Biomedical subjects

M J Young

Publications and source records attributed to M J Young.

At least 19 recordsLinked to original sources

PubMed2001

Acute hypoglycemia impairs the functioning of the central but not peripheral nervous system.

Acute hypoglycemia impairs functions of the central nervous system, but few controlled studies have assessed the impact of hypoglycemia on the function of the peripheral nervous system. Sixteen non-diabetic humans underwent two separate hyperinsulinemic glucose clamp procedures on different study days, in a counter-balanced fashion. On one occasion, euglycemia was maintained (blood glucose, 5.0 mmol l(-1)), and on the other occasion, hypoglycemia (blood glucose, 2.6 mmol l(-1)) was induced. During each condition, subjects performed a combined psychometric, cognitive-experimental and psychophysical test battery, and measures were made (in the dominant median and common peroneal nerves) of the motor nerve conduction velocities and the amplitudes of the motor action potentials. Hypoglycemia caused impaired performance of general cognitive and information processing tasks (P<.05), but nerve conduction velocities and the amplitudes of motor action potentials were unaffected. Conduction velocities of the common peroneal nerve decreased from baseline within each experimental condition, perhaps due to hyperinsulinemia. Overall, these results demonstrate that multiple levels of information processing in the brain may alter while peripheral nerve function remains intact, and imply that peripheral neurons do not have the same obligate requirement for glucose as a metabolic fuel as neurons of the central nervous system.

Acute Disease↗

PubMed2000

Mechanism of capsid assembly for an icosahedral plant virus.

Capsids of spherical viruses share a common architecture: an icosahedral arrangement of identical proteins. We suggest that there may be a limited number of common assembly mechanisms for such viruses. Previous assembly mechanisms were proposed on the basis of virion structure but were not rigorously tested. Here we apply a rigorous analysis of assembly to cowpea chlorotic mottle virus (CCMV), a typical, small, positive-strand RNA virus. The atomic resolution structure of CCMV revealed an interleaving of subunits around the quasi-sixfold vertices, which suggested that capsid assembly was initiated by a hexamer of dimers (Speir et al., 1995, Structure 3, 63-78). However, we find that the capsid protein readily forms pentamers of dimers in solution, based on polymerization kinetics observed by light scattering. Capsid assembly is nucleated by a pentamer, determined from analysis of the extent of assembly by size-exclusion chromatography. Subsequent assembly likely proceeds by the cooperative addition of dimers, leading to the T = 3 icosahedral capsid. At high protein concentrations, the concentration-dependent nucleation reaction causes an overabundance of five-dimer nuclei that can be identified by classical light scattering. In turn these associate to form incomplete capsids and pseudo-T = 2 capsids, assembled by oligomerization of 12 pentamers of dimers. The experimentally derived assembly mechanisms of T = 3 and pseudo-T = 2 CCMV capsids are directly relevant to interpreting the structure and assembly of other T = 3 viruses such as Norwalk virus and pseudo-T = 2 viruses such as the vp3 core of blue tongue virus.

Bromovirus↗

PubMed2000

How should xanthine oxidase-generated superoxide yields be measured?

The rate of formation of superoxide measured by its reduction of tetranitromethane (TNM) and by its reduction of ferric cytochrome c (Fe(III) cc) are in excellent agreement when the superoxide is generated from a simple chemical precursor. In contrast, the rate of formation of superoxide generated in the reaction of xanthine oxidase with acetaldehyde is much higher (up to a factor of 6) when measured with TNM and compared with Fe(III) cc. It is shown that Fe(III) cc measures superoxide that has diffused from the enzyme, and that TNM probably scavenges all the dioxygen that is reduced by one electron by the enzyme. The TNM traps enzyme-bound superoxide in competition with the second-electron transfer and proton transfer, which normally yield hydrogen peroxide. The proton transfer is probably rate determining, k(p) </= 3.8x10(3)s(-1).

Acetaldehyde↗

PubMed2000

Systemic immune deviation in the brain that does not depend on the integrity of the blood-brain barrier.

OVA injected into the brain of normal mice evoked a deviant immune response (brain-associated immune deviation (BRAID)) that was deficient in OVA-specific delayed-type hypersensitivity. This response was not dependent on an intact blood-brain barrier since BRAID was induced even when OVA was injected into a newly created lesion site with extensive BBB leakage. However, newly activated microglia at the injection site 2 days after ablation of the striatum correlated with the loss of BRAID. At day 4 after trauma, when activated microglia were only visible further away from the injection site, BRAID was again able to be induced. In contrast to immune deviation elicited via the eye, an intact spleen was not required for BRAID, nor was BRAID adoptively transferable with spleen cells. In contrast i.v. injection of cervical lymph node cells harvested 8 days after OVA injection into the striatum was able to transfer BRAID into naive animals. Together, these data indicate that immune privilege in the brain is actively maintained and is mediated by an immune deviation mechanism that differs from eye-derived immune deviation and arises even when the BBB is compromised.

Adoptive Transfer↗

PubMed2000

Strand cleavage of supercoiled DNA by water-soluble peroxyl radicals. The overlooked importance of peroxyl radical charge.

It is well established that the peroxyl radicals formed during the thermal decomposition of 2,2'-azobis(amidinopropane), ABAP, in oxygenated water can cleave double-stranded DNA, from which fact it has been concluded that peroxyl radicals, as a general class, can induce DNA strand scission. However, the ABAP-derived radicals are positively charged, and DNA is a negatively charged polyanion. Moreover, the relatively small and, therefore, free to diffuse peroxyl radicals likely to be formed in vivo will generally be negatively charged or neutral. Plasmid supercoiled DNA [pBR 322, 4361 base pairs (bp)] was reacted with known, equal fluxes of two positively charged peroxyl radicals, a negatively charged peroxyl radical, and a neutral peroxyl radical. The two positively charged peroxyl radicals degraded >/=80% of the supercoiled pBR 322 at a flux of 4 radicals/bp, but the negatively charged and neutral peroxyl radicals had no significant effect even at a flux as high as 24 radicals/bp. The same lack of effect on the DNA was also observed with high fluxes of superoxide/hydroperoxyl radicals. Similar results were obtained with another supercoiled DNA, pUC 19, except that pUC 19 is somewhat more sensitive to strand scission by positively charged peroxyl radicals than pBR 322. We conclude that most of the peroxyl radicals likely to be formed in vivo have little or no ability to induce DNA strand scission and that the potential role of electrostatics in radical/DNA reactions should always be considered.

Animals↗

PubMed2000

Neuronal differentiation and morphological integration of hippocampal progenitor cells transplanted to the retina of immature and mature dystrophic rats.

Attempts to repopulate the retina with grafted neurons have been unsuccessful, in large part because donor cells prefer not to integrate with those of the host. Here we describe the first use of neural progenitor cells in the diseased adult retina. Adult rat hippocampal progenitor cells were injected into the eyes of rats with a genetic retinal degeneration. After survival times up to 16 weeks, the retinae of 1-, 4-, and 10-week-old recipients exhibited widespread incorporation of green fluorescent protein-expressing (GFP+) donor cells into the host retina. The 18-week-old recipients showed a similar pattern, but with fewer cells. Grafted cells expressed the mature neuronal markers NF-200, MAP-5, and calbindin. GFP+ cells extended numerous neurites into the host plexiform layers and these processes were intimately associated with synaptophysin+ profiles. GFP+ neurites also extended into the host optic nerve head. These results demonstrate the differentiation of substantial numbers of new neurons within the mature dystrophic retina.

Aging↗

PubMed2000

Urinary hyaluronic acid and hyaluronidase: markers for bladder cancer detection and evaluation of grade.

PURPOSE: Specific patterns of progression and frequent recurrence of bladder tumors determine the choice of treatment, frequency of surveillance, quality of life, and ultimately, patient prognosis. The prognosis would be improved if an accurate noninvasive test was available for diagnosis. Identification of markers that function in bladder cancer progression would be helpful in designing such diagnostic tests. The glycosaminoglycan, hyaluronic acid (HA), promotes tumor metastasis. Hyaluronidase (HAase), an endoglycosidase, degrades HA into small fragments that promote angiogenesis. We have previously shown that both HA and HAase are associated with bladder cancer and may function in bladder tumor angiogenesis. In this study we examined whether urinary HA and HAase levels serve as bladder cancer markers. MATERIALS AND METHODS: Among the 513 urine specimens analyzed, 261 were from transitional cell carcinoma (TCC) patients, 9 from patients with non-TCC tumors, and 243 from controls (normals, patients with other genitourinary (GU) conditions or a history of bladder cancer (HxBCa)). The urinary HA and HAase levels were measured by two ELISA-like assays that utilize a biotinylated HA binding protein for detection. These levels were normalized to total urinary protein and were expressed as ng./mg. (HA test) and mU/mg. (HAase test), respectively. RESULTS: The urinary HA levels were elevated (2.5 to 6.5 fold) in bladder cancer patients (1173.7+/-173.4; n = 261) as compared with normals (246.1+/-38.5; n = 41); GU patients (306.6+/-32.2; n = 133), and patients with a HxBCa (351.1+/-49.1; n = 69) (p <0.001). The urinary HAase levels were elevated (3 to 7 fold) in G2/G3 bladder cancer patients (26.2+/-3.2) as compared with normals (4.5+/-0.9) and patients with either GU conditions (5.8+/-1.3), HxBCa (8.2+/-2.6) or G1 tumors (9.7+/-2.5) (p <0.001). The HA test showed 83.1% sensitivity, 90.1% specificity and 86.5% accuracy in detecting bladder cancer, regardless of the tumor grade. The HAase test showed 81.5% sensitivity, 83.8% specificity and 82.9% accuracy to detect G2/G3 patients. Combining the inferences of the HA and HAase tests (HA-HAase test) resulted in detection of bladder cancer, regardless of tumor grade and stage, with higher sensitivity (91.2%) and accuracy (88.3%), and comparable specificity (84.4%). CONCLUSION: Our results show that the HA-HAase urine test is a noninvasive, highly sensitive and specific method for detecting bladder cancer and evaluating its grade.

Adult↗

PubMed2000

Using a SANE interdisciplinary approach to care of sexual assault victims.

BACKGROUND: Many hospitals have recognized the need to develop policies and procedures for female sexual assault victims' prompt access to emergency medical care and for collecting law enforcement evidence. At Lehigh Valley Hospital (Allentown, Penn), care in the emergency department (ED) for sexual assault victims was covered by oncall obstetricians and gynecologists. Although many aspects of rape management were in place, a busy ED with varying levels of physician response and exposure to the process of rape management contributed to a lack of standardized, objective, timely, and compassionate medical management of sexual assault victims. DEVELOPING THE PROGRAM: The Sexual Assault Nurse Examiner (SANE) interdisciplinary approach to care of sexual assault victims was implemented in May 1998. Community education and awareness projects emphasized prevention of sexual assault and domestic violence, as well as minimization of trauma for victims by promoting services that provide a supportive, caring, and healing environment. RESULTS: Comparing a baseline group of 130 sexual assault victims with 39 patients who were evaluated after the SANE approach was implemented indicated increased clinical interaction and significant improvements in quality indicators, such as completeness of evaluation and information gathered relevant to medical-legal issues. DISCUSSION: Law enforcement staff developed a more collaborative relationship with SANE examiners through the interdisciplinary team approach. Collaborative relationships were initiated with several other hospitals in the hospital's integrated delivery system to help offset some of the program's training, continuing education, and on-call costs and to allow for joint outcomes collection. The SANE program became a core ED service in July 1999.

Emergency Service, Hospital↗

PubMed2000

Evaluation of guidelines for the use of telemetry in the non-intensive-care setting.

To determine if the American College of Cardiology (ACC) cardiac monitoring guidelines accurately stratify patients according to their risks for developing clinically significant arrhythmias in non-intensive-care settings, we conducted a prospective cohort study of 2,240 consecutive patients admitted to a non-intensive-care telemetry unit over 7 months. Sixty-one percent of patients were assigned to ACC class I (telemetry indicated in most patients), 38% to class II (telemetry indicated in some), and 1% to class III (telemetry not indicated). Arrhythmias were detected in 13.5% of the class I patients, 40.7% of the class II patients, and 12% of the class III patients (p <.001). Telemetry detected an arrhythmia resulting in transfer to an intensive care unit in 0.4% of the class I patients, 1.6% of the class II patients, and none of the class III patients (p =.006). Telemetry led to a change in management for 3.4% of the class I patients, 12.7% of the class II patients, and 4% of the class III patients (p <.001). When patients with chest pain as the reason for admission were moved from class I to class II and patients with arrhythmias as the reason for admission were moved from class II to class I, more arrhythmias and more clinically significant arrhythmias occurred in class I patients and the trends from class I to class III were more consistent with the purpose of the guidelines. These findings indicate that when the ACC guidelines are reexamined, consideration should be given to changing them so they are more useful in non-intensive-care settings.

Arrhythmias, Cardiac↗

PubMed2000

Differences in the performance of commercially available 10-g monofilaments.

OBJECTIVE: This independent study was designed to determine the accuracy of 10-g monofilaments manufactured and supplied by popular commercial companies. RESEARCH DESIGN AND METHODS: A total of 160 new 10-g monofilaments (30 Semmes-Weinstein monofilaments [North Coast Medical], 30 Timesco/Sensory Testing Systems monofilaments, 50 Owen Mumford Neuropens, and 50 Bailey Instruments monofilaments) were tested using a calibrated load cell. Each monofilament was subjected to 10 mechanical bucklings of 10 mm while the load cell detected the maximum buckling force. Longevity testing was performed on a subset of the monofilaments by subjecting them to continuous compressions until the buckling force was <9 g. RESULTS: The accuracy of monofilaments to produce a buckling force of 10 g varies among manufacturers. Bailey Instruments and Owen Mumford filaments were the most accurate with 100% buckling within +/-1.0 g of 10 g. Only 70% of the Semmes-Weinstein monofilaments from North Coast Medical buckled within +/-1.0 g of 10 g. A total of 80% of Timesco filaments buckled at <8 g. Longevity tests on Bailey Instruments and Owen Mumford monofilaments demonstrated that 80% continued to buckle within 10% of 10 g after 100 compressions, but only 50% were within this range after 200 compressions. The maximum amount of recovery achieved in any monofilament occurred within 24 h. CONCLUSIONS: Monofilaments made by either Bailey Instruments or Owen Mumford are recommended for use in clinical practice. North Coast Medical monofilaments may operate differently in the U.S. because of different environmental conditions such as differences in humidity. Timesco/Sensory Testing Systems monofilaments were neither accurate enough nor Conformity European marked to recommend their use in the U.K. Longevity and recovery testing suggest that each monofilament will survive usage on approximately 10 patients before needing a recovery time of 24 h before further use.

Calibration↗

PubMed1999

Intracellular and cell-surface distribution of amyloid precursor protein in cortical astrocytes.

Amyloid peptides that aggregate to form plaques in Alzheimer's disease are derived from secretory processing of the amyloid precursor protein (APP). Transport of APP to the cell surface may be prerequisite for non-amyloidogenic APP processing and the secretion of soluble APP (APPs), while missorting or reinternalization of APP to intracellular compartments can promote amyloid formation. In cultured astrocytes, APP mRNA and holoprotein are increased by elevations in cAMP levels, and 8-Bromo-cAMP promotes process formation on these cells. We now report that treatment of cultured astrocytes with 8-Bromo-cAMP increased intracellular and cell surface APP in the soma and perinuclear region as detected by immunolabeling with monoclonal antibody 22C11 and polyclonal antibody Kunitz-type protease inhibitor (KPI) (against the N-terminus and KPI domain of APP, respectively) and led to intense but discontinuous labelling of APP on the surface of astrocytic processes. Northern and Western blot analyses confirmed that 8-Bromo-cAMP treatment of cultured astrocytes also increased APP mRNA and KPI-containing APP holoprotein, implying that the intense APP immunolabeling observed in 8-Bromo-cAMP treated astrocytes was not derived from truncated forms of APP (e.g., APPs), but reflected high levels of APP holoprotein containing intact amyloid peptides. Discontinuous cell surface staining in process-bearing astrocytes may be caused by miscompartmentalization of APP related to rearrangement of the cytoskeleton. Inasmuch as intracellular APP is not accessible for non-amyloidogenic processing, we suggest that the increased immunoreactivity of intracellular APP in process-bearing astrocytes may predispose the cells to increased amyloid production.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed1999

Identification of bladder tumor-derived hyaluronidase: its similarity to HYAL1.

The glycosaminoglycan hyaluronic acid (HA) and its degrading enzyme, hyaluronidase, are intricately associated with tumor metastasis and angiogenesis. HA promotes tumor cell adhesion and migration, whereas its small fragments stimulate angiogenesis. Such small HA fragments are generated from the degradation of HA by hyaluronidase. We have previously shown (V. B. Lokeshwar et al., Cancer Res., 57: 773-777, 1997) that the HA levels are elevated in the urine and tumor tissues of bladder cancer patients regardless of the tumor grade (G). The hyaluronidase levels were found to be elevated in the urine and tumor tissues of G2 and G3 bladder cancer patients. Furthermore, angiogenic HA fragments were isolated from the urine of G2/G3 bladder cancer patients, which stimulated endothelial cell proliferation, a key event in angiogenesis. In this study, we characterized the bladder tumor-derived hyaluronidase. Analysis of hyaluronidase activity in the culture-conditioned media (CM) of 11 bladder cancer cell lines, using an ELISA-like assay and a substrate (HA)-gel technique, showed that the invasive bladder cancer cell lines secrete elevated levels of a Mr approximately 60,000 hyaluronidase. Reverse transcription-polymerase chain reaction, cloning, and sequence analyses revealed the expression of an HYAL1 transcript in bladder cancer lines. HYAL1 encodes for a hyaluronidase that is present in serum. Immunoblot analysis using an anti-HYAL1 peptide IgG confirmed the presence of a Mr approximately 60,000 HYAL1-related protein in the CM of bladder cancer cell lines, in the urine specimens from G2 and G3 bladder cancer patients, and in the partially purified preparations of bladder tumor-derived hyaluronidase. No HYAL1-related protein was detected in urine specimens from normal individuals, G1 bladder cancer patients, and patients with a history of bladder cancer but no disease at the time of testing. The bladder tumor-derived hyaluronidase present in CM and partially purified preparations was found to have maximum activity at a pH range of 4.1-4.3. The identification of bladder tumor-derived hyaluronidase should help in elucidating its role in bladder tumor progression.

Aged↗

PubMed1999

Complications of advanced prostate cancer.

Currently, there is a lot of focus directed toward discovering treatments for patients with hormone refractory prostate cancer (HRPC) that will lead to increased survival. Until such treatments emerge, palliation is important to ensure patients the highest possible quality of life. Most disabling among symptoms associated with disease progression are bone pain, bone fracture, urinary tract obstruction, spinal cord compression, coagulation disorders, anemia, and edema. Diverse treatments, such as radiation therapy, surgery, chemotherapy, and supportive measures, can improve the impact of these problems, although improved symptom control is needed in some areas.

Anemia↗

PubMed1999

Luteovirus interactions with aphid vector cellular components.

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Animals↗

PubMed1999

Evidence for the Will Rogers phenomenon in migration of employees to managed care plans.

Employees have increasing opportunities to enroll in managed care plans, and employers tend to favor these plans because of their lower costs. However, lower costs may be the result of selection of healthier patients into managed care plans. This study measured differences in health care utilization across an indemnity plan and a managed care plan, and for all employees together. We found that apparent increases in utilization in both indemnity and managed care plans disappeared when the plans were viewed together, reflecting the migration of sicker patients from indemnity plans to managed care plans.

Employer Health Costs↗

PubMed1998

Comparison of the native CCMV virion with in vitro assembled CCMV virions by cryoelectron microscopy and image reconstruction.

Cryoelectron microscopy and three-dimensional image reconstruction analysis has been used to determine the structure of native and in vitro assembled cowpea chlorotic mottle virus (CCMV) virions and capsids to 25-A resolution. Purified CCMV coat protein was used in conjunction with in vitro transcribed viral RNAs to assemble RNA 1 only, RNA 2 only, RNA 3/4 only, and empty (RNA lacking) virions. The image reconstructions demonstrate that the in vitro assembled CCMV virions are morphologically indistinguishable from native virions purified from infected plants. The viral RNA (vRNA) is packaged similarly within the different types of virions. The centers of all assembled particles are generally devoid of density and the vRNA packs against the interior surface of the virion shell. The vRNA appears to adopt an ordered conformation at each of the quasi-threefold axes.

Bromovirus↗

PubMed1998

The retinal ganglion cells that drive the pupilloconstrictor response in rats.

It is well established that the pupillary light reflex (PLR) in rats is mediated by a direct retinal projection to the olivary pretectal nucleus (OPN). Although several authors have commented on the specific subpopulation of retinal ganglion cells (RGC) that project to the rat pretectum, much of this evidence is circumstantial, and depends mostly upon electrophysiological data (e.g., conduction velocity). Here, we have used microinjections of Fluoro-Gold into the OPN (pretectum and superior colliculus as controls) to retrogradely label RGCs projecting to this region. The retinae were whole-mounted, viewed under fluorescence, and the regional distribution pattern, laterality of projection, and cell soma sizes determined. The results show OPN injections label a small subpopulation of RGCs. In the contralateral retinae, labeled RGCs were most numerous and widespread, with 97% projecting to the contralateral pretectum. The highest density of cells in the contralateral retinae was found in the inferior and nasal retinal quadrants. In the ipsilateral retinae, the small number of labeled cells were concentrated in the periphery of the inferior and nasal retinal quadrants. A striking feature of both ipsilateral and contralateral retinae was the paucity of labeled cells found in the dorsal hemiretina (lower visual field). Cell size measurements indicate 90-95% of labeled RGCs had diameters of 9-13 microm, while most of the remaining cells had diameters of 20-25 microm. This would suggest class III cells may be the predominant RGC type mediating pupilloconstriction, although a smaller population of larger cells (e.g., class I and/or II) may also contribute to this pathway. The recent reports utilizing the PLR as an assay for the efficacy of intraretinal grafts has highlighted the significance of the regional distribution results. The extremely low number of labeled cells in the dorsal hemiretina would argue for the placement of such grafts in the ventral hemiretina.

Animals↗

PubMed1998

Changes in the pupillary light reflex of pigmented royal college of surgeons rats with Age.

We studied the latency and amplitude of the pupillary light reflex response of the Royal College of Surgeons rat from 10 to 52 weeks of age. The responses of these dystrophic rats were diminished compared to those of normal, non-dystrophic rats at all ages examined. This was most marked at the dimmest light intensity studied here and for the latency of dystrophic animals' responses. The latency deteriorated over the course of 52 weeks, although there was some evidence of improvement beyond 36 weeks of age. The amplitude of the dystrophic animals' responses also suggested some deterioration occurring up to 36 weeks of age, but with a substantial improvement beyond this time. In addition to these parameters, we also observed a break in the constriction phase of the pupillary light reflex that was unique to the dystrophic animals' responses. The frequency with which the anomaly occurred decreased in a light-dependent manner with age. The improvement of the pupillary light reflex at older ages, even when very few photoreceptors remain, may reflect compensatory events occurring in the inner retinal layers and/or in the central connections of the pupillary light reflex pathway. We suggest that the break in the constriction phase is a reflection of dual inputs driving the response, one of which is affected more by the degenerative events. This study provides baseline data on the effect of degeneration on function over time which can be used to evaluate the efficacy of repair strategies such as transplantation.

Aging↗