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Biomedical subjects

S Spencer

Publications and source records attributed to S Spencer.

At least 37 records · Page 2Linked to original sources
PubMed2000

Pressure relieving interventions for preventing and treating diabetic foot ulcers.

BACKGROUND: Foot ulceration is thought to affect 15% of all people with diabetes at some time during their life. OBJECTIVES: To assess the effectiveness of pressure relieving interventions in the prevention and treatment of diabetic foot ulcers. SEARCH STRATEGY: Searches of 19 databases, hand searching of journals, bibliographies and identification of unpublished work by written communication with recognised experts in the diabetic foot. SELECTION CRITERIA: Randomised controlled trials evaluating pressure relieving interventions either in the prevention or the treatment of diabetic foot ulcers. There was no restriction on articles/trials based on language or publication status. DATA COLLECTION AND ANALYSIS: Data extraction and assessment of study quality was undertaken by two reviewers independently. Each trial was analysed separately, no pooling of results was possible due to the difference in patients, comparisons and outcomes. MAIN RESULTS: Prevention 4 RCTs of pressure relieving interventions were identified. Interventions for the prevention of diabetic foot ulcers indicated that in-shoe orthotics are of benefit. The relative merits of different in-shoe orthotics are unclear; cushioning and pressure redistribution appear of equal benefit. Other pressure relieving interventions such as running shoes have not been adequately evaluated and removable casts (Scotchcast or Hope) or foam inlays do not appear to have been evaluated at all in randomised controlled studies. Treatment 1 RCT of total contact casting indicated that it was effective in the treatment of diabetic ulcers although the evidence was limited. REVIEWER'S CONCLUSIONS: Prevention There is limited evidence of the effectiveness of orthotic interventions over removal of callus. There is some evidence evaluating the relative effectiveness of two types orthotic devices. There is very limited evidence of the effectiveness of therapeutic shoes. Treatment There is very limited evidence of the effectiveness of total contact casts in the treatment of diabetic foot ulcers. Overall there is a need to measure the effectiveness of the range of pressure relieving interventions for the prevention and treatment of diabetic foot ulcers as there is a small amount of poor quality research in this area.

Casts, Surgical↗
PubMed2000

Cytoskeletal protein PSTPIP1 directs the PEST-type protein tyrosine phosphatase to the c-Abl kinase to mediate Abl dephosphorylation.

A search for c-Abl interacting proteins resulted in the recovery of PSTPIP1, originally identified as a binding protein of the PEST-type protein tyrosine phosphatases (PTP). PSTPIP1 was phosphorylated by c-Abl, and growth factor-induced PSTPIP1 phosphorylation was diminished in Abl null fibroblasts. PSTPIP1 was able to bridge c-Abl to the PEST-type PTPs. Several experiments suggest that the PEST-type PTPs negatively regulate c-Abl activity: c-Abl was hyperphosphorylated in PTP-PEST-deficient cells; disruption of the c-Abl-PSTPIP1-PEST-type PTP ternary complex by overexpression of PSTPIP1 mutants increased c-Abl phosphotyrosine content; and PDGF-induced c-Abl kinase activation was prolonged in PTP-PEST-deficient cells. Dephosphorylation of c-Abl by PEST-type PTP represents a novel mechanism by which c-Abl activity is regulated.

Adaptor Proteins, Signal Transducing↗
PubMed2000

N-Acetylaspartate concentration in the anterior cingulate of maltreated children and adolescents with PTSD.

OBJECTIVE: Anterior cingulate dysfunction has been implicated in the pathophysiology of posttraumatic stress disorder (PTSD). The authors hypothesized that integrity of the anterior cingulate may be affected in childhood PTSD. METHOD: Single voxel proton magnetic resonance spectroscopy (proton MRS) was used to measure the relative concentration of N-acetylaspartate and creatine, a marker of neural integrity, in the anterior cingulate of 11 children and adolescents who met DSM-IV criteria for PTSD secondary to maltreatment and 11 healthy matched comparison subjects. RESULTS: The ratio of N-acetylaspartate to creatine was significantly lower in the maltreated subjects with PTSD than in the comparison subjects. CONCLUSIONS: The lower N-acetylaspartate/creatine ratio in subjects with PTSD suggests that anterior cingulate neuronal metabolism may be altered in childhood PTSD.

Adolescent↗
PubMed1999

Chemoradiotherapy of locally advanced esophageal cancer: long-term follow-up of a prospective randomized trial (RTOG 85-01). Radiation Therapy Oncology Group.

CONTEXT: Carcinoma of the esophagus traditionally has been treated by surgery or radiation therapy (RT), but 5-year overall survival rates have been only 5% to 10%. We previously reported results of a study conducted from January 1986 to April 1990 of combined chemotherapy and RT vs RT alone when an interim analysis revealed significant benefit for combined therapy. OBJECTIVE: To report the long-term outcomes of a previously reported trial designed to determine if adding chemotherapy during RT improves the survival rate of patients with esophageal carcinoma. DESIGN: Randomized controlled trial conducted 1985 to 1990 with follow-up of at least 5 years, followed by a prospective cohort study conducted between May 1990 and April 1991. SETTING: Multi-institution participation, ranging from tertiary academic referral centers to general community practices. PATIENTS: Patients had squamous cell or adenocarcinoma of the esophagus, T1-3 N0-1 M0, adequate renal and bone marrow reserve, and a Karnofsky score of at least 50. Interventions Combined modality therapy (n = 134): 50 Gy in 25 fractions over 5 weeks, plus cisplatin intravenously on the first day of weeks 1, 5, 8, and 11, and fluorouracil, 1 g/m2 per day by continuous infusion on the first 4 days of weeks 1, 5, 8, and 11. In the randomized study, combined therapy was compared with RT only (n = 62): 64 Gy in 32 fractions over 6.4 weeks. MAIN OUTCOME MEASURES: Overall survival, patterns of failure, and toxic effects. RESULTS: Combined therapy significantly increased overall survival compared with RT alone. In the randomized part of the trial, at 5 years of follow-up the overall survival for combined therapy was 26% (95% confidence interval [CI], 15%-37%) compared with 0% following RT. In the succeeding nonrandomized part, combined therapy produced a 5-year overall survival of 14% (95% CI, 6%-23%). Persistence of disease (despite therapy) was the most common mode of treatment failure; however, it was less common in the groups receiving combined therapy (34/130 [26%]) than in the group treated with RT only (23/62 [37%]). Severe acute toxic effects also were greater in the combined therapy groups. There were no significant differences in severe late toxic effects between the groups. However, chemotherapy could be administered as planned in only 89 (68%) of 130 patients (10% had life-threatening toxic effects with combined therapy vs 2% in the RT only group). CONCLUSION: Combined therapy increases the survival of patients who have squamous cell or adenocarcinoma of the esophagus, T1-3 N0-1 M0, compared with RT alone.

Adenocarcinoma↗
PubMed1999

Protein tyrosine phosphatase-PEST regulates focal adhesion disassembly, migration, and cytokinesis in fibroblasts.

In this article, we show that, in transfected COS-1 cells, protein tyrosine phosphatase (PTP)-PEST translocates to the membrane periphery following stimulation by the extracellular matrix protein fibronectin. When plated on fibronectin, PTP-PEST (-/-) fibroblasts display a strong defect in motility. 3 h after plating on fibronectin, the number and size of vinculin containing focal adhesions were greatly increased in the homozygous PTP-PEST mutant cells as compared with heterozygous cells. This phenomenon appears to be due in part to a constitutive increase in tyrosine phosphorylation of p130(CAS), a known PTP-PEST substrate, paxillin, which associates with PTP-PEST in vitro, and focal adhesion kinase (FAK). Another effect of this constitutive hyperphosphorylation, consistent with the focal adhesion regulation defect, is that (-/-) cells spread faster than the control cell line when plated on fibronectin. In the PTP-PEST (-/-) cells, an increase in affinity for the SH2 domains of Src and Crk towards p130(CAS) was also observed. In (-/-) cells, we found a significant increase in the level of tyrosine phosphorylation of PSTPIP, a cleavage furrow-associated protein that interacts physically with all PEST family members. An effect of PSTPIP hyperphosphorylation appears to be that some cells remain attached at the site of the cleavage furrow for an extended period of time. In conclusion, our data suggest PTP-PEST plays a dual role in cell cytoskeleton organization, by promoting the turnover of focal adhesions required for cell migration, and by directly or indirectly regulating the proline, serine, threonine phosphatase interacting protein (PSTPIP) tyrosine phosphorylation level which may be involved in regulating cleavage furrow formation or disassembly during normal cell division.

Animals↗
PubMed1999

Investigation into the role of the response regulator NtrC in the metabolism and virulence of Brucella suis.

During infection, Brucella species have to adapt to a range of different environments. Environmental sensing in bacteria often involves the concerted action of two-component regulatory systems consisting of sensor and response regulator components. In this study, we identified, cloned and sequenced four independent response regulator gene fragments from Brucella melitensis. One amplified gene fragment showed nearly 90% identity to the response regulator subfamily of NtrC transcriptional activators, and further analysis revealed the presence of an adjacent gene encoding the sensor protein NtrB. The NtrBC two-component regulatory system has been shown to play varying roles in nitrogen metabolism and potentially in virulence in other bacterial species. A B. suis ntrC isogenic mutant was constructed which showed no significant differences in growth rates compared to the wild-type strain when grown at different temperatures in vitro. However, the mutant exhibited a reduction in metabolic activity in the presence of many amino acids. The mutation did not affect survival or multiplication of B. suis in macrophages, but during the initial stages of infection in the murine brucellosis model, the ntrC mutant showed a reduced ability to multiply rapidly in splenic tissue.

Amino Acid Sequence↗
PubMed1999

The animal scientist in a changing society.

Despite the lack of any credible scientific evidence to oppose the use of animal performance-enhancing agents, acceptance of performance enhancers seems no closer than it was a decade ago--at least among the European Community and its major trading partners. Consumers are suspicious of new technologies, and politicians are wary of legalizing growth promoters when the relative price of animal products has never been cheaper. Among the factors that have recently re-fuelled consumer concerns over farming methods are: bovine spongiform encephalopathy, cloning of farm animals, and genetic manipulation of crops. Meanwhile, politicians try to balance the interests of the environmentalist, farming, and welfare lobbies with the politico-economic realities of an expanding European Community and the demands of the GATT agreement. In the United States, where corporate influence over political actions is more overtly established than in Europe, some new technologies have been introduced. This has further antagonized many consumers. As scientists with a direct interest in animal performance enhancers, we need to re-assess our positions--if for no other reason than to protect our research (and personal) incomes. We could probably better protect our own interests--and those of the farming community--if we raised our eyes from the microscope to look at the wider view. There are two challenges for animal production scientists: to identify truly acceptable ways of enhancing animal performance and to be highly active in bringing scientific consensus to the attention of both the public and the political establishments.

Animal Husbandry↗
PubMed1999

Why do foot ulcers recur in diabetic patients?

AIM: To investigate factors predisposing to recurrent foot ulceration in patients with diabetes mellitus. METHODS: Two groups of patients who had attended a specialist Diabetes Foot Centre were assessed: relapsers (n = 26), whose foot ulceration had recurred at least twice, and nonrelapsers (n = 25), whose initial ulcer had not recurred for at least 2 years. RESULTS: In the relapser group 10/26 patients waited at least 24 h before reporting symptoms compared with only 2/25 in the nonrelapser group (P < 0.05). Vibration perception threshold (volts) was 38 +/- 12 (mean +/- SD) in relapsers compared with 25 +/- 13 in nonrelapsers (P < 0.005). Cold perception threshold (degrees C) was 9.1 +/- 4.6 in relapsers compared with 5.1 +/- 3.5 in nonrelapsers (P<0.005). HbA1c (%) was significantly raised at 8.5 +/- 1.7 in relapsers compared with 7.6 +/- 1.2 in nonrelapsers (P = 0.03). Alcohol intake was 0.5 (median, interquartile range 0-2) units per day in relapsers compared with 0.0 (median, interquartile range 0-0.25) units in nonrelapsers (P = 0.04). Smoking habits, housing conditions, visual acuity, threshold for warm perception and the Doppler pressure index were not significantly different in the two groups. CONCLUSIONS: Patients who develop recurrent foot ulceration delay in reporting symptoms, when compared with diabetic patients whose foot ulceration does not recur. The relapsers also have evidence of poorer glycaemic control, more neuropathy and increased alcohol intake.

Adult↗
PubMed1999

Monoclonal antibodies as potentiators of radiotherapy and chemotherapy in the management of head and neck cancer.

The overall survival of patients with squamous cell cancer of the head and neck has not significantly improved over the past 2 decades. Preclinical studies suggest that combining a monoclonal antibody to the epidermal growth factor receptor with irradiation or chemotherapy agents active in squamous cell cancer of the head and neck could increase treatment efficacy. Completed phase I studies have shown these combinations to be both feasible and tolerable. Phase III studies are now beginning to establish firmly the efficacy of this innovative new approach.

Antibodies, Monoclonal↗
PubMed1999

Multimodality therapy of patients with locally advanced squamous cell cancer of the head and neck: preliminary results of two pilot trials using paclitaxel and cisplatin.

Chemotherapy has been integrated into the initial treatment of patients with locally advanced squamous cell cancer of the head and neck to improve locoregional control and survival. Two strategies for improving these outcomes are the use of new, potentially more effective drugs either with concurrent radiotherapy or as induction regimens. Because of its inherent activity against squamous cell cancer of the head and neck and its radiation-sensitizing properties, paclitaxel may be a valuable agent in the treatment of this patient population. We describe the preliminary results of two trials that evaluated the combination of paclitaxel and cisplatin in patients with locally advanced disease: a phase I trial of weekly paclitaxel and cisplatin with concurrent postoperative radiation therapy in patients with high-risk disease and a phase I/II trial of paclitaxel as a 96-hour infusion in combination with cisplatin as induction therapy. These studies identified tolerable doses of paclitaxel and cisplatin administered in these settings, with apparent clinical activity. These trials formed the basis for subsequent evaluation of induction paclitaxel and cisplatin followed by definitive radiotherapy and concurrent weekly paclitaxel and cisplatin plus radiotherapy.

Adult↗
PubMed1999

UFT/oral calcium folinate plus radiation in pancreatic cancer.

A phase I, single-center, open-label, dose-escalation study (University of Alabama [UAB] 9614) has been undertaken to evaluate the feasibility and safety of uracil and tegafur (in a molar ratio of 4:1 [UFT]) plus oral calcium folinate (Orzel) plus radiotherapy in patients with pancreatic cancer. A total of 11 patients with a median age of 59 years have been treated for 35 days with 150 mg/m2/day of UFT and 90 mg/day of oral calcium folinate, divided into three daily doses. Radiotherapy began on day 1, to a total dose of 45 Gy at 1.8 Gy per day (for approximately 5 weeks). Dose escalation of UFT will be performed until the maximum tolerated dose is defined. Overall, therapy has been well tolerated and the maximum tolerated dose has not yet been reached.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1998

Concurrent tirapazamine and radiotherapy for advanced head and neck carcinomas: a Phase II study.

PURPOSE: To evaluate the efficacy and toxicity of tirapazamine, a hypoxic cytotoxin, combined with conventional radiotherapy (RT) for advanced head and neck carcinomas. MATERIALS AND METHODS: From Oct. 1994 to Nov. 1996, 40 patients with stage III or IV carcinomas of the head and neck were enrolled in a Phase II trial to receive conventional RT (70 Gy in 7 weeks) with concurrent tirapazamine (159 mg/m2 intravenously, 3 times per week for 12 doses). One patient subsequently withdrew from the protocol treatment, and was excluded from analyses. Among the 39 cases, the primary sites were located in the oropharynx (n = 28), supraglottic larynx (n = 6), or hypopharynx (n = 5). Twenty-seven patients had T3 or T4, and 27 had N2 or N3 disease. RESULTS: Thirty-two (82%) patients received full 12 drug doses. Thirty-two patients (82%) received full 70 Gy of RT. The most frequent drug toxicities were muscle cramps (77%) and nausea/vomiting (62%), usually grade 1 or 2. Overall, 13 patients (33%) experienced grade 3 or 4 drug-related toxicities. No excessive RT-associated acute normal tissue reactions were observed. With a median follow-up of 13 months, the 1-year and 2-year local control rate was 64% and 59% respectively. CONCLUSION: The tirapazamine regimen was well tolerated with a compliance rate of 82%. The toxicity of RT with concurrent tirapazamine was acceptable in treating advanced head and neck carcinomas. The disease control trend was encouraging. Further clinical studies are warranted.

Adult↗
PubMed1998

Identification, cloning and initial characterisation of FeuPQ in Brucella suis: a new sub-family of two-component regulatory systems.

To cause disease, Brucella species have to adapt to a range of different environments. Environmental sensing and adaptive responses in bacteria often involve the concerted action of a two-component regulatory system, consisting of sensor and response regulator components. Amplification and sequence analysis of response regulators from Brucella species identified a response regulator sequence with 96% similarity to Rhizobium leguminosarum FeuP. In R. leguminosarum, the FeuPQ two-component system is involved in the regulation of iron uptake. A Brucella suis feuP isogenic mutant was constructed but was not attenuated in the murine brucellosis model. The survival and multiplication of the mutant in macrophages was also unaffected. The FeuPQ regulon represents a newly characterised sub-family of response regulators.

Amino Acid Sequence↗
PubMed1998

Identification of a novel polyproline recognition site in the cytoskeletal associated protein, proline serine threonine phosphatase interacting protein.

Protein-protein interactions are often mediated by the recognition of proline-rich domains by SH3 or WW modules. Previously, we demonstrated that the PEST-type protein-tyrosine phosphatase, PTP HSCF (hematopoietic stem cell fraction), bound to a novel cytoskeletal associated protein, proline serine threonine phosphatase interacting protein (PST PIP), via an interaction between the proline-rich COOH terminus of the PTP and a site within the putative coiled-coil domain of PST PIP. Here we describe a more detailed analysis of this interaction. Earlier data suggested that the NH2 terminus of PST PIP was important for binding to the phosphatase, and deletion of the NH2-terminal 50 amino acids of the PST PIP resulted in an apparently misfolded protein that was incapable of binding PTP HSCF. To examine the region involved with binding to PTP HSCF, alanine-scanning mutants were produced at intervals throughout PST PIP. This analysis demonstrated that a tryptophan at position 232 was essential for binding in vitro. Transfection experiments demonstrated that the Trp232 mutant protein was capable of association with the cortical cytoskeleton but was not bound to PTP HSCF in vivo. Alanine scanning of a peptide derived from the COOH-terminal proline-rich domain of PTP HSCF revealed that a subset of prolines, as well as other residues, was required for efficient binding to PST PIP, and introduction of alanines at some of these positions in the protein resulted in decreased binding to PST PIP in vitro and in vivo. Analysis of in vivo tyrosine phosphorylation of the Trp232 mutant of PST PIP in the presence of v-Src revealed that this protein was phosphorylated more efficiently than the wild-type molecule. Thus, the interaction between PTP HSCF and PST PIP is mediated by a novel site in the cytoskeletal associated protein which interacts with residues within the proline-rich COOH terminus of the phosphatase.

Amino Acid Sequence↗
PubMed1998

Intratumoral cisplatin/epinephrine-injectable gel as a palliative treatment for accessible solid tumors: a multicenter pilot study.

Intratumoral injections of cisplatin/epinephrine-injectable gel were administered weekly for 4 weeks in 45 patients with malignant tumors of various histologic types. Tumors were located on the skin and subcutaneous tissue primarily of the head, neck, and trunk, and on the tongue, oral pharynx, and esophagus. Patients were not candidates for surgery, radiation, or systemic chemotherapy. Each of the treated tumors (n = 82) was evaluated 2, 4, 8, and 12 weeks after the final injection. The initial dose of cisplatin was 1 mg/cm3 tumor volume, with escalation to 6 mg/cm3 allowed, depending on observed toxicities. The mean cumulative dose per patient for the four treatments ranged from 0.56 to 380 mg cisplatin. No dose-limiting cisplatin-related toxicities, such as nephrotoxicity, neurotoxicity, or ototoxicity, were observed. The overall objective tumor response rate was 50% (41 of 82), with 40% (33 of 82) complete responses and a median response duration of 160 days. Complete responses for adenocarcinoma and squamous cell carcinoma were 58% (21 of 36) and 38% (12 of 32), respectively. These results justified further clinical trials to evaluate the role of local chemotherapy with intratumoral cisplatin/epinephrine-injectable gel in the palliative treatment of patients with selected accessible solid tumors.

Adenocarcinoma↗
PubMed1998

Collaborative approach to improve the detection and management of trichomoniasis in a low prevalence district.

We describe a simple collaborative approach developed by the departments of cytology, microbiology and genitourinary (GU) medicine for the detection, diagnosis and management of microbiologically confirmed Trichomonas vaginalis (TV) infection. Over a 2-year period, 54 (0.1%) of 52,440 cervical smears were reported to show TV, but microbiological confirmation was made in only 76% of 34 patients from whom a vaginal swab was subsequently taken. Trichomoniasis should not be diagnosed by cytology alone and clinicians need further education on the role of cytology in diagnosing sexually transmitted diseases (STDs). Over the same period, from a total of 96 cases of TV identified in the district, only 12 (13%) were first diagnosed in the department of GU medicine. Forty per cent of the other 84 patients were subsequently seen in the GU clinic for test of cure, contact tracing and screening for other STDs. Collaborations between departments may improve the management of trichomoniasis and other conditions in the community and their development should be encouraged.

Animals↗