Biomedical subjects

J L Gooch

Publications and source records attributed to J L Gooch.

At least 19 recordsLinked to original sources

PubMed2001

Insulin-like growth factor-I induces renal cell hypertrophy via a calcineurin-dependent mechanism.

Insulin-like growth factor-I (IGF-I) may play an important role in the development of renal hypertrophy. In this study we determined the effect of IGF-I on cultured mesangial cells (MCs) and examined activation of key signaling pathways. IGF-I induced hypertrophy as determined by an increase in cell size and an increase in protein to DNA ratio and increased accumulation of extracellular matrix (ECM) proteins. IGF-I also activated both Erk1/Erk2 MAPK and phosphatidylinositol 3-kinase (PI3K) in MCs. Inhibition of either MAPK or PI3K, however, had no effect on IGF-I-induced hypertrophy or ECM production. Next, we examined the effect of IGF-I on activation of the calcium-dependent phosphatase calcineurin. IGF-I treatment stimulated calcineurin activity and increased the protein levels of calcineurin and the calcineurin binding protein, calmodulin. Cyclosporin A, an inhibitor of calcineurin, blocked both IGF-I-mediated hypertrophy and up-regulation of ECM. In addition, calcineurin resulted in sustained Akt activation, indicating possible cross-talk with other signaling pathways. Finally, IGF-I treatment resulted in the calcineurindependent nuclear localization of NFATc1. Therefore, IGF-I induces hypertrophy and increases ECM accumulation in MCs. IGF-I-mediated hypertrophy is associated with activation of Erk1/Erk2 MAPK and PI3K but does not require either of these pathways. Instead, IGF-I mediates hypertrophy via a calcineurin-dependent pathway.

Animals↗

PubMed2001

Reliability of listener transcriptions of compensatory articulations.

OBJECTIVE: This study examined the ability of speech-language pathologists to transcribe compensatory articulation errors. DESIGN: Speech-language pathologists phonetically transcribed audiorecordings of 130 monosyllabic words, 70 of which contained compensatory articulations. PARTICIPANTS: The participants for this study were two groups of 10 speech-language pathologists. Group I included speech-language pathologists who were experienced in evaluating children with cleft palate, and group II speech-language pathologists were not. RESULTS: Marked variability was evident across listeners, with percentages of agreement ranging from 19 to 71 (mean agreement = 41%). The experienced listeners performed significantly better on the transcription task than the inexperienced listeners, but poor interjudge agreement was evident across both groups. CONCLUSIONS: The results of this study suggest that speech-language pathologists may differ in their understanding of the auditory perceptual characteristics of compensatory articulations. The results underscore the need for increased training and standardization of transcription procedures.

Analog-Digital Conversion↗

PubMed2000

Insulin-like growth factor I-induced degradation of insulin receptor substrate 1 is mediated by the 26S proteasome and blocked by phosphatidylinositol 3'-kinase inhibition.

Insulin receptor substrate 1 (IRS-1) is a critical adapter protein involved in both insulin and insulin-like growth factor (IGF) signaling. Due to the fact that alteration of IRS-1 levels can affect the sensitivity and response to both insulin and IGF-I, we examined the ability of each of these ligands to affect IRS-1 expression. IGF-I (10 nM) stimulation of MCF-7 breast cancer cells caused a transient tyrosine phosphorylation of IRS-1 that was maximal at 15 min and decreased thereafter. The decrease in tyrosine phosphorylation of IRS-1 was paralleled by an apparent decrease in IRS-1 levels. The IGF-mediated decrease in IRS-1 expression was posttranscriptional and due to a decrease in the half-life of the IRS-1 protein. Insulin (10 nM) caused tyrosine phosphorylation of IRS-1 but not degradation, whereas high concentrations of insulin (10 microM) resulted in degradation of IRS-1. IGF-I (10 nM) stimulation resulted in transient IRS-1 phosphorylation and extracellular signal-related kinase (ERK) activation. In contrast, insulin (10 nM) caused sustained IRS-1 phosphorylation and ERK activation. Inhibition of 26S proteasome activity by the use of lactacystin or MG132 completely blocked IGF-mediated degradation of IRS-1. Furthermore, coimmunoprecipitation experiments showed an association between ubiquitin and IRS-1 that was increased by treatment of cells with IGF-I. Finally, IGF-mediated degradation of IRS-1 was blocked by inhibition of phosphatidylinositol 3'-kinase activity but was not affected by inhibition of ERK, suggesting that this may represent a direct negative-feedback mechanism resulting from downstream IRS-1 signaling. We conclude that IGF-I can cause ligand-mediated degradation of IRS-1 via the ubiquitin-mediated 26S proteasome and a phosphatidylinositol 3'-kinase-dependent mechanism and that control of degradation may have profound effects on downstream activation of signaling pathways.

Animals↗

PubMed2000

The role of p21 in interferon gamma-mediated growth inhibition of human breast cancer cells.

IFN-gamma-mediated growth inhibition requires signal transducers and activators of transcription (STAT)-1 activation and may require induction of the cyclin-dependent kinase inhibitor p21. Using an electrophoretic mobility shift assay, we identified STAT1 activation after IFN-gamma treatment in breast cancer cell lines. Accordingly, IFN-gamma inhibited proliferation of monolayer cultured MCF-7 and MDA-MB-231 breast cancer cells. Interestingly, IFN-gamma inhibited anchorage-independent growth of MCF-7 cells but had no effect on MDA-MB-231 colony formation. Because p21 has been shown to play a role in anchorage-independent growth and is a transcriptional target of STAT1, we examined the effect of IFN-gamma on p21 mRNA. We found that IFN-gamma induced p21 mRNA in MCF-7 cells but not in MDA-MB-231 cells. Furthermore, IFN-gamma induced activation of a p21 promoter-luciferase reporter construct that contained the STAT1-inducible element in MCF-7 cells, but not in MDA-MB-231 cells. IFN-gamma treatment resulted in increased p21 protein in MCF-7 cells, whereas MDA-MB-231 cells did not appear to express detectable p21, even after IFN-gamma treatment. However, in MDA-MB-231 cells, p21 protein was detected only after proteosome inhibition, suggesting that degradation may be responsible for the undetectable level of p21 in these cells, despite the abundant mRNA levels. Finally, focus formation of MDA-MB-231 cells was inhibited by overexpression of p21. In conclusion, STAT1 activation does not appear to be sufficient for IFN-gamma-mediated growth inhibition. Furthermore, the role of p21 appears to be complex because monolayer growth inhibition occurs in the absence of p21, but anchorage-independent growth inhibition may require p21. Breast cancer cells may provide a unique model for further study of IFN-gamma signaling.

Blotting, Western↗

PubMed1999

Strain-specific differences in formation of apoptotic DNA ladders in MCF-7 breast cancer cells.

We tested the ability of seven MCF-7 strains to undergo DNA fragmentation, as measured by DNA laddering, following doxorubicin-induced apoptosis. Four strains were found to undergo DNA laddering while three were not. All strains were inhibited by doxorubicin, although sensitivity differed. Finally, we show by detection of sub-G1 DNA that doxorubicin induced the same fold increase in apoptosis in MCF-7-ATCC, which did not ladder, and MCF-7-MG, which did ladder. Therefore, detection of DNA ladders is not an accurate indicator of apoptosis in MCF-7 cells as fragmentation of DNA appears to vary between strains.

Apoptosis↗

PubMed1999

Insulin-like growth factor (IGF)-I rescues breast cancer cells from chemotherapy-induced cell death--proliferative and anti-apoptotic effects.

Insulin-like growth factor (IGF)-I protects many cell types from apoptosis. As a result, it is possible that IGF-I-responsive cancer cells may be resistant to apoptosis-inducing chemotherapies. Therefore, we examined the effects of IGF-I on paclitaxel and doxorubicin-induced apoptosis in the IGF-I-responsive breast cancer cell line MCF-7. Both drugs caused DNA laddering in a dose-dependent fashion, and IGF-I reduced the formation of ladders. We next examined the effects of IGF-I and estradiol on cell survival following drug treatment in monolayer culture. IGF-I, but not estradiol, increased survival of MCF-7 cells in the presence of either drug. Cell cycle progression and counting of trypan-blue stained cells showed that IGF-I was inducing proliferation in paclitaxel-treated but not doxorubicin-treated cells. However, IGF-I decreased the fraction of apoptotic cells in doxorubicin- but not paclitaxel-treated cells. Recent work has shown that mitogen-activated protein kinase (MAPK) and phosphotidylinositol-3 (PI-3) kinase are activated by IGF-I in these cells. PI-3 kinase activation has been linked to anti-apoptotic functions while MAPK activation is associated with proliferation. We found that IGF-I rescue of doxorubicin-induced apoptosis required PI-3 kinase but not MAPK function, suggesting that IGF-I inhibited apoptosis. In contrast, IGF-I rescue of paclitaxel-induced apoptosis required both PI-3 kinase and MAPK, suggesting that IGF-I-mediated protection was due to enhancement of proliferation. Therefore, IGF-I attenuated the response of breast cancer cells to doxorubicin and paclitaxel by at least two mechanisms: induction of proliferation and inhibition of apoptosis. Thus, inhibition of IGF-I action could be a useful adjuvant to cytotoxic chemotherapy in breast cancer.

Antineoplastic Agents, Phytogenic↗

PubMed1999

Enhancement of insulin-like growth factor signaling in human breast cancer: estrogen regulation of insulin receptor substrate-1 expression in vitro and in vivo.

Cross-talk between insulin-like growth factor (IGF)- and estrogen receptor (ER)-signaling pathways results in synergistic growth. We show here that estrogen enhances IGF signaling by inducing expression of three key IGF-regulatory molecules, the type 1 IGF receptor (IGFR1) and its downstream signaling molecules, insulin receptor substrate (IRS)-1 and IRS-2. Estrogen induction of IGFR1 and IRS expression resulted in enhanced tyrosine phosphorylation of IRS-1 after IGF-I stimulation, followed by enhanced mitogen-activated protein kinase activation. To examine whether these pathways were similarly activated in vivo, we examined MCF-7 cells grown as xenografts in athymic mice. IRS-1 was expressed at high levels in estrogen-dependent growth of MCF-7 xenografts, but withdrawal of estrogen, which decreased tumor growth, resulted in a dramatic decrease in IRS-1 expression. Finally, we have shown that high IRS-1 expression is an indicator of early disease recurrence in ER-positive human primary breast tumors. Taken together, these data not only reinforce the concept of cross-talk between IGF- and ER-signaling pathways, but indicate that IGF molecules may be critical regulators of estrogen-mediated growth and breast cancer pathogenesis.

Animals↗

PubMed1998

Interleukin 4 inhibits growth and induces apoptosis in human breast cancer cells.

Interleukin-4 (IL-4) is a pleiotropic cytokine produced by mast cells and T lymphocytes that promotes proliferation and immunoglobulin class-switching in B cells. IL-4 receptors (IL-4Rs) are also expressed by nonhematopoietic cells as well as some tumor cells. Unlike its mitogenic effect on B cells, IL-4 inhibits the growth of some cancer cells in vitro. In this study, we show that IL-4R is expressed by breast and ovarian cancer cell lines. Furthermore, anchorage-dependent and -independent growth of breast cancer cell lines MCF-7 and MDA-MB-231 is inhibited by IL-4 treatment, and this effect requires IL-4R. Interestingly, IL-4 only inhibited proliferating breast cancer cells and had no effect on basal, unstimulated growth. We therefore characterized the effect of IL-4 on breast cancer cell growth stimulated by either estradiol or insulin-like growth factor I (IGF-I). In both anchorage-dependent and -independent growth assays, IL-4 inhibited estradiol-stimulated growth. The antiestrogen effect of IL-4 was not due to IL-4 interference with the estrogen receptor, because IL-4 did not interfere with estrogen receptor-mediated reporter gene transactivation. In contrast, IL-4 had no effect on IGF-I-stimulated proliferation. Because IGF-I is known to inhibit programmed cell death, we examined apoptosis as a possible mechanism of IL-4 action. We established that IL-4 induced apoptosis in breast cancer cells by five independent criteria: (a) morphological indicators including pyknotic nuclei and cytoplasmic condensation; (b) DNA fragmentation; (c) the formation of DNA laddering; (d) the cleavage of poly(ADP-ribose) polymerase; and (e) the presence of cells with sub-G1 DNA content. IL-4 increased the percentage of apoptotic cells in MCF-7 and MDA-MB-231 cells 6.0- and 6.7-fold over that of the control, respectively. Finally, the addition of IGF-I reversed IL-4-induced apoptosis, suggesting that the mechanism of IL-4-induced growth inhibition in human breast cancer cells is the induction of programmed cell death.

Antineoplastic Agents, Phytogenic↗

PubMed1997

Behavioral management of conversion disorder in children.

OBJECTIVE: To describe the behavioral management of conversion disorder in children and to preliminarily assess its effectiveness. DESIGN: Retrospective case series. SETTING: Inpatient pediatric rehabilitation unit. PATIENTS: The first eight patients with conversion disorder treated on our pediatric rehabilitation unit, between 9 and 18 years of age. Six were girls. Three cases are described in detail. INTERVENTIONS: All patients were treated as inpatients, using a behavioral approach. Inadvertent reinforcement of illness behavior was identified, and a reward system was established for good attainment. Some patients had a "level" system instituted, with increasing privileges for goal achievement. All patients and their families had psychological assessment and instruction in pain and stress management strategies. MAIN OUTCOME MEASURES: Restoration of normal gait and function, independence in activities of daily living (ADL), and symptom recurrence after discharge. RESULTS: All patients attained normal gait and ADL function before discharge. CONCLUSIONS: (1) Behavioral management of conversion disorder in children appears to be as effective as in adults, although at times a behavioral reward or "level" system may be necessary for adequate reinforcement. (2) Instruction of the patient and family in appropriate stress and pain management appears key to maintaining treatment effect over time.

Adolescent↗

PubMed1996

Botulinum toxin for spasticity and athetosis in children with cerebral palsy.

Botulinum toxin A has been used therapeutically in humans for a variety of conditions since 1980. Over the past few years, it has been used more frequently for spasticity management. We describe the use of botulinum toxin for spasticity or athetosis management in three children with cerebral palsy. Two of these children had severe spasticity or athetosis that was unresponsive to other forms of treatment. The injection of botulinum toxin decreased pain and improved ease of care in these two children. Another child with left hemiparetic cerebral palsy underwent injection of botulinum toxin into upper and lower limb muscles to improve function. In this patient, the injections were combined with other forms of treatment. In this patient spasticity was decreased and function was increased temporarily. The use of botulinum toxin in general is discussed and related to these three cases.

Adolescent↗

PubMed1996

Spinal stenosis after total lumbar laminectomy for selective dorsal rhizotomy.

Knowledge of long-term outcome and complications of selective dorsal rhizotomy is limited due to the relatively recent introduction of the procedure. We describe 2 patients with cerebral palsy who developed lumbar spinal stenosis several years after selective dorsal rhizotomy. These patients also had substantial lateral trunk sway during gait and walked for several years with limited assistive devices. This abnormal gait pattern in combination with the changes from the selective dorsal rhizotomy may lead to the development of spinal stenosis.

Cerebral Palsy↗

PubMed1995

AAEM case report #29: Prolonged paralysis after neuromuscular blockade.

Nondepolarizing neuromuscular blocking agents (NMBA) are being used with increasing frequency in critically ill patients. Recently, many centers have described patients with prolonged muscle weakness after long-term use of these agents, either alone or in combination with other agents or disorders. Brief weakness lasting several hours to several days is probably the result of prolonged neuromuscular blockade, while more prolonged weakness lasting several weeks to months is, in all likelihood, caused by a myopathy. Patients with this myopathic disorder have flaccid paralysis with intact cognition and sensation. Electrodiagnostic findings include decreased M-wave amplitudes, positive waves and fibrillations, and rapid recruitment of small amplitude short duration, polyphasic motor unit potentials. Muscle biopsy findings include atrophy of type I and type II fibers, myofiber necrosis, and selective loss of thick myofilaments. The myopathy is believed to be related to the prolonged use of NMBA either alone or in combination with other disorders or medications, particularly corticosteroids. The weakness experienced by these patients leads to additional respiratory compromise, difficulty weaning from the ventilator, and prolonged hospitalization.

Adrenal Cortex Hormones↗

PubMed1995

Prolonged paralysis after neuromuscular blockade.

Non-depolarizing neuromuscular blocking agents have been used with increasing frequency in critically ill patients. Recently, numerous reports have described patients with prolonged muscle weakness after use of these agents for more than two days. Brief weakness lasting several hours to several days is likely the result of prolonged neuromuscular blockade, while more prolonged weakness lasting several weeks to months is likely caused by a myopathy. Specific features of this myopathic disorder are reviewed. Clinically, patients have flaccid paralysis with intact sensation and cognition. Electrodiagnostic findings include decreased M-wave amplitudes, mild positive waves and fibrillations and small, polyphasic motor unit potentials. Muscle biopsy findings include atrophy of type I and type II fibers, myofiber necrosis and selective loss of thick myofilaments. This myopathic disorder is felt to be related to the prolonged use of non-depolarizing neuromuscular blocking agents either alone or in combination with other medications or disorders. Many authors feel that the disorder is caused specifically by a combination of prolonged neuromuscular blockade and corticosteroids. Selective loss of thick myofilaments on muscle biopsy has been produced experimentally in rats by combing denervation with high doses of corticosteroids. As this disorder likely leads to additional respiratory compromise, difficulty weaning from the ventilator, and prolonged hospitalization, prevention is warranted. Methods of prevention include minimizing the dosage of non-depolarizing neuromuscular blocking agents and of other drugs with an effect on the neuromuscular junction, twitch monitoring with a peripheral nerve stimulator and allowing patients to come to an unparalyzed state for brief periods.

Adrenal Cortex Hormones↗

PubMed1993

Design of a device to exercise hip extensor muscles in children with cerebral palsy.

Children with cerebral palsy (CP) often have weak hip extensor muscles and gait-related difficulties. Current therapeutic techniques do not provide sufficient exercise for this muscle group. In addition to calisthenics, therapists use a traditional tricycle to strengthen leg muscles, yet the mechanics of traditional tricycles are not effective in exercising hip extensor muscles. A new therapeutic tricycle was designed specifically to exercise the hip extensor muscles, and tests compared the traditional tricycle to the new hip extensor tricycle in effectiveness of promoting hip extensor activity in two subjects without CP. The tests demonstrated that the hip extensor tricycle was more effective in promoting hip extensor activity. Tests are underway to investigate the effect of the hip extensor tricycle in improving hip extensor strength and gait in patients with cerebral palsy. This paper describes the design of the hip extensor tricycle and a preliminary investigation of its effectiveness.

Cerebral Palsy↗

PubMed1993

Evaluation of the hip-extensor tricycle in improving gait in children with cerebral palsy.

Weakness of the hip extensor muscles contributes to the walking impairment of children with cerebral palsy, but it is difficult to strengthen these muscles. This study demonstrates greater activation of the hip extensor muscles when using a tricycle developed for this purpose than when using a traditional tricycle. The hip-extensor tricycle was also found to be more stable than a traditional tricycle. A 10-week field trial of the hip-extensor tricycle showed that visually analysed gait improved, but hip extensor strength did not. However, children used and enjoyed the tricycle, and parental reports were positive. This tricycle could be used to supplement other means of improving gait in children with CP.

Bicycling↗

PubMed1993

Force perception before and after maximal voluntary contraction.

Capacity to match a low level of elbow flexion force maintained in the control arm was measured in the experimental arm in 16 subjects before and after maximal voluntary contraction (MVC). Prior to a 1-min. MVC, the mean force exerted by the experimental arm was 3.4 +/- 1.0 kg when attempting to match the tension of a 2.3-kg weight in the control arm. After the MVC, the mean force exerted in the experimental arm was 4.4 +/- 2.6 kg. The change in perception of force after a prolonged MVC as demonstrated in this study may be due to postcontraction potentiation of contraction, which has been demonstrated by others after a brief MVC.

Adult↗

PubMed1993

Prolonged paralysis after neuromuscular junction blockade: case reports and electrodiagnostic findings.

Previous reports have described prolonged paralysis after treatment with neuromuscular junction (NMJ) blocking agents in critically ill patients. The purpose of this study was to describe the clinical and electrodiagnostic findings in 12 such patients. All patients developed prolonged and often profound weakness with no sensory loss after discontinuation of NMJ blockers. Nerve conduction studies generally showed decreased motor evoked response amplitudes with normal conduction velocities and normal sensory studies. Repetitive nerve stimulation demonstrated no decrement or increment in most patients, with a decrement to 3 Hz stimulation in one patient. Needle examination showed frequent fibrillation potentials and normal or low amplitude, short duration, polyphasic motor units. Physicians prescribing NMJ blockers in critically ill patients should be made aware of this potential complication and of the other agents (ie, corticosteroids) that may exacerbate the problem.

Adult↗

PubMed1993

Sports medicine. 2. Upper extremity injuries.

This self-directed learning module highlights recent advances in this topic area. It is part of the chapter on sports medicine in the Self-Directed Medical Knowledge Program for practitioners and trainees in physical medicine and rehabilitation. In this article, shoulder and elbow problems of the throwing athlete are emphasized. Common injuries involving the wrist and hand are also covered.

Acromioclavicular Joint↗