Design and use of questionnaires: a review of best practice applicable to surveys of health service staff and patients.
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Benchmarking↗
Biomedical subjects
L Thomas
Publications and source records attributed to L Thomas.
[Standards, Options and Recommendations for the surgical management of carcinoma of the endometrium].
CONTEXT: The "Standards, Options and Recommendations" (SOR) project, started in 1993, is a collaboration between the Federation of the French Cancer Centres (FNCLCC), the 20 French Cancer Centres and specialists from French Public Universities, General Hospitals and Private Clinics. The main objective is the development of clinical practice guidelines to improve the quality of health care and outcome for cancer patients. The methodology is based on literature review and critical appraisal by a multidisciplinary group of experts, with feedback from specialists in cancer care delivery. OBJECTIVES: To develop clinical practice guidelines according to the definitions of the Standards, Options and Recommendations project for the surgical management of carcinoma of the endometrium. METHODS: Data were identified by searching Medline and personal reference lists of members of the expert groups. Once the guidelines were defined, the document was submitted for review to independent reviewers, and to the medical committees of the 20 French Cancer Centres. RESULTS: The main recommendations for the surgical management of carcinoma of the endometrium are: 1) where-ever possible, surgery is the primary treatment of both localised and advanced disease; 2) surgery is performed according to the stage of the cancer and the status of the patient; 3) surgery for stages I and II disease entails total abdominal hysterectomy and bilateral salpingo-oophorectomy. A modified radical hysterectomy is undertaken in cases of macroscopic cervical involvement. An omenectomy is recommended for serous papillary types. Pelvic lymphadenectomy for the purposes of precise staging is undertaken if the patient is of good performance status and without bad pronostic factors. Para-aortic lymphadenectomy can be undertaken to determine involvement of para-aortic nodes; 4) surgery for stages III and IV: radical surgery must be undertaken if at all possible with additional treatment as indicated. In the case of advanced disease, debulking surgery is indicated.
Algorithms↗
[Standards, options, and recommendations for the radiotherapy of patients with endometrial cancer. FNCLCC (National Federation of Cancer Campaign Centers) and CRLCC (Regional Cancer Campaign Centers)].
OBJECTIVES: To develop clinical practice guidelines according to the definitions of the Standards, Options and Recommendations project for the radiotherapy of carcinoma of the endometrium. METHODS: Data were identified by searching Medline and personal reference lists of members of the expert groups. Once the guidelines were defined, the document was submitted for review to independent reviewers, and to the medical committees of the 20 French Cancer Centres. RESULTS: The main recommendations for the radiotherapy of carcinoma of the endometrium are: 1) For grade 1 and 2 stage IA tumours, follow-up alone is standard as additional treatment. For grade 1 and 2 stage IB tumours, vaginal brachytherapy or follow-up alone are options. For grade 3, stage IB tumours and stage IC disease, there are two treatment options: external pelvic radiotherapy with a brachytherapy boost or vaginal brachytherapy. 2) Treatment for stage II disease can be preoperative when stage II disease has been suggested by a positive endometrial curettage. Postoperative vaginal brachytherapy is given for stage IIA tumours if the penetration of the myometrium is less than 50% or if the tumour is grade 1 or 2. In the case of deep penetration, or higher grade disease, or for stage IIB external radiotherapy with brachytherapy boosting must be undertaken routinely. 3) After surgery, for stage IIIA disease, either external pelvic radiotherapy or abdomino-pelvic radiotherapy is indicated, along with medical treatment in certain patients. For stage IIIB tumours, postoperative external radiotherapy with brachytherapy (if possible) should be undertaken. For stage IIIC tumours, standard treatment is external (pelvic or pelvic and para-aortic) radiotherapy followed or not by a brachytherapy boost. In case of extrauterine sites involved abdomino-pelvic irradiation is recommended. 4) Standard treatment for inoperable stage I and II disease is external radiotherapy and brachytherapy. For patients with inoperable stage III or IV disease, treatment is often symptomatic, combining external radiotherapy and medical treatment.
Brachytherapy↗
Evidence-based laboratory medicine.
Evidence-based medicine (EBM) is a method for solving problems concerning the assessment of laboratory testing in patient care. Practising EBM involves the use of the available evidence to make health care decisions. The best way to practice EBM is the development, validation and implementation of guidelines. Guidelines are considered as the process by which healthcare research and experience are translated into improved patient care. In laboratory diagnostics EBM can be best demonstrated in high-prevalence conditions. Because of the number of patients encountered, high-prevalence conditions have a greater impact on patient morbidity and health care expenditure. In evidence-based laboratory medicine the best evidence comes from systematic reviewing studies of diagnostic tests. The reviewing of diagnostic trials and the development of good practice guidelines on the basis of these studies must be an important task of the scientific associations of clinical chemistry and laboratory medicine.
Clinical Chemistry Tests↗
[Standards, options, and recommendations for initial management of patients with malignant ovarian epithelial tumors].
UNLABELLED: Suprapubic and transvaginal pelvic ultrasound exploration is indicated for suspected ovarian tumor (standard). Diagnosis and search for extension require surgery and pathology examination. Systematic preoperative computed tomography is not recommended (standard). Surgery for cancer of the ovary is a specialized procedure requiring skill in cancer, gynecology, visceral surgery and laparoscopic surgery. If the patient is referred to a specialized center after a primary procedure considered to be inadequate, a new procedure is recommended for staging. Residual tumor volume after the primary procedure has prognostic value. Systematic second look procedures are not recommended for routine practice (standard). For patients with grade IA G1 tumors, there is no indication for complementary treatment (standard). For patients with grade IA G2-3 or clear cell tumors, IB, IC, IIA, there is no standard. OPTIONS: no complementary treatment, complementary chemotherapy using platinum, complementary external abdominopelvic radiotherapy. A complementary treatment is recommended for grades IC and IIA. Complementary treatment for grades IIB (no residual tissue), IIC (with residual tissue), III (no residual tissue), is based on: complementary chemotherapy with platinium, complementary external abdominopelvic radiotherapy (options). Complementary treatment for advanced forms (IIB (with residual tissue), IIC (with residual tissue), III (with residual tissue) and IV) is based on polychemotherapy with platinium (standard). OPTIONS: platinium combined with paclitaxel (intravenous), platinium combined with cyclophosphamide and/or doxorubicin (intravenous) or intraperitoneal cisplatin combined with cyclophosphamide (intravenous). The chemotherapy work-up includes physical examination, assay of serum markers (particularly CA125) and abdominopelvic computed tomography (proof level B) (standard). Physical examination is recommended for monitoring patients in complete remission with no sign of suspected recurrence (standard). This document was reviewed in April 1977. The working group again validated the Standards, OPTIONS and Recommendations, without modifications in June 1999.
Antineoplastic Agents, Hormonal↗
Novel omega-conotoxins from Conus catus discriminate among neuronal calcium channel subtypes.
omega-Conotoxins selective for N-type calcium channels are useful in the management of severe pain. In an attempt to expand the therapeutic potential of this class, four new omega-conotoxins (CVIA-D) have been discovered in the venom of the piscivorous cone snail, Conus catus, using assay-guided fractionation and gene cloning. Compared with other omega-conotoxins, CVID has a novel loop 4 sequence and the highest selectivity for N-type over P/Q-type calcium channels in radioligand binding assays. CVIA-D also inhibited contractions of electrically stimulated rat vas deferens. In electrophysiological studies, omega-conotoxins CVID and MVIIA had similar potencies to inhibit current through central (alpha(1B-d)) and peripheral (alpha(1B-b)) splice variants of the rat N-type calcium channels when coexpressed with rat beta(3) in Xenopus oocytes. However, the potency of CVID and MVIIA increased when alpha(1B-d) and alpha(1B-b) were expressed in the absence of rat beta(3), an effect most pronounced for CVID at alpha(1B-d) (up to 540-fold) and least pronounced for MVIIA at alpha(1B-d) (3-fold). The novel selectivity of CVID may have therapeutic implications. (1)H NMR studies reveal that CVID possesses a combination of unique structural features, including two hydrogen bonds that stabilize loop 2 and place loop 2 proximal to loop 4, creating a globular surface that is rigid and well defined.
Alternative Splicing↗
A new Mr 55,000 surface protein implicated in melanoma progression: association with a metastatic phenotype.
Emergence of the invasive phenotype is a key event in the progression of human melanoma from benign proliferative lesions to malignant lesions. Recently we successfully selected in vivo from a poorly metastatic M4Beu. human melanoma cell line two variants (7GP and T1P26) that generate a higher frequency of spontaneous metastases to the lungs into immune-suppressed neonatal rats. Both cell lines showed no significant differences in the integrin profile of the subunits analyzed except for beta3, which was reduced to a background level in metastatic variants. To investigate how these variant sublines of human melanomas manage to sustain growth in the absence of alpha(v)beta3, a subtractive immunization approach was used to elicit host antibody response against cell surface proteins expressed on metastatic variants. In this study, a new monoclonal antibody (MoAb), LY1, that is highly specific for the 7GP and T1P26 variants, was isolated. LY1 identifies a membrane protein of Mr 55,000 on melanoma variants with epitopes that were resistant to sugar-cleaving enzymes. Immunostaining cells from variants by LY1 showed that staining is distributed to the cell periphery with high labeling intensity at the cell-to-cell contact points. This MoAb significantly inhibited invasion of metastatic variants through a reconstituted basement membrane (Matrigel) in vitro. Moreover, tumor growth of melanoma variants was dramatically affected in vivo with this MoAb. In vitro studies indicate that the LY1 MoAb does not inhibit chemotactic migration of the metastatic variants, the adhesion of tumor cells to vitronectin, collagen IV, fibronectin, and laminin, or cell proliferation. Expression of this antigen is high in human striated muscle, heart, spleen, brain, and lung and absent in kidney, liver, and pancreas. Using 59 fixed, paraffin-embedded archival tissues of human melanomas and nevi, LY1-reactive cells were not observed in melanocytes, nevi, or radial growth phase primary melanomas. In sharp contrast, LY1 selectively stained melanocytes derived from the vertical growth phase of many primary melanomas and metastatic melanomas. These results provide evidence that the Mr 55,000 protein expressed by selected variants with increased metastatic properties in vivo plays a functionally important role in determining metastasis. This molecule may represent a new metastatic risk marker in human melanoma and may be of biological importance in the identification of fatal metastatic subpopulations that have acquired competence for metastasis production.
Animals↗
Ectodermal abnormalities associated with methimazole intrauterine exposure.
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Abnormalities, Drug-Induced↗
Tropomyosin and actin isoforms modulate the localization of tropomyosin strands on actin filaments.
Tropomyosin is present in virtually all eucaryotic cells, where it functions to modulate actin-myosin interaction and to stabilize actin filament structure. In striated muscle, tropomyosin regulates contractility by sterically blocking myosin-binding sites on actin in the relaxed state. On activation, tropomyosin moves away from these sites in two steps, one induced by Ca(2+) binding to troponin and a second by the binding of myosin to actin. In smooth muscle and non-muscle cells, where troponin is absent, the precise role and structural dynamics of tropomyosin on actin are poorly understood. Here, the location of tropomyosin on F-actin filaments free of troponin and other actin-binding proteins was determined to better understand the structural basis of its functioning in muscle and non-muscle cells. Using electron microscopy and three-dimensional image reconstruction, the association of a diverse set of wild-type and mutant actin and tropomyosin isoforms, from both muscle and non-muscle sources, was investigated. Tropomyosin position on actin appeared to be defined by two sets of binding interactions and tropomyosin localized on either the inner or the outer domain of actin, depending on the specific actin or tropomyosin isoform examined. Since these equilibrium positions depended on minor amino acid sequence differences among isoforms, we conclude that the energy barrier between thin filament states is small. Our results imply that, in striated muscles, troponin and myosin serve to stabilize tropomyosin in inhibitory and activating states, respectively. In addition, they are consistent with tropomyosin-dependent cooperative switching on and off of actomyosin-based motility. Finally, the locations of tropomyosin that we have determined suggest the possibility of significant competition between tropomyosin and other cellular actin-binding proteins. Based on these results, we present a general framework for tropomyosin modulation of motility and cytoskeletal modelling.
Actin Cytoskeleton↗
Evidence that 12-lipoxygenase product 12-hydroxyeicosatetraenoic acid activates p21-activated kinase.
The effect of 12-hydroxyeicosatetraenoic acid (12-HETE), an arachidonic acid metabolite of 12-lipoxygenase, to activate p21(Rac/Cdc42)-activated kinase (PAK1) was studied in a Chinese hamster ovary fibroblast cell line overexpressing the rat vascular type-1a angiotensin II receptor (CHO-AT(1a)). 12-HETE (0.1 microM) treatment induced a time-dependent activation of PAK1, with a peak effect at 10 min (335 +/- 16% of control; n=3, P<0.001). The stimulatory effect of 12-HETE on PAK1 activity was dose-dependent, with the maximal activation at 0.01 microM (350+/-15% of control; n=3, P<0.001). A PAK1 fragment encoding the Cdc42/Rac binding domain (amino acid residues 67-150 of hPAK1 termed PBD), was transfected into CHO-AT(1a) cells. PBD transfection markedly reduced 12-HETE-induced PAK1 activation. Furthermore, transfection of dominant negative Cdc42 and Rac1 inhibited 12-HETE-induced PAK1, strongly suggesting that Cdc42 and Rac1 are the upstream activators of 12-HETE-induced PAK1 activation. Low concentrations (1.5 microM) of LY294002, a highly specific inhibitor of phosphoinositide 3-kinase (PI-3K), abolished 12-HETE-induced PAK1 activation, suggesting that PI-3K activation is upstream of 12-HETE-induced PAK1 activation. Transfection of dominant negative PAK1 blocked 12-HETE-induced PAK1, cJun N-terminal kinase (JNK1) and extracellular-signal-regulated kinase (ERK) activity, while transfection of constitutively active PAK1 stimulated PAK1, JNK1 and ERK activity, suggesting that PAK1 is an upstream activator of 12-HETE-induced JNK1 and ERK activation in these cells. We conclude that 12-HETE can activate Cdc42, Rac1 and PI-3K, which then participate as upstream signalling molecules for PAK1 and JNK1 activation.
12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
Genetically modified anthrax lethal toxin safely delivers whole HIV protein antigens into the cytosol to induce T cell immunity.
Bacillus anthrax lethal toxin can be engineered to deliver foreign proteins to the cytosol for antigen presentation to CD8 T cells. Vaccination with modified toxins carrying 8-9 amino acid peptide epitopes induces protective immunity in mice. To evaluate whether large protein antigens can be used with this system, recombinant constructs encoding several HIV antigens up to 500 amino acids were produced. These candidate HIV vaccines are safe in animals and induce CD8 T cells in mice. Constructs encoding gag p24 and nef stimulate gag-specific CD4 proliferation and a secondary cytotoxic T lymphocyte response in HIV-infected donor peripheral blood mononuclear cells in vitro. These results lay the foundation for future clinical vaccine studies.
AIDS Vaccines↗
Bacterial lipopolysaccharide activates NF-kappaB through toll-like receptor 4 (TLR-4) in cultured human dermal endothelial cells. Differential expression of TLR-4 and TLR-2 in endothelial cells.
A missense mutation in the cytoplasmic domain of the Toll-like receptor-4 (TLR-4) has been identified as the defect responsible for lipopolysaccharide (LPS) hyporesponsiveness in C3H/HeJ mice. TLR-4 and TLR-2 have recently been implicated in LPS signaling in studies where these receptors were overexpressed in LPS non-responsive 293 human embryonic kidney cells. However, the signaling role of TLR-4 or TLR-2 in human cells with natural LPS response remains largely undefined. Here we show that human dermal microvessel endothelial cells (HMEC) and human umbilical vein endothelial cells express predominantly TLR-4 but very weak TLR-2 and respond vigorously to LPS but not to Mycobacterium tuberculosis 19-kDa lipoprotein. Transient transfection of non-signaling mutant forms of TLR-4 and anti-TLR-4 monoclonal antibody inhibited LPS-induced NF-kappaB activation in HMEC, while a monoclonal antibody against TLR-2 was ineffective. In contrast to LPS responsiveness, the ability of HMEC to respond to 19-kDa lipoprotein correlated with the expression of TLR-2. Transfection of TLR-2 into HMEC conferred responsiveness to 19-kDa lipoprotein. These data indicate that TLR-4 is the LPS signaling receptor in HMEC and that human endothelial cells (EC) express predominantly TLR-4 and weak TLR-2, which may explain why they do not respond to 19-kDa lipoprotein. The differential expression of TLRs on human EC may have important implications in the participation of vascular EC in innate immune defense mechanisms against various infectious pathogens, which may use different TLRs to signal.
Animals↗
Oscillatory decay of magnetization induced by domain-wall stray fields
The demagnetization of a hard ferromagnetic layer via the fringing fields of domain walls created by reversing the moment of a neighboring soft ferromagnetic layer is explored experimentally. An unusual oscillatory decay of the magnetic moment of the hard layer is observed using structures in which the demagnetization occurs after a few hundred cycles. This surprising observation is confirmed on a microscopic scale by detailed imaging of the magnetization of the hard layer using high resolution photoemission electron microscopy and by micromagnetic simulations.
Journal Article↗
Low-dose-rate intraoperative brachytherapy combined with external beam irradiation in the conservative treatment of soft tissue sarcoma.
PURPOSE: Conservative treatment of soft tissue sarcomas most often implies combination of surgical resection and irradiation. The aim of this study was to evaluate low-dose-rate intraoperative brachytherapy, delivered as a boost, in the local control of primary tumors, with special concern about treatment complications. METHODS AND MATERIALS: Between 1986 and 1995, 112 patients underwent intraoperative implant. This report focuses on the group of 58 patients with primary sarcomas treated by combination of conservative surgery, intraoperative brachytherapy, and external irradiation. Most of the tumors were located in the lower limbs (46/58-79%). Median size of the tumor was 10 cm, most of the lesions being T2-T3 (51/58-88%), Grade 2 or 3 (48/58-83%). The mean brachytherapy dose was 20 Gy and external beam irradiation dose 45 Gy. In 36/58 cases, iridium wires had to be placed on contact with neurovascular structures. RESULTS: With a median follow-up of 54 months, the 5-year actuarial survival was 64.9%, with a 5-year actuarial local control of 89%. Of the 6 patients with local relapse, 3 were salvaged. Acute side effects, essentially wound healing problems, occurred in 20/58 patients, late side effects in 16/58 patients (7 neuropathies G2 to G4). No amputation was required. The only significant factor correlated with early side effects was the location of the tumor in the lower limb (p = 0.003), and with late side effects the vicinity of the tumor with neurovascular structures (p = 0.009). CONCLUSION: Brachytherapy allows early delivery of a boost dose in a reduced volume of tissue, precisely mapped by the intraoperative procedure. Combined with external beam irradiation, it is a safe and efficient treatment technique leading to high local control rates and limited functional impairment.
Adolescent↗
A protein-based therapeutic for human cytomegalovirus infection.
Current antiviral strategies target viral gene products. Although initially successful, their severe toxicity and susceptibility to circumvention by the generation of drug-resistant variants limit their usefulness. By contrast, the central role of the host cell serine endoprotease furin in the proteolytic activation of numerous pathogens points to the endoprotease as a strategic target for therapeutics. Herein, we show that the production of infectious human cytomegalovirus is dramatically reduced by exogenous addition of a bioengineered serpin, alpha(1)-PDX. This protein is a potent and selective furin inhibitor (K(i) = 0.6 nM) and is 10-fold more effective than currently used antiherpetic agents in cell-culture models. The requirement of furin for the processing of envelope glycoproteins from many pathogenic viruses and for the activation of several bacterial toxins suggests that selective inhibitors of furin have potential as broad-based anti-pathogens.
Blotting, Western↗
Domain-wall induced coupling between ferromagnetic layers
The remanent magnetization of a hard ferromagnetic CoPtCr layer is progressively decreased by repeated switching of a neighboring soft magnetic layer. We show that this effect depends strongly on the thickness of the CoPtCr layer and the spacing between the hard and soft layers. We propose a model that accounts for these results: An interlayer magnetostatic coupling is induced by large stray fields from domain walls that form within the soft layer during its magnetization reversal.
Journal Article↗
[Does cannabis play a role in scuba diving accidents?].
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Cannabinoids↗