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Biomedical subjects

R Rosenfeld

Publications and source records attributed to R Rosenfeld.

At least 19 recordsLinked to original sources
PubMed2003

Future e(+)e(-) colliders' sensitivity to Hbb coupling and CP violation.

We perform a complete simulation of the process e(+)e(-)-->bbvv, where nu can be an electron, muon, or tau neutrino, in the context of a general Higgs coupling to b quarks. We parametrize the Hbb; coupling as (m(b)/v)(a+igamma(5)b). Taking into account interference effects between pure Higgs and Standard Model contributions, we find that sensitivities of the order of 2% and 20% can be obtained at a future e(+)e(-) collider for deviations of the a and b parameters, respectively, from their Standard Model values. Combining our analysis with an independent measurement of Gamma(H-->bb) can provide evidence about the CP nature of the Higgs sector.

Journal Article↗
PubMed2002

The metabolic effects of short-term administration of physiological versus high doses of GH therapy in GH deficient adults.

OBJECTIVE: GH treatment has demonstrated favourable effects on most features of GH deficiency in hypopituitary adults. However, most studies employed supraphysiological GH doses, resulting in deterioration in insulin sensitivity (SI). The short-term metabolic effects of physiological doses of GH therapy in GH deficient (GHD) adults are largely unknown. We therefore compared the effects of short-term administration of two 'physiological' ('lowest' dose: 0.0017 mg/kg/day; 'low' dose: 0.0033 mg/kg/day) with two 'supraphy-siological' ('high' dose: 0.010 mg/kg/day; 'highest' dose: 0.025 mg/kg/day) GH doses on SI, beta-cell function, IGF-1 and IGFBPs -1 and -3 in a group of GHD adults. PATIENTS AND METHODS: Thirteen GHD adults were recruited (seven men, aged 23-63 years). For each of the four doses, six patients (three men) were allocated randomly to undergo a 7-day treatment phase. Fasting blood samples were collected daily (days 1-8), and SI and beta-cell function were calculated using the homeostasis model assessment (HOMA). RESULTS: All four GH doses increased IGF-1, IGFBP-3 and IGF-1/IGFBP-3 ratio, and decreased IGFBP-1 from day 3 onwards (P < 0.05). The highest dose increased fasting glucose (P < 0.001), insulin (P < 0.001) and beta-cell function (P < 0.001), but decreased SI (P < 0.001). The high and low doses did not modify fasting glucose and insulin, SI or beta-cell function, whereas the lowest dose enhanced beta-cell function (P < 0.05). The overall increase in the GH dose increased IGF-1, IGFBP-3, fasting glucose and insulin (P < 0.001), demonstrated a positive correlation with the final change in fasting glucose (r = 0.5, P < 0.05) and insulin (r = 0.8, P < 0.001) and a negative correlation with final SI (r = -0.5, P < 0.05). CONCLUSIONS: Our results suggest that short-term administration of the highest GH dose induced insulin resistance, whereas the lowest dose (0.0017 mg/kg/day) could represent the optimal starting dose in GHD adults due to its beneficial effects on beta-cell function without compromising SI. It is, however, yet to be determined whether the positive effects of the lowest GH dose on beta-cell function can be demonstrated over a longer period of time.

Adult↗
PubMed2001

A bicyclic and hsst2 selective somatostatin analogue: design, synthesis, conformational analysis and binding.

A backbone bridged and disulfide bridged bicyclic somatostatin analogue, compound 1 (PTR-3205), was designed and synthesized by solid-phase methodology. The binding of compound 1 to the five different somatostatin receptors, expressed in CHO or COS-7 cells, indicate a high degree of selectivity towards hsstr2. The three-dimensional structure of this compound has been determined in DMSO-d(6) and in water by 1H NMR and by molecular dynamics simulations. Similar backbone conformations were observed in both solvents. We have established direct evidence that the backbone of this bicyclic somatostatin analogue assumes a 'folded' conformation in solution, where the lactam ring extends roughly in the plane of the beta-turn. The pharmacophoric region Phe-(D)-Trp-Lys-Thr of compound 1 is in accord with that of both the Veber compound L-363,301 (Merck) and sandostatin. We believe that the enhanced selectivity towards the hsst2 receptor, in comparison with other analogues, is due to its large hydrophobic region, composed of the lactam ring and the Phe side chains at positions 1 and 8.

Animals↗
PubMed2001

Novel long-acting somatostatin analog with endocrine selectivity: potent suppression of growth hormone but not of insulin.

Somatostatin, also known as somatotropin release-inhibiting factor (SRIF), is a natural cyclic peptide inhibitor of pituitary, pancreatic, and gastrointestinal secretion. Its long-acting analogs are in clinical use for treatment of various endocrine syndromes and gastrointestinal anomalies. These analogs are more potent inhibitors of the endocrine release of GH, glucagon, and insulin than the native SRIF; hence, they do not display considerable physiological selectivity. Our goal was to design effective and physiologically selective SRIF analogs with potential therapeutic value. We employed an integrated approach consisting of screening of backbone cyclic peptide libraries constructed on the basis of molecular modeling of known SRIF agonists and of high throughput receptor binding assays with each of the five cloned human SRIF receptors (hsst1-5). By using this approach, we identified a novel, high affinity, enzymatically stable, and long-acting SRIF analog, PTR-3173, which binds with nanomolar affinity to human SRIF receptors hsst2, hsst4, and hsst5. The hsst5 and the rat sst5 (rsst5) forms have the same nanomolar affinity for this analog. In the human carcinoid-derived cell line BON-1, PTR-3173 inhibits forskolin-stimulated cAMP accumulation as efficiently as the drug octreotide, indicating its agonistic effect in this human cell system. In hormone secretion studies with rats, we found that PTR-3173 is 1000-fold and more than 10,000-fold more potent in inhibiting GH release than glucagon and insulin release, respectively. These results suggest that PTR-3173 is the first highly selective somatostatinergic analog for the in vivo inhibition of GH secretion, with minimal or no effect on glucagon and insulin release, respectively.

Animals↗
PubMed2001

Recommendations for the diagnosis and management of Turner syndrome.

Comprehensive recommendations on the diagnosis of Turner syndrome (TS) and the care of affected individuals were published in 1994. In the light of recent advances in diagnosis and treatment of TS, an international multidisciplinary workshop was convened in March 2000, in Naples, Italy, in conjunction with the Fifth International Symposium on Turner Syndrome to update these recommendations. The present paper details the outcome from this workshop. The genetics and diagnosis of the syndrome are described, and practical treatment guidelines are presented.

Adolescent↗
PubMed2001

Quality of life after great auricular nerve sacrifice during parotidectomy.

OBJECTIVE: To determine the impact of great auricular nerve (GAN) sacrifice during parotidectomy on patients' quality of life. DESIGN: Historical cohort survey of patients who had undergone GAN sacrifice during parotidectomy. SETTING: Tertiary academic otolaryngologic practice. PATIENTS AND METHODS: Fifty-three patients who had undergone GAN sacrifice during parotidectomy completed an 8-item quality-of-life survey with a 7-point response scale designed to measure outcome after GAN sacrifice during parotidectomy. RESULTS: Thirty patients (57%) reported experiencing at least 1 abnormal symptom, but the mean number of symptoms decreased significantly with time, from a mean of 2.3 during the first year to 0.2 after 5 years (P<.001). Even among patients experiencing symptoms, 23 (77%) reported only a little or no bother caused by the symptoms, and 27 (90%) reported no interference or almost none with their daily activities. The degree of bother or interference reported had a moderate positive correlation with the number of abnormal sensations reported. CONCLUSIONS: The results suggest that, while many patients experienced sensory deficits, the overall quality of life was not significantly affected after GAN sacrifice during parotidectomy. Patients who report multiple abnormal sensations, however, would benefit from additional counseling and from reassurance that the number of sensations will diminish with time. Further study evaluating the effect of preservation of the posterior branch of the GAN during parotidectomy on patients' quality of life is needed.

Adult↗
PubMed2000

Regulation of somatic growth by the p160 coactivator p/CIP.

A family of p160 coactivators was initially identified based on ligand-dependent interactions with nuclear receptors and thought to function, in part, by recruiting CREB-binding protein/p300 to several classes of transcription factors. One of the p160 factors, p/CIP/AIB1, often amplified and overexpressed in breast cancer, also exhibits particularly strong interaction with CREB-binding protein/p300. In this manuscript, we report that p/CIP, which exhibits regulated transfer from cytoplasm to nucleus, is required for normal somatic growth from embryonic day 13.5 through maturity. Our data suggest that a short stature phenotype of p/CIP gene-deleted mice reflect both altered regulation of insulin-like growth factor-1 (IGF-1) gene expression in specific tissues and a cell-autonomous defect of response to IGF-1, including ineffective transcriptional activities by several classes of regulated transcription factors under specific conditions. The actions of p/CIP are therefore required for full expression of a subset of genes critical for regulating physiological patterns of somatic growth in mammals.

Animals↗
PubMed2000

Impact of column bending in high-resolution transmission electron microscopy on the strain evaluation of GaAs/InAs/GaAs heterostructures

The accuracy of strain profiles obtained by a quantitative analysis of lattice fringe spacings from high-resolution micrographs is discussed. Focusing on highly lattice mismatched GaAs/InAs/GaAs heterostructures the local strain distribution of the layers is calculated by finite element simulations to determine the atom positions in elastically relaxed transmission electron microscopy specimens. By analysing simulated images a significant decoupling between the layer structure and the contrast pattern motifs is found for relevant imaging conditions, which may result in an incorrect determination of strain profiles and layer compositions when examining experimental micrographs.

Journal Article↗
PubMed2000

Study on the cyclization tendency of backbone cyclic tetrapeptides.

The cyclization kinetics of five backbone-cyclic tetrapeptides was investigated both experimentally and computationally. The aim was to both accurately measure the cyclization rates in solution and develop a method that efficiently estimates the relative cyclization tendencies computationally. Progression of the cyclization reaction was monitored directly, yielding the kinetics of changes in the amounts of the linear precursor and the products. These measurements were used to calculate the reaction rates; the results were consistent with a first-order reaction kinetics. In order to predict the cyclization rates computationally, the conformation space of the linear precursors was mapped and used to construct an approximate partition function. We assumed that the cyclization tendency was correlated with the relative probability of being found in a cyclization-prone conformation of the backbone, this probability was estimated from the partition function. The results supported this assumption and demonstrated that, within reasonable accuracy, we are able to predict the relative cyclization tendencies of the peptides measured.

Chromatography↗
PubMed2000

The rise and decline of homicide--and why.

A dramatic rise in homicide in the latter half of the 1980s peaked during the 1990s and then declined at an equally dramatic rate. Such trends in homicide rates can be understood only by examining rates in specific age, sex, and racial groups. The increase primarily involved young males, especially black males, occurred first in the big cities, and was related to the sudden appearance of crack cocaine in the drug markets of the big cities around 1985. This development led to an increased need for and use of guns and was accompanied by a general diffusion of guns into the larger community. The decline in homicide since the early 1990s has been caused by changes in the drug markets, police response to gun carrying by young males, especially those under 18 years old, the economic expansion, and efforts to decrease general access to guns, as well as an increase in the prison population and a continued decline in homicide among those over age 24. The lessons learned from the recent homicide trends and the factors associated with them have important implications for public health and the criminal justice system.

Adolescent↗
PubMed2000

Growth hormone use in pediatric growth hormone deficiency and other pediatric growth disorders.

The diagnosis and management of growth disorders in children, particularly disorders that respond to therapy with growth hormone (GH), raise challenging clinical and economic issues. Several such issues are presented in the following article in which Dr. Ron Rosenfeld examines the evaluation and diagnosis of the child with short stature; Dr. David B. Allen discusses the anabolic and metabolic indications for GH treatment in children; Dr. Margaret H. MacGillivray reviews GH dosing, height outcomes, and follow up; and Dr. Craig Alter presents the payer's perspective on the diagnosis and treatment of pediatric GH deficiency. In addressing the use of GH in other pediatric populations, Dr. Paul Saenger focuses on Turner syndrome, Dr. Henry Anhalt on chronic renal insufficiency of childhood, and Dr. Ray Hintz on idiopathic short stature. Dr. Harvey P. Katz presents one managed care organization's policy and implementation plan that is used to guide decisions regarding coverage for GH treatment.

Body Height↗
PubMed1999

Connective tissue growth factor (IGFBP-rP2) expression and regulation in cultured bovine endothelial cells.

Media from large vessel endothelial cells (pulmonary artery, aorta) contained intact connective tissue growth factor (CTGF) and a dominant 19-kDa band. N-terminal analysis of the 19-kDa band showed sequence corresponding to CTGF amino acid 181-190, suggesting that the 19-kDa band represented a proteolytic fragment of CTGF. Intact CTGF was increased by cAMP but not by transforming growth factor-beta (TGFbeta). CTGF messenger RNA (mRNA) was not changed by cAMP nor TGFbeta. In two microvessel endothelial cells, mRNA was found at low levels by PCR and Northern analysis, but no CTGF protein was seen on Western analysis. In the microvessel cells, TGFbeta increased and cAMP did not change CTGF mRNA levels, with neither TGFbeta nor cAMP increasing CTGF protein. The discordance between protein and mRNA levels in large vessel and microvessel endothelial cells was mostly explained by the effects of cAMP and TGFbeta on media proteolytic activity; in large vessel cells, cAMP inhibited degradation of CTGF, whereas in microvessel cells, TGFbeta and cAMP stimulated proteolytic activity against CTGF. We conclude that in large vessel endothelial cells, cAMP increased intact CTGF protein by inhibiting degradation of CTGF, whereas TGFbeta stimulated neither CTGF mRNA nor protein; in microvessel cells, TGFbeta increased CTGF mRNA, while both TGFbeta and cAMP stimulated CTGF degradation.

Animals↗
PubMed1998

Empirical modifications to the Amber/OPLS potential for predicting the solution conformations of cyclic peptides by vacuum calculations.

BACKGROUND: Peptides have ubiquitous roles in all biological systems and are thus of interest in both basic and applied research. The rational design of bioactive peptides could be greatly enhanced by an efficient method for accurately predicting the conformations that these molecules can adopt in solution. As a design process inevitably requires testing numerous molecules, an efficient method would require the calculations to be performed in vacuum. RESULTS: Attempts to predict the conformations of cyclic peptides using a simulated annealing protocol with the Amber/OPLS potential in vacuum resulted, not unexpectedly, in overly packed, non-native conformations. We therefore empirically modified the potential by several cycles of structure prediction and function refinement until a good fit between experimental and predicted conformations was obtained. Three major modifications to the potential were required in order to reproduce the solution structures of cyclic peptides: explicit torsional energies for the peptide backbone torsional angles; explicit hydrogen-bonding energies for backbone hydrogen bonds; and a penalty for close approaches between uncharged and charged atoms. CONCLUSIONS: Using the modified potential, we predicted the solution conformations of cyclic peptides in the size range of 5-10 residues with reasonable accuracy.

Amino Acid Sequence↗