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Biomedical subjects

C Nelson

Publications and source records attributed to C Nelson.

At least 37 records · Page 2Linked to original sources
PubMed1999

Targeting bcl-2 gene to delay androgen-independent progression and enhance chemosensitivity in prostate cancer using antisense bcl-2 oligodeoxynucleotides.

Bcl-2 expression is upregulated in prostate cancer cells after androgen withdrawal and is associated with the development of androgen independence and chemoresistance. Induction of apoptotic cell death after androgen ablation, or chemotherapy, may be enhanced through functional inhibition of bcl-2. In this report, we tested the effects of antisense bcl-2 oligodeoxynucleotides (ODN) with androgen ablation and taxane therapy on time to androgen-independent (Al) progression in the androgen-dependent Shionogi tumor model. Treatment of Shionogi tumor cells in vitro with 500 nmol/L antisense bcl-2 ODN decreased bcl-2 mRNA by 85%, compared with treatment with 500 nmol/L mismatch control ODN. Although bcl-2 expression levels in Shionogi cells were not changed by docetaxel treatment, docetaxel treatment induced bcl-2 phosphorylation. Consequently, the formation of bcl-2/Bax heterodimer formation was inhibited in a dose-dependent manner. Treatment of Shionogi tumors in vitro with either 500 nmol/L antisense bcl-2 ODN or 10 nmol/L docetaxel alone did not induce apoptosis or reduce growth rates. However, combined treatment reduced the concentration that reduces cell viability by 50% (IC50) of docetaxel from 100 nmol/L to 10 nmol/L and induced characteristic apoptotic DNA laddering and cleavage of the poly(ADP-ribose)polymerase (PARP) protein. Adjuvant in vivo administration of antisense bcl-2 ODN and polymeric micellar paclitaxel after castration resulted in a significant delay in time to Al recurrence when compared with administration of either agent alone. Furthermore, combined treatment of mice bearing Al recurrent Shionogi tumors with antisense bcl-2 ODN and micellar paclitaxel synergistically induced tumor regression and growth inhibition when compared with treatment with either agent alone. These findings suggest that down-regulation of bcl-2 by antisense ODN chemosensitizes Al Shionogi tumors to taxanes, over and above the effects of taxane-induced phosphorylation of bcl-2. Antisense bcl-2 ODN combined with taxanes may be a novel approach to the treatment of both established and emerging Al disease.

Androgens↗
PubMed1999

Startle potentiation by threat of aversive stimuli and darkness in adolescents: a multi-site study.

In recent years, the startle reflex has become an exciting new tool to investigate affective responses to aversive stimuli in humans. The popularity of this methodology is largely based on the substantial amount of animal research available on this topic. Several procedures have been developed to examine startle potentiation in humans, but most studies have been carried out in adults and may not be appropriate for children or adolescents. The present study is a multi-site project (Yale University, Harvard University, and the University of Minnesota) investigating two new procedures to examine the potentiation of startle in adolescents. The subjects were 50 male and female aged 13-17 years old. One procedure examined fear-potentiated startle to the threat of an unpleasant airblast directed to the larynx. The second examined the facilitation of startle in darkness. Potentiation was found using each procedure and the degree of potentiation was similar across laboratories. These results suggest that both the threat of an airblast and darkness can reliably be used to examine startle potentiation in young subjects.

Adolescent↗
PubMed1999

Maskless fabrication of light-directed oligonucleotide microarrays using a digital micromirror array.

Oligonucleotide microarrays, also called "DNA chips," are currently made by a light-directed chemistry that requires a large number of photolithographic masks for each chip. Here we describe a maskless array synthesizer (MAS) that replaces the chrome masks with virtual masks generated on a computer, which are relayed to a digital micromirror array. A 1:1 reflective imaging system forms an ultraviolet image of the virtual mask on the active surface of the glass substrate, which is mounted in a flow cell reaction chamber connected to a DNA synthesizer. Programmed chemical coupling cycles follow light exposure, and these steps are repeated with different virtual masks to grow desired oligonucleotides in a selected pattern. This instrument has been used to synthesize oligonucleotide microarrays containing more than 76,000 features measuring 16 microm 2. The oligonucleotides were synthesized at high repetitive yield and, after hybridization, could readily discriminate single-base pair mismatches. The MAS is adaptable to the fabrication of DNA chips containing probes for thousands of genes, as well as any other solid-phase combinatorial chemistry to be performed in high-density microarrays.

Base Sequence↗
PubMed1999

p53, mdm-2, and p21 waf-1 in the porokeratoses.

The etiology of the porokeratoses is unknown. Overexpression of the p53 tumor suppressor protein and disregulated cell cycle control have been pathogenically implicated. The p53 tumor suppressor gene product is regulated by mdm2 and both gene products influence cell cycle progression through the cyclin-dependent kinase inhibitor p21. Thirty-three cases of the various types of porokeratosis were immunohistochemically studied for p53, mdm2, and p21 proteins. Each of the cases showed increased p53 and decreased mdm2 and p21 expression within keratinocytes underlying cornoid lamella. This study confirms the previous findings of increased p53 staining and expands the potential roles of mdm2 and p21 in the pathogenesis of the porokeratoses.

Cyclin-Dependent Kinase Inhibitor p21↗
PubMed1999

Progression to androgen independence is delayed by adjuvant treatment with antisense Bcl-2 oligodeoxynucleotides after castration in the LNCaP prostate tumor model.

Bcl-2 has emerged as a critical regulator of apoptosis in a variety of cell systems and is up-regulated during progression to androgen independence in prostate cancer cells. The objectives of this study were to characterize changes in Bcl-2 after androgen withdrawal and during progression to androgen independence in the human prostate LNCaP tumor model and determine whether adjuvant use of antisense Bcl-2 oligodeoxynucleotides (ODNs) with androgen ablation delays progression to androgen independence. Bcl-2 expression in LNCaP cells is down-regulated to undetectable levels by androgen in vitro and up-regulated after castration in vivo. Antisense Bcl-2 ODN treatment reduced LNCaP cell Bcl-2 messenger RNA and protein levels by >90% in a sequence-specific and dose-dependent manner at concentrations >50 nM. Bcl-2 mRNA levels returned to pretreatment levels by 48 h after discontinuing treatment. Athymic male mice bearing SQ LNCaP tumors were castrated and injected i.p. with 12.5 mg/kg/day with two-base mismatch ODN control, reverse polarity ODN control, or antisense Bcl-2 ODN. Tumor volume in control mice gradually increased 5-fold (range, 3-6) by 12 weeks after castration compared to a 10-50% decrease in precastrate tumor volume in mice treated with antisense Bcl-2 ODN. Changes in serum PSA paralleled changes in tumor volume, increasing 4-fold faster above nadir in controls than in mice treated with antisense Bcl-2 ODN. After decreasing 70% by 1 week after castration, PSA increased 1.6-fold above precastrate levels by 11 weeks in controls while staying 30% below precastrate levels in antisense-treated mice. In a second group of experiments, LNCaP tumor growth and serum PSA levels were 90% lower (P<0.01) in mice treated with antisense Bcl-2 ODN compared with mismatch or reverse polarity ODN controls. These results support the hypothesis that Bcl-2 helps mediate progression to androgen independence and is an appropriate target for antisense therapy.

Androgens↗
PubMed1999

Sterilizable syringes: excessive risk or cost-effective option?

In recent years, many poorer countries have chosen to use disposable instead of sterilizable syringes. Unfortunately, the infrastructure and management systems that are vital if disposables are to be used safely do not exist. WHO estimates that up to 30% of injections administered are unsafe. The traditional sterilizable syringe had many disadvantages, some of which have been minimized through better design and the use of modern materials; others have been overcome because staff are able to demonstrate that they have performed safely. For example, the time-steam saturation-temperature (TST) indicator has enabled staff to demonstrate that a sterilizing cycle has been successfully completed. Health facility staff must be able to sterilize equipment, and the sterilizable syringe remains the least costly means of administering an injection. Data from countries that have acceptable systems for processing clinical waste indicate that safe and environmentally acceptable disposal, destruction and final containment cost nearly as much as the original cost of a disposable syringe. By careful supervision of staff behaviour and good management, some countries have demonstrated that they are able to administer safe injections with sterilizable syringes at a price they can afford.

Cost-Benefit Analysis↗
PubMed1999

National Ambulatory Medical Care Survey: 1995-96 summary.

OBJECTIVE: This report describes ambulatory medical care visits to nonfederally employed, office-based physicians in the United States during 1995 and 1996. Statistics are presented on selected physician, patient, and visit characteristics. METHODS: The data in this report were collected in the 1995 and 1996 National Ambulatory Medical Care Surveys (NAMCS). The NAMCS is part of the ambulatory care component of the National Health Care Survey (NHCS), which measures health care utilization across a variety of providers. The NAMCS is a national probability sample survey of visits to nonfederally employed, office-based physicians in the United States. Sample data were weighted to produce annual estimates. Estimates are presented in this report as annual averages unless otherwise noted. RESULTS: During 1995-96, an estimated 1.4 billion visits were made to physician offices in the United States, an annual average of 715.8 million visits. The visit rate was 2.7 visits per person per year. This rate did not differ significantly from visit rates observed in any previous survey year. Females made 59.4 percent of the visits, or 3.2 visits per person annually. This was higher than the visit rate for males. White persons had a higher visit rate than black persons. Six of every 10 visits were to primary care providers. Injury-related visits accounted for 11.8 percent of all office visits, or 84.6 million per year. The annual rate of injury-related office visits was 32.2 visits per 100 persons. The most frequent reason for visiting the physician was for a general medical examination (6.8 percent). Cough was the most frequent symptomatic reason. Acute respiratory infections and essential hypertension were the diagnoses reported most frequently.

Adolescent↗
PubMed1999

Strategies for safe injections.

In 1998, faced with growing international concern, WHO set out an approach for achieving injection safety that encompassed all elements from patients' expectations and doctors' prescribing habits to waste disposal. This article follows that lead and describes the implications of the approach for two injection technologies: sterilizable and disposable. It argues that focusing on any single technology diverts attention from the more fundamental need for health services to develop their own comprehensive strategies for safe injections. National health authorities will only be able to ensure that injections are administered safely if they take an approach that encompasses the whole system, and choose injection technologies that fit their circumstances.

Disposable Equipment↗
PubMed1998

Synaptic competition during the reformation of a neuromuscular map.

We have been studying the mechanisms whereby pools of motor neurons establish a rostrocaudal bias in the position of their synapses in some skeletal muscles. The serratus anterior (SA) muscle of the rat displays a rostrocaudal topographic map before birth, and the topography is re-established after denervation. In this report, we explore the potential role of synaptic competition between innervating axons as a means of generating topographic specificity. We followed the progress of the reformation of this map in neonatal animals under conditions that enhanced the likelihood of observing synaptic competition. This was accomplished by forcing caudal axons to regenerate ahead of rostral axons onto a surgically reduced SA muscle. In this way, caudal (C7) motor neurons had unopposed access to vacated synaptic sites on the remaining rostral half of the SA before the return of the rostral (C6) axons. Intracellular recording revealed that 2 d after the second denervation, most of the reinnervated end plates contained only axons from the C7 branch; the remaining reinnervated end plates received input from C6 only or were multiply innervated by C6 and C7 axons. After 6 d, the pattern was reversed, with most end plates innervated exclusively by C6. After 17 d, axons from C6 were the sole input to reinnervated end plates. During the transition from C7- to C6-dominated input, at end plates coinnervated by C6 and C7 axons, the average quantal content from C6 was the same as that from C7; after 7 d, the quantal content of C6 was greater than that of C7. We have thus developed an experimental situation in which the outcome of synaptic competition is predictable and can be influenced by the positional labels associated with axons from different levels in the spinal cord.

Animals↗
PubMed1998

Cytospin-enhanced direct immunofluorescence assay versus cell culture for detection of herpes simplex virus in clinical specimens.

The reliability of a cytospin-enhanced direct immunofluorescence assay (DFA), using Syva Micro Trak monoclonal antibodies, for detection of herpes simplex virus (HSV) was evaluated by comparing results with those of conventional cell culture. Of 250 clinical specimens, 64 were positive for HSV by cell culture, and 22 were positive by cytospin-enhanced DFA, two of which were negative by culture. The sensitivity, specificity, and positive and negative predictive values for cytospin-enhanced DFA were 31.25, 98.9, 90.9, and 80.7%, respectively. Cytospin-enhanced DFA is not an acceptable alternative to cell culture for detection of HSV.

Centrifugation↗
PubMed1998

Ropivacaine-induced seizure after extradural anaesthesia.

Ropivacaine is considered safer than bupivacaine, on the basis of experimental and human data that indicate a lower systemic toxicity. Here we report the occurrence of a single seizure after i.v. administration of ropivacaine 120 mg intended for extradural block in a patient having postpartum, tubal ligation. The only prodromal symptom was nervousness, and the only cardiovascular manifestation was sinus tachycardia. Systemic toxicity, although less than that expected with bupivacaine, can occur with ropivacaine.

Adult↗
PubMed1998

The value of orbital echography in orbital practice.

Twenty-three consecutive patients with orbital masses who were referred to a major medical center and later had biopsies underwent ophthalmic echographic evaluation. The efficacy of orbital echography was compared with both the clinical evaluation and other orbital imaging methods (computed tomography and magnetic resonance imaging). Echography was successful in all patients (100%) in detecting the orbital mass. The diagnosis was accurate in 18 of 22 patients (82%) echographically, 12 of 14 patients (86%) clinically, and 11 of 13 patients (85%) radiologically when a short differential was attempted. If all the patients examined were considered, echographic evaluation arrived at an accurate diagnosis in 18 of 23 patients (78%), clinical impression was accurate in 12 of 23 patients (52%), and radiologic evaluation was accurate in 11 of 20 patients (55%). In three patients, echography was the only imaging method used. The role of ophthalmic echography in the diagnosis of orbital masses is discussed.

Adult↗
PubMed1998

A population-based survey of Haemophilus influenzae type b nasopharyngeal carriage prevalence in Lombok Island, Indonesia.

BACKGROUND: The Haemophilus influenzae type b (Hib) nasopharyngeal carriage prevalence and invasive disease incidence rates are unknown in Indonesia; consequently Hib vaccine is not included in the routine vaccine schedule. METHODS: To determine carriage prevalence we conducted a population-based, island-wide prospective study of a systematic sample of 484 children 0 to 2 years of age in Lombok, Indonesia. We conducted a risk factor questionnaire and determined serotypes and antibiotic sensitivity patterns. RESULTS: We identified 155 H. influenzae isolates, of which 22 were type b and 12 were encapsulated but not type b. The age- and population-weighted Hib carriage prevalence, adjusted for the sampling design, was 4.6% (95% confidence interval, 3.7 to 5.5%). Children younger than 6 months of age had a carriage prevalence less than one-half that of older children, and carriage varied within the four administrative regions of the island; otherwise no risk factors for Hib carriage were identified. All Hib specimens were sensitive to ampicillin and 20 (91%) were sensitive to chloramphenicol. CONCLUSIONS: The Hib carriage prevalence in Lombok is similar to that found in developed countries before vaccine introduction. This suggests that further studies should proceed to determine whether Lombok has invasive disease rates as high as those that justified vaccine introduction in developed countries.

Carrier State↗
PubMed1998

Haploinsufficiency of MSX1: a mechanism for selective tooth agenesis.

Previously, we found that the cause of autosomal dominant selective tooth agenesis in one family is a missense mutation resulting in an arginine-to-proline substitution in the homeodomain of MSX1. To determine whether the tooth agenesis phenotype may result from haploinsufficiency or a dominant-negative mechanism, we have performed biochemical and functional analyses of the mutant protein Msx1(R31P). We show that Msx1(R31P) has perturbed structure and reduced thermostability compared with wild-type Msx1. As a consequence, the biochemical activities of Msx1(R31P) are severely impaired, since it exhibits little or no ability to interact with DNA or other protein factors or to function in transcriptional repression. We also show that Msx1(R31P) is inactive in vivo, since it does not display the activities of wild-type Msx1 in assays of ectopic expression in the limb. Furthermore, Msx1(R31P) does not antagonize the activity of wild-type Msx1 in any of these assays. Because Msx1(R31P) appears to be inactive and does not affect the action of wild-type Msx1, we propose that the phenotype of affected individuals with selective tooth agenesis is due to haploinsufficiency.

Amino Acid Substitution↗
PubMed1998

A prefilled injection device for outreach tetanus immunization by Bolivian traditional birth attendants.

This study evaluated the performance, acceptability, and appropriateness of a new, single-use, prefilled injection device called UniJect for an outreach immunization application. Between April and June 1995, UniJect devices were used by 36 traditional birth attendants to administer tetanus toxoid injections to 2,240 pregnant women during routine, antenatal home visits in the Northern, Ichilos, and Warnes Districts of Santa Cruz, Bolivia. Because tetanus toxoid is relatively heat stable, the traditional birth attendants were able to keep the tetanus toxoid-filled UniJect devices in their homes for up to one month without refrigeration. The devices were stored, transported, and disposed of in an outreach carrier designed to reduce the risks of improper handling and disposal. Data were collected from injection recipients, traditional birth attendants, and supervisors via observation, questionnaires, and post-study interviews. The performance of the UniJect device and its acceptability among all groups was very high. The traditional birth attendants used UniJect properly and safely; there were no reports or observations of device misuse, reuse, or needle-stick. Advantages cited included the fact that the device required no assembly, offered assured sterility, and reduced vaccine wastage sometimes associated with multi-dose vials. The ability to store and transport the vaccine-filled devices without ice also greatly simplified logistics.

Bolivia↗
PubMed1998

National Ambulatory Medical Care Survey: 1993 summary.

OBJECTIVE: This report describes ambulatory care visits made to private office-based settings in the United States during 1993. Ambulatory medical care services are described in terms of physician, patient, and visit characteristics. METHODS: The data presented in this report are from the 1993 National Ambulatory Medical Care Survey (NAMCS). This survey is part of the ambulatory care component of the National Health Care Survey (NHCS), which measures health care utilization across a variety of providers. The NAMCS is a national probability sample survey of visits to office-based physicians in the United States. Sample data were weighted to produce annual estimates. RESULTS: During 1993, an estimated 717.2 million visits were made to physician offices in the United States, resulting in an average of 2.8 visits per person per year. This rate did not differ significantly from the overall visit rate of 3.0 in 1992. Females made 60 percent of the visits. White persons had a significantly higher rate of visits to physicians than black persons (3.0 visits per person per year and 1.8 visits per person per year, respectively). Over one-quarter (27.6 percent) of the visits were to general and family physicians. About 84 million, or 12 percent, of the visits were injury related. The annual rate of injury-related office visits was 33.0 visits per 100 persons. Essential hypertension was the most common diagnosis made by physicians in 1993 as it has been since the survey began in 1973. Two-thirds of the visits resulted in another scheduled appointment and the mean duration was 18 minutes.

Adolescent↗
PubMed1997

A cysteine-rich domain defined by a novel exon in a slo variant in rat adrenal chromaffin cells and PC12 cells.

cDNA libraries from rat chromaffin cells and PC12 cells were screened for homologs to the mouse mSlo gene that encodes a large conductance, calcium (Ca2+)- and voltage-activated potassium channel (BK channel). One Slo variant contained sequence encoding a cysteine-rich, 59-amino acid insert for a previously described site of alternative splicing. This insert is reminiscent of zinc-finger domains. The exon was found in RNA from pancreas, anterior pituitary, cerebellum, and hippocampus. Expression in Xenopus oocytes of a Slo construct containing this exon conferred a -30 to -20 mV shift of the conductance-voltage curve. A previously uncharacterized alternative splice junction near the C-terminal end of Slo was also identified. In contrast to BK channels in rat chromaffin cells, none of the Slo variants exhibited inactivation when expressed in Xenopus oocytes. PCR screening of chromaffin cell RNA failed to reveal a homolog of an accessory beta subunit known to influence Slo channel function. Furthermore, a beta-subunit-dependent Slo channel activator, dehydrosoyasaponin I, was without effect on chromaffin cell BK current. The results argue that an accessory subunit may not be a required component of the native chromaffin cell BK channel.

Adrenal Medulla↗