Advanced breast conservation and partial breast reconstruction - a review of current available options for oncoplastic breast surgery.

Breast cancer is the most common cancer affecting one in three women with new cancer diagnosis in England. Breast-conserving surgery is the primary surgical option in a vast majority of these patients. Use of oncoplastic techniques in breast conservation surgery has significantly improved the aesthetic outcomes without compromising the oncological safety of cancer resections. Oncoplastic breast-conserving surgery (OPBCS) has transformed the specialty with a paradigm shift in ideology and the recognition that aesthetic and oncological resections are synonymous when planning surgical intervention for patients with breast cancer. The two main options for OPBCS are therapeutic mammoplasty and partial beast reconstruction using pedicle-based flaps. This review aims to highlight key concepts in OPBCS demonstrating an overview of these surgical techniques, their safety, outcomes and the emergence of extreme oncoplastic breast surgery.

Clinical frailty and its effect on the septuagenarian population after emergency laparotomy.

INTRODUCTION: The UK has an ageing population with an increased prevalence of frailty in the over 70s. Emergency laparotomy for acute intra-abdominal pathology is increasingly offered to this population. This can challenge decision making and information given to patients should not only be based on mortality outcomes but on relative expected quality of life and change to frailty syndromes. MATERIALS AND METHODS: This was a single site National Emergency Laparotomy Audit (NELA)-based retrospective cohort audit for consecutive cases in the septuagenarian population assessing mortality, length of stay outcome and subjective postoperative functioning. Follow-up was conducted between one and two years postoperatively to determine this. RESULTS: Some 153 patients were identified throughout the single site NELA database. Median age was 79 years with a ratio of 1.7 men to women. Median rate of all-cause mortality was 35.3% at the median follow-up of 19 months. Median time from admission to death was 120 days. Of those who had died by the time of follow-up, significant preoperative indicators included clinical frailty scale (p < 0.0001), preoperative P-POSSUM (mortality). At follow-up, 35% responded to a quality of life follow-up. This revealed a decline in mid-term physical functioning, lower energy, higher fatigue and reduction in social functioning. There was also an increase in pre- and postoperative clinical frailty scale score. CONCLUSION: In the septuagenarian-plus population it is important to consider not only risk stratification with mortality scoring (P-POSSUM or NELA-adjusted risk), but to take into account frailty. Postoperative rehabilitation and careful recovery is paramount. Where possible, during the counselling and consent for emergency laparotomy, significant postoperative long-term deterioration in physical, emotional and social function should be considered.

Single-visit endovenous laser treatment and tributary procedures for symptomatic great saphenous varicose veins.

INTRODUCTION: Endovenous ablation of saphenous varicose veins has decreased morbidity and recovery time compared with open surgery. This study assessed the outcome and mid-term patient satisfaction of single-visit endovenous laser treatment (EVLT) alone, EVLT combined with phlebectomies and endovenous chemical ablation. METHODS: A retrospective review was conducted of all patients (n=91) in 2008-2009 who underwent single-visit day-case EVLT using local anaesthesia under a single surgeon. Postoperative venous ultrasonography at 2 and 14 months was reviewed. A telephone questionnaire was carried out to assess recurrence of symptoms and quality of life at 42 months. RESULTS: Overall, 124 limbs underwent day-case EVLT under local anaesthesia using an 810nm diode laser at a continuous setting of 14W. Forty-eight of these underwent EVLT alone while fifty underwent EVLT with phlebectomies and twenty-six underwent EVLT with endovenous chemical ablation. Ninety-one per cent of limbs underwent two-month postoperative imaging. All had satisfactory great saphenous vein (GSV) ablation (anterior thigh vein patency: n=1). The majority (84%) of limbs underwent 14-month imaging with a 98% GSV ablation rate. Three per cent had anterior thigh vein and saphenofemoral junction incompetence. Recurrence of GSV patency and reflux was <1%. The response rate to the questionnaire was 60%: 95% of respondents confirmed improvement following treatment, 62% remained symptom free at 42 months while 65% of patients with a return of symptoms deemed them mild. The questionnaire was scored out of 56 for symptoms and quality of life. Those with symptoms scored significantly higher. CONCLUSIONS: At 42 months, the majority of limbs remained asymptomatic. The short-term GSV ablation rates were excellent. Overall mid-term review of patients has shown a well received single-visit service with concomitant phlebectomy or endovenous ablation, and good ablation and patient satisfaction rates.

Giant rectal gastrointestinal stromal tumours: a diagnostic and therapeutic challenge.

Gastrointestinal stromal tumour (GIST are the most common mesenchymal tumours; however, rectal GISTs account for <5%. In the pelvis they represent a diagnostic challenge with giant GISTs likely to be malignant. They may present with urological, gynaecological or rectal symptoms. Sphincter-preserving surgery can be aided by neoadjuvant therapy. We present an uncommon case of giant rectal GIST masquerading as acute urinary retention.

Estimation of measurement uncertainty in pesticide residue analysis.

Proficiency test results from 5 countries involving 61 separate interlaboratory proficiency tests for pesticide residues were examined in this study. A total of 24 different matrixes and 869 relative standard deviations of the mean (or median) pesticide residue concentration were statistically evaluated in relation to the Horwitz function. The aim was to determine whether or not the concentration-dependent relationship described by Horwitz would hold for the much narrower range of chemicals and concentrations covered in routine pesticide residue analysis. Although for fatty (animal-derived) matrixes the variability increased as the concentration decreased in line with the Horwitz equation, the between-laboratories relative standard deviations for nonfatty matrixes (fruit, vegetables, and grain) remained at 25% over the entire concentration range of 1 microg/kg to 10 mg/kg for the pesticides studied. Given these findings, the Horwitz equation remains valid for calculating uncertainties involving pesticide residues in fatty matrixes. However, for pesticide residue analyses involving nonfatty matrixes, a constant relative standard deviation of 25% is more appropriate for calculating uncertainties, particularly when a reported result is assessed against a regulatory limit.

Effect of alpha subunit on allosteric modulation of ion channel function in stably expressed human recombinant gamma-aminobutyric acid(A) receptors determined using (36)Cl ion flux.

Inhibitory gamma-aminobutyric acid (GABA)(A) receptors are subject to modulation at a variety of allosteric sites, with pharmacology dependent on receptor subunit combination. The influence of different alpha subunits in combination with beta3gamma2s was examined in stably expressed human recombinant GABA(A) receptors by measuring (36)Cl influx through the ion channel pore. Muscimol and GABA exhibited similar maximal efficacy at each receptor subtype, although muscimol was more potent, with responses blocked by picrotoxin and bicuculline. Receptors containing the alpha3 subunit exhibited slightly lower potency. The comparative pharmacology of a range of benzodiazepine site ligands was examined, revealing a range of intrinsic efficacies at different receptor subtypes. Of the diazepam-sensitive GABA(A) receptors (alpha1, alpha2, alpha3, alpha5), alpha5 showed the most divergence, being discriminated by zolpidem in terms of very low affinity, and CL218,872 and CGS9895 with different efficacies. Benzodiazepine potentiation at alpha3beta3gamma2s with nonselective agonist chlordiazepoxide was greater than at alpha1, alpha2, or alpha5 (P < 0.001). The presence of an alpha4 subunit conferred a unique pharmacological profile. The partial agonist bretazenil was the most efficacious benzodiazepine, despite lower alpha4 affinity, and FG8205 displayed similar efficacy. Most striking were the lack of affinity/efficacy for classical benzodiazepines and the relatively high efficacy of Ro15-1788 (53 +/- 12%), CGS8216 (56 +/- 6%), CGS9895 (65 +/- 6%), and the weak partial inverse agonist Ro15-4513 (87 +/- 5%). Each receptor subtype was modulated by pentobarbital, loreclezole, and 5alpha-pregnan-3alpha-ol-20-one, but the type of alpha subunit influenced the level of potentiation. The maximal pentobarbital response was significantly greater at alpha4beta3gamma2s (226 +/- 10% increase in the EC(20) response to GABA) than any other modulator. The rank order of potentiation for pregnanolone was alpha5 > alpha2 > alpha3 = alpha4 > alpha1, for loreclezole alpha1 = alpha2 = alpha3 > alpha5 > alpha4, and for pentobarbital alpha4 = alpha5 = alpha2 > alpha1 = alpha3.

Identification and characterization of A-105972, an antineoplastic agent.

A high-throughput screening assay was designed to select compounds that inhibit the growth of cultured mammalian cells. After screening more than 60,000 compounds, A-105972 was identified and selected for further testing. A-105972 is a small molecule that inhibits the growth of breast, central nervous system, colon, liver, lung, and prostate cancer cell lines, including multidrug-resistant cells. The cytotoxic IC50 values of A-105972 were between 20 and 200 nM, depending on the specific cell type. The potency of A-105972 is similar in cells expressing wild-type or mutant p53. A majority of cells treated with A-105972 were trapped in the G2-M phases, suggesting that A-105972 inhibits the progression of the cell cycle. Using [3H]A-105972, we found that A-105972 bound to purified tubulin. Unlabeled A-105972 competed with [3H]A-105972 binding with an IC50 value of 3.6 microL. Colchicine partially inhibited [3H]A-105972 binding with an IC50 value of approximately 90 microM, whereas paclitaxel and vinblastine had no significant effect. Tumor cells treated with A-105972 were observed to contain abnormal microtubule arrangement and apoptotic bodies. DNA ladder studies also indicated that A-105972 induced apoptosis. A-105972 caused a mobility shift of bcl-2 on SDS-PAGE, suggesting that A-105972 induced bcl-2 phosphorylation. A-105972 treatment increased the life span of mice inoculated with B16 melanoma, P388 leukemia, and Adriamycin-resistant P388. These results suggest that A-105972 is a small molecule that interacts with microtubules, arrests cells in G2-M phases, and induces apoptosis in both multidrug resistance-negative and multidrug resistance-positive cancer cells. A-105972 and its analogues may be useful for treating cell proliferative disorders such as cancer.

Gamma-aminobutyric acid type B receptors with specific heterodimer composition and postsynaptic actions in hippocampal neurons are targets of anticonvulsant gabapentin action.

Gamma-aminobutyric acid (GABA) activates two qualitatively different inhibitory mechanisms through ionotropic GABA(A) multisubunit chloride channel receptors and metabotropic GABA(B) G protein-coupled receptors. Evidence suggests that pharmacologically distinct GABA(B) receptor subtypes mediate presynaptic inhibition of neurotransmitter release by reducing Ca2+ conductance, and postsynaptic inhibition of neuronal excitability by activating inwardly rectifying K+ (Kir) conductance. However, the cloning of GABA(B) gb1 and gb2 receptor genes and identification of the functional GABA(B) gb1-gb2 receptor heterodimer have so far failed to substantiate the existence of pharmacologically distinct receptor subtypes. The anticonvulsant, antihyperalgesic, and anxiolytic agent gabapentin (Neurontin) is a 3-alkylated GABA analog with an unknown mechanism of action. Here we report that gabapentin is an agonist at the GABA(B) gb1a-gb2 heterodimer coupled to Kir 3.1/3.2 inwardly rectifying K+ channels in Xenopus laevis oocytes. Gabapentin was practically inactive at the human gb1b-gb2 heterodimer, a novel human gb1c-gb2 heterodimer and did not block GABA agonism at these heterodimer subtypes. Gabapentin was not an agonist at recombinant GABA(A) receptors as well. In CA1 pyramidal neurons of rat hippocampal slices, gabapentin activated postsynaptic K+ currents, probably via the gb1a-gb2 heterodimer coupled to inward rectifiers, but did not presynaptically depress monosynaptic GABA(A) inhibitory postsynaptic currents. Gabapentin is the first GABA(B) receptor subtype-selective agonist identified providing proof of pharmacologically and physiologically distinct receptor subtypes. This selective agonism of postsynaptic GABA(B) receptor subtypes by gabapentin in hippocampal neurons may be its key therapeutic advantage as an anticonvulsant.

Reasons for the decomposition of the fungicide thiram during preparation of fruit and vegetable samples and consequences for residue analysis.

The concentration of thiram in aqueous solution decreases by 50-75% within 20 min in the presence of cut pieces of apple, cucumber or celeriac with a section surface area of 160 cm2 each. The decomposition rate is predominantly influenced by the section surface area of the cut fruit and vegetable samples. Denaturing reaction conditions (exchange of the solvent water by methanol; boiling of sample material) will significantly slow down the decomposition rate. It was concluded that the thiram decomposition had been caused by enzymes on the section surface of the fruit and vegetable samples. For a specific determination of thiram, a simple rinsing of the intact fruit and vegetable material was appropriate as extraction method. For the screening of thiram residues, the often used Keppel method, which determines CS2 from thiram or dithiocarbamates seems to be applicable even if samples had been coarsely cut, since decomposition of the CS2-forming intermediates is slower than the breakdown of thiram itself. Therefore, specific determination of thiram is necessary only, if maximum residue limits for dithiocarbamates are not adhered to.

Determination of Q1, an unknown organochlorine contaminant, in human milk, Antarctic air, and further environmental samples.

Q1, an organochlorine component with the molecular formula C(9)H(3)Cl(7)N(2) and of unknown origin was recently identified in seal blubber samples from the Namibian coast (southwest of Africa) and the Antarctic. In these samples, Q1 was more abundant than PCBs and on the level of DDT residues. Furthermore, Q1 was more abundant in seals from the Antarctic than the Arctic. To prove this assumption, gas chromatography-electron-capture negative ion mass spectrometry (GC/ECNI-MS), which is sensitive and selective for Q1, allowed for screening of traces of Q1 even in samples with particularly high levels of other organochlorine contaminants. Q1 was isolated by high-performance liquid chromatography (HPLC) from a skua liver sample. A 1:1 mixture with trans-nonachlor in electron-capture detectors (ECDs) was used to determine the relative response factor with ECNI-MS. The ECNI-MS response of Q1 turned out to be 4.5 times higher than that of trans-nonachlor in an ECD. With GC/ECNI-MS in the selected ion-monitoring mode, four Antarctic and four Arctic air samples were investigated for the presence of Q1. In the Antarctic air samples, Q1 levels ranged from 0.7 to 0.9 fg/m(3). In Arctic air samples, however, Q1 was below the detection limit (<0.06 fg/m(3) or 60 ag/m(3)). We also report on high Q1 levels in selected human milk samples (12-230 microg/kg lipid) and, therefore, suggested that the unknown Q1 is an environmental compound whose origin and distribution should be investigated in detail. Our data confirm that Q1 is a bioaccumulative natural organochlorine product. Detection of a highly chlorinated natural organochlorine compound in air and human milk is novel.

Variation of toxaphene indicator compounds in fish from single fishing grounds: conclusions for sampling.

The levels of three toxaphene indicator compounds were determined in individual lots of herring, redfish, Greenland halibut and farmed salmon. Concentration levels of the three marine fish species were characterised by a right-skewed frequency distribution whereas residue concentrations in farmed salmon were normally distributed. The toxaphene concentrations in the edible part of redfish, herring and Greenland halibut were found to be positively correlated to the sizes and thus to age. As results show, for representative sampling of a landed catch, not more than 10 individual fishes from typical size classes of a lot are necessary for a pooled sample.

Mass spectrometric characterization of Q1, a C(9)H(3)Cl(7)N(2) contaminant in environmental samples

Q1, a heptachloro component of unknown structure and origin, was recently identified as a major organochlorine contaminant in samples from Africa and the Antarctic. Gas chromatography in combination with low resolution mass spectrometry (LRMS) was applied to establish a molecular weight of m/z 384 including seven chlorine atoms. Three possible molecular formulae (C(11)H(7)Cl(7), C(10)H(3)Cl(7)O, and C(9)H(3)Cl(7)N(2)) were proposed which could not be distinguished by LRMS. In this presentation the molecular composition of Q1 was studied using gas chromatography in combination with high resolution electron impact ionization mass spectrometry. With the option of further heteroatoms (P, S, N, O, F, and Br), 17 molecular formulae were obtained for the molecular weight of 384 u. In the selected ion monitoring (SIM) mode, performed with a resolution of 16,000, highest response was found at 383.812 or C(9)H(3)Cl(7)N(2). 11 fragment ions detected in the low resolution full scan mass spectrum of Q1 were also investigated in the high resolution SIM mode. In every case, the nitrogen-variant showed highest abundance while the other 16 structural variants could be definitely excluded. These investigations revealed that the molecular formula of Q1 is C(9)H(3)Cl(7)N(2). No stable component with this molecular formula has ever been reported in the literature, to our knowledge. Copyright 1999 John Wiley & Sons, Ltd.

Contribution of stabilizing agents present in intravenous immunoglobulin preparations to modulation of mononuclear cell proliferation in vitro.

Intravenous immunoglobulin (IVIG) preparations have been shown to suppress lymphocyte proliferation in vitro. This study aimed to investigate the effects of an IVIG produced by fractionation/DEAE-Sephadex adsorption on lymphocyte proliferation in vitro, with particular reference to contributions of the stabilizing agents present in the IVIG to the modulation of mononuclear cell proliferation. It was found that glycine significantly inhibited stimulation by the mitogenic lectin phytohaemagglutinin (PHA; 58% inhibition, P < 0.01). Glucose and human albumin also reduced the response to PHA but to a lesser extent (20% and 30%, respectively). In further experiments the effects of sucrose and maltose, two disaccharides used as stabilizing agents in IVIG preparations, were studied. Three doses were used (2.5 mM, 25 mM and 250 mM), representing levels likely to be found in vivo after infusion of IVIG at immunotherapeutic doses, on four different proliferative stimuli. Maltose was found to inhibit proliferation to PHA, anti-CD3 and PMA in a dose responsive manner. Sucrose also inhibited proliferation to these stimuli, but a dose response was not observed. For both sugars, only the highest dose (250 mM) inhibited the proliferative response of mononuclear cells to PMA and a calcium ionophore (ionomycin). The repurified IgG component of the IVIG preparation did not inhibit PBMC responses to PHA in this system. Kinetic analyses, in which the sugars were added 24 h after proliferative stimuli, indicated that both sugars still inhibited responses to PHA, and, to a lesser extent, PMA, but only maltose inhibited the anti-CD3 response. These findings show that stabilizing agents currently found in commercial IVIG preparations make a significant contribution to modulating mononuclear cell proliferation and need to be considered when assessing the immunomodulatory role of IVIG in vitro.

Fusacandins A and B; novel antifungal antibiotics of the papulacandin class from Fusarium sambucinum. II. Isolation and structural elucidation.

Two novel antifungal compounds of the papulacandin class, named fusacandins A and B, have been isolated from Fusarium sambucinum. Each compound contains two units of galactose and one of glucose, the latter connected as a C-glycoside to an aromatic moiety. Fusacandin A is esterified at two sites with long-chain, unsaturated fatty acids and fusacandin B at only one site. The structures of the fusacandins were elucidated through analysis of mass spectral and 1-D and 2-D homonuclear and heteronuclear NMR data.

Aselacins, novel compounds that inhibit binding of endothelin to its receptor. I. The producing organism, fermentation and biological activity.

A radioligand test to detect inhibitors of endothelin-1 binding to its receptors in bovine atrial and porcine cerebral membranes was used to screen fungal metabolites from stationary fermentations. Inhibitory activity, observed in culture extracts of two Acremonium species, led to the discovery of aselacins A, B and C. Aselacin A inhibits binding to both membrane fractions with IC50s of approximately 20 micrograms/ml.

Occurrence of 9- and 13-keto-octadecadienoic acid in biological membranes oxygenated by the reticulocyte lipoxygenase.

Membranes of intact rabbit reticulocytes and rat liver mitochondrial membranes oxygenated by the pure reticulocyte lipoxygenase contain 13-keto-9Z,11E-octadecadienoic acid and 9-keto-10E,12Z-octadecadienoic acid. In mitochondrial membranes not treated with lipoxygenase and in rabbit erythrocyte membranes these products were not detected. The chemical structure of the compounds has been identified by cochromatography with authentic standards on various types of HPLC columns, by uv and ir spectroscopy and GC/MS. In the membranes of rabbit reticulocytes up to 2% of the linoleate residues are present as its 9- and 13-keto derivatives. Most of the keto compounds (up to 90%) are esterified in the membrane ester lipids, only about 10% were found in the free fatty acid fraction. It is proposed that the keto dienoic fatty acids are formed via decomposition of hydroperoxy polyenoic fatty acids originating from the oxygenation of the membrane lipids by the reticulocyte lipoxygenase.

Occurrence of free and esterified lipoxygenase products in leaves of Glechoma hederacea L. and other Labiatae.

Leaves of Glechoma hederacea L. and other Labiatae contain (9S,10E,12Z,15Z)-9-hydroxy-10,12,15-octadecatrienoic acid, (10E,12Z,15Z)-9-oxo-10,12,15-octadecatrienoic acid, (9S,10E,12Z)-9-hydroxy-10,12-octadecadienoic acid and (10E,12Z)-9-oxo-10,12-octadecadienoic acid in a ratio of 71/14/12/3 (by mass), predominantly esterified in the membrane ester lipids. The leaves contain the highest level of these products, whereas only small amounts were found in the stalk and the roots. The chemical structures of these compounds were established by ultraviolet and infrared spectroscopy, by co-chromatography with authentic standards on various types of HPLC columns including chiral-phase HPLC and gas chromatography/mass spectrometry. The stereochemical specificity indicates the enzymatic origin of the products, most probably via a lipoxygenase reaction. Freshly harvested specimens of G. hederacea L. contain only small amounts of hydroxy-polyenoic fatty acids. Air-drying causes a strong increase in the content of free and esterified (9S,10E,12Z,15Z)-9-hydroxy-10,12,15-octadecatrienoic acid. Up to 80% of the hydroxy fatty acids of the total lipid extracts were esterified in the cellular lipids. The data presented indicate that lipoxygenase products occur in the cellular ester lipids of G. hederacea L. and other Labiatae. The results are discussed in the light of a possible involvement of the lipoxygenase pathway in the natural senescence of leaves.