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Biomedical subjects

J Welsh

Publications and source records attributed to J Welsh.

At least 19 recordsLinked to original sources
PubMed2001

Two distinct oscillatory states determined by the NMDA receptor in rat inferior olive.

1. The effects of N-methyl-D-aspartate (NMDA) receptor activation and blockade on subthreshold membrane potential oscillations of inferior olivary neurones were studied in brainstem slices from 12- to 21-day-old rats. 2. Dizocilpine (MK-801), a non-competitive NMDA antagonist, at 1-45 microM abolished spontaneous subthreshold oscillations, without affecting membrane potential, input resistance, or the low-threshold calcium current, I(T). Ketamine (100 microM), a non-competitive NMDA antagonist, and L-689,560 (20 microM), an antagonist at the glycine site of the NMDA receptor, also abolished the oscillations, while the competitive non-NMDA antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 20-50 microM) had no effect. 3. NMDA (100 microM) induced 4.1 Hz subthreshold oscillations and reversibly depolarized olivary neurones by 13.7 mV. In contrast, 10 microM alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and 20 microM kainic acid depolarized the membrane equivalently but did not induce oscillations. 4. Both NMDA-induced and spontaneous subthreshold oscillations were unaffected by 1 microM tetrodotoxin and were prevented by substituting extracellular calcium with cobalt. 5. Removing magnesium from the perfusate did not affect spontaneous subthreshold oscillations but did prevent NMDA-induced oscillations. 6. NMDA-induced oscillations were resistant to 50 microM mibefradil, an I(T) blocker, in contrast to spontaneous oscillations. Both oscillations were inhibited by 20 microM nifedipine, an L-type calcium channel antagonist, and 200 nM omega-agatoxin IVA, a P-type calcium channel blocker. Bay K 8644 (10 microM), an L-type Ca(2+) agonist, significantly enhanced the amplitude of both spontaneous and NMDA-induced oscillations. 7. The data indicate that NMDA receptor activation induces olivary neurones to manifest high amplitude membrane potential oscillations in part mediated by L- and P- but not T-type calcium currents. Moreover, the data demonstrate that NMDA receptor currents are necessary for generation of spontaneous subthreshold oscillations in the inferior olive.

Animals↗
PubMed2001

The natural history of embouchure dystonia.

Focal task-specific dystonias are unusual disorders of motor control, often affecting individuals who perform complex repetitive movements. Musicians are especially prone to develop these disorders because of their training regimens and intense practice schedules. Task-specific dystonia occurring in keyboard or string instrumentalists usually affects the hand. In contrast, there have been few descriptions of musicians with task-specific dystonia affecting the muscles of the face and jaw. We report detailed clinical observations of 26 professional brass and woodwind players afflicted with focal task-specific dystonia of the embouchure (the pattern of lip, jaw, and tongue muscles used to control the flow of air into a mouthpiece). This is the largest and most comprehensively studied series of such patients. Patients developed embouchure dystonia in the fourth decade, and initial symptoms were usually limited to one range of notes or style of playing. Once present, dystonia progressed without remission and responded poorly to oral medications and botulinum toxin injection. Patients with embouchure dystonia could be separated by the pattern of their abnormal movements into several groups, including embouchure tremor, involuntary lip movements, and jaw closure. Dystonia not infrequently spread to other oral tasks, often producing significant disability. Effective treatments are needed for this challenging and unusual disorder.

Adolescent↗
PubMed2001

Use of simplified transcriptors for the analysis of gene expression profiles in laser-microdissected cell populations.

Because colorectal epithelia are prone to malignant transformation, it is important to understand their normal regulation and then to identify differences between the normal cells and the transformed cells. We investigated the gene expression pattern along colonic crypts using a novel gene expression analysis strategy. We combined laser-mediated microdissection of distinct areas within colonic crypts and used modified RNA arbitrarily primed PCR to generate probes for cDNA array hybridization. In the basal part of the crypt, proliferation-related and cell cycle-related genes such as the multifunctional transcription factor e2f-1 or the mismatch-related gene p58/HHR23B were predominantly expressed. In the lumenal part of the crypt, up-regulations of the cysteine protease mch4 and the proto-oncogene c-jun were found. Our findings indicate that e2f1, p58/HHR23B, and mch4 may be involved in key mechanisms leading to malignant transformation in the colonic crypt. Our results also suggest that the technique elucidated here allows identification of gene expression patterns in distinct areas of intestinal tissue samples.

Biopsy↗
PubMed2001

Radiofrequency transmission to monitoring devices in the operating room: a simulation study.

We evaluated radiofrequency (RF) transmission to various monitoring devices using circuits that simulated potentially hazardous conditions for patients in the operating room. Right heart ejection fraction (REF) pulmonary artery catheters, transesophageal atrial pacing stethoscopes, and temperature-sensing esophageal stethoscopes were subjected to RF transmission from an electrosurgery unit. Peak voltage and spark intensity were measured in circuits between the electrocautery dispersive pad and conductive elements of the various medical devices. All monitoring devices with an exposed conductive surface were found to have induced voltages and even spark generation. The ranking for peak voltage from least to most was as follows: disrupted esophageal stethoscope (620 volts), the transesophageal pacemaker (640 volts), and the REF pulmonary artery catheter (PAC) (680 volts). Peak voltage measurements of the REF PAC significantly decreased from 388 +/- 23 to 142 +/- 22 volts (P < 0.0001, Student's t-tests) in a fluid medium compared to air. In a fluid medium, peak voltage significantly decreased from 142 +/- 22 to 85 +/- 15 volts (P < 0.0001, Student's t-tests) when the REF PAC was connected to the cardiopulmonary monitor.

Humans↗
PubMed2000

Role of mitochondria and caspases in vitamin D-mediated apoptosis of MCF-7 breast cancer cells.

Vitamin D(3) compounds are currently in clinical trials for human breast cancer and offer an alternative approach to anti-hormonal therapies for this disease. 1alpha,25-Dihydroxyvitamin D(3) (1alpha,25(OH)(2)D(3)), the active form of vitamin D(3), induces apoptosis in breast cancer cells and tumors, but the underlying mechanisms are poorly characterized. In these studies, we focused on the role of caspase activation and mitochondrial disruption in 1alpha,25(OH)(2)D(3)-mediated apoptosis in breast cancer cells (MCF-7) in vitro. The effect of 1alpha,25(OH)(2)D(3) on MCF-7 cells was compared with that of tumor necrosis factor alpha, which induces apoptosis via a caspase-dependent pathway. Our major findings are that 1alpha,25(OH)(2)D(3) induces apoptosis in MCF-7 cells by disruption of mitochondrial function, which is associated with Bax translocation to mitochondria, cytochrome c release, and production of reactive oxygen species. Moreover, we show that Bax translocation and mitochondrial disruption do not occur after 1alpha,25(OH)(2)D(3) treatment of a MCF-7 cell clone selected for resistance to 1alpha,25(OH)(2)D(3)-mediated apoptosis. These mitochondrial effects of 1alpha,25(OH)(2)D(3) do not require caspase activation, since they are not blocked by the cell-permeable caspase inhibitor z-Val-Ala-Asp-fluoromethylketone. Although caspase inhibition blocks 1alpha,25(OH)(2)D(3)-mediated events downstream of mitochondria such as poly(ADP-ribose) polymerase cleavage, external display of phosphatidylserine, and DNA fragmentation, MCF-7 cells still execute apoptosis in the presence of z-Val-Ala-Asp-fluoromethylketone, indicating that the commitment to 1alpha,25(OH)(2)D(3)-mediated cell death is caspase-independent.

Apoptosis↗
PubMed2000

The rates of false-positive lumbar discography in select patients without low back symptoms.

STUDY DESIGN: Experimental disc injections in subjects with no history of low back symptoms. OBJECTIVE: To determine in an experimental setting the relative pain response and pain-related behavior in selected subjects without a history of low back pain undergoing lumbar discography. This study aimed to select a study population that more closely represented patients undergoing discography in clinical practice. SUMMARY OF BACKGROUND DATA: Previous work has shown that in young, healthy men with little degenerative disc disease and no history of low back problems, discographic injections usually did not cause significant pain. This group differed from the patients who usually undergo discographic evaluation in clinical practice. Most clinical patients are older, have significant degenerative disc disease, have behavioral changes associated with chronic pain, and often have confounding psychosocial troubles. The authors undertook to study discography in subjects without low back pain but with clinical profiles similar to patients undergoing discography in clinical practice. METHODS: Twenty-six individuals, mean age 43 years, with no history of low back pain had lumber discography according to the strict protocol of Walsh et al. Of these, 10 were pain-free; 10 had chronic neck and arm pain, but no low back symptoms; and 6 had primary somatization disorders without low back symptoms.- RESULTS: Significant positive pain response and pain-related behavior with discography were found in 10% of the pain-free group, in 40% of the chronic cervical pain group, and in 83% of the somatization disorder group completing the injections. Twenty-four subjects had negative control discs. Discs with annular disruption were more likely to be painful on injection, particularly in those individuals with ongoing compensation issues, chronic pain, or abnormal psychological testing.- CONCLUSION: If strict criteria are applied, the rate of false-positive discography may be low in subjects with normal psychometric profiles and without chronic pain. Significantly painful injections were very common in subjects with annular disruption and chronic pain or abnormal psychometric testing.

Adult↗
PubMed2000

Major transcript variants of VAV3, a new member of the VAV family of guanine nucleotide exchange factors.

VAV3 is a new member of the VAV oncogene family with a strong homology to VAV and VAV2. A conceptual translation of the cDNA indicates that VAV3 is between 40 and 77% identical to VAV and VAV2 at the amino acid level in all identified functional motifs. This homology suggests that VAV3 occupies a similar position in signal transduction as the other family members. A major variant transcript, VAV3.1, found in both humans and mice, appears to encode only the 3' SH3-SH2-SH3 region, which suggests that it may substitute for the full-length isoform in functions mediated by this domain, or compete with the full-length isoform in functions mediated by more N-terminal motifs. VAV3.1 either is a partly unspliced mRNA or originates from a different promoter. VAV3 transcripts are found in cells of hematopoietic origin, where VAV is primarily expressed. However, unlike, VAV, the VAV3 and VAV3.1 transcripts are also found at varying levels in a wide variety of other tissues and cell lines. TGF-beta and EGF reversibly down-regulate the abundance of the VAV3. 1 transcript in HaCaT keratinocytes, representing the first observation of transcript regulation of a member of the VAV family by a growth factor.

Amino Acid Sequence↗
PubMed2000

Radiation therapy.

Radiation therapy is commonly used to alleviate the pain associated with bone metastases. This article reviews the components of the radiation oncology evaluation. The options for use of ionizing radiation including postoperative treatment, limited-volume external beam radiotherapy, wide-field radiotherapy, and radioisotope therapy are compared and contrasted. Side effects and toxicities of radiotherapy are discussed.

Bone Neoplasms↗
PubMed2000

Vav3 mediates receptor protein tyrosine kinase signaling, regulates GTPase activity, modulates cell morphology, and induces cell transformation.

A recently reported new member of the Vav family proteins, Vav3 has been identified as a Ros receptor protein tyrosine kinase (RPTK) interacting protein by yeast two-hybrid screening. Northern analysis shows that Vav3 has a broad tissue expression profile that is distinct from those of Vav and Vav2. Two species of Vav3 transcripts, 3.4 and 5.4 kb, were detected with a differential expression pattern in various tissues. Transient expression of Vav in 293T and NIH 3T3 cells demonstrated that ligand stimulation of several RPTKs (epidermal growth factor receptor [EGFR], Ros, insulin receptor [IR], and insulin-like growth factor I receptor [IGFR]) led to tyrosine phosphorylation of Vav3 and its association with the receptors as well as their downstream signaling molecules, including Shc, Grb2, phospholipase C (PLC-gamma), and phosphatidylinositol 3 kinase. In vitro binding assays using glutathione S-transferase-fusion polypeptides containing the GTPase-binding domains of Rok-alpha, Pak, or Ack revealed that overexpression of Vav3 in NIH 3T3 cells resulted in the activation of Rac-1 and Cdc42 whereas a deletion mutant lacking the N-terminal calponin homology and acidic region domains activated RhoA and Rac-1 but lost the ability to activate Cdc42. Vav3 induced marked membrane ruffles and microspikes in NIH 3T3 cells, while the N-terminal truncation mutants of Vav3 significantly enhanced membrane ruffle formation but had a reduced ability to induce microspikes. Activation of IR further enhanced the ability of Vav3 to induce membrane ruffles, but IGFR activation specifically promoted Vav3-mediated microspike formation. N-terminal truncation of Vav3 activated its transforming potential, as measured by focus-formation assays. We conclude that Vav3 mediates RPTK signaling and regulates GTPase activity, its native and mutant forms are able to modulate cell morphology, and it has the potential to induce cell transformation.

3T3 Cells↗
PubMed2000

Reducing patient stress in theatre. Alison Bell Memorial Award.

For most patients, admission to hospital for surgery can be very stressful. It is well recognised that stress, created by prolonged anxiety, can produce harmful effects and may even delay a patient's recovery following surgery. This article, submitted for the 1999 Alison Bell award (sponsored by NATN and Regent Medical), looks at key ways to reduce the effects of such stress.

Adaptation, Psychological↗
PubMed2000

Identification of a hormone-responsive promoter immediately upstream of exon 1c in the human vitamin D receptor gene.

To gain insight into the molecular regulation of the human vitamin D3 receptor (hVDR), we have cloned and sequenced the 5' flanking region of exon 1c and examined promoter activity of this region in breast cancer cells. Sequence analysis of the first 1300 bp upstream of exon 1c reveals several characteristics of a class II promoter, including GC-rich regions and the presence of a TATA box at -29 bp. Putative transcription factor binding sites identified in this potential hVDR promoter include AP-2, Sp-1, and glucocorticoid response elements. No consensus vitamin D3 (VDRE) or estrogen (ERE) responsive elements were identified in the promoter sequence. Primer extension analysis performed with a primer specific for exon 1c confirms that transcription initiated in the 5' flanking region of exon 1c occurs in MCF-7 cells. Transient transfection of MCF-7 cells with this putative promoter region cloned into the pRLnull luciferase reporter vector generates significant reporter gene activity that is enhanced by treatment with forskolin, retinoic acid, and 17beta-estradiol. The enhancement of exon 1c promoter activity by 17beta-estradiol is blocked by the selective estrogen response modifier (SERM) tamoxifen and is not observed in estrogen receptor-negative breast cancer cells. In summary, we have cloned and characterized a TATA containing promoter upstream of exon 1c of the hVDR and provide evidence that this region represents a hormonally regulated hVDR promoter.

Base Sequence↗