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Biomedical subjects

D M Long

Publications and source records attributed to D M Long.

At least 55 records · Page 3Linked to original sources
PubMed1995

Divalent metal ions and the internal equilibrium of the hammerhead ribozyme.

Thermodynamics of RNA cleavage/ligation were measured for a self-cleaving hammerhead ribozyme in the presence of Ca2+, Co2+, Mg2+, and Mn2+. The internal equilibrium, the ratio of cleaved to ligated RNA, decreases with increasing concentrations of each of the four divalent metal ions in a hyperbolic dependence that shows saturation. The metal ion dependence is not due to changes in ionic strength, and the value of the equilibrium constant at saturation is different for each metal ion. The concentration required to achieve half-saturation of the equilibrium is also different for each metal ion, and the order of apparent metal ion dissociation constants correlates with those measured for dissociation of the same metal ions complexed with tRNA and nucleotides. We interpret the divalent metal ion dependence of the equilibrium in terms of a thermodynamic model invoking noncooperative metal ion dissociation from the cleaved RNA. Thus, at 10 mM Mg2+, a commonly employed condition for hammerhead kinetic studies, metal ion dissociation contributes substantially to the free energy of the equilibrium and drives the hammerhead reaction toward cleaved RNA. Temperature dependencies of the equilibrium reveal that while the entropy and enthalpy changes of the equilibrium depend on the identity of the divalent metal ion, in each case a large entropic driving force overcomes an unfavorable change in enthalpy. This agrees with thermodynamics previously measured for an intermolecular hammerhead in the presence of Mg2+ [Hertel, K. J., & Uhlenbeck, O. C. (1995) Biochemistry 34, 1744-1749].

Base Composition↗
PubMed1995

Association of heterotopic neuroglial tissue with an arachnoid cyst in the internal auditory canal.

An arachnoid cyst arising within the internal auditory canal, or within the cerebellopontine angle and subsequently extending into the internal meatus and enlarging it, is a rare occurrence. Nevertheless, the neurootologist and the neurosurgeon have an interest in its existence because its clinical manifestations are identical with the ones produced by a schwannoma, involving overwhelmingly the cochleovestibular nerve in that region. An equally rare observation in that location is the presence of ectopic neuroglial tissue. The two can occur independently or in combination. Examples of such lesions are presented, and their possible pathogenesis is discussed.

Journal Article↗
PubMed1994

Kinetic characterization of intramolecular and intermolecular hammerhead RNAs with stem II deletions.

A method is described to obtain intramolecular cleavage rates for the hammerhead ribozyme during in vitro transcription. By avoiding RNA purification and renaturation, the potential for formation of inactive conformations of the RNA is minimized. By showing that an intramolecular hammerhead and a closely related intermolecular hammerhead cleave at the same rate under a given set of conditions, we confirm that both reactions probably have the same rate-limiting step. An in vitro selection strategy was used to isolate active hammerheads from a library of molecules where six randomized nucleotides replaced stem-loop II. The sequence and number of nucleotides which replace stem-loop II have large effects on hammerhead cleavage activity. The relative activities of three sequences selected from the intramolecular library are the same when the sequences are transferred into an intermolecular hammerhead background.

Base Sequence↗
PubMed1994

The effects of topical dexamethasone on experimental brain tumors and peritumoral brain edema.

To determine if topical dexamethasone administered to brain tumor beds would not only control peritumoral edema and suppress tumor growth but also prevent systemic steroid complications, we studied experimental brain tumors produced in 102 rabbits by implanted VX2 carcinoma cells. We separated 58 animals into three groups: 1) untreated rabbits (n = 15), 2) systemic dexamethasone-treated (4 mg/kg/day) rabbits (n = 18), and 3) topical dexamethasone-treated (2.5 microliters/h, osmotic pump) rabbits (n = 25). We administered systemic or topical dexamethasone from the third day or from the seventh day after tumor implantation, and sacrificed the animals on the 13th day. We compared survival in these three groups with that of another 44 rabbits, beginning treatment on the seventh day. We measured brain water content in the white matter of the sacrificed rabbits by the specific gravity method. We measured the length and width of the brain tumors of all the rabbits and estimated tumor volume. Systemic and topical dexamethasone administered from the third day produced statistically significant inhibition of tumor volume as well as a mean reduction in peritumoral brain edema in most tested sites. Systemic and topical dexamethasone treatment resulted in a statistically significant increase in survival relative to the untreated group. These results suggest that topical dexamethasone is efficacious in a brain tumor model and its administration to brain tumor beds constitutes a new therapeutic modality.

Administration, Topical↗
PubMed1994

Proposed toxic oxidant inhibitors fail to reduce brain edema.

Toxic oxidants (oxygen free radicals) have been implicated in the formation of brain edema from ischemia-reperfusion injury or tumor growth. We investigated the ability of an iron chelator, a calcium channel blocker, and a xanthine oxidase inhibitor to reduce formation of brain edema following a cold lesion in cats. The agents were given independently of each other in an attempt to inhibit the Haber-Weiss reaction, prevent Ca++ modulated uncoupling of oxidative phosphorylation, and inhibit the generation of toxic oxidants via xanthine oxidase, respectively. Pentastarch-deferoxamine conjugate at a dose of 50 mg/kg was given 15 minutes before and 60 minutes after the cold lesion. Nimodipine was given at a dose of 1 mg/kg 1 hour before and 2 hours after the cold lesion. Allopurinol was given at a dose of 50 mg/kg 24 hours before, at the time of the lesion and, 24 and 48 hours after the lesion. Gravimetric measurements of multiple brain areas were performed at 24 hours post-lesion in the pentastarch-deferoxamine and nimodipine groups and at 72 hours post-lesion in the allopurinol group. None of these agents led to significant reduction in brain edema formation as measured with a gravimetric column of kerosene and bromobenzene. Pentastarch-deferoxamine conjugate was utilized to avoid the confounding effects of arterial hypotension which is seen with intravenous deferoxamine. There was even a suggestion of increased edema in the periventricular white matter in animals treated with nimodipine. Taken together, independent inhibition of the Haber-Weiss reaction, of calcium channels, or of xanthine oxidase does not reduce formation of brain edema in the cold lesion model.

Allopurinol↗
PubMed1994

Pregnancy alters cerebrovascular adaptation to high-altitude hypoxia.

We have previously shown alterations in cerebrovascular composition, contractility, and endothelial function in normoxic pregnant (P) and chronically hypoxic nonpregnant (HNP) adult sheep compared with nonpregnant normoxic controls (NP). This study focuses on a fourth group, pregnant sheep exposed to chronic high-altitude hypoxia (HP) (110 days at 3,820 m). The combined challenges of pregnancy and high-altitude hypoxia resulted in significant alterations in cerebrovascular function that were not simply the summation of the responses seen in the P and HNP animals. Compared with NP, HP arteries had increased protein content and increased intracranial arterial wall thickness. Both P and HP arteries showed increased contractility, while HNP artery maximum tensions were depressed. Endothelial function was depressed in the P common carotid and was enhanced in all HNP arteries. In contrast, an increased endothelial response was shown only in the HP common carotid. Thus, for contractility, the effects of pregnancy predominated in the HP arteries. For endothelial function, hypoxia effects were dominant in the common carotid but not in the intracranial arteries. Clearly, cerebrovascular characteristics are dynamic in nature, with artery-specific responses to both pregnancy and hypoxia.

Adaptation, Physiological↗
PubMed1994

Effects of maturation on cyclic GMP-dependent vasodilation in ovine basilar and carotid arteries.

The present experiments examine the effects of maturation on cyclic GMP (cGMP)-mediated vasodilation in 688 segments of common carotid (COM) and basilar (BAS) arteries taken from newborn (3- to 7-d-old) and nonpregnant adult sheep. The main finding is that maximum efficacy for relaxation decreased with maturation in both artery types for the nitric oxide releasing vasodilators S-nitroso-N-acetyl-penicillamine and nitroglycerin. These decreases could not be explained by changes in the -log ED50 concentrations for either vasodilator. Determination of the time course of cGMP responses to S-nitroso-N-acetyl-penicillamine or nitroglycerin at 10 microM revealed that the peak cGMP responses to these agents (range: 5.3 +/- 0.8 to 8.3 +/- 1.6 pmol/mg of protein) also did not vary significantly with age. However, cGMP attained peak values more rapidly in adult (COM: 50 s; BAS 30 s) than in newborn (COM: 60-80 s: BAS, 40-60 s) segments and returned to baseline more slowly in newborn than in adult segments, suggesting that maturation accelerates cGMP turnover. Correspondingly, baseline levels of cGMP were higher in newborn (COM: 1.0 +/- 0.1; BAS: 3.3 +/- 0.5 pmol/mg of protein) than in adult (COM: 0.3 +/- 0.1; BAS: 1.7 +/- 0.2 pmol/mg of protein) segments. Despite these differences in cGMP time course, rates of relaxation in response to S-nitroso-N-acetyl-penicillamine and nitroglycerin did not vary significantly with age, indicating that the temporal relation between cGMP and relaxation is different in newborn and adult arteries.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Self-cleaving catalytic RNA.

We describe the structures and catalytic properties of several naturally occurring self-cleaving RNA motifs that give 2', 3' cyclic phosphate products. The hammerhead and hairpin motifs are derived from plant pathogenic RNAs and the delta motif is part of the human hepatitis delta element. A fourth motif from Neurospora is less well characterized. By assembling the self-cleaving RNAs from more than one oligoribonucleotide, the cleavage reaction can be examined under a variety of conditions and catalytic turnover can be demonstrated. Mutagenesis and chemical methods to introduce modified nucleotides allowed the structural requirements to be deduced. The role of divalent cations in the catalytic mechanism is discussed.

Base Sequence↗
PubMed1993

Frameless stereotaxic integration of CT imaging data: accuracy and initial applications.

To evaluate the spatial accuracy of a rapid interactive method of transferring computed tomographic (CT) information between its display on a computer screen to its source (test object, operating field), a multidimensional computer combined with a six-jointed position-sensing mechanical arm was tested with a Plexiglas model consisting of 50 rods of varied height and known location, a plastic replica of the skull, and, subsequently, three patients. The median error value between image and real location was 1-2 mm (P > .95), regardless of the registration target sites. The accuracy, however, increased with the selection of widespread registration points, and 95% of all errors were below 3.70 mm (P > .95). The results compare favorably with the four most commonly used stereotaxic framed units. A misregistration error of 0.3-2.2 mm was found during intraoperative correlation between anatomy on the CT display and actual anatomic location in the operative field.

Child↗
PubMed1993

Cerebrovascular adaptations to high-altitude hypoxemia in fetal and adult sheep.

In the fetus and infant, high-altitude hypoxemia is associated with increased cerebrovascular morbidity. To test the hypothesis that this increased morbidity involves changes in cerebrovascular endothelial and smooth muscle function, we examined middle cerebral, posterior communicating, basilar, and common carotid arteries obtained from 23 normoxic fetuses, 19 hypoxemic fetuses maintained at high altitude (3,820 m) from 30 days gestation to near term (approximately 143 days), 55 normoxic non-pregnant adults, and 24 hypoxemic nonpregnant adults maintained at the same altitude and duration as the hypoxemic fetuses. Long-term hypoxemia was associated with several significant changes in both fetal and adult arteries, including a generalized increase in base-soluble protein (5-50%), a depression of the maximum potassium-induced tensions (16-49%), and a depression of the relaxation responses to S-nitroso-N-acetylpenicillamine (1-11%), which releases nitric oxide into solution upon hydration. Altitude acclimatization significantly enhanced amine-to-potassium ratios (the ratio of tension produced by 10 microM serotonin with 20 microM histamine to that produced by 122 mM potassium) only in adult cerebral arteries (51-87%) and significantly depressed potassium-induced stresses (up to 41%) and serotonin/histamine-induced tensions (20-37%) only in fetuses. Endothelium-dependent relaxations to A23187 were significantly depressed in hypoxemic fetuses (4-11%) but were significantly enhanced in hypoxemic adults (2-14%). We conclude that chronic hypoxemia depresses both vascular smooth muscle and endothelial function to a greater extent in fetal than in adult cerebral arteries and that this effect could contribute to the greater postnatal vulnerability to asphyxic and hypertensive insults seen in hypoxemic neonates.

Acclimatization↗
PubMed1993

Spinal cord stimulation for chronic, intractable pain: experience over two decades.

Over the past two decades, spinal cord stimulation devices and techniques have evolved from single-channel systems, with electrodes requiring laminectomy, into programmable "multichannel" systems with electrodes that may be placed percutaneously. We have reviewed our experience in 320 consecutive patients treated with these devices at our institution between 1972 and 1990. Technical details of treatment as well as patient characteristics have been assessed as predictors of clinical outcome and of hardware reliability by univariate and multivariate statistical methods. Current follow-up has been obtained at intervals from 2 to 20 years (mean, 7.1 yr) postoperatively on 205 patients. All clinical outcome measures have been based on disinterested third-party interview data--standard analog pain ratings, employment status, activities of daily living, and use of analgesics. At 7-year mean follow-up, 52% of the 171 patients who received permanent implants reported at least 50% continued pain relief. A majority had maintained improvements in activities of daily living and analgesic use. Analysis of hardware reliability for 298 permanent implants revealed significantly fewer clinical failures (P < 0.001) and technical failures (in particular, electrode migration and malposition, P = 0.025) as single-channel implants have evolved into programmable, multichannel devices. Our analysis of technical and clinical prognostic factors may be useful to the clinician in selecting patients for this procedure.

Adult↗
PubMed1993

Therapeutic effects of local delivery of dexamethasone on experimental brain tumors and peritumoral brain edema.

To determine if dexamethasone administered by osmotic pump directly to brain tumors would control peritumoral edema and at the same time suppress tumor growth and prolong survival, the authors studied experimental brain tumors produced in 102 rabbits by implanting VX2 carcinoma cells. Of these, 58 animals were separated into three treatment groups: Group 1 included 15 untreated rabbits; Group 2 included 18 rabbits treated with systemic dexamethasone (4 mg/kg/day); and Group 3 included 25 rabbits treated with local dexamethasone (0.24 mg/day) delivered by osmotic pump. Systemic or local dexamethasone was administered from Day 3 or Day 7 after tumor implantation, and animals were sacrificed on Day 13. A survival study was performed with 44 rabbits separated into the same treatment groups, beginning drug delivery on Day 7. Brain water content in the white matter of sacrificed animals was measured by the specific gravity method. The length and width of the brain tumors in all animals were measured and the tumor volume estimated. Findings showed that systemic and local dexamethasone administered from Day 3 or Day 7 was associated with a significant (5% level) inhibition of tumor volume as well as a mean reduction of brain edema in most tested sites. Systemic and local dexamethasone therapy also resulted in a significant (5% level) increase in survival time relative to the untreated group. These short-term results suggest that locally delivered dexamethasone may constitute a clinically important therapeutic modality.

Animals↗
PubMed1993

Lumbar and cervical spondylosis and spondylotic myelopathy.

The problem of chronic spondylitic spinal disease is markedly underrepresented in the literature. The principal focus is on procedures and diagnostic techniques. It has been suggested that the classic clinical syndromes are rare and that interventional protocols based on them are likely to be inadequate. New diagnostic techniques have revolutionized the evaluation of patients: magnetic resonance imaging is now the standard whereas myelography use is being steadily reduced. It is clear that the outcome of spinal surgery for herniated disk, in expert hands, is excellent. Nevertheless, there is an emphasis on minimally invasive and percutaneous techniques to try to avoid major surgery, which has been the standard. The natural history of these problems is still understood incompletely. Long-term follow-ups are generally not available and the value of nearly every form of conservative care remains unproven.

Cervical Vertebrae↗
PubMed1992

The utility of magnetic resonance imaging in the diagnosis of intranasal meningoencephaloceles.

We present three patients in whom the diagnosis of intranasal meningoencephalocele was made by magnetic resonance imaging. The initial clinical evaluation and computed tomographic examinations of these patients failed to distinguish between chronic inflammation and intranasal meningoencephalocele. Although both computed tomography and magnetic resonance imaging are used to distinguish between normal, inflammatory, and neoplastic tissue in the nasal cavity and paranasal sinuses, limitations do exist and these are the focus of our communication. A clear understanding of the efficacy of these radiographic modalities will enhance surgical planning and can preclude severe complications.

Encephalocele↗
PubMed1992

Rate of progression and severity of neuro-ophthalmologic manifestations of cavernous sinus meningiomas.

The progression of neuro-ophthalmologic signs and symptoms caused by cavernous sinus meningiomas (CSMs) was evaluated in 24 patients. Ten patients had primary involvement of the cavernous sinus by meningioma, and 14 patients had extension of a sphenoid ridge meningioma into the cavernous sinus. Eighteen patients were followed after intradural meningioma debulking. Two of these patients underwent conventional radiation therapy after surgery. The other six patients were followed without treatment. Optic neuropathy caused by extension of the CSM was the most frequently (67%) seen manifestation at the beginning of the follow-up period. Proptosis (50%), ocular motor nerve palsies (46%), and trigeminal neuropathy (33%) were also common. During a mean follow-up period of 57 months, 14 patients (58%) had no change in neurologic status, four patients (17%) had improvement in one or more parameters and six patients (25%) worsened. The patients who worsened had progression of preexisting cranial nerve palsies (two patients), developed new cranial neuropathies (three patients), or both (one patient). Patients who worsened had a significantly longer mean follow-up (76 months) than patients who remained stable or improved (47 months) (p = 0.01). Although the signs and symptoms of CSMs may worsen with time, the rate is slow and the degree is mild. These factors are important when considering treatment options.

Journal Article↗