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Biomedical subjects

A Symes

Publications and source records attributed to A Symes.

14 recordsLinked to original sources

Variations in the surface anatomy of the spinal accessory nerve in the posterior triangle.

Iatrogenic injury to the spinal accessory nerve has been widely documented and can have medico-legal implications. The resulting syndrome of pain, paralysis and winging of the scapula are often the source of considerable morbidity. This paper researches the degree of accuracy achievable in mapping the surface anatomy of the spinal accessory nerve in the region of the posterior triangle with a view to creating a cartographical aid to surgical procedures. The necks of 25 adult cadavers were dissected bilaterally to expose the spinal accessory nerve. Variations in the course and distribution of the spinal accessory nerve in the posterior triangle were recorded along with its relationship to the borders of sternocleidomastoid and trapezius. Considerable variation was seen in the surface and regional anatomy of the nerve and in the contribution of the cervical plexus to the spinal accessory nerve in the posterior triangle. Measurements of the running course and exit point of the nerve into and from the posterior triangle differed significantly from those previously recorded. Delineation of an accurate surface anatomy was not possible. Creating a map to define the surface anatomy of the spinal accessory nerve in the posterior triangle is an unrealistic goal given its wide variations in man. Avoidance of damage to the spinal accessory nerve cannot be achieved by slavishly adhering to surface markings given in textbooks, but only by cautious dissection during operations on the posterior triangle.

Accessory Nerve↗

Pelvi-calyceal height, a predictor of success when treating lower pole stones with extracorporeal shockwave lithotripsy.

Extra corporeal shockwave lithotripsy (ESWL) is the treatment of choice for the majority of renal stones, however, it has the lowest success rate in complete clearance of stones located in the lower pole. We assess whether pelvi-calyceal height is a useful measurement in predicting successful stone clearance from the lower pole. A total of 105 patients with a solitary lower pole calculus of less than 20 mm treated with ESWL were reviewed. Stone size, location and pelvi-calyceal height were measured by intravenous urogram. Success was defined as complete stone clearance. Fifty-four patients (51.4%) had successful treatments, with the remaining 51 (48.6%) having incomplete stone clearance (including two patients in whom treatment had no effect). There was a statistically significant difference (P<0.0001) in pelvi-calyceal height between the two groups. Mean pelvi-calyceal height in patients with complete stone clearance was 15.1 mm (SD=3.9) compared with 22.9 mm (SD=5.2) for those with incomplete clearance. Pelvi-calyceal height is a useful predictor of success when treating lower pole renal stones with ESWL.

Adult↗

Dystrophic ureteral calcification associated with Churg-Strauss vasculitis.

Churg-Strauss syndrome is an uncommon systemic vasculitis affecting small blood vessels. Renal involvement is typical; however, calcinosis of the urinary tract has not previously been described. Dystrophic calcification in the urinary tract is rare, although it is occasionally associated with schistosomiasis, tuberculosis, and polyarteritis nodosa. We report the case of a 19-year-old man with newly diagnosed Churg-Strauss syndrome who presented to us with dystrophic calcification in both ureters causing bilateral obstruction.

Adult↗

Leptin and TGF-beta synergistically regulate VIP cytokine response element transcription.

Leptin was originally described as an adipocyte-derived cytokine that signals to the hypothalamus to regulate food intake and energy expenditure. Leptin signals through the Ob receptor, which is closely related to the gp130 cytokine receptor. Here we show that leptin can induce expression of the neuropeptide gene vasoactive intestinal peptide (VIP) through the VIP cytokine response element, the same element that mediates the response to the gp130 cytokines. Leptin acts synergistically with TGF-beta to activate transcription through this element. Transcriptional responses to leptin are increased when transmitted through ObR mutated at Tyr986, the SHP-2 docking domain, yet this mutation does not alter the synergy between TGF-beta and leptin. These data emphasize the functional similarity between leptin and the gp130 cytokines.

Animals↗

Enhancing leptin response by preventing SH2-containing phosphatase 2 interaction with Ob receptor.

Leptin is an adipocyte-derived cytokine that regulates food intake and body weight via interaction with its Ob receptor (ObR). Serum leptin levels are chronically elevated in obese humans, suggesting that obesity may be associated with leptin resistance and the inability to generate an adequate ObR response. Evidence suggests that transcriptional activation of target genes by STAT3 (signal transducer and activator of transcription) in the hypothalamus is a critical pathway that mediates leptin's action. Herein we report that activation of ObR induces the tyrosine phosphorylation of the tyrosine phosphatase SH2-containing phosphatase 2 (SHP-2) and demonstrate that Tyr986 within the ObR cytoplasmic domain is essential to mediate phosphorylation of SHP-2 and binding of SHP-2 to ObR. Surprisingly, mutation of Tyr986 to Phe, which abrogates SHP-2 phosphorylation and binding to the receptor, dramatically increases gene induction mediated by STAT3. Our findings indicate that SHP-2 is a negative regulator of STAT3-mediated gene induction after activation of ObR and raise the possibility that blocking the interaction of SHP-2 with ObR could overcome leptin resistance by boosting leptin's weight-reducing effects in obese individuals.

Animals↗

NFAT interactions with the vasoactive intestinal peptide cytokine response element.

The vasoactive intestinal peptide cytokine response element (VIP CyRE) is responsible for mediating the transcriptional induction of the VIP gene to the neuropoietic cytokines leukemia inhibitory factor (LIF) and ciliary neurotrophic factor (CNTF). In investigating the sequence and function of the CyRE, we found a region of DNA with homology to the distal NFAT site in the IL-2 promoter. In this paper we characterize this sequence and show that the VIP NFAT site recognizes T cell NFAT with similar affinity to the previously characterized IL-2 NFAT site. However, despite its location in the middle of the CyRE, we find no CNTF/LIF induced binding to it. Instead we show that in NBFL neuroblastoma cells, the calcium ionophore A23187 induces a protein to bind to the VIP NFAT site. This A23187-mediated induction of nuclear protein binding to an NFAT oligonucleotide is dependent on extracellular calcium but not dependent on de novo protein synthesis. Thus, this protein has the characteristics of an NFAT-like protein and is recognized by an NFAT3-specific antiserum suggesting that it is indeed an NFAT protein. The location of the NFAT site in the VIP CyRE suggests that this may be one mechanism through which different signaling pathways engage in cross talk to alter VIP gene transcription.

Animals↗

Coordinate regulation of STAT signaling and c-fos expression by the tyrosine phosphatase SHP-2.

The src homology 2 (SH2) domain-containing protein-tyrosine phosphatase SHP-2 has been implicated as an important positive regulator of several mitogenic signaling pathways. SHP-2 has more recently been shown to be tyrosine phosphorylated and recruited to the gp130 component of the ciliary neurotrophic factor (CNTF) receptor complex upon stimulation with CNTF. CNTF does not, however, have a proliferative effect on responsive cells, but rather enhances the survival and differentiation of sympathetic, motor, and sensory neurons. In this study, expression of an interfering mutant of SHP-2 in the neuroblastoma cell line NBFL increased CNTF induction of a vasoactive intestinal peptide (VIP) reporter gene, and in cultures of sympathetic neurons, it resulted in an up-regulation of endogenous VIP and substance P (SP) gene expression. Members of the CNTF family of cytokines transmit their signal by activating signaling pathways involving both STAT and Fos-Jun transcription factors. In CNTF-stimulated NBFL cells that constitutively express the SHP-2 interfering mutant, there was increased and prolonged formation of STAT/DNA complexes, but decreased AP-1 binding activity, that mirrored a down-regulation of c-fos expression both at the mRNA and protein level. Taken together, these data indicate that SHP-2 has dual and opposing roles in a signaling cascade triggered by the same ligand, as illustrated by its ability to differentially regulate the levels of activity of both STAT and AP-1 transcription factors.

Animals↗

Integration of Jak-Stat and AP-1 signaling pathways at the vasoactive intestinal peptide cytokine response element regulates ciliary neurotrophic factor-dependent transcription.

Ciliary neurotrophic factor (CNTF)-dependent induction of expression of the neuropeptide vasoactive intestinal peptide (VIP) gene is mediated by a 180-base pair cytokine response element (CyRE) in the VIP promoter. To elucidate the molecular mechanisms mediating the transcriptional activation by CNTF, intracellular signaling to the CyRE has been studied in a neuroblastoma cell line. It has been shown previously that CNTF induces Stat proteins to bind to a site within the CyRE. CNTF also induces a second protein to bind to a C/EBP-like site within the CyRE. In this report, we show that this inducible CyRE binding protein is composed of the AP-1 proteins c-Fos, JunB, and JunD. These proteins bind to a non-canonical AP-1 site located near the previously characterized C/EBP site. The serine/threonine kinase inhibitor H7 prevents CNTF-dependent induction of AP-1 binding and CyRE-mediated transcription, suggesting that an H7-sensitive kinase is important to mediating CNTF effects on VIP transcription. The integration at the VIP CyRE of the Jak-Stat and AP-1 signaling pathways with other pre-existing proteins provides a cellular mechanism for cell- and cytokine-specific signaling.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

A minimal CGRP gene promoter is inducible by nerve growth factor in adult rat dorsal root ganglion neurons but not in PC12 phaeochromocytoma cells.

The calcitonin/CGRP gene is transcribed in thyroid C cells and some neuronal cells but not in other cell types. Although the promoter sequences mediating gene activity in thyroid C cells have been extensively studied, the elements responsible for promoter activity in neuronal cells and its stimulation by nerve growth factor (NGF) have not previously been defined. We report the first use of the calcium phosphate procedure to successfully transfect adult rat dorsal root ganglion neurons, which naturally express the calcitonin/calcitonin gene-related peptide (CGRP) in an NGF-inducible manner. This method was used to characterize the elements in the calcitonin/CGRP promoter which are responsible for its basal activity and NGF inducibility in DRG neurons and in PC12 cells, a neuronally derived cell line which does not naturally express the calcitonin/CGRP gene. Although the sequences required for basal activity are similar in each cell type, we show that a minimal calcitonin/CGRP promoter is NGF-responsive in dorsal root ganglion cells, but that upstream sequences are required for such inducibility in PC12 cells.

Animals↗

STAT proteins participate in the regulation of the vasoactive intestinal peptide gene by the ciliary neurotrophic factor family of cytokines.

Ciliary neurotrophic factor (CNTF) and leukemia inhibitory factor (LIF) are members of a family of neuropoietic cytokines that have a broad range of actions on many different neuronal populations. In cultured sympathetic neurons, CNTF and LIF induce transcription of the VIP and other neuropeptide genes as part of a program of differentiation. To gain insight into the nuclear events involved in cytokine-mediated activation of the neuropeptide genes involved in neuronal differentiation, we have investigated the mechanisms of transcriptional activation of the vasoactive intestinal peptide (VIP) gene by the CNTF family of cytokines. In the neuroblastoma cell line NBFL, CNTF, LIF, and a related cytokine, oncostatin-M, activate VIP gene transcription through a 180-base pair cytokine response element (CyRE). Deletion analysis of the VIP CyRE showed that multiple regions within the 180 base-pairs are important for cytokine-mediated transcriptional activation of the VIP gene. To one of these regions within the CyRE, cytokine treatment induces binding of a protein complex composed of members of the signal transducers and activators of transcription (STAT) transcription factor family. Mutation of this STAT-binding site attenuates cytokine-mediated transcriptional activation. LIF treatment of primary sympathetic neurons also induced binding of a STAT-containing protein complex to the VIP CyRE. Thus, activation of STAT transcription factors contributes to the induction of the VIp gene by the CNTF family of cytokines and may be involved in cytokine-mediated differentiation of sympathetic neurons.

Base Sequence↗

Oncostatin M regulates VIP expression in a human neuroblastoma cell line.

Oncostatin-M (OM), a recently described glycoprotein cytokine, is structurally and functionally related to cholinergic differentiation factor/leukemia inhibitory factor (CDF/LIF) and ciliary neurotrophic factor (CNTF). To determine whether OM, like CDF/LIF and CNTF, possesses trophic or differentiative functions for neurons we examined the effects of recombinant human OM on ciliary neuron survival and neurotransmitter expression in sympathetic neurons. Like CDF/LIF, but in contrast to CNTF, OM had no effect on ciliary neuronal survival at any concentration tested. OM produced small but reproducible increases in choline acetyl transferase (ChAT) activity and vasoactive intestinal peptide (VIP) levels in rat sympathetic neuron cultures, but this effect was significantly less than that of CNTF or CDF/LIF. To determine if human OM would elicit a more robust response from human cells, we utilized a human neuroblastoma cell line, NBFL, that responds to CNTF and CDF/LIF by altering vasoactive intestinal peptide (VIP) levels. OM specifically elevated VIP and c-fos mRNA levels in NBFL cells and was as potent as CDF/LIF in this assay. Our data provides evidence that OM acts on neurons and identifies a neural cell line responsive to OM, CNTF, CDF/LIF.

Animals↗

Comparative effects of two cimetidine regimens on 24-hour intragastric acidity in patients with asymptomatic duodenal ulcer.

The effect of 600 mg of cimetidine given twice daily on 24-hour intragastric hydrogen ion (H+) concentration was compared with that of the standard regimen of 300 mg of cimetidine given four times daily in six patients with asymptomatic duodenal ulcer. According to the double-blind, Latin-square, repeated-measures design, all subjects followed each cimetidine regimen and a placebo regimen for one week. Acid secretion studies and determinations of drug and gastrin levels in the blood were carried out on the last day of each treatment week. Although 600 mg of cimetidine BID suppressed H+ after breakfast and during the night, compared with placebo treatment (P less than 0.01), the 300-mg QID regimen suppressed H+ only after breakfast and supper (P less than 0.05). A higher percentage of pH readings greater than or equal to 3.0 were obtained with 600 mg of cimetidine BID than with 300 mg of cimetidine QID during the night (P less than 0.05); compared with percentages when placebo was taken, the percentages of pH readings greater than or equal to 3.0 were greater both overnight and during a 24-hour period only when 600 mg of cimetidine was given BID (P less than 0.01). The observed difference in intragastric H+ suppression after each regimen could not be explained by variations in serum concentrations of cimetidine or serum concentrations of gastrin. Despite similar peaks of serum cimetidine after evening doses of 300 or 600 mg of cimetidine, nocturnal intragastric acidity was lower in subjects given 600 mg BID. Further, H+ levels after lunch were similar in both cimetidine-treated groups, despite markedly higher serum cimetidine concentrations in patients receiving 600 mg BID. Pharmacokinetic studies showed equivalent elimination half-times and 24-hour areas under the curve of serum cimetidine concentration in patients on the two cimetidine regimens. Postprandial integrated gastrin responses were of similar magnitude in patients on either cimetidine regimen. There was no significant difference in mean serum gastrin concentrations during the night in placebo-treated and cimetidine-treated patients. Only a weak correlation was observed between H+ and serum gastrin concentration. Although a fluctuation of the H+:gastrin ratio occurred after each meal in all groups, the ratio was suppressed by both dosages of cimetidine. The findings suggest that a regimen of 600 mg of cimetidine BID is superior to the standard regimen of 300 mg QID in suppressing intragastric acidity in patients with asymptomatic duodenal ulcer.

Adult↗

Toxic nephropathy after low-dose methoxyflurane anesthesia: drug interaction with secobarbital?

Vasopressin-resistant nonoliguric renal insufficiency developed in a 57-year-old man after 2 1/2 hours of low-dose methoxyflurane anesthesia. Secobarbital, 100 mg daily, had been taken for 1 month before. Of 13 patients in whom the influence of methoxyflurane on renal function was being studied, he was the only one to have taken a drug that induces microsomal enzymes. Blood values of methoxyflurane in this patient were lower than group means on all five occasions during anesthesia. Postoperatively his serum inorganic fluoride value reached 114 mumol/l -- more than two standard deviations greater than the group mean. Peak values for serum urea nitrogen, creatinine and uric acid and postvasopressin urine osmolality, and the lowest creatinine clearance in this patient also differed by more than 2 SD from the group mean, and the peak amount of oxalate excreted in his urine was double the group mean. Pretreatment with the barbiturate appears to have altered methoxyflurane metabolism and led to toxic concentrations of metabolites in the blood.

Drug Interactions↗