A comparison of sub-Tenon's with peribulbar anaesthesia in patients undergoing sequential bilateral cataract surgery.

The aim of this study was to compare efficacy and particularly patient preference of sub-Tenon's anaesthesia with peribulbar anaesthesia in patients undergoing sequential, bilateral, cataract surgery. Fifty patients were randomised to either sub-Tenon's or peribulbar anaesthesia for their first operation and the alternative technique for their subsequent operation. Intra-ocular pressure was measured, globe and lid akinesia were scored, patients completed a visual rating score of injection and operative pain and their preference for anaesthesia was assessed. Intra-ocular pressure rose significantly following peribulbar injection (p = 0.02) but was comparable at 5 min. There was no significant difference in lid or globe movement. Injection and operative pain scores were low and comparable. Both methods provided similar anaesthesia and akinesia. The majority (86%) chose the method they received first irrespective of whether it was sub-Tenon's or peribulbar, but 10% of patients preferred sub-Tenon's, disliking the facial numbness from peribulbar anaesthesia.

Peripheral-type benzodiazepine receptor levels correlate with the ability of human breast cancer MDA-MB-231 cell line to grow in SCID mice.

MDA-MB-231 (MDA-231) human breast cancer cells have a high proliferation rate, lack the estrogen receptor, express the intermediate filament vimentin, the hyaluronan receptor CD44, and are able to form tumors in nude mice. The MDA-231 cell line has been used in our laboratory to examine the role of the peripheral-type benzodiazepine receptor (PBR) in the progression of cancer. During these studies 2 populations of MDA-231 cells were subcloned based on the levels of PBR. The subclones proliferated at approximately the same rate, lacked the estrogen receptor, expressed vimentin and CD44, and had the same in vitro chemoinvasive and chemotactic potential. Both restriction fragment length polymorphism and comparative genomic hybridization analyses of genomic DNA from these cells indicated that both subclones are of the same genetic lineage. Only the subclone with high PBR levels, however, was able to form tumors when injected in SCID mice. These data suggest that the ability of MDA-231 cells to form tumors in vivo may depend on the amount of PBR present in the cells.

A single-centre study of 1000 consecutive peribulbar blocks.

PURPOSE: To assess the efficacy and safety of the peribulbar block as practised by anaesthetists in a District General Hospital and also to assess the effect of using the 'painless local' subconjunctival injection on the pain of the peribulbar block. METHOD: Audit data collected from 1000 consecutive patients undergoing peribulbar blocks with 2% lignocaine were analysed. Efficacy was assessed by visual rating scores for operative pain, eye movement, intraocular pressure and reinjection rate, and safety by looking at complications. Comparison of pain of injection scores was used to assess the effect of the 'painless local' injection. Visual rating scores for pain were analysed using the Mann-Whitney U-test. RESULTS: Akinesia was achieved in 79% of blocks and operative pain scores were very low (median = 0, IQR = 0). All complications recorded were minor and there were no sight- or life-threatening events. The 'painless local' injection given to 499 patients resulted in significantly lower visual rating scores for pain of injection (p<0.05). CONCLUSION: These data suggest that the peribulbar block is a safe and effective method of providing anaesthesia for eye surgery provided that it is taught methodically and practised by experienced staff. The 'painless local' injection reduces the pain experienced during administration of this block.

Drug-induced inhibition of the peripheral-type benzodiazepine receptor expression and cell proliferation in human breast cancer cells.

The peripheral-type benzodiazepine receptor (PBR) expression and localization correlate with human breast cancer cell proliferation and aggressive phenotype expression. The standardized extract of Ginkgo biloba leaves (EGb 761) and isolated ginkgolide B (GKB) were shown to decrease PBR mRNA expression in adrenal cells. We examined the effect of EGb 761 and GKB on PBR expression and cell proliferation in human breast cancer cells. EGb 761 and GKB decreased in a time- and dose-dependent manner PBR expression and cell proliferation in the highly aggressive, rich in PBR, human breast cancer cell line MDA-231 whereas they did not affect the proliferation of the non-aggressive human breast cancer cell line MCF-7, which contains very low PBR levels. This effect was reversible and not due to the antioxidant properties of the compounds tested. Using a human cDNA expression array we determined that EGb 761 treatment altered, in addition to PBR, the expression of 36 gene products involved in various pathways regulating cell proliferation. These in vitro data were further validated in an in vivo model where EGb 761 and GKB significantly inhibited the nuclear PBR expression and growth of MDA-231 cell xenografts in nude mice. Taken together, these data suggest that the manipulation of PBR expression could be used to control tumor growth and that EGb 761 and GKB, under the conditions used, exert cytostatic properties.

Comparison of enoxaparin and warfarin for the prevention of venous thromboembolic disease after total hip arthroplasty. Evaluation during hospitalization and three months after discharge.

BACKGROUND: Venous thromboembolic disease in the form of deep venous thrombosis and pulmonary embolism is a major risk after a total hip arthroplasty. Enoxaparin, a low-molecular-weight heparin, has been shown to reduce the prevalence of deep venous thrombosis after total hip arthroplasty. Warfarin, an orally administered anticoagulant, has been used historically to reduce the risk of deep venous thrombosis after total hip arthroplasty. METHODS: We compared enoxaparin and adjusted-dose warfarin with respect to their safety and their efficacy in the prevention of clinically important venous thromboembolic disease, defined as distal or proximal deep venous thrombosis or pulmonary embolism, or both, during hospitalization after total hip arthroplasty. We also evaluated the prevalence of complications and mortality from venous thromboembolic disease within three months after discharge. RESULTS: Three thousand and eleven patients at 156 centers were randomly assigned to prophylactic treatment with injection of enoxaparin or oral administration of adjusted-dose warfarin during hospitalization. During the study, fifty-five (3.6 percent) of the 1516 patients who were managed with enoxaparin and fifty-six (3.7 percent) of the 1495 patients who were managed with warfarin had venous thromboembolic disease. Twenty-one patients (0.7 percent), which included four (0.3 percent) of those managed with enoxaparin and seventeen (1.1 percent) of those managed with warfarin (p = 0.0083), had venous thromboembolic disease during hospitalization. After discharge from the hospital, venous thromboembolic disease developed in ninety patients (3.0 percent): fifty-one (3.4 percent) of those managed with enoxaparin and thirty-nine (2.6 percent) of those managed with warfarin. One patient who had been managed with enoxaparin died because of a pulmonary embolism, which was confirmed at autopsy. Three additional patients (one who had been managed with enoxaparin and two who had been managed with warfarin) died, and the deaths were attributed to venous thromboembolic disease; however, no autopsies were performed. Twenty-six patients (0.9 percent) (eighteen managed with enoxaparin and eight managed with warfarin) had clinically important bleeding. CONCLUSIONS: Inpatient programs providing treatment with either enoxaparin (thirty milligrams every twelve hours) or adjusted-dose warfarin for a mean of 7.3 days afforded protection against venous thromboembolic disease, with overall rates of morbidity and mortality of 3.7 and 0.6 percent, respectively, and a very low rate of major bleeding complications (0.9 percent) for three months after total hip arthroplasty. During hospitalization, the patients managed with enoxaparin had a lower rate of venous thromboembolic disease than those managed with adjusted-dose warfarin (p = 0.0083). This benefit was lost after the medication was discontinued, with no difference in the prevalences of venous thromboembolic disease between the two groups at three months after discharge from the hospital.

Peripheral-type benzodiazepine receptor (PBR) in human breast cancer: correlation of breast cancer cell aggressive phenotype with PBR expression, nuclear localization, and PBR-mediated cell proliferation and nuclear transport of cholesterol.

Aberrant cell proliferation and increased invasive and metastatic behavior are hallmarks of the advancement of breast cancer. Numerous studies implicate a role for cholesterol in the mechanisms underlying cell proliferation and cancer progression. The peripheral-type benzodiazepine receptor (PBR) is an Mr 18,000 protein primarily localized to the mitochondria. PBR mediates cholesterol transport across the mitochondrial membranes in steroidogenic cells. A role for PBR in the regulation of tumor cell proliferation has also been shown. In this study, we examined the expression, characteristics, localization, and function of PBR in a battery of human breast cancer cell lines differing in their invasive and chemotactic potential as well as in several human tissue biopsies. Expression of PBR ligand binding and mRNA was dramatically increased in the highly aggressive cell lines, such as MDA-231, relative to nonaggressive cell lines, such as MCF-7. PBR was also found to be expressed at high levels in aggressive metastatic human breast tumor biopsies compared with normal breast tissues. Subcellular localization with both antibodies and a fluorescent PBR drug ligand revealed that PBR from the MDA-231 cell line as well as from aggressive metastatic human breast tumor biopsies localized primarily in and around the nucleus. This localization is in direct contrast to the largely cytoplasmic localization seen in MCF-7 cells, normal breast tissue, and to the typical mitochondrial localization seen in mouse tumor Leydig cells. Pharmacological characterization of the receptor and partial nucleotide sequencing of PBR cDNA revealed that the MDA-231 PBR is similar, although not identical, to previously described PBR. Addition of high affinity PBR drug ligands to MDA-231 cells increased the incorporation of bromodeoxyuridine into the cells in a dose-dependent manner, suggesting a role for PBR in the regulation of MDA-231 cell proliferation. Cholesterol uptake into isolated MDA-231 nuclei was found to be 30% greater than into MCF-7 nuclei. High-affinity PBR drug ligands regulated the levels of cholesterol present in MDA-231 nuclei but not in MCF-7. In addition, the PBR-dependent MDA-231 cell proliferation was found to highly correlate (r = -0.99) with the PBR-mediated changes in nuclear membrane cholesterol levels. In conclusion, these data suggest that PBR expression, nuclear localization, and PBR-mediated cholesterol transport into the nucleus are involved in human breast cancer cell proliferation and aggressive phenotype expression, thus participating in the advancement of the disease.

The use of low molecular weight heparins in the prevention of venous thromboembolic disease.

Deep vein thrombosis (DVT) and pulmonary embolism (PE) are leading causes of morbidity and mortality in the United States. Estimates range between 300,000 and 600,000 hospitalizations a year, with approximately 50,000 deaths related to PE. The incidence of the complication of DVT following total joint replacement is reported to occur in 50% to 75% of all unprotected patients. The increasing number of adults who undergo a total joint replacement dictates that orthopaedic nurses become a vital part of the development team that (1) identifies contributing factors to each patient's risk profile, (2) decreases this risk, and (3) refines the patient's transition through the acute hospitalization into the home or rehabilitation environment. The results of recent studies with a new class of heparins, the low molecular weight heparins, suggest their superiority and demonstrate improvement in decreasing the risk of developing DVT and subsequent PE in the total hip and knee patient population.

Hemodilution with other blood reinfusion techniques in total hip arthroplasty.

Acute normovolemic hemodilution has been reported to result in blood savings varying from 18% to 90%. Very few of these are randomized prospective studies. This study attempts to determine the blood transfusion savings if acute normovolemic hemodilution is used in combination with autologous predonated blood and cell saver. Thirty-three patients undergoing total hip arthroplasty were assigned randomly to one of two groups (control, n = 16; hemodilution, n = 17). Patients in both groups entered an autologous predonation program if cleared medically and were placed on Cell Saver intraoperatively and in the postanesthesia care unit. In addition, the hemodilution group underwent acute normovolemic hemodilution preoperatively. Only 41% of the patients in the hemodilution group required any autologous blood transfusion as compared with 75% of the control group. In addition, the hemodilution group required a mean lower quantity of autologous blood transfusion (41% of the estimated blood loss) as compared with the control group (71%). The net anesthesia time increased by an average of 11.4 minutes in the hemodilution group. Acute normovolemic hemodilution is a safe procedure even in an older patient population. Hemodilution resulted in fewer patients needing autologous predonated blood transfusions. The major benefit of hemodilution was seen when predonation was not possible.

Peripheral benzodiazepine receptor in cholesterol transport and steroidogenesis.

Steroidogenesis begins with the metabolism of cholesterol to pregnenolone by the inner mitochondrial membrane cytochrome P450 side-chain cleavage (P450scc) enzyme. The rate of steroid formation, however, depends on the rate of cholesterol transport from intracellular stores to the inner mitochondrial membrane and loading of P450scc with cholesterol. In previous in vitro studies, we demonstrated that a key element in the regulation of cholesterol transport is the mitochondrial peripheral-type benzodiazepine receptor (PBR). We also showed that the polypeptide diazepam binding inhibitor (DBI), an endogenous PBR ligand, stimulates cholesterol transport and promotes loading of cholesterol to P450scc in vitro, and that its presence is vital for hCG-induced steroidogenesis by Leydig cells. Based on these data and the observations that i) the mitochondrial PBR binding and topography are regulated by hormones; ii) the 18-kDa PBR protein is functionally coupled to the mitochondrial contact site voltage-dependent anion channel protein; iii) the 18-kDa PBR protein is a channel for cholesterol, as shown by molecular modeling and in vitro reconstitution studies; iv) targeted disruption of the PBR gene in steroidogenic cells dramatically reduces the ability of the cells to transport cholesterol in the mitochondria and produce steroids; v) endocrine disruptors, with known anisteroidogenic effect, inhibit PBR ligand binding; and vi) in vivo reduction of adrenal PBR expression results in reduced circulating glucocorticoid levels, we conclude that PBR is an indispensable element of the steroidogenic machinery.

The effect of preoperative exercise on total knee replacement outcomes.

This study compared the effects of preoperative physical therapy of general cardiovascular conditioning exercises with the routine procedure of no preoperative physical therapy on patients undergoing primary total knee replacement. Thirty patients were randomly assigned to 1 of 3 groups. Group 1 was the control group. Group 2 participated in a physical therapy program designed to strengthen the upper and lower limbs and improve knee range of motion. Group 3 participated in a cardiovascular conditioning program, consisting of arm ergometry, cycle ergometry, aquatic exercises, and aerobic activity. All patients were evaluated preoperatively and postoperatively using the Hospital for Special Surgery Knee Rating, the Arthritis Impact Measurement Scale, and the Quality of Well Being instrument. Both experimental groups tolerated their respective exercise protocols extremely well. All 3 groups showed significant improvement postoperatively as measured by the Hospital for Special Surgery Knee Rating, the Arthritis Impact Measurement Scale and the Quality of Well Being measurement scales. However, neither type of preoperative exercise added to the degree of improvement after surgery at any of the postoperative evaluations.

Use of the Inspiron nebuliser during continuous positive airway pressure ventilation.

The Inspiron Nebuliser 002305 with air entrainment was assessed as a gas delivery device in a continuous positive airway pressure system. Inspired oxygen concentrations, total gas flows and pressures within the system were measured over a range of settings, with and without positive and expiratory pressure. Inspired oxygen concentrations and total flows were completely disrupted when a positive and expiratory pressure valve was applied, and the system failed to generate continuous positive airway pressure. We would not therefore recommend the Inspiron nebuliser as a gas delivery system for continuous positive airway pressure.

Intravenous methylprednisolone in the treatment of Graves' ophthalmopathy.

Eleven euthyroid patients with severe Graves' eye disease were treated with intravenous methylprednisolone and followed up for six months or more by ophthalmological assessment, orbital computed tomography (CT), photographs, and antibody measurements. Papilloedema resolved in the single patient in whom it was present; visual acuity was abnormal in seven eyes initially and in only one eye after treatment; the intraocular pressure differential, which reflects muscle dysfunction, was initially abnormal in 18 eyes but showed a progressive and distinct improvement; nine patients showed substantial improvement in inflammatory signs. Exophthalmos improved early after treatment, but this improvement was not maintained. Orbital CT showed a pronounced reduction in the bulk of eye muscles after treatment in eight of nine patients. Autoantibodies to the thyroid stimulating hormone receptor declined. Adverse effects were trivial. Thus eight patients showed a clear response to intravenous methylprednisolone as judged by ophthalmic assessment and CT scan. The two patients who showed little response and one who had none all had a long history (more than a year) of ophthalmopathy. Results were better than those with oral steroids and adverse effects less. Treatment of Graves' eye disease is more likely to be effective if given early; patients should be referred promptly to specialist centres, where treatment with intravenous methylprednisolone should be considered.

Thyrotrophin-blocking antibodies in goitrous primary hypothyroidism: detection by a highly sensitive bioassay and determination of site of action.

Using a highly sensitive bioassay technique, the presence of antibodies capable of blocking the stimulation of thyrocyte function by TSH has been investigated in the sera of a group of 50 patients with primary hypothyroidism. TSH-blocking activity was detected in immunoglobulin (IgG) preparations from the sera of 13 patients (26%). All 13 IgG preparations blocked both TSH-stimulated iodide uptake and cyclic AMP generation (Spearman's rank correlation = 0.6, p = 0.02). However, only one IgG preparation blocked dibutyryl cyclic AMP-stimulated iodide uptake. The presence of TSH-blocking antibody activity was associated with goitrous (ten out of thirteen patients) as well as atrophic (two out of thirteen patients) primary hypothyroidism. Furthermore, TSH-blocking activity was not associated with other thyroid autoantibodies, as thyrotrophin-binding-inhibiting immunoglobulins and anti-TSH antibodies were undetectable in all cases and there was no correlation between TSH-blocking activity and the presence or titre of anti-thyroglobulin or anti-microsomal antibodies. This study indicates that TSH-blocking antibodies are present in the serum of some patients with primary hypothyroidism and are directed towards a site, presumably adjacent to or contiguous with the TSH receptor, that is not the binding site for TSH. The coexistence of TSH-blocking activity and goitre in the majority of these patients implies that these antibodies, although capable of blocking TSH-stimulated thyroid hormone biosynthesis, do not necessarily inhibit the mitogenic action of TSH in vivo.

EMLA cream reduces the pain of venepuncture in children.

EMLA cream (eutectic mixture of local anaesthetics) was tested in a double-blind clinical trial to examine its effect on the pain of venepuncture at induction of anaesthesia in 40 children (aged 3-13 yrs). Four pain-assessment methods were used and an assessment of the technical ease of venepuncture was made. EMLA was found to reduce significantly the pain and technical difficulty of venepuncture. This study confirms that EMLA is an effective method of reducing the pain and technical difficulty of paediatric venepuncture using 25-gauge needles for induction of anaesthesia in children.

Complete sequence of the Rous sarcoma virus env gene: identification of structural and functional regions of its product.

The amino-terminal amino acid sequences of gp85 and gp37, the envelope glycoproteins of Rous sarcoma virus (RSV), were determined. Alignment of these sequences with the amino acid sequence predicted from the complete nucleotide sequence of the Prague strain of RSV, subgroup C (PR-C), has allowed us to delineate the env gene-coding region of this virus. The coding sequences for gp85 and gp37 have been placed in an open reading frame that extends from nucleotide 5045 to nucleotide 6862 and predict sizes of 341 amino acids (36,962 molecular weight) for gp85 and 198 amino acids (21,566 molecular weight) for gp37. Carbohydrate makes a significant contribution to the observed molecular weights of these polypeptides--the amino acid sequence contains 14 potential glycosylation sites (Asn-X-Ser/Thr) in gp85 and two in gp37. Experiments aimed at estimating the number of carbohydrate side chains yielded results consistent with most or all of these sites being occupied. Although an initiation codon is located early (codon 4) in the open reading frame, it is likely that splicing yields an mRNA on which translation initiates at the same AUG as that of the gag gene to produce a nascent polypeptide in which gp85 is preceded by a 62-amino-acid-long leader peptide. This leader contains the hydrophobic sequence (signal sequence) necessary for translocation across the endoplasmic reticulum and is completely removed from the env gene product during translation. The polyprotein precursor, Pr95env, is cleaved to gp85 and gp37 at the carboxyl side of the basic sequence:-Arg-Arg-Lys-Arg-. gp85 is attached through a disulphide linkage to gp37, and although the positions of the cysteines involved in this linkage are not known, the presence of a 27-amino-acid-long hydrophobic region at the carboxy-terminus of gp37 is consistent with its role as a membrane anchor for the viral glycoprotein complex. The location of host range variable regions with respect to the possible tertiary structure of the complex is discussed.