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Biomedical subjects

D Sussman

Publications and source records attributed to D Sussman.

At least 19 recordsLinked to original sources
PubMed2001

Interleukin 1 upregulates ovarian prostaglandin endoperoxide synthase-2 expression: evidence for prostaglandin-dependent/ceramide-independent transcriptional stimulation and for message stabilization.

We have recently documented a marked dependence of ovarian prostaglandin endoperoxide synthase (PGS)-2 transcripts, proteins, and activity on interleukin (IL) 1, a putative intermediary in the ovulatory cascade. The purpose of the present study was to characterize the cellular and molecular mechanisms underlying the ability of IL-1beta to upregulate the steady-state levels of ovarian transcripts corresponding to PGS-2. Results of studies designed to enrich or deplete nitric oxide strongly suggest that the stimulatory effect of IL-1beta on ovarian PGS-2 expression is independent of nitric oxide. Utilization of a series of agents designed to simulate or enhance transduction via the sphingomyelin ceramide cycle suggests that the long-term stimulatory effect of IL-1beta on ovarian PGS-2 gene expression is independent of ceramide. In contrast, inhibition of prostaglandin biosynthesis with a series of distinct inhibitors suggests that the ability of IL-1beta to upregulate ovarian PGS-2 transcripts is due, if only in part, to the generation of endogenous prostaglandin estradiol-17beta (E(2)). Inhibition of protein biosynthesis suggested that the IL-1beta-induced PGS-2 gene expression required de novo protein biosynthesis. Our findings revealed substantial IL-1beta-mediated stabilization of PGS-2 transcripts, as assessed by a threefold increase in the half-life of the message. We have also observed the ability of IL-1beta to upregulate the transcription of PGS-2 promoter constructs subjected to transient transfection into whole-ovarian dispersates (twofold increase as assessed by activation of the luciferase reporter gene). Taken together, these findings suggest that the stimulatory effect of IL-1beta on PGS-2 expression is 1) independent of nitric oxide as well as ceramide, 2) dependent on prostaglandin E(2), 3) contingent on de novo protein biosynthesis, and 4) accounted for by both increased transcription and message stabilization. These observations provide indirect support for the hypothesis that IL-1beta, acting in part through PGS-2 (an obligatory ovulatory principal), may constitute a key intermediary in the ovulatory cascade.

Animals↗
PubMed2000

Impact of baseline symptom severity on future risk of benign prostatic hyperplasia-related outcomes and long-term response to finasteride. The Pless Study Group.

OBJECTIVES: To evaluate the long-term effects of finasteride on symptoms, acute urinary retention (AUR), and the need for benign prostatic hyperplasia (BPH)-related surgery in relationship to baseline symptom severity. METHODS: A total of 3040 men with BPH were treated for 4 years with finasteride or placebo. The changes from baseline in symptoms and the incidence of BPH-related surgery and AUR were determined in men with mild (less than 8), low-moderate (8 to 12), high-moderate (13 to 19), and severe (greater than 19) baseline quasi-American Urological Association symptoms for all patients and for the subgroup with a baseline prostate-specific antigen (PSA) level of 1.4 ng/mL or greater. RESULTS: In patients who completed the 4-year study, the change in symptom score, stratified by baseline symptom severity, was +1.4 +/- 0.5 (mild), -0.8 +/- 0.3 (low-moderate), -3.6 +/- 0.3 (high-moderate), and -7.7 +/- 0.5 (severe) in finasteride-treated patients and, respectively, +3.4 +/- 0.5, +0.7 +/- 0.3, -1.4 +/- 0.3, and -5.3 +/- 0.6 in placebo-treated patients (between-group P <0.01). The between-group differences were greater in the subgroup of patients with a baseline PSA of 1.4 ng/mL or greater. The risk of BPH-related surgery increased among placebo patients with increasing baseline symptom severity to a greater extent than the risk of AUR. Finasteride reduced the risk of AUR or the need for BPH-related surgery in all subgroups (P <0.001), especially in men with a baseline PSA of 1.4 ng/mL or greater. CONCLUSIONS: Compared with placebo, finasteride had a beneficial effect on symptoms, AUR, and BPH-related surgery in all symptom categories. BPH-related surgery, but not AUR, occurred more commonly in placebo-treated men with more severe baseline symptoms. The greatest absolute benefit of finasteride on symptoms and the reduction in risk of AUR and surgery was in men with higher baseline symptom scores and a baseline PSA level of 1.4 ng/mL or greater.

Aged↗
PubMed2000

A water channel in the core of the vitamin B(12) RNA aptamer.

BACKGROUND: The 3.0 A crystal structure of the vitamin B(12) RNA aptamer revealed an unusual tertiary structure that is rich in novel RNA structural motifs. Important details of the interactions that stabilize noncanonical base pairing and the role of solvent in the structure were not apparent owing to the limited resolution. RESULTS: The structure of the vitamin B(12) RNA aptamer in complex with its ligand has been determined at 2.3 A resolution by X-ray crystallography. The crystallographic asymmetric unit contains five independent copies of the aptamer-vitamin B(12) complex, making it possible to accurately define well-conserved features. The core of the aptamer contains an unusual water-filled channel that is buried between the three strands of an RNA triplex. Well-ordered water molecules positioned within this channel form bridging hydrogen bonds and stabilize planar base triples that otherwise lack significant direct base-base contacts. The water channel terminates at the interface between the RNA and the bound ligand, leaving a pair of water molecules appropriately positioned to hydrogen bond with the highly polarized cyanide nitrogen of vitamin B(12). Analysis of the general solvation patterns for each nucleotide suggests that water molecules are not precisely positioned, as observed in previous RNA duplex structures, but instead might adjust in response to the varying local environment. Unusual intermolecular base pairing contributes to the formation of three different dimerization contacts that drive formation of the crystal lattice. CONCLUSIONS: The structure demonstrates the important role of water molecules and noncanonical base pairing in driving the formation of RNA tertiary structure and facilitating specific interactions of RNAs with other molecules.

Computer Simulation↗
PubMed2000

The 1.3 A crystal structure of a biotin-binding pseudoknot and the basis for RNA molecular recognition.

A pseudoknot-containing aptamer isolated from a pool of random sequence molecules has been shown previously to represent an optimal RNA solution to the problem of binding biotin. The affinity of this RNA molecule is nonetheless orders of magnitude weaker than that of its highly evolved protein analogs, avidin and streptavidin. To understand the structural basis for biotin binding and to compare directly strategies for ligand recognition available to proteins and RNA molecules, we have determined the 1.3 A crystal structure of the aptamer complexed with its ligand. Biotin is bound at the interface between the pseudoknot's stacked helices in a pocket defined almost entirely by base-paired nucleotides. In comparison to the protein avidin, the aptamer packs more tightly around the biotin headgroup and makes fewer contacts with its fatty acid tail. Whereas biotin is deeply buried within the hydrophobic core in the avidin complex, the aptamer relies on a combination of hydrated magnesium ions and immobilized water molecules to surround its ligand. In addition to demonstrating fundamentally different approaches to molecular recognition by proteins and RNA, the structure provides general insight into the mechanisms by which RNA function is mediated by divalent metals.

Avidin↗
PubMed2000

The structural basis for molecular recognition by the vitamin B 12 RNA aptamer.

Previous solution structures of ligand-binding RNA aptamers have shown that molecular recognition is achieved by the folding of an initially unstructured RNA around its cognate ligand, coupling the processes of RNA folding and binding. The 3 A crystal structure of the cyanocobalamin (vitamin B12) aptamer reported here suggests a different approach to molecular recognition in which elements of RNA secondary structure combine to create a solvent-accessible docking surface for a large, complex ligand. Central to this structure is a locally folding RNA triplex, stabilized by a novel three-stranded zipper. Perpendicular stacking of a duplex on this triplex creates a cleft that functions as the vitamin B12 binding site. Complementary packing of hydrophobic surfaces, direct hydrogen bonding and dipolar interactions between the ligand and the RNA appear to contribute to binding. The nature of the interactions that stabilize complex formation and the possible uncoupling of folding and binding for this RNA suggest a strong mechanistic similarity to typical protein-ligand complexes.

Base Pairing↗
PubMed1999

Preliminary characterization of crystals of an in vitro evolved cyanocobalamin (vitamin B12) binding RNA.

A 35-nucleotide pseudoknot that binds vitamin B12 been isolated using systematic evolution of ligands by exponential enrichment (SELEX). Affinity chromatography was used to purify functional, properly folded molecules and the hanging-drop vapor-diffusion method was used to crystallize this aptamer. Two crystal forms have been obtained and the preliminary crystallographic characterization is reported here. Both crystal forms (space groups I222 or I212121 and C2221) diffract to 2.9 A and should prove sufficient for structure determination.

Base Sequence↗
PubMed1999

Airbags: an exploratory survey of public knowledge and attitudes.

The present study examines public knowledge and opinion in the United States on issues related to airbag safety. Data were obtained through a national random digit-dial telephone survey of 1005 people living in the contiguous 48 United States. A majority of respondents (1) know that airbags can harm drivers seated too close to the steering wheel; (2) know that rear-facing infant seats should not be placed in the front seat of a car with passenger-side airbags; and (3) know that airbags are saving more lives of women drivers than are being lost. However, most respondents did not know that (1) airbags are killing more children than they are saving; (2) airbags can injure properly belted drivers; and (3) the majority of the lives saved by airbags have been among people who were not wearing safety belts. Knowledge of airbag risks to children and properly belted drivers was significantly associated with a less favorable attitude toward airbags, and with opposition toward the law mandating airbags on all new cars. Drivers of vehicles equipped with airbags held more favorable attitudes toward airbag technology. Further analysis suggests that as the public begins to understand the risks associated with airbags, the current high level of public support for the technology and the mandatory regulation may decline.

Accidents, Traffic↗
PubMed1999

Current activities at the Centers for Disease Control and Prevention's National Diabetes Laboratory.

In 1997, the Centers for Disease Control and Prevention established the National Diabetes Laboratory in order to help prevent and treat type 1 diabetes. This state-of-the-art laboratory collaborates with research scientists and key national and international organizations throughout the world to identify and study risk factors for type 1 diabetes by developing measurements for glycosylated proteins, developing and evaluating technology for measuring genetic risk factors for the disease, and working to standardize autoantibody measurements. Developing improved technologies for diagnosing and managing diabetes and developing reference materials for properly calibrating and standardizing blood glucose meters are also critical aspects of the laboratory's work. In addition, the laboratory provides quality storage for valuable collections of biologics and other materials and facilitates sharing of specimens, associated epidemiologic data, and test results. Working with our partners in diabetes research, we are improving the diagnosis, treatment, and prevention of type 1 diabetes.

Autoantibodies↗
PubMed1999

Expanding the physician's role in pediatric environmental health.

In rural Georgia, a nurse and an environmental health specialist from the local health department visit the home of a young nursing mother to evaluate her home for the presence of lead hazards. The mother's older child, a 3-year old girl, has a blood lead level of 22 micrograms per deciliter, which was discovered through routine (EPSTD) health department screening. In examining the home, the specialist finds classic environmental risks; peeling and chipping lead-based paint on windows and door frames, lead dust on window wells and floors, and a backyard that serves as a burial ground for defunct car parts and dead batteries. In the course of talking with the mother about the lead hazards he has found, he notices that she and her 8-week-old infant seem quite listless, so he asks the mother how she's coping with her new baby. Eventually, the mother discloses that during her pregnancy she craved dirt and that she had eaten bowels of it scooped from her backyard. Once she had the baby, she says, she lost her craving. The nurse immediately contacts the physician involved in this case, who arranges for the mother and infant to be admitted to a nearby medical center for chelation therapy. Testing reveals the mother's lead level at 90 micrograms per deciliter; the infant's level is staggering 85 micrograms per deciliter. Once lead levels are reduced,the physician and public health nurse arrange for a host of social services, including psychological and nutritional counseling for the mother and periodic retesting of the children. The family moves from the dilapidated rental home. However, the mother misses her appointments, and despite repeated attempts to locate her, the family is lost to follow-up.

Adolescent↗
PubMed1994

Unilateral retinoblastoma: new intraocular tumours after treatment.

A retrospective chart review of 427 eyes diagnosed with unilateral retinoblastoma was performed to determine which eyes, which patients, and when new intraocular tumours would develop after treatment. Mean follow up was 8.16 years. Twenty five (6%) of 427 unilateral retinoblastoma patients developed new intraocular tumours after treatment. Five (1%) unilateral patients who were previously treated with enucleation developed new tumours (in the fellow eye). Fifteen (24%) unilateral patients who were previously treated with external beam radiation developed new tumours (equally in either eye). New tumours did not develop in the macula of either eye. The relative risk of developing new intraocular tumours after treatment was 16% in patients diagnosed before 1 year old and 2.2% for patients diagnosed after 1 year old (p < 0.001). The mean time to onset for the development of new tumours after treatment was 0.74 years; no new tumours appeared after 7.5 years of age. Those patients who are diagnosed with unilateral retinoblastoma in the first 6 months of life and have a family history of the disease are at greatest risk of developing new intraocular tumours.

Age Factors↗
PubMed1992

Expression and transforming activity of a variant of the heparin-binding fibroblast growth factor receptor (flg) gene resulting from splicing of the alpha exon at an alternate 3'-acceptor site.

Splicing at an alternate 3'-acceptor site results in deletion of a CCCAG in the 5'-sequence of the exon coding for the NH2-terminal immunoglobulin-like disulfide loop of the heparin-binding fibroblast growth factor receptor (flg) alpha isoform. The result is an in-frame stop codon 138 base pairs after the first flg consensus translational initiation site. The next more favorable site predicts the same two loop intracellular receptor isoform, gamma, which was predicted from two different human cDNAs that arise by alternate use of two exons at the same site. Although expressed in normal tissue, the gamma mRNA is increased in rat prostate tumors and confers ability of anchorage-dependent cells expressing non-secreted heparin-binding fibroblast growth factors to grow in soft agar.

Amino Acid Sequence↗
PubMed1989

Lower limb salvage with autoclaved autogenous tibial diaphysis: case report.

A massive crush injury of the lower extremity associated with avulsion of a 30-cm segment of the diaphysis of the tibia is reported. The patient refused consideration of amputation. Therefore, in this unique case, the noncomminuted fragment was autoclaved and replaced as a nonvascularized autogenous graft. Graft-host union was observed without complication, leading to full weight-bearing ambulation with a molded orthosis within 1 year of the injury.

Adult↗
PubMed1989

Trace anesthetic gases during xenon arc photocoagulation for retinoblastoma.

In pediatric ocular examinations, administration of continuous-flow anesthetic gases containing nitrous oxide, halothane, and oxygen enables the physician to do safe, controlled, reproducible examinations. We did a study in which the levels of waste anesthetic gases were measured during xenon arc photocoagulation procedures used for retinoblastoma. Waste nitrous oxide and halothane gases measured during these procedures significantly exceeded the levels recommended by the National Institute of Safety and Health. These high levels are of particular importance because of the physician's proximity to the patient during the procedure. The high levels of waste gases may have immediate deleterious effects on the physician's functioning capacity and may also pose long-term health hazards for the physician and operating room personnel.

Air Pollutants, Occupational↗
PubMed1975

The Pickwickian syndrome with hypertrophy of tonsils: a re-appraisal.

Pronounced tonsilar hypertrophy was found in two obese patients suffering from hypersomnolence, periodic attacks of apnea and disturbing snoring at night. Both patients underwent tonsillectomy. Immediately after the operation the hypersomnolence disappeared, the breathing became normal, and the disturbing snoring at night ceased. Follow-up over a period of three years did not reveal any recurrence of these symptoms, even though the patients had not lost any weight during this period.

Adult↗