Assessing paralysis.
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Electric Stimulation↗
Biomedical subjects
J Norman
Publications and source records attributed to J Norman.
Association of reduced selenium status in the aetiology of recurrent miscarriage.
OBJECTIVE: To determine whether recurrent miscarriage is associated with reduced selenium status. DESIGN: Case-control study. SETTING: Department of Obstetrics and Gynaecology, Glasgow Royal Infirmary and Glasgow Royal Maternity Hospital. POPULATION: Twenty nonpregnant women with a history of unexplained recurrent miscarriage, and 47 nonpregnant parous women with a history of at least one successful pregnancy and no more than one miscarriage. METHODS: A 7 mL blood sample from each woman was collected into lithium heparin 'vacutainer' tubes. Samples were centrifuged at 3000 g for 15 minutes, and plasma was extracted and stored at -20 degrees C. Selenium concentrations were measured using a fluorescence spectrophotometer. The selenium concentrations in the two groups were compared and the differences examined using the Student's t test. MAIN OUTCOME MEASURES: Plasma selenium concentration (microg/L). RESULTS: The mean selenium concentration for women with a history of unexplained recurrent miscarriage was 67.7 microg/L (SD 16.4). The selenium level for the women with no history of recurrent miscarriage was 70.3 microg/L (SD 12.7). There was no difference in selenium concentrations between the two groups (P = 0.53). CONCLUSIONS: In this study there is no association between unexplained recurrent miscarriage and reduced selenium status, implying that reduced selenium status is not a factor in the pathogenesis of recurrent miscarriage. We can find no rationale for a trial of selenium therapy in women with a history of recurrent miscarriage.
Abortion, Habitual↗
Laparoscopic Adrenal Resection: Changing Techniques for Established Indications.
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Journal Article↗
Potential new therapies for the treatment of acute pancreatitis.
The treatment of acute pancreatitis has remained virtually unchanged for the past 50 years, in large part due to a poor understanding of the initial intracellular events. Furthermore, there is a lack of knowledge regarding the mediator(s) responsible for the progression of the disease from local pancreatic inflammation to a systemic inflammatory disease, as well as the mediator(s) responsible for distant organ dysfunction and failure. With recent advances in the pathophysiology of pancreatitis, in particular the role of the inflammatory mediators interleukin-1 beta, tumour necrosis factor alpha and platelet-activating factor, the potential for new effective therapies has been realised. At present, a number of inflammatory mediator antagonists are being tested in humans, with the hope that we may soon develop a specific treatment for a disease, which thus far, has none.
Journal Article↗
Integrin-mediated cell adhesion: the cytoskeletal connection.
Members of the integrin family of cell adhesion molecules play a pivotal role in the interaction between animal cells and the extracellular matrix. This article reviews the evidence (i) that the integrin beta-subunit cytoplasmic domain is important in the localization of integrins to focal adhesions, and for integrin-mediated cell adhesion/spreading; and (ii) that the integrin beta-subunit can be linked to F-actin via the actin-binding proteins talin, alpha-actinin and filamin. Talin has two or more actin-binding sites, and three binding sites for the cytoskeletal protein vinculin. Because vinculin can also bind F-actin, it may cross-link talin and actin, thereby stabilizing the interaction. In addition, vinculin contains a binding site for VASP (vasodilator-stimulated phospho-protein), a protein which may serve to recruit a profilin/G-actin complex to talin, which has actin-nucleating activity. Evidence that talin, vinculin and alpha-actinin are important in the assembly of focal adhesions, obtained using antisense technology and protein microinjection, is reviewed. To analyse the role of talin in focal adhesions, we have disrupted both copies of the talin gene in mouse embryonic stem (ES) cells. Undifferentiated talin (-/-) ES cell mutants are unable to assemble focal adhesions when plated on fibronectin, whereas vinculin (-/-) ES cells are able to do so. Finally, the role of small GTP-binding proteins in the assembly of focal adhesions is discussed, along with our recent studies using streptolysin-O-permeabilized Swiss 3T3 cells which suggest that the GTP-binding protein ADP-ribosylation factor-1 (ARF-1) is important in targeting the protein paxillin to focal adhesions.
Actins↗
Re: Cost utility of routine imaging with Tc-99m-Sestamibi in primary hyperparathyroidism before initial surgery.
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Cost Control↗
Minimally invasive radioguided parathyroidectomy.
The last decade has been characterized by an emphasis on minimizing interventional techniques, hospital stays, and overall costs of patient care. It is clear that most patients with sporadic HPT do not require a complete neck exploration. We now know that a minimal approach is appropriate for this disease. Importantly, the MIRP technique can be applied to most patients with sporadic HPT and can be performed by surgeons with modest advanced training. The use of a gamma probe as a surgical tool converts the sestamibi to a functional and anatomical scan eliminating the need for any other preoperative localizing study. Quantification of the radioactivity within the removed gland eliminates the need for routine frozen section histologic examination and obviates the need for costly intraoperative parathyroid hormone measurements. This radioguided technique allows the benefit of local anesthesia, dramatically reduces operative times, eliminates postoperative blood tests, provides a smaller scar, requires minimal time spent in the hospital, and almost assures a rapid, near pain-free recovery. This combination is beneficial to the patient whereas helping achieve a reduction in overall costs.
Adenoma↗
Evidence of a central role for p38 map kinase induction of tumor necrosis factor alpha in pancreatitis-associated pulmonary injury.
BACKGROUND: Tumor necrosis factor alpha (TNF alpha) has been implicated as an important mediator in acute pancreatitis-associated adult respiratory distress syndrome, but the precise pathogenesis remains unclear. The purpose of this work was to clarify the role of TNF alpha that is produced within the lung parenchyma in the inducement of pancreatitis-related pulmonary injury and to examine 1 of the potential pathways leading to the production of pulmonary TNF alpha. METHODS: Bile salt pancreatitis was induced in rats (n = 40) that were randomized to receive a p38 mitogen-activated protein (MAP) kinase inhibitor or vehicle. A separate group (n = 16) underwent sham operation. Pulmonary capillary permeability was determined with fluorescein isothiocyanate-labeled albumin and Evans blue dye, and lung histologic analysis was performed. TNF alpha protein was measured in bronchoalveolar lavage fluid, and p38 MAP kinase was activity determined by Western blot analysis. RESULTS: The induction of pancreatitis resulted in increased pulmonary capillary leakage and worsened histologic condition (P < .01 vs sham). Effective inhibition of p38 MAP kinase-induced TNF alpha production completely prevented pancreatitis-associated pulmonary injury (P < .01 vs vehicle). CONCLUSIONS: p38 MAP kinase-induced TNF alpha production plays a central role in the development of pulmonary dysfunction, which accompanies severe acute pancreatitis in this rodent model.
Acute Disease↗
A novel pancreatic model: the snip method of pancreatic isolation for in vitro study.
We aimed to devise a method of preparing the pancreas for in vitro study that would provide tissue that is viable and functional for 24 h, with preservation of integral functional cell-membrane structures. Pancreata of NIH Swiss mice were excised, gently insufflated with media, and carefully snipped into portions of < 0.5 mm. Snips were incubated in cell culture for 0, 8, 24, and 48 h, with viability measured by 3-[4,5-dimethylthiazol-2-yl]-2,3-diphenyltetrazolium bromide (MTT) assay and amylase production quantified after stimulation with cerulein. Recombinant tumor necrosis factor-alpha (TNF-alpha) was added to cell culture, and apoptosis demonstrated by Hoechst staining at 0, 24, and 48 h. At 0, 8, and 24 h, pancreatic snips were determined to be viable by MTT assay. They also were functional with intact cell-membrane apparatuses at these same time points, as evidenced by amylase production in response to a cholecystokinin analogue. We were able to induce apoptosis with TNF-alpha ligand in these pancreatic snips in support of viability and overall cellular function. We conclude that the snip method provides an effective in vitro pancreatic model. Acinar cells are viable and functional for > or = 24 h, with evidence that their cell-surface receptors are preserved in their operational state.
Amylases↗
Enhancer and promoter chimeras in plasmids designed for intramuscular injection: a comparative in vivo and in vitro study.
Enhancers and promoters from various muscle-specific genes were substituted for or combined with the enhancer/promoter of the human cytomegalovirus (CMV) IE gene in a luciferase reporter gene plasmid in an effort to identify new promoter chimeras with increased expression activity after direct intramuscular injection. The regulatory sequence substitutions or additions varied in content, location, and orientation relative to the CMV regulatory sequences. The expression activities of the derivative and parent plasmids were compared quantitatively in vivo using a standard mouse intramuscular injection assay, and in vitro by transfection of differentiated C2C12 mouse myoblasts and BHK hamster kidney cells, to test whether cultured cell transfection could substitute for at least some animal experimentation. In vivo, 1 of 19 of the enhancer/promoter chimeras increased expression levels. In vitro, some chimeras showed significant expression augmentation in C2C12 cells, but not in BHK cells. We conclude that because of differences in plasmid expression profiles, these cell culture systems cannot readily substitute for in vivo testing of new plasmid constructs.
Animals↗
Disparate roles for TNF-alpha and Fas ligand in concanavalin A-induced hepatitis.
Apoptosis is a physiologic process that serves to eliminate cells during development or in response to immunologic regulation. In acute inflammation, however, apoptosis triggered by the overproduction of "death factors" such as TNF-alpha or Fas ligand (FasL) may contribute to tissue injury. Both TNF-alpha and FasL are presumed to convey an apoptotic signal by activating a cascade of cysteine-aspartate proteases, which includes IL-1beta-converting enzyme or caspase-1. In the present study, we evaluated the contribution of TNF-alpha and FasL, as well as the role of caspase-1, in Con A-induced hepatitis. We report here that TNF-alpha and FasL mRNA and protein levels are both increased in the livers of Con A-challenged mice. Using a novel inhibitor of TNF-alpha, we can confirm that Con A-induced hepatitis is primarily TNF-alpha dependent. Blockade of FasL with a soluble Fas immunoadhesin does not prevent liver injury in animals treated with Con A alone. However, administration of a matrix metalloproteinase inhibitor exacerbates liver injury, in part through a FasL-dependent process, since pretreatment with the soluble Fas immunoadhesin reduces liver injury in this model. In addition, mice lacking functional caspase-1 are resistant to Con A-induced hepatitis, even after pretreatment with a matrix metalloproteinase inhibitor. We conclude that TNF-alpha plays a predominant role in Con A-induced liver injury, although concomitant activation of FasL can also lead to apoptotic injury. Furthermore, Con A-induced hepatitis is caspase-1 dependent.
Animals↗
Macrophage pacification reduces rodent pancreatitis-induced hepatocellular injury through down-regulation of hepatic tumor necrosis factor alpha and interleukin-1beta.
Overproduction of tumor necrosis factor (TNF-), interleukin-1beta (IL-1beta), and nitric oxide (NO) is believed to be detrimental during the progression of acute pancreatitis, yet little is known about the hepatic production of these mediators and their role in mediating pancreatitis-induced hepatic dysfunction. Rats were randomized to receive a single intraperitoneal injection of the macrophage-pacifying compound, CNI-1493 (1.0 mg/kg), or vehicle 1 hour before the induction of retrograde bile salt pancreatitis. Sham-operated animals served as controls. Animals were killed 18 hours later, with serum and livers harvested to determine the degree of hepatocellular injury and the induction of TNF-, IL-1beta, and inducible nitric oxide synthase (iNOS). In addition, serum TNF- and nitrites (end-product of NO breakdown) were determined in each group to assess the mechanism of action of CNI-1493. TNF-, IL-1beta, and iNOS gene expression (by reverse-transcription polymerase chain reaction) as well as aspartate transaminase (AST), alanine transaminase (ALT), and lactic dehydrogenase (LDH) (but not alkaline phosphatase [ALP]) increased following the development of pancreatitis (all P < .05). Macrophage pacification significantly prevented the induction of TNF- and IL-1beta mRNA (but not iNOS), resulting in lessened serum AST, ALT, and LDH (all P < .05). Serum TNF- protein and nitrites correlated with gene induction in that both were increased following the onset of pancreatitis, and TNF- protein production was significantly attenuated in animals receiving CNI-1493. Hepatocellular, but not bile duct, injury occurs during experimental pancreatitis that is associated with hepatic TNF-, IL-1beta, and iNOS mRNA gene induction, as well as TNF- protein and nitrite production. Preventing the production of TNF- and IL-1beta by macrophage pacification attenuates the hepatocellular damage, suggesting that these mediators play a role in pancreatitis-induced hepatic injury.
Alanine Transaminase↗
TNF but not IL-1 decreases pancreatic acinar cell survival without affecting exocrine function: a study in the perfused human pancreas.
Substantial quantities of interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) are produced within the pancreatic parenchyma during acute pancreatitis. Recent evidence suggests that IL-1 beta and TNF-alpha propagate acute pancreatitis and intensify the resulting pancreatic acinar cell death. This study examines the direct effect of IL-1 beta and TNF-alpha on pancreatic acinar cells. Human pancreata (n = 6), harvested during organ procurement, were perfused ex vivo through the splenic artery using a sterile, oxygenated colloid solution. Each pancreas was perfused with either recombinant human IL-1 beta or TNF-alpha for 2 h and subsequently with the cholecystokinin analogue caerulein (positive control). Venous effluent was collected continuously and amylase and lipase were determined at 15-min intervals. Pancreatic histology was graded at baseline and following cytokine and caerulein perfusion. To examine the long-term effects of these cytokines on acinar cell viability, additional in vitro studies utilized the AR42J acinar cell line which was exposed to either IL-1 beta or TNF-alpha with survival determined daily by MTT assay. Perfusion of the human pancreas with either IL-1 beta or TNF-alpha did not alter amylase, lipase, or histology. Caerulein did induce pancreatitis as measured by increased amylase, lipase, and pancreatic histology. Survival of pancreatic acinar cells decreased when they were incubated with TNF-alpha but not IL-1 beta. Although present in large amounts within the pancreas during acute pancreatitis, IL-1 beta and TNF-alpha have no direct effect on acinar cell viability or exocrine function acutely nor do they induce pancreatitis. When present for more than 24 h, however, TNF-alpha but not IL-1 beta has a dramatic effect on acinar cell survival.
Acute Disease↗
The role of cytokines in the pathogenesis of acute pancreatitis.
BACKGROUND: The systemic manifestations of acute pancreatitis are responsible for the majority of pancreatitis-associated morbidity and mortality and are now believed to be due to the actions of specific inflammatory cytokines. This report summarizes what is known about the role of cytokines in the pathogenesis of acute pancreatitis. METHODS: Comprehensive literature review of experimental pancreatitis as well as all reports of cytokine involvement during clinical pancreatitis. RESULTS: Several cytokines and other noncytokine inflammatory mediators are produced rapidly during pancreatitis. These mediators arise in many tissues in a predictable fashion independent of the animal model used or the underlying etiology in human disease. Preventing the activities of these mediators has a profound beneficial effect in experimental animals. CONCLUSIONS: A few recently described inflammatory mediators are believed to be primarily responsible for the systemic manifestations of acute pancreatitis and its associated distant organ dysfunction. The predictable nature in which they are produced may allow for novel approaches to treating this disease. Am J Surg.
Acute Disease↗
Endoscopic versus radioguided parathyroidectomy.
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Animals↗
Cost-effectiveness of preoperative sestamibi scan for primary hyperparathyroidism is dependent solely upon the surgeon's choice of operative procedure.
BACKGROUND: In 1991, a National Institutes of Health Consensus Panel stated that preoperative localization for primary hyperparathyroidism is not cost effective. Since then, the sestamibi scan has been applied to parathyroid disease with excellent results, even allowing unilateral exploration under local anesthesia. STUDY DESIGN: A metaanalysis of the English literature over the past 10 years was performed to determine the collective sensitivity and specificity of sestamibi scanning to establish its utility in directing a unilateral procedure. The cost effectiveness of scanning all patients with sporadic primary hyperparathyroidism was examined by determining the costs of seven operative technique-dependent variables that could be reduced with a limited procedure. RESULTS: The average sensitivity and specificity of sestamibi were 90.7% and 98.8%, respectively, indicating its ability to guide an accurate unilateral exploration. The analysis of 6,331 patients showed that 87% had solitary adenomas. An average cost savings of $650 was demonstrated for a unilateral operation, which could be realized in as many as 90% (sestamibi sensitivity) of those with solitary adenomas. CONCLUSIONS: A preoperative sestamibi scan is specific enough in identifying solitary adenomas to allow unilateral exploration with a < 1% failure rate. The sensitivity of this scan suggests that 78% of all patients with sporadic primary hyperparathyroidism (90% of the 87% with solitary adenomas) are candidates for unilateral exploration. This rate is significantly higher than the 51% rate at which scanning all patients becomes cost effective.
Adenoma↗
Minimally invasive radioguided parathyroidectomy in the reoperative neck.
BACKGROUND: Operations for hyperparathyroidism (HPT) in a previously operated neck present a significant challenge and carry much higher morbidity rates than first-time operations. Our extensive experience with minimally invasive radioguided parathyroidectomy (MIRP) for first-time surgery for HPT has shown this method to be a directed approach to the offending adenoma, suggesting that the technique could be used to minimize reoperative neck surgery as well. METHODS: Over an 11-month period 24 consecutive patients with primary HPT who had undergone at least one previous neck operation were referred for re-exploration. All patients underwent preoperative sestamibi scanning; 21 localized sufficiently to undergo MIRP. RESULTS: All patients were cured after reoperation. Eighteen patients underwent MIRP under local anesthesia as outpatients; 3 MIRPs were done under general anesthesia. Average total operative time was 44 minutes, average incision length was 3.0 cm +/- 0.2 cm. Nineteen of the procedures were completed without any frozen sections. There were no complications. CONCLUSION: MIRP is extremely effective in patients with HPT who have undergone previous neck exploration for parathyroid or thyroid disease. The technique allows for such a directed dissection that smaller incisions and local anesthesia in an outpatient setting are routine.
Adenoma↗
Transient human gene therapy: a novel cytokine regulatory strategy for experimental pancreatitis.
OBJECTIVE: The purpose of this study was to evaluate the ability to transfect a murine pancreas with a human cytokine regulatory gene (interleukin-10 [IL-10]) and examine the duration of transgene expression, its effect on the normal pancreas, and its antiinflammatory effect during acute pancreatitis. SUMMARY BACKGROUND DATA: Interleukin-1beta and tumor necrosis factor-alpha are known detrimental mediators during the progression of acute pancreatitis, and blockade of either cytokine results in decreased severity of pancreatitis and improved survival. Although gene therapy has been proposed as a method to deliver protein-based therapy during a number of conditions, no means of effectively transfecting the pancreas without inducing injury has been developed. METHODS: A plasmid-human IL-10 construct (pMP6-hIL-10) complexed with cationic liposomes was administered by single intraperitoneal injection to healthy mice. Effective transfection (reverse transcriptase-polymerase chain reaction for hIL-10 mRNA), transfected cell type (in situ polymerase chain reaction for hIL-10 DNA), and the effect on the normal pancreas were determined. Additional animals were transfected to determine the effects of this regulatory gene on the severity of pancreatitis. RESULTS: Nearly 80% of all pancreatic cells expressed human DNA that was subsequently transcribed into mRNA through day 14. The transfection event had no effect on amylase, lipase, or pancreatic histologic appearance. Successful transfection could attenuate subsequently induced pancreatitis (all parameters p < 0.05). CONCLUSIONS: Transient transfection of a human IL-10 gene can be accomplished into all cell types of murine pancreata using a plasmid/ liposome vector. The DNA is effectively transcribed into intact mRNA and does not cause inflammation or acinar cell damage. Transfer of this cytokine regulatory gene decreases the severity of pancreatitis, demonstrating a benefit of gene therapy during this acute inflammatory process.
Amylases↗