germline mosaicism for trisomy 21 in one of the parents has important implications for recurrence risk. Molecular analysis was therefore undertaken in this family to determine the parental origin and the stage of nondisjunction of the extra chromosome 21 in both cases. Although a maternal origin of both instances of trisomy 21 was observed, the mosaic case showed homozygosity for all markers along the duplicated maternal chromosome. Such a finding would normally suggest a postzygotic origin of the trisomy 21. However, the diploid cell line in this same case showed maternal uniparental disomy 21, implying that it was the result of a trisomic conception. We suggest that a somatic nondisjunction in the maternal germ cells is the most likely explanation for these findings. The apparent meiotic II stage of nondisjunction of the nonmosaic trisomy 21 fetus was consistent with maternal mosaicism. A review of the literature for recurrent trisomy 21 cases studied by molecular means, suggests that mosaicism in germ cells may account for more cases than is detected cytogenetically. These results also show that DNA marker analysis does not provide a valuable tool for patient counseling in case of recurrent trisomy 21.

Child↗