Radical resection of large metastatic non-functioning pancreatic neuroendocrine carcinoma complicated by splenic vein thrombosis and sinistral portal hypertension.

INTRODUCTION AND IMPORTANCE: There are limited reports in the literature of radical surgical resection for pancreatic neuroendocrine carcinoma (PNEC). In patients with non-functioning PNEC (NF-PNEC) within the tail of the pancreas tumours can cause splenic vein thrombosis (SVT) and subsequent sinitral portal hypertension (SPH). Radical surgical resection in such patients with concomitant liver metastasis has not previously been reported. CASE PRESENTATION: We present a 67-year old female patient who presented with a large NF-PNEC within the tail of the pancreas with liver metastasis. We performed a distal pancreatectomy, splenectomy, partial gastrectomy and liver resection to achieve radical resecton. DISCUSSION: All patients with NF-PNEC within the tail of the pancreatic should be considered for radical surgical resection. In the presence of multi-visceral involvement and complications such as SVT and/or SPH multi-speciality surgical expertise is likely to be required. CONCLUSION: Radical multi-visceral resection for large NF-PNEC can be safely performed in the presence of SVT and SPH.

Prognostic relevance of the posterior resection margin for predicting disease free survival in ampullary adenocarcinoma.

BACKGROUND: Pancreaticoduodenectomy is the only curative treatment option for patients with resectable ampullary adenocarcinoma (AA). Excellent disease free survival (DFS) can be achieved in patients with clear resection margins but it is poorly understood which patients are at increased risk of recurrence and hence would benefit from adjuvant chemotherapy. There is evolving evidence that the anatomical location of incomplete resection margins influences DFS in pancreatic adenocarcinoma. It is unknown if this also pertains to AA and therefore this study aimed to assess individual resection margin status and other predictors of DFS in AA. MATERIAL & METHODS: Consecutive patients undergoing pancreaticoduodenectomy for AA at our institution from 1996 to 2017 were analysed. Pancreas neck, posterior and superior mesenteric vein margins were assessed individually. Cox proportional hazards modelling was used to identify predictors of 5-year DFS. Factors with p < 0.1 on univariate analysis were included for multivariate analysis. RESULTS: Analysis of 104 patients revealed median OS and DFS of 56 and 34 months, respectively. Predictors associated with worse DFS on multivariate analysis were T3-stage (HR 3.6, p = 0.048), N1 (HR 2.9, p = 0.01) and N2 -stage (HR 3.6, p = 0.006), R1 status at the posterior margin (HR 3.0, p = 0.009) and a visible mass on CT (HR 2.0, p = 0.039). CONCLUSION: Routine histopathological assessment of individual resection margins may aid in predicting recurrence of AA. Future studies to assess if routine mesopancreas excision during pancreaticoduodenectomy can reduce the incidence of R1 status at the posterior margin are warranted.

Changes in epidermal morphology associated with dandruff.

OBJECTIVE: Dandruff is a very common scalp condition characterized by flaking and pruritus usually with no visible signs of inflammation, such as redness and erythema. Dandruff is considered a multifactorial condition with both microbial colonization and host factors such as sebum production thought to play a role. There is evidence of changes in epidermal morphology in the scalp skin of dandruff sufferers, with reports of an increase in mean thickness and more nucleated cell layers. The underlying mechanisms driving these morphological changes are currently unclear. The objective of this study was to fully characterize epidermal morphology in dandruff compared to healthy scalp skin and to evaluate potential mechanisms underlying any changes observed. METHODS: Scalp skin biopsies were taken from 22 healthy female subjects and 21 dandruff sufferers, from both lesional and non-lesional sites. Samples were processed, sectioned and stained using haematoxylin and eosin (H&E). To fully characterize epidermal morphology, measurements were taken of epidermal thickness, the convolution of the dermal-epidermal junction and the depth of epidermal rete ridges. To analyse changes in epidermal proliferation immunohistochemical staining was performed using Ki67, a well-established marker of cell proliferation, and quantified using image analysis. RESULTS: Histochemical analysis of skin sections revealed that in dandruff lesional samples, the epidermis was thicker, had a more convoluted dermal epidermal junction and the rete ridges were elongated, compared to healthy scalp skin. Similar directional changes in epidermal morphology, were observed in non-lesional dandruff samples, albeit to a lesser extent. Image analysis of Ki67 expression in the epidermis revealed dandruff lesional skin contained significantly more Ki67-positive proliferating keratinocytes than healthy controls samples. This suggests dandruff scalp skin epidermal keratinocytes are in a hyper-proliferative state. CONCLUSION: There were significant changes in epidermal morphology in dandruff lesional skin compared to healthy scalp skin including increased epidermal thickness, a more convoluted dermal-epidermal junction and elongation of rete ridges. Interestingly, we found there was evidence of an increase in the percentage of epidermal Ki67-positive cells, which has not been reported previously, and demonstrates dandruff is a condition displaying epidermal hyper-proliferation.

OBJECTIF: Les pellicules constituent une affection du cuir chevelu très fréquente caractérisée par une desquamation et un prurit ne présentant pas, en général, des signes visibles d'inflammation, comme une rougeur et un érythème. Les pellicules sont considérées être une affection multifactorielle présentant une colonisation microbienne ainsi que des facteurs-hôtes, tels que la production de sébum, qui pourraient avoir un rôle à jouer. Il existe des preuves qu'il se produit des changements dans la morphologie épidermique de la peau du cuir chevelu des personnes qui ont des pellicules, et des rapports font cas d'une augmentation de l'épaisseur moyenne et d'un plus grand nombre de couches de cellules nucléées. Les mécanismes sous-jacents à ces changements morphologiques sont jusqu'ici peu élucidés. L'objectif de cette étude était de caractériser pleinement la morphologie épidermique en la présence de pellicules par comparaison à la peau du cuir chevelu sain, et d'évaluer les mécanismes potentiels sous-jacents à tout changement observé. MÉTHODES: Des biopsies de la peau du cuir chevelu ont été pratiquées chez 22 femmes en bonne santé et 21 femmes présentant des pellicules, dans des sites lésionnés et non lésionnés. Les échantillons ont été traités, coupés en lamelles et colorés en utilisant de l'hématoxyline et de l'éosine (H&E). Pour caractériser pleinement la morphologie épidermique, des mesures de l'épaisseur épidermique, de la convolution de la jonction dermo-épidermique et de la profondeur des crêtes du réseau épidermique ont été effectuées. Pour analyser les changements dans la prolifération épidermique, une coloration immunohistochimique a été réalisée en utilisant du Ki67, un marqueur bien établi de la prolifération cellulaire, et quantifiée à l'aide de l'analyse d'images. RÉSULTATS: L'analyse histochimique des sections de peau a révélé que, dans les échantillons de lésions avec pellicules, l'épiderme était plus épais, présentait une jonction dermo-épidermique plus compliquée et des crêtes du réseau plus allongées, par comparaison à la peau du cuir chevelu en bonne santé. Des changements directionnels analogues de la morphologie épidermique ont été observés dans les échantillons sans lésions et avec pellicules, toutefois en une moindre mesure. L'analyse des images de l'expression de Ki67 dans l'épiderme a révélé que la peau avec lésions et pellicules contenait des kératinocytes prolifératifs bien plus Ki67-positifs que les échantillons de témoins en bonne santé. Cela suggère que les kératinocytes épidermiques de la peau du cuir chevelu présentant des pellicules sont dans un état hyper-prolifératif. CONCLUSION: Il s'est produit des changements significatifs dans la morphologie épidermique de la peau avec lésions et pellicules, par comparaison à la peau du cuir chevelu en bonne santé, y compris un épaississement de l'épiderme, une jonction dermo-épidermique plus compliquée et un allongement des crêtes du réseau. Fait intéressant, nous avons découvert des signes d'augmentation du pourcentage de cellules épidermiques Ki67-positives, ce qui n'avait encore jamais été rapporté, et qui démontre que la présence de pellicules est une affection affichant une hyper-prolifération épidermique.

Cost impact of a non-invasive, portable device for patient self-administration of chronic migraine in a UK National Health Service setting.

BACKGROUND: Chronic migraine (CM) is a neurological disorder associated with substantial disability. Botulinum toxin type A (Botox) is an approved and effective preventive treatment option for adult patients with CM. Transcranial magnetic stimulation (TMS) is an alternative treatment device delivering a brief pre-set magnetic pulse used for self-administration by the patient at home. Despite being available in a risk share scheme TMS is perceived to be more costly in the UK. The objective of this study was to analyse the incremental costs of TMS compared to Botox in refractory CM patients both for a UK individual funding request setting as well as for an average UK specialist center setting. METHODS: Cost impact results were derived from a decision-tree model simulating treatment pathways over 1 year. Costs were applied from the most recently available UK data sources. Sensitivity analysis was performed for all variables. RESULTS: Based on published utilisation data 45.5 % of CM patients would continuously receive Botox over 1 year, whereas 53.7 % of TMS patients would be still on treatment at the end of year one. Total costs of Botox treatment accrue to £2923 in an individual funding request NHS cost setting, whereas TMS treatment results in £1466 in the first year. Applying a time-based NHS cost setting expenditures accrue to £1747 for the Botox treatment and to £1361 for the TMS treatment. In both cost settings variation of cost assumptions did have a minor impact on the cost increment from Botox to TMS. CONCLUSION: The current risk share based remuneration model of TMS allows the UK NHS to reimburse only the cost of those patients experiencing reduction in migraine days resulting in lower costs for treating migraine attacks. Treatment of chronic refractory migraine using TMS implies a substantial cost reduction potential for the management of chronic treatment of refractory migraine patients compared to conventional Botox treatment.

Protease activity, localization and inhibition in the human hair follicle.

OBJECTIVE: In humans, the process of hair shedding, referred to as exogen, is believed to occur independently of the other hair cycle phases. Although the actual mechanisms involved in hair shedding are not fully known, it has been hypothesized that the processes leading to the final step of hair shedding may be driven by proteases and/or protease inhibitor activity. In this study, we investigated the presence of proteases and protease activity in naturally shed human hairs and assessed enzyme inhibition activity of test materials. METHODS: We measured enzyme activity using a fluorescence-based assay and protein localization by indirect immunohistochemistry (IHC). We also developed an ex vivo skin model for measuring the force required to pull hair fibres from skin. RESULTS: Our data demonstrate the presence of protease activity in the tissue material surrounding club roots. We also demonstrated the localization of specific serine protease protein expression in human hair follicle by IHC. These data provide evidence demonstrating the presence of proteases around the hair club roots, which may play a role during exogen. We further tested the hypothesis that a novel protease inhibitor system (combination of Trichogen) and climbazole) could inhibit protease activity in hair fibre club root extracts collected from a range of ethnic groups (U.K., Brazil, China, first-generation Mexicans in the U.S.A., Thailand and Turkey) in both males and females. Furthermore, we demonstrated that this combination is capable of increasing the force required to remove hair in an ex vivo skin model system. CONCLUSION: These studies indicate the presence of proteolytic activity in the tissue surrounding the human hair club root and show that it is possible to inhibit this activity with a combination of Trichogen and climbazole. This technology may have potential to reduce excessive hair shedding.

Can foam sclerotherapy be used to safely treat bilateral varicose veins?

OBJECTIVE: We assessed the use of ultrasound guided foam sclerotherapy (UGFS) to treat bilateral varicose veins either as synchronous or interval procedures. We specifically assessed total foam volume usage and its influence on early outcome and complications. METHODS: We reviewed our prospectively compiled computerised database of patients with bilateral varicose veins who have undergone UGFS. Duplex findings, foam volumes used and clinical outcome were assessed. RESULTS: One hundred and twelve patients had undergone UGFS for bilateral varicose veins. Sixty-one had bilateral UGFS (122 legs) and 51 had interval UGFS (102 legs). Seventy-eight percent bilateral and 60% interval procedures were for single trunk disease. Median foam volumes per treatment episode were: 17.5 mls bilateral, and 10 mls interval FS. At two weeks 81% of legs had complete occlusion after bilateral UGFS compared to 70% after interval UGFS. One patient in the bilateral UGFS developed transient visual disturbance. There was no systemic complications in the interval UGFS. CONCLUSIONS: Bilateral foam sclerotherapy treatment did not adversly affect vein occlusion rates and there was no significant difference in complication rates between the two groups. Bilateral UGFS can be safely performed in selected patient presenting with bilateral varicose veins.

Should all patients undergo postoperative duplex imaging to detect a deep vein thrombosis after varicose vein surgery?

OBJECTIVES: Deep vein thrombosis (DVT) is a serious complication of varicose vein surgery, with attendant risks of pulmonary embolization. Prospective duplex screening identifies DVT in 5% of patients compared to clinical incidence of approximately 1%. Universal duplex screening is costly, and the benefits of diagnosing subclinical DVT are unproven. This study evaluates whether a policy of using clinical indications (leg swelling) to determine the need for duplex imaging is safe after varicose vein surgery. METHODS: Patients undergoing varicose vein surgery over a 4-year period were studied. Postoperative venous duplex imaging was performed if leg swelling occurred within 6 weeks of surgery. Long-term follow-up was performed to detect any missed occurrence of clinical DVT or pulmonary embolism. RESULTS: A total of 411 patients had 491 leg operations with 80 bilateral procedures (27%); 29 patients with leg swelling underwent duplex imaging, 5 of whom had duplex-proven DVT. No patient without early clinical signs went on to develop clinical DVT on long-term follow-up. CONCLUSION: A policy of using clinical signs as a triage for duplex imaging detected all clinically significant DVTs and generated manageable workloads for our vascular laboratory.

Arylsulphonyl hydroxamic acids: potent and selective matrix metalloproteinase inhibitors.

A series of novel matrix metalloproteinase inhibitors is described in which selectivity between MMP and 'sheddase' activity has been achieved and which demonstrate potent in vivo activity in models of arthritis and cancer.

Solid-phase synthesis and biological screening of N-alpha-mercaptoamide template-based matrix metalloprotease inhibitors.

A series of N-alpha-mercaptoacetyl containing dipeptides have been prepared on solid-phase supports as putative matrix metalloprotease (MMP) inhibitors. Inhibitor design was based on a positional scanning approach of the amino acids present within a template molecule, previously shown to be an MMP inhibitor with good pharmacological characteristics. This study is the first step in a unique programme, designed to expand the repertoire of molecular templates which can be chosen as starting points for the development of more focused parallel and/or combinatorial libraries of MMP inhibitors as a means to accelerate the lead discovery process. This paper reports the success of such an approach in the development of agents with activity against a number of pathologically important MMPs. After screening of these positional scanning libraries, we have obtained important SAR information, in particular, pharmacophores with the ability to impart selectivity for particular MMP species.

The effect of an inhibitor of matrix metalloproteinases on colonic inflammation in a trinitrobenzenesulphonic acid rat model of inflammatory bowel disease.

BACKGROUND: Recent publications have reported that matrix metalloproteinases (MMPs) are expressed in colonic tissue taken from ulcerative colitis and Crohn's disease patients. AIM: To evaluate the effects of a matrix metalloproteinase inhibitor, marimastat, on colonic inflammation in experimental colitis induced by trinitrobenzenesulphonic acid (TNBS)-ethanol in the rat. METHODS: Rats were dosed (by mouth) for 7 days (b.d.) with either sulphasalazine (50 mg/kg), marimastat (40 mg/kg) or vehicle. TNBS-ethanol was administered rectally on the 4th day of dosing. On the last day of dosing, colons were removed and assessed for inflammation using myeloperoxidase activity, production of soluble TNFalpha (tumour necrosis factor alpha), clinical score and histological assessment. In addition, the bioavailability and effect of marimastat on a range of MMPs were assessed in-vitro. RESULTS: In this study we have confirmed that marimastat is a broad spectrum MMPI with a bioavailability of 5%. TNBS rats dosed with sulphasalazine had a significantly lower (P < 0.05) myeloperoxidase activity, TNFalpha production and a markedly lower clinical score. Similarly, rats dosed with marimastat had a significantly lower (P < 0.05) myeloperoxidase activity and clinical score, but the TNFalpha production was not significantly reduced. CONCLUSIONS: Dosing rats with TNBS-induced colitis using sulphasalazine or marimastat produced a significant reduction in tissue injury and inflammation.

Differential expression of DCC mRNA in adult rat forebrain.

DCC is a member of the immunoglobulin superfamily of cell adhesion molecules, whose role in the function of the adult nervous system is unknown. DCC mRNA expression was studied in adult rat dorsal hippocampal sections using in situ hybridization histochemistry. High levels of DCC transcript were detected in hippocampus and medial habenula, whereas lower mRNA expression was found in cerebral cortex, hypothalamus and thalamus. The higher relative expression of DCC mRNA in hippocampus, compared with the remainder of the brain was confirmed using RT-PCR analysis. These data confirm the presence of DCC mRNA in adult rat brain and indicate that DCC mRNA is differentially expressed between forebrain regions, suggesting a role for DCC in the function of the adult rat central nervous system.

An integrated YAC clone contig for the WAGR region on human chromosome 11p13-p14.1.

The WAGR syndrome (Wilms tumor, aniridia, genitourinary anomalies, and mental retardation) deletion region on chromosome 11p13 has been extensively characterized by deletion analysis and long-range restriction mapping. A dense probe set is available for this genomic region, which harbors a number of disease gene loci, some of which still are not cloned. The identification of candidates for these genes would be greatly facilitated by a complete gene map for this chromosomal segment. As an initial step toward this goal, we have isolated the entire region in 58 overlapping YAC clones. The contig spanning 8 Mb from RAG1 to KCNA4 has been assembled by STS and probe content mapping for 76 loci with an average spacing of about 100 kb. A subset of clones has been analyzed by PFG analysis to position these within the known physical map. Common microsatellite markers permit an alignment of the YAC contig with the genetic and radiation hybrid maps of chromosome 11. Ten known genes, some with much more refined map positions, are placed in the contig. The severalfold coverage of 11p13-p14.1 provides a reliable resource for the future development of a complete gene map of this region.

Binding sites for islet amyloid polypeptide in mammalian lung: species variation and effects on adenylyl cyclase.

Islet amyloid polypeptide (IAPP) and calcitonin gene related peptide (CGRP) share a 47% sequence homology. IAPP can interact with adenylyl cyclase coupled CGRP receptors. We have examined [125I]IAPP binding in mouse, pig, and guinea pig lung membranes in competition with IAPP, CGRP, and CGRP(8-37). Three types of site were shown by order of potency: (i) mouse, IAPP > CGRP(8-37) >> CGRP; (ii) pig, CGRP > IAPP > CGRP(8-37); and (iii) guinea pig, CGRP = IAPP = CGRP(8-37). Chemical cross-linking of [125I]IAPP and [125I]CGRP binding sites in lung demonstrated that both sites had similar molecular weights in any one species but differed across species, i.e., mouse M(r) = 70,000 and 98,000; pig M(r) = 68,000, 56,000, and 47,000; and guinea pig M(r) = 106,000 and 56,000. Adenylyl cyclase activity was stimulated by forskolin and AlCl3-NaF in rat, mouse, pig, and guinea pig membranes. Only in mouse and pig were CGRP and IAPP able to stimulate adenylyl cyclase activity. In mouse lung CGRP and IAPP stimulated adenylyl cyclase activity with EC50 values of 642 +/- 222 nM (n = 4) and 325 +/- 115 nM (n = 4), respectively. In pig lung membranes EC50 values were 5.7 +/- nM (n = 4) for CGRP and 1230 +/- 1130 nM (n = 4) for IAPP. Thus IAPP either did not stimulate adenylyl cyclase activity in these lung membranes or did so with a low potency.

Expression of a novel receptor for the calcitonin peptide family and a salmon calcitonin-like peptide in the alpha-thyrotropin thyrotroph cell line.

We have previously shown an increased incidence of alpha-subunit-producing thyrotroph tumors after salmon calcitonin (sCT) injection into rats. However, it is not clear whether the effects of CT are direct or indirect. Our hypothesis was that for sCT to act directly, it must have a binding site on thyrotrophs. The alpha TSH cell line was used as a model for thyrotrophs. Receptor binding studies using alpha TSH membranes revealed a high affinity binding site for sCT [IC50 = 0.97 +/- 0.18 nM (n = 4); Kd = 5.45 +/- 0.43 nM (n = 3); binding capacity = 6.6 pmol/mg protein (n = 3)]. Rat CT did not compete with binding at this site. Receptor screening for other CT peptide family members revealed high specific binding for CT gene-related peptide (CGRP; IC50 = 0.25 +/- 0.08 nM; n = 3) and islet amyloid polypeptide (IC50 = 4.36 +/- 1.1 nM; n = 3). This together with the absence of rat CT binding excluded a conventional CT-binding site, and we propose a site similar to the CGRP subtype III receptor described in the rat nucleus accumbens. Guanosine 5'O-(3-thiotriphosphate) (GTP gamma S) (20 microM), reduced [125I]CGRP binding to 38% of maximal, indicating that this site is G-protein coupled. Immunocytochemically, all of the cells displayed intense sCT-like immunoreactivity, which was totally abolished by preabsorption of the antibody with sCT. The presence of this receptor supports the hypothesis that sCT mediates tumorigenesis via a direct pituitary action and, together with the coexistence of a sCT-like peptide in these cells, provides evidence for a possible autocrine role of this peptide in the control of thyrotroph function.

An abundant and specific binding site for the novel vasodilator adrenomedullin in the rat.

Rat adrenomedullin is a novel 50-amino acid peptide with structural similarities to the calcitonin family of peptides, calcitonin, calcitonin gene-related peptide (CGRP), and islet amyloid polypeptide (IAPP). Using rat [125I]adrenomedullin, specific binding sites were demonstrated in heart, lung, spleen, liver, soleus, diaphragm, gastrocnemius, and spinal cord membranes. The highest binding was present in heart and lung, which was further characterized. These sites exhibited saturation, dissociation, and competition. In rat lung, only rat (IC50 = 5.8 nM) and human (IC50 = 94 nM) adrenomedullin competed with [125I]adrenomedullin. However, in rat heart, rat (IC50 = 0.2 nM) and human (IC50 = 4.2 nM) adrenomedullin, IAPP (IC50 = 240 nM), and CGRP (IC50 = 1050 nM) all competed with [125I] adrenomedullin. Saturation analysis revealed binding capacities and dissociation constants of 2.8 +/- 0.3 pmol/mg protein and 1.3 +/- 0.3 nM, respectively, in lung and 0.47 +/- 0.11 pmol/mg protein and 0.41 +/- 0.14 nM in heart. Comparison with [125I]CGRP- and [125I]IAPP-binding sites in lung showed that rat adrenomedullin could potently inhibit at these sites (IC50 = 5 and 6 nM, respectively). Chemical cross-linking demonstrated a major band of 83,000 mol wt in lung, diaphragm, spleen, and liver and a band of 94,000 mol wt in heart, soleus, and gastrocnemius. Thus, [125I]adrenomedullin-binding sites in rat lung are abundant and can be differentiated from binding sites in rat heart, both pharmacologically and by mol wt.

The presence of islet amyloid polypeptide/calcitonin gene-related peptide/salmon calcitonin binding sites in the rat nucleus accumbens.

Receptor autoradiographic analysis of binding in rat brain sections for [125I]islet amyloid polypeptide (IAPP), [125I]calcitonin gene-related peptide (CGRP) and [125I]salmon calcitonin indicated dense binding for all three ligands in the nucleus accumbens. Membrane binding studies revealed the existence of high affinity sites for all three peptides. The order of potency of various related peptides at each binding site was investigated and found for [125I]IAPP to be salmon calcitonin > IAPP = alpha CGRP > salmon calcitonin-(8-32); for [125I]CGRP to be alpha CGRP > IAPP > salmon calcitonin; and for [125I]salmon calcitonin to be salmon calcitonin > alpha CGRP > rat calcitonin > salmon calcitonin-(8-32) > IAPP, suggesting that [125I]IAPP targets the CGRP3 receptor subtype. This study confirms the existence of two receptors in the rat nucleus accumbens binding salmon calcitonin, one of which binds alpha CGRP and IAPP with a high affinity.