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Biomedical subjects

J A Wolf

Publications and source records attributed to J A Wolf.

At least 19 recordsLinked to original sources
PubMed2001

Traumatic axonal injury induces calcium influx modulated by tetrodotoxin-sensitive sodium channels.

Diffuse axonal injury (DAI) is one of the most common and important pathologies resulting from the mechanical deformation of the brain during trauma. It has been hypothesized that calcium influx into axons plays a major role in the pathophysiology of DAI. However, there is little direct evidence to support this hypothesis, and mechanisms of potential calcium entry have not been explored. In the present study, we used an in vitro model of axonal stretch injury to evaluate the extent and modulation of calcium entry after trauma. Using a calcium-sensitive dye, we observed a dramatic increase in intra-axonal calcium levels immediately after injury. Axonal injury in a calcium-free extracellular solution resulted in no change in calcium concentration, suggesting an extracellular source for the increased post-traumatic calcium levels. We also found that the post-traumatic change in intra-axonal calcium was completely abolished by the application of the sodium channel blocker tetrodotoxin or by replacement of sodium with N-methyl-d-glucamine. In addition, application of the voltage-gated calcium channel (VGCC) blocker omega-conotoxin MVIIC attenuated the post-traumatic increase in calcium. Furthermore, blockade of the Na(+)-Ca(2+) exchanger with bepridil modestly reduced the calcium influx after injury. In contrast to previously proposed mechanisms of calcium entry after axonal trauma, we found no evidence of calcium entry through mechanically produced pores (mechanoporation). Rather, our results suggest that traumatic deformation of axons induces abnormal sodium influx through mechanically sensitive Na(+) channels, which subsequently triggers an increase in intra-axonal calcium via the opening of VGCCs and reversal of the Na(+)-Ca(2+) exchanger.

Axons↗
PubMed2001

A new strategy to produce sustained growth of central nervous system axons: continuous mechanical tension.

Although a primary strategy to repair spinal cord and other nerve injuries is to bridge the damage with axons, producing axons of sufficient length and number has posed a significant challenge. Here, we explored the ability of integrated central nervous system (CNS) axons to grow long distances in response to continuous mechanical tension. Neurons were plated on adjacent membranes and allowed to integrate, including the growth of axons across a 50-microm border between the two membranes. Using a microstepper motor system, we then progressively separated the two membranes further apart from each other at the rate of 3.5 microm every 5 min. In the expanding gap, we found thick bundles comprised of thousands of axons that responded to this tensile elongation by growing a remarkable 1 cm in length by 10 days of stretch. This is the first evidence that the center portion of synapsed CNS axons can exhibit sustained "stretch-induced growth." This may represent an important growth mechanism for the elongation of established white matter tracts during development. We also found by doubling the stretch rate to 7 microm/5 min that the axon bundles could not maintain growth and disconnected in the center of the gap by 3 days of stretch, demonstrating a tolerance limit for the rate of axonal growth. We propose that this newfound stretch-induced growth ability of integrated CNS axons may be exploited to produce transplant materials to bridge extensive nerve damage.

Animals↗
PubMed1999

High tolerance and delayed elastic response of cultured axons to dynamic stretch injury.

Although axonal injury is a common feature of brain trauma, little is known of the immediate morphological responses of individual axons to mechanical injury. Here, we developed an in vitro model system that selectively stretches axons bridging two populations of human neurons derived from the cell line N-Tera2. We found that these axons demonstrated a remarkably high tolerance to dynamic stretch injury, with no primary axotomy at strains <65%. In addition, the axolemma remained impermeable to small molecules after injury unless axotomy had occurred. We also found that injured axons exhibited the behavior of "delayed elasticity" after injury, going from a straight orientation before injury to developing an undulating course as an immediate response to injury, yet gradually recovering their original orientation. Surprisingly, some portions of the axons were found to be up to 60% longer immediately after injury. Subsequent to returning to their original length, injured axons developed swellings of appearance remarkably similar to that found in brain-injured humans. These findings may offer insight into mechanical-loading conditions leading to traumatic axonal injury and into potential mechanisms of axon reassembly after brain trauma.

Axons↗
PubMed1999

Economic implications of an early postoperative enteral feeding protocol.

OBJECTIVE: To study the cost-effectiveness of an early postoperative feeding protocol for patients undergoing bowel resections. DESIGN: A nonrandomized, prospective, clinical trial. Surgeons elected to participate in the treatment arm before the study's outset. SUBJECTS/SETTING: Treatment (n = 66) and control (n = 159) patients were admitted to a nonprofit general teaching hospital in the Texas Medical Center for similar diagnoses and subsequent bowel resections during an 18-month period. INTERVENTION: Treatment patients who met specific inclusion criteria had a jejunal feeding tube placed during surgery. Tube feedings were initiated within 12 hours after surgery. Control patients who met the same inclusion criteria received usual care. OUTCOMES: A successful outcome was defined as a patient developing no postoperative infection. The average cost of a nosocomial infection is presented. Variable direct and total costs (fixed plus variable) are compared between patient groups. STATISTICAL ANALYSIS: Mean cost was adjusted for rate of success in each patient group according to an analytic model. The mean cost difference between groups was analyzed by independent-samples t tests. Nonparametric Mann-Whitney rank sum tests were used to determine the cost significance of a nosocomial infection. RESULTS: The average variable direct cost savings per successful treatment patient was $1,531, which required an additional variable cost of $108.30 for the dietitian's time. The protocol resulted in a total cost savings of $4,450 per success in the treatment group. CONCLUSION: An early postoperative enteral feeding protocol as part of an outcomes management program for patients undergoing bowel resection is cost-effective.

Clinical Protocols↗
PubMed1999

Prolonged activation of NF-kappaB following traumatic brain injury in rats.

Activation of transcription factor, nuclear factor kappa B (NF-kappaB), has been shown to play a key role in inflammatory response, neuronal survival and signaling. We investigated the regional and temporal distribution of activated NF-kappaB in rats at 1 h, 2 h, 24 h, 48 h, 1 week, 2 weeks, 1 month, 2 months, 6 months, and 1 year following brain injury in rats. Early after trauma (1-2 h), activated NF-kappaB was detected in axons, and subsequently found in the cytoplasm and nucleus of neurons by 24 h and lasting up to 1 week. In addition, by 24 h posttrauma, activated NF-kappaB was detected in microglia/macrophages and astrocytes in injured cortex. Surprisingly, this activation persisted for at least 1 year following injury in the cortex, primarily at the margins of progressively enlarging ventricle. Activated NF-kappaB was also detected in endothelial cells, as early as 1 h, and persisted for up to 1 year. These results suggest that a neuronal response to brain trauma includes the activation of NF-kappaB first in the axon with subsequent translocation to the nucleus. Furthermore, these results demonstrate that remarkably prolonged activation of NF-kappaB in glia is found in the same regions undergoing persistent atrophy, suggesting NF-kappaB activation may play a role in long-term inflammatory processes following brain trauma.

Animals↗
PubMed1999

Evolution of neurofilament subtype accumulation in axons following diffuse brain injury in the pig.

Although accumulation of neurofilament (NF) proteins in axons has been recognized as a prominent feature of brain trauma, the temporal course of the accumulation of specific NF subtypes has not been well established. In the present study, 17 miniature swine were subjected to nonimpact inertial brain injury. At 3 hours (h), 6 h, 24 h, 3 days, 7 days, and 10 days post-trauma, immunohistochemical analysis was performed to determine axonal accumulation of NF-light (NF-L), the rod and sidearm domains and sidearm phosphorylation states of NF-medium (NF-M), and heavy (NF-H). We found that NF-L accumulation was easily identified in damaged axons by 6 h post-trauma, but NF-M and H accumulation was not clearly visualized until 3 days following injury. In addition, the axonal accumulation of NF-M and H appeared to be primarily comprised of the sidearm domains. While the accumulating NF was found to be predominantly dephosphorylated, we also detected accumulation of phosphorylated NF. Finally, we found that developing axonal pathology may proceed either towards axotomy with discrete terminal bulb formation or towards the development of varicose swellings encompassing long portions of axons. These findings suggest that there is a differential temporal course in NF subtype disassembly, dephosphorylation, and accumulation in axons following initial brain trauma and that these processes occur in morphologically distinct phenotypes of maturing axonal pathology.

Animals↗
PubMed1999

Accumulation of amyloid beta and tau and the formation of neurofilament inclusions following diffuse brain injury in the pig.

Brain trauma in humans increases the risk for developing Alzheimer disease (AD) and may induce the acute formation of AD-like plaques containing amyloid beta (A beta). To further explore the potential link between brain trauma and neurodegeneration, we conducted neuropathological studies using a pig model of diffuse brain injury. Brain injury was induced in anesthetized animals via nonimpact head rotational acceleration of 110 degrees over 20 ms in the coronal plane (n = 15 injured, n = 3 noninjured). At 1, 3, 7, and 10 days post-trauma, control and injured animals were euthanized and immunohistochemical analysis was performed on brain sections using antibodies specific for A beta, beta-amyloid precursor protein (betaPP), tau, and neurofilament (NF) proteins. In addition to diffuse axonal pathology, we detected accumulation of A beta and tau that colocalized with immunoreactive betaPP and NF in damaged axons throughout the white matter in all injured animals at 3-10 days post-trauma. In a subset of brain injured animals, diffuse A beta-containing plaque-like profiles were found in both the gray and white matter, and accumulations of tau and NF rich inclusions were observed in neuronal perikarya. These results show that this pig model of diffuse brain injury is characterized by accumulations of proteins that also form pathological aggregates in AD and related neurodegenerative diseases.

Amyloid beta-Peptides↗
PubMed1997

Progressive atrophy and neuron death for one year following brain trauma in the rat.

Although atrophic changes have been well described following traumatic brain injury (TBI) in humans, little is known concerning the mechanisms or progression of brain tissue loss. In the present study, we evaluated the temporal profile of histopathological changes following parasagittal fluid-percussion (FP) brain injury in rats over 1 year postinjury. Anesthetized 3-4 month-old Sprague-Dawley Rats (n = 51) were subjected to FP brain injury of high severity (2.5-2.9 atm, n = 51) or sham treatment (n = 27). At 1 h, 2 h, 48 h, 1 week, 2 weeks, 1 month, 2 months, 6 months and 1 year after brain injury or sham treatment, these animals were humanely euthanized. Brain sections were analyzed with image-processing techniques to determine the extent of cortical tissue loss and shrinkage of the hippocampal pyramidal cell layer. In addition, cell counting was performed to determine the number of neurons in the dentate hilus of the hippocampus, and glial fibrillary acidic protein (GFAP) immunostaining was used to reveal reactive astrocytosis. Examination of the injured brains revealed substantial and progressive tissue loss with concomitant ventriculomegaly in the hemisphere ipsilateral to injury. The regions with the most notable progressive atrophy included the cortex, hippocampus, thalamus, and septum. Quantitative analysis demonstrated a significantly progressive loss of cortical tissue as well as shrinkage of the hippocampal pyramidal cell layer ipsilateral to injury over 1 year following injury. In addition, reactive astrocytosis in regions of atrophy and progressive bilateral death of neurons in the dentate hilus was observed for 1 year following injury. These results suggest that a chronically progressive degenerative process may be initiated by brain trauma. Thus, there is a temporally broad window within which to introduce novel therapeutic strategies designed to ameliorate the short and long-term consequences of brain trauma.

Animals↗
PubMed1995

Stimulation of fetal hemoglobin production by short chain fatty acids.

Butyrate, a four-carbon fatty acid, and its two-carbon metabolic product, acetate, are inducers of gamma-globin synthesis. To test whether other short-chain fatty acids share this property, we first examined whether propionic acid, a three-carbon fatty acid that is not catabolized to acetate, induces gamma-globin expression. Sodium propionate increased the frequency of fetal hemoglobin containing erythroblasts and the gamma/gamma + beta mRNA ratios in adult erythroid cell cultures and F reticulocyte production in a nonanemic juvenile baboon. Short-chain fatty acids containing five (pentanoic), six (hexanoic), seven (heptanoic), eight (octanoic), and nine (nonanoic) carbons induced gamma-globin expression (as measured by increase in gamma-positive erythroblasts and gamma/gamma + beta mRNA ratios) in adult erythroid burst-forming unit cultures. There was a clear-cut relationship between the concentration of fatty acids in culture and the degree of induction of gamma-globin expression. Three-, four-, and five-carbon fatty acids were better inducers of gamma globin in culture as compared with six- to nine-carbon fatty acids. These results suggest that all short-chain fatty acids share the property of gamma-globin gene inducibility. The fact that valproic acid, a derivative of pentanoic acid, also induces gamma-globin expression suggests that short-chain fatty acid derivatives that are already approved for human use may possess the property of gamma-globin inducibility and may be of therapeutic relevance to the beta-chain hemoglobinopathies.

Adult↗
PubMed1993

Expression of four myosin heavy chain isoforms with development in mouse uterus.

In smooth muscle tissue, two or three isoforms of myosin heavy chain (MHC) have been reported (SM1, SM2, and/or NM). In mouse uterus tissue, four bands in the region of the MHC's can be resolved on high resolution SDS polyacrylamide gels. Western blots using smooth muscle (SM) MHC-specific and nonmuscle (NM) MHC-specific polyclonal antibodies show the upper two bands in the MHC region are SM isoforms, whereas the lower two bands are NM isoforms. One-dimensional peptide maps of these four bands show each to have a unique pattern of polypeptide fragments following alpha-chymotrypsin digestion. Developmental expression of myosin heavy chains (MHC) in mouse uterus, aorta, bladder, and stomach (6 ages, 10-150 days) was determined using tissue homogenates. In the uterus, both SM MHC's show an increase in relative content with increasing age, whereas the NM MHC's show a decrease. The mouse aorta shows a significant increase in the SM MHC's and a significant decrease in the NM MHC from day 10 to day 30, which is similar to data reported for the rat aorta. Whereas both the bladder and stomach contain relatively small amounts of NM MHC's (approximately 10% or less), these quantities do show decreases with development. The SM1:SM2 ratio for the uterus remains high (3.4 at 150 days) through development; the aorta, bladder, and stomach also start out high, but tend toward 1.0 in the 150-day animals. The presence of four MHC isoforms in the uterus with unique developmental regulation of expression is consistent with hypotheses of unique functional roles for these isoforms.

Analysis of Variance↗
PubMed1983

Gestational carcinoma of the female breast.

Few neoplastic diseases can equal the amazing complexity and sheer perversity of carcinoma of the breast. No doubt as many decades of research lie ahead in its study as already have passed. Clinicians have long appreciated the special relationship of the disease to gestation. Diagnosis and treatment of breast cancer during pregnancy represent only a small part of this fascinating relationship. Although indispensable as research tools, animal models pertain to the human disease only in limited, ill-defined ways. The etiology of human breast cancer remains unclear; chemical, viral, hormonal, genetic, and immunologic theories have all been put forward as possibilities. Although gestation clearly alters both the initiation and growth of mammary tumors, its exact role in the various theoretical considerations remains a mystery. The obstetrician-gynecologist holds an important front-line position in the war against breast cancer, as does any provider of primary care to women, and, indeed, as do women themselves. Rather than decrease vigilance during pregnancy, the physician should pursue with extra vigor any breast mass discovered in the gravid patient, when the clinical examination is even less reliable than usual. The finding of a breast mass usually necessitates biopsy. Except for the inclusion of specific pregnancy-related problems, such as galactocele, the diagnostic spectrum of breast masses removed during pregnancy does not differ from that in nonpregnant women. The discovery of a highly suspicious breast mass, or the confirmed biopsy diagnosis of malignancy, in a pregnant patient should indicate the need for referral to a surgical oncologist versed in this unusual problem. The best approach to gestational breast cancer continues to be the team approach, with consultation from specialists in obstetrics, surgical oncology, anesthesiology, nuclear medicine, radiology, radiation oncology, pathology, and medical oncology. The age and general condition of the patient, the extent of the tumor, the stage of gestation, and the informed opinions of the patient and her spouse help to determine the therapeutic strategy. Careful staging not only guides present therapy but also the therapy of future victims through continued investigation. Most surgeons favor operation without delay if cure seems within reach. Mastectomy, with or without cesarean section, can be accomplished without detriment in the hands of a knowledgeable surgeon-anesthesiologist team. By following certain guidelines, the search for metastasis can be conducted safely and appropriately. The clinical situation occasionally may require the initiation of adjuvant radiotherapy or chemotherapy during pregnancy, by experienced consultants. Ongoing studies of tissue hormone receptors and cell kinetics will continue to give insight into the effects of gestational hormones on breast cancer and can aid in the selection of treatment options for the individual patient...

Abortion, Therapeutic↗
PubMed1983

Classes of unitarizable derived functor modules.

For a real semisimple Lie group G, the description of the unitary dual remains an elusive question. One of the difficulties has been the lack of technique for constructing unitary representations. Unitary induction from parabolic subgroups of G yields unitary representations by the very definition of these representations. However, not all unitary irreducible representations of G are obtained by this type of induction. In addition, we need derived functor parabolic induction [ef. Vogan, D. (1981) Representations of Real Reductive Lie Groups (Birkhäuser, Boston)] to describe all irreducible representations of G. For this second type of induction, the obvious analogues from parabolic subgroup induction regarding unitarity are false. In this announcement, we describe a setting where derived functor parabolic induction yields unitary representations of G. These results include proofs of unitarity for some of the representations conjectured to be unitary by Vogan and Zuckerman [(1983) Invent. Math., in press] and also proofs of unitarity for some which lie outside the domain described in those conjectures.

Journal Article↗
PubMed1981

Focal lymphoid hyperplasia of the stomach preceding gastric lymphoma: case report and review of the literature.

A case is reported in which focal lymphoid hyperplasia (pseudolymphoma) of the stomach preceded by 45 months the development of gastric diffuse lymphocytic lymphoma. Review of the literature discloses only two similar cases reported with satisfactory histopathologic documentation. Analogous cases, in other anatomic sites, of an apparent association between benign and malignant lymphoid lesions are reviewed. The cases suggest that occasionally lymphoid hyperplasia of the stomach may precede lymphoma. Lymphoid hyperplasia is not yet considered a consistent precursor of lymphoma.

Female↗
PubMed1979

Suppression of vasopressin secretion by clonidine: effect of alpha-adrenoceptor antagonists.

Studies were performed in anesthetized dogs to determine if the diuretic effect of clonidine results from inhibition of vasopressin secretion. Intravenous clonidine (30 microgram/kg) decreased plasma vasopressin concentration (as measured by RIA) from 10.9 +/- 1.5 to 5.0 +/- 1.1 ng/ml (P less than 0.01) in association with a transient increase in arterial blood pressure and a decrease in heart rate. Intravenous administration of two alpha-adrenoceptor antagonists, piperoxane and phentolamine, virtually abolished the pressor effect of clonidine but did not prevent the suppression of plasma vasopressin concentration. Clonidine decreased plasma vasopressin concentration from 11.9 +/- 3.1 to 3.3 +/- 1.0 pg/ml in the phentolamine-treated dogs (P less than 0.01) and from 18.1 +/- 4.5 to 12.4 +/- 3.6 pg/ml in the piperoxane-treated dogs (P less than 0.05). These results provide direct evidence that the diuretic effect of clonidine results from inhibition of the secretion of vasopressin. This inhibition does not appear to be a consequence of the pressor effect of the drug but may result from a direct action in the central nervous system.

Animals↗