Showing papers by "University of Texas Medical Branch published in 1992"

An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat.

Abstract: SummaryWe attempted to develop an experimental animal model for peripheral neuropathic pain Under sodium pentobarbital anesthesia, both the L5 and L6 spinal nerves (group 1) or the L5 spinal nerve alone (group 2) of one side of the rat were tightly ligated For comparison, a parallel study was cond

Protein kinase C reduces Mg2+ block of NMDA-receptor channels as a mechanism of modulation.

Abstract: The roles of N-methyl-D-aspartate (NMDA) receptors and protein kinase C (PKC) are critical in generating and maintaining a variety of sustained neuronal responses. In the nociceptive (pain-sensing) system, tissue injury or repetitive stimulation of small-diameter afferent fibres triggers a dramatic increase in discharge (wind-up) or prolonged depolarization of spinal cord neurons. This central sensitization can neither be induced nor maintained when NMDA receptor channels are blocked. In the trigeminal subnucleus caudalis (a centre for processing nociceptive information from the orofacial areas), a mu-opioid receptor agonist causes a sustained increase in NMDA-activated currents by activating intracellular PKC. There is also evidence that PKC enhances NMDA-receptor-mediated glutamate responses and regulates long-term potentiation of synaptic transmission. Despite the importance of NMDA-receptors and PKC, the mechanism by which PKC alters the NMDA response has remained unclear. Here we examine the actions of intracellularly applied PKC on NMDA-activated currents in isolated trigeminal neurons. We find that PKC potentiates the NMDA response by increasing the probability of channel openings and by reducing the voltage-dependent Mg2+ block of NMDA-receptor channels.

A meta-analysis of studies of the Health Belief Model with adults

Abstract: The Health Belief Model (HBM) relates a socio-psychologic theory of decision making to individual health-related behaviors. We conducted a meta-analysis of the relationships between four HBM dimensions (Susceptibility, Severity, Benefits and Costs) and health behavior on 16 studies that measured all four of the dimensions, measured a behavioral dependent variable and included some measures of reliability, minimal criteria for establishing the validity of the dimensions. Mean effect sizes were computed for all the studies, subgroupings representing studies of screening, risk reduction and adherence to medical regimen, and prospective and retrospective study designs. Of 24 mean effect sizes, 22 were found to be positive and statistically significant. The actual variance accounted for ranged from 0.001 to 0.09. Homogeneity was rejected for 15 of the 22, however, suggesting that the same underlying construct was not measured. Retrospective studies were found to have significantly large effect sizes for benefits and costs and smaller effect sizes for severity when compared to prospective studies. The weak effect sizes and lack of homogeneity indicate that it is premature to draw conclusions about the predictive validity of the HBM as operationalized in these studies. Our finding of only 16 studies meeting minimal criteria for valid representation of the HBM dimensions indicates that future studies should focus more on such issues.

The role of NMDA and non-NMDA excitatory amino acid receptors in the excitation of primate spinothalamic tract neurons by mechanical, chemical, thermal, and electrical stimuli

Abstract: The role of excitatory amino acids (EAAs) in the excitation of monkey spinothalamic tract (STT) neurons following activation of cutaneous primary afferent fibers by noxious and non-noxious stimuli was investigated. The responses of STT neurons to either NMDA or non-NMDA EAA ligands were blocked by infusion of specific antagonists through a microdialysis fiber into the region surrounding the cells. Our results show that blockade of non-NMDA receptors results in a nearly complete elimination of the responses of STT neurons to all stimuli. Blockade of NMDA receptors results in an attenuation of the responses to noxious stimuli but, in addition, prevents the development of the sensitization of STT neurons that is often observed after intradermal injection of capsaicin. These observations further support a role of EAAs in the transmission of sensory information from primary afferent fibers to dorsal horn neurons and a role for NMDA receptors in the generation of hyperalgesia.

In vitro and in vivo evaluation of antibiotic diffusion from antibiotic-impregnated polymethylmethacrylate beads.

Abstract: The elution of antibiotics from antibiotic-impregnated polymethylmethacrylate (PMMA) beads was measured in mongrel dogs. The antibiotics, used in mixture with Simplex cement, included cefazolin (Ancef; 4.5 g/40 g cement powder), ciprofloxacin (Cipro; 6 g/40 g powder), clindamycin (Cleocin; 6 g/40 g powder), ticarcillin (Ticar; 12 g/40 g powder), tobramycin (Nebcin; 9.8 g/40 g powder), and vancomycin (Vancocin; 4 g/40 g powder). After a pneumatic drill was used to dredge a trough in the tibia, five beads were implanted. During the next 28 days, seroma samples and serum samples were taken for antibiotic measurements. On Day 28, the dogs were killed, beads removed, and the seroma, serum, bone, and granulation tissue sampled. The results of the study showed that clindamycin, vancomycin, and tobramycin exhibited good elution characteristics and had consistently high levels in bone and granulation tissue.

The safety and effect of topically applied recombinant basic fibroblast growth factor on the healing of chronic pressure sores.

Abstract: The first randomized, blinded, placebo-controlled human trials of recombinant basic fibroblast growth factor (bFGF) for pressure sore treatment were performed. Three different concentrations of bFGF in five dosing schedules were tested for safety using hematology, serum chemistries, urinalysis, absorption, antibody formation, and signs of toxicity. Efficacy was evaluated by wound volumes, histology, and photography. No toxicity, significant serum absorption, or antibody formation occurred. In six of eight subgroups, there was a trend toward efficacy with bFGF treatment. When all subgroups were combined, comparison of the slopes of the regression curves of volume decrease over initial pressure sore volume demonstrated a greater healing effect for the bFGF-treated patients (p 70% wound closure (p < 0.05). Blinded observers were able to distinguish differences in visual wound improvement between bFGF and placebo groups. These data suggest that bFGF may be effective in the treatment of chronic wounds.

Induction of Covalent DNA Adducts in Rodents by Tamoxifen

Abstract: The antiestrogen tamoxifen, increasingly used as adjuvant treatment for breast cancer, has been found to covalently modify DNA of rodents. For instance, the liver DNA of female Sprague-Dawley rats treated with a single injection of tamoxifen contained two DNA adducts. Four additional DNA adducts were formed and adduct concentrations increased 5–7- and 10–15-fold after three and six tamoxifen injections, respectively, from levels observed after a single dose. The accumulation of DNA adducts with repeated administrations of tamoxifen to rodents may make this drug a poor choice for the chronic preventative treatment of breast cancer.

Serial MRI and neurobehavioural findings after mild to moderate closed head injury.

Abstract: Fifty patients who sustained mild to moderate closed head injury (CHI) underwent a CT scan, MRI, and neurobehavioural testing. At baseline 40 patients had intracranial hyperintensities detected by MRI which predominated in the frontal and temporal regions, whereas 10 patients had lesions detected by CT. Neurobehavioural data obtained during the first admission to hospital disclosed no distinctive pattern in subgroups of patients characterised by lesions confined to the frontal, temporal, or frontotemporal regions, whereas all three groups exhibited pervasive deficits in relation to normal control subjects. The size of extraparenchymal lesion was significantly related to the initial Glasgow Coma Scale score, whereas this relation was not present in parenchymal lesions. One and three month follow up MRI findings showed substantial resolution of lesion while neuropsychological data reflected impressive recovery. The follow up data disclosed a trend from pervasive deficits to more specific impairments which were inconsistently related to the site of brain lesion. These results corroborate and extend previous findings, indicating that intracranial lesions detected by MRI are present in most patients hospitalised after mild to moderate CHI. Individual differences in the relation between site of lesion and the pattern of neuropsychological findings, which persist over one to three months after mild to moderate CHI, remain unexplained.

Smoking, alcohol, dentition and diet in the epidemiology of oral cancer.

Abstract: This matched case-control study was conducted in Western New York. The smoking, alcohol consumption, dental hygiene and diet of 290 cases were compared with those of 290 sex-, age-, and neighbourhood-matched controls. The results confirm earlier findings that cigarette smoking and alcohol consumption impart substantial risk of oral cancer. The results also confirm that poor oral hygiene increases the risk of oral cancer, although this effect is much smaller than those of cigarette smoking and alcohol consumption. The results suggest that, of macronutrients, intake of fat is more likely than those of protein or carbohydrate to be related to risk. Of micronutrients, calcium, sodium, riboflavin and retinol are associated with risk, while thiamin, niacin, and dietary fibre are associated with decreased risk. Although patterns of dietary effects are discernable, these effects are in general much weaker than are those of smoking and alcohol consumption.

Diffuse brain swelling in severely head-injured children. A report from the NIH Traumatic Coma Data Bank.

Abstract: In this study, data were prospectively collected from 753 patients (111 children and 642 adults) with severe head injury and examined for evidence of diffuse brain swelling and its association with outcome. Diffuse brain swelling occurred approximately twice as often in children (aged 16 years or younger) as in adults. A high mortality rate (53%) was found in these children, which was three times that of the children without diffuse brain swelling (16%). Adults with diffuse brain swelling had a mortality rate (46%) similar to that of children, but only slightly higher than that for adults without diffuse brain swelling (39%). When the diagnosis of diffuse brain swelling was expanded to include patients with diffuse brain swelling plus small parenchymal hemorrhages (less than 15 cu cm), these mortality rates were virtually unchanged.

Severe head injury in children: experience of the Traumatic Coma Data Bank.

Abstract: The outcome at discharge, 6 months, and 1 year after they had sustained severe head injuries was investigated in children (0-15 yr old at injury) who were admitted to the neurosurgery service at one of four centers participating in the Traumatic Coma Data Bank. Of 103 eligible children, the quality of recovery was assessed by the Glasgow Outcome Scale (GOS) at 6 months after injury in 92 patients (86% of series) and at 1 year in 82 patients (73% of series). The lowest post-resuscitation Glasgow Coma Scale score and pupillary reactivity were predictive of the 6-month GOS as were their interaction. Analysis of the first computed tomographic scan disclosed that bilateral swelling with/without midline shift was related to a poor outcome as was the presence of mass lesions. Comparison of age-defined subgroups of patients revealed that outcome was poorest in the 0- to 4-year-old patients, as reflected by their mortality, which increased to 62% by 1 year. Distinctive features of the injuries in the 0- to 4-year-olds included evacuated subdural hematomas (20% of patients) and hypotension (32% of patients). The most favorable outcome was attained by 5- to 10-year-olds (2/3 had a good recovery by 1 yr), whereas the GOS distribution of adolescents was intermediate between the children and adults. In summary, the GOS data reflect heterogeneity in the quality of outcome after severe head injury depending on age, neurological indices, and computed tomographic scan diagnostic category.

Ploidy of lymphoblasts is the strongest predictor of treatment outcome in B-progenitor cell acute lymphoblastic leukemia of childhood: a Pediatric Oncology Group study.

Abstract: PURPOSEUsing the technique of recursive partitioning and amalgamation analysis with verification, the Pediatric Oncology Group (POG) investigated the independent prognostic significance of previously published prognostic factors significantly associated with event-free survival (EFS) in B-progenitor cell acute lymphoblastic leukemia (ALL).PATIENTS AND METHODSAge, leukocyte count, sex, immunophenotype (expression of cytoplasmic immunoglobulin [Ig] and of surface antigens CD10 and CD34), and DNA index (ratio of the flow cytometry-determined DNA content of leukemia cells to that of normal diploid cells) were the variables used in the evaluation of four antimetabolite-based chemotherapy regimens in 1,535 children with the newly diagnosed B-progenitor cell ALL between February 1986 and May 1990.RESULTSThere were three subgroups at widely different risks of treatment failure. A DNA index greater than 1.16 was the most prognostic feature. The final prognostic subgrouping was as follows: (1) DNA index greater tha...

The SCL gene product : a positive regulator of erythroid differentiation

Abstract: The SCL (tal-1, TCL5) gene is a member of the basic domain, helix-loop-helix (bHLH) class of putative transcription factors. We found that (i) the SCL promoter for exon Ia contains a potential recognition site for GATA-binding transcription factors, (ii) SCL mRNA is expressed in all erythroid tissues and cell lines examined, and (iii) SCL mRNA increases upon induced differentiation of murine erythroleukemia (MEL) cells, and inferred that SCL may play a physiologic role in erythroid differentiation. We used gel shift and transfection assays to demonstrate that the GATA motif in the SCL promoter binds GATA-1 (and GATA-2), and also mediates transcriptional transactivation. To identify a role for SCL in erythroid differentiation, we generated stable transfectants of MEL and K562 (a human chronic myelogenous leukemia cell line that can differentiate along the erythroid pathway) cells overexpressing wild-type, antisense or mutant SCL cDNA. Increasing the level of SCL expression in two independent MEL lines (F4-6 and C19, a 745 derivative) and K562 cells increased the rate of spontaneous (i.e. in the absence of inducer) erythroid differentiation. Conversely, induced differentiation was inhibited in MEL transfectants expressing either antisense SCL cDNA or a mutant SCL lacking the basic domain. Our experiments suggest that the SCL gene can be a target for the erythroid transcription factor GATA-1 and that the SCL gene product serves as a positive regulator of erythroid differentiation.

Enhanced responses of spinothalamic tract neurons to excitatory amino acids accompany capsaicin-induced sensitization in the monkey.

Abstract: Sensitization of the responses of dorsal horn neurons to mechanical stimulation may play a role in the generation of hyperalgesia. Intradermal injection of capsaicin (CAP) provides a model of experimental hyperalgesia that possesses a component of allodynia. This hyperalgesia is produced by chemical stimulation of C-fibers, leading to sensitization of dorsal horn neurons, including spinothalamic tract (STT) cells. The changes in the physiological responses of STT neurons following intradermal CAP in monkeys parallel the acute pain and hyperalgesia produced by intradermal CAP in humans. The present study addresses the role that excitatory amino acids (EAAs) may play in the sensitization of STT neurons by intradermal CAP. Our results show that the background discharge rate and the responses of STT cells to mechanical stimulation increase following intradermal CAP. In addition, the responses of the sensitized cells to one or more iontophoretically released EAA agonists, including NMDA, glutamate, aspartate, kainate, DL-alpha-amino-3-hydroxy-5-methyl-isoxazoleproprionic acid, and/or quisqualate, increase following intradermal CAP. It is proposed that an increase in the responses of STT neurons to EAAs contributes to the hyperalgesia produced by this noxious chemical stimulus.

A variant of Leber hereditary optic neuropathy characterized by recovery of vision and by an unusual mitochondrial genetic etiology.

Abstract: The Tas2 and Vic2 Australian families are affected with a variant of Leber hereditary optic neuropathy (LHON). The risk of developing the optic neuropathy shows strict maternal inheritance, and the ophthalmological changes in affected family members are characteristic of LHON. However, in contrast to the common form of the disease, members of these two families show a high frequency of vision recovery. To ascertain the mitochondrial genetic etiology of the LHON in these families, both (a) the the nucleotide sequences of the seven mitochondrial genes encoding subunits of respiratory-chain complex I and (b) the mitochondrial cytochrome b gene were determined for representatives of both families. Neither family carries any of the previously identified primary mitochondrial LHON mutations: ND4/11778, ND1/3460, or ND1/4160. Instead, both LHON families carry multiple nucleotide changes in the mitochondrial complex I genes, which produce conservative amino acid changes. From the available sequence data, it is inferred that the Vic2 and Tas2 LHON families are phylogenetically related to each other and to a cluster of LHON families in which mutations in the mitochondrial cytochrome b gene have been hypothesized to play a primary etiological role. However, sequencing analysis establishes that the Vic2 and Tas2 LHON families do not carry these cytochrome b mutations. There are two hypotheses to account for the unusual mitochondrial genetic etiology of the LHON in the Tas2 and Vic2 LHON families. One possibility is that there is a primary LHON mutation within the mitochondrial genome but that it is at a site that was not included in the sequencing analyses. Alternatively, the disease in these families may result from the cumulative effects of multiple secondary LHON mutations that have less severe phenotypic consequences.

p53 mutations in basal cell carcinomas.

Abstract: Genomic DNA from 14 basal cell carcinoma biopsies was screened for the presence of mutations in the p53 gene, using the polymerase chain reaction followed by direct DNA sequencing. Heterozygous mutations were detected in 7 of 14 (50%) samples investigated. All mutations were G:C-A:T transitions, and five (71%) of these mutations were transitions at hot spots with CpG sites, three at codon 248 and two at codon 273. The striking similarity of the type of mutations detected in this study and with the UV mutagenesis studies reported in literature suggest the hypothesis that UV may act on the p53 gene in a carcinogenic-specific fashion.

Prevalence of dust mites in the homes of people with asthma living in eight different geographic areas of the United States

Abstract: The density and species prevalence of dust mites were determined at various times over a 5-year-period in 252 homes of dust mite sensitive people with asthma who lived in eight geographic areas of the United States (Cincinnati, Ohio; New Orleans, La.; Memphis, Tenn.; Galveston, Texas; Greenville, N.C.; Delray Beach, Fla.; San Diego and Los Angeles, Calif.). The most common dust mites found in the homes were Dermatophagoides farinae (DF), D. pteronyssinus (DP), Euroglyphus maynei (EM), and Blomia tropicalis. All homes in all locations contained Dermatophagoides spp. mites, but few homes were populated exclusively by either DF or DP alone. Most homes (81.7%) were coinhabitated by both DF and DP. In coinhabited homes one species was predominant and usually made up at least 75% of the total mite population. Prevalence of the dominant or only species present varied between homes within a geographic area. EM occurred in significant numbers in 35.7% of homes in New Orleans, Memphis, Galveston, Delray Beach, and San Diego. Blomia tropicalis occurred in these same cities but in low densities. For all dust samples, only 13 homes of the 252 sampled had 100 or fewer mites/gm dust, which is considered to be the threshold for sensitivity. Most homes had average mite densities of 500 or more mites/gm dust. The results of the present study suggest a significant and widespread occurrence of both DF and DP. Therefore extracts of both mite species should be considered for diagnostic tests and immunotherapy. Significant levels of EM were present in some areas. Thus sensitivity to EM should be considered in these areas.

Ischemic preconditioning attenuates acidosis and postischemic dysfunction in isolated rat heart

Abstract: The hypothesis that brief ischemia (preconditioning) protects the isolated heart from prolonged global ischemia was tested. Isovolumic rat hearts were preconditioned with either 5 min of ischemia followed by 5 min of perfusion (P1) or two 5-min episodes of ischemia separated by 5 min of perfusion (P2). Control hearts received no preconditioning. All hearts received 40 min of sustained ischemia and 30 min of reperfusion. Preconditioning (P1 or P2) significantly (P less than 0.0005) improved recovery of the rate-pressure product; percentage recoveries were 17.8 +/- 3.2 (n = 14), 59.9 +/- 5.5 (n = 6), and 46.4 +/- 4.7 (n = 8) for control, P1, and P2, respectively. Improved functional recovery of preconditioned hearts was associated with reduced end-diastolic pressure and improved myocardial perfusion. During the 40-min ischemic period, myocardial pH decreased from approximately 7.4 to 6.3 +/- 0.1 (n = 7) in the control hearts and to 6.7 +/- 0.1 (n = 7) in the preconditioned hearts (P less than 0.01). Also during the 40-min ischemic period, myocardial lactate (expressed as nmol/mg protein) increased to 146 +/- 11 (n = 7) and 101 +/- 12 (n = 8) in control and preconditioned hearts, respectively (P less than 0.02). The results demonstrate that a brief episode of ischemia can protect the isolated rat heart from a prolonged period of ischemia. This protection is associated with decreased tissue acidosis and anaerobic glycolysis during the sustained ischemic period.

Responses of spinothalamic tract cells to mechanical and thermal stimulation of skin in rats with experimental peripheral neuropathy.

Abstract: 1. Responses of spinothalamic tract (STT) neurons to mechanical and thermal stimulation of skin were recorded under urethane and pentobarbital anesthesia in 12 control rats and in 20 rats with experimental neuropathy. Activity of the STT cells in neuropathic rats was recorded 7, 14, and 28 days after inducing the neuropathy by placing four loose ligatures on the sciatic nerve. 2. All neuropathic animals showed guarding of the injured hindpaw and a shorter withdrawal latency from a radiant heat source of the neuropathic hindpaw than that of the sham-operated paw. 3. STT neurons in neuropathic animals showed the most profound changes 7 and 14 days after the nerve ligation. When compared with STT cells in unoperated animals, approximately half of the neurons had high background activity, responses to innocuous stimuli represented a larger percentage of the total evoked activity in wide dynamic range neurons, and the occurrence and magnitude of afterdischarges to mechanical and thermal stimuli were increased. 4. The mean threshold temperatures of heat-evoked responses of the STT cells in neuropathic animals were not different than those of cells from control animals. However, in neuropathic rats, cells reacting to small heat stimuli usually already had afterdischarges. 5. The increase in the background activity of STT cells is consistent with behavioral observations of spontaneous pain in this model of experimental neuropathy. Furthermore, the afterdischarges of STT cells may parallel the prolonged paw withdrawal in response to noxious stimuli that is seen in these animals and that is evidence for hyperalgesia. However, there was no indication of a lowered threshold for thermal stimuli as might be expected if the animals have thermal allodynia. Mechanical allodynia may have resulted from a relative increase in responsiveness to innocuous mechanical stimuli. However, responses to noxious mechanical stimuli were reduced compared with control, at least at 28 days after the ligation. Peripheral and central mechanisms responsible for the changes in responses of STT cells in neuropathic animals are suggested.

Macrophage inflammatory protein-1 alpha activates basophils and mast cells.

Abstract: Macrophage inflammatory protein-1 (MIP) is a recently cloned cytokine that causes neutrophilic infiltration and induces an inflammatory response. We studied the effect of MIP-1 alpha on histamine secretion from basophils and mast cells. Leukocytes from allergic and normal subjects were studied. MIP-1 alpha caused dose-dependent release of histamine from basophils of 14 of 20 allergic donors at concentrations of 10(-9)-10(-7) M, and the mean release was 13.50 +/- 2.9% at the highest concentration. In the same experiments, the mean histamine release by anti-immunoglobulin E and monocyte chemotactic and activating factor (MCAF) (10(-7) M) was 32 +/- 7% and 31 +/- 3%, respectively. The cells from only 2 of 10 normal subjects released histamine in response to MIP-1 alpha. Histamine release by MIP-1 alpha was rapid, and almost complete within the first 3 min. MIP-1 alpha-induced degranulation was a calcium-dependent noncytotoxic process. MIP-1 alpha showed chemotactic activity for purified basophils that was comparable to MCAF. Both MIP-1 alpha and MCAF at 10(-7) M concentration elicited a chemotactic response that was 40% of the maximal response to C5a (1 microgram/ml). Murine MIP-1 alpha induced histamine release from mouse peritoneal mast cells in a dose-dependent manner. Thus, we have established that MIP-1 alpha is a novel activator of basophils and mast cells.

Recombinant Human Platelet-derived Growth Factor-BB for the Treatment of Chronic Pressure Ulcers

Abstract: A randomized phase I/II double-blind, placebo-controlled study was designed to evaluate 1, 10, and 100 micrograms/ml (0.01, 0.1, and 1.0 micrograms/cm2) recombinant human BB homodimeric platelet-derived growth factor (rPDGF-BB) applied topically to chronic pressure ulcers for 28 days. Twenty patients were enrolled and completed the trial. No toxicities were associated with rPDGF-BB treatment. Patients treated with 100 micrograms/ml of rPDGF-BB had a pronounced healing response compared with placebo-treated patients. By day 29, ulcers treated with 100 micrograms/ml of rPDGF-BB were smaller in remaining size compared with those of placebo-treated patients when the following specific parameters were measured: percentage of initial depth (14.1 +/- 7.4 vs. 34.9 +/- 6.7) and percentage of initial volume (6.4 +/- 4.0 vs. 21.8 +/- 5.6). Histological analyses of biopsies revealed active wound healing processes in all groups with no disruption in the normal healing sequence in rPDGF-BB-treated wounds. The results of this small, descriptive study suggest rPDGF-BB is a potent vulnerary agent for accelerating soft-tissue repair, warranting further study.