Long-term outcomes of endovenous laser ablation and conventional surgery for great saphenous varicose veins.

BACKGROUND: Clinical guidelines recommend endovenous laser ablation (EVLA) over surgery based on short-term evidence, yet there are few studies reporting mid- to long-term outcomes. The aim of this study was to report the 5-year outcomes from an RCT of surgery versus EVLA for treatment of symptomatic great saphenous varicose veins. METHODS: Patients with symptomatic varicose veins due to great saphenous vein (GSV) incompetence were followed up 5 years after enrolment in a randomized trial of either surgery (saphenofemoral junction ligation, GSV strip to the knee and multiple avulsions of varicosities) or EVLA plus multiple avulsions. Outcomes included: clinical recurrence, defined as new varicose veins greater than 3 mm in diameter; Venous Clinical Severity Score (VCSS); quality of life measured by means of Short Form 36, EuroQol Five Dimensions (EQ-5D™) and Aberdeen Varicose Vein Questionnaire (AVVQ); patient satisfaction; and duplex ultrasound examination (DUS) findings. RESULTS: Some 218 of the 276 patients enrolled in the trial (79·0 per cent) were available for follow-up. Clinical recurrence was more frequent following surgery than EVLA at 5 years (34·3 versus 20·9 per cent; P = 0·010). Both groups demonstrated sustained significant improvements at 5 years over baseline in VCSS (surgery: median (i.q.r.) 1 (0-2) from 4 (3-5), P < 0·001; EVLA: 0 (0-1) from 4 (3-5), P < 0·001), AVVQ (surgery: 4·59 (0·56-9·78) from 13·69 (9·81-18·11), P < 0·001; EVLA: 3·35 (0·17 to 6·55) from 12·73 (9·41-17·32), P < 0·001) and EQ-5D™ (surgery: 1·000 (0·796-1·000) from 0·859 (0·796-1·000), P = 0·002; EVLA: 1·000 (0·796-1·000) from 0·808 (0·796-1·000), P = 0·002). VCSS was better for EVLA than surgery at 5 years (P = 0·031). Technical success assessed by DUS remained high at 5 years (85·4 per cent for surgery and 93·2 per cent for EVLA; P = 0·074). DUS-detected anatomical patterns of recurrence differed between the groups. CONCLUSION: EVLA was more effective than surgery in preventing clinical recurrence 5 years after treatment of great saphenous varicose veins. Patient-reported outcome measures were similar. Registration number: NCT00759434 (http://www.clinicaltrials.gov).

Modeling psychiatric disorders: from genomic findings to cellular phenotypes.

Major programs in psychiatric genetics have identified >150 risk loci for psychiatric disorders. These loci converge on a small number of functional pathways, which span conventional diagnostic criteria, suggesting a partly common biology underlying schizophrenia, autism and other psychiatric disorders. Nevertheless, the cellular phenotypes that capture the fundamental features of psychiatric disorders have not yet been determined. Recent advances in genetics and stem cell biology offer new prospects for cell-based modeling of psychiatric disorders. The advent of cell reprogramming and induced pluripotent stem cells (iPSC) provides an opportunity to translate genetic findings into patient-specific in vitro models. iPSC technology is less than a decade old but holds great promise for bridging the gaps between patients, genetics and biology. Despite many obvious advantages, iPSC studies still present multiple challenges. In this expert review, we critically review the challenges for modeling of psychiatric disorders, potential solutions and how iPSC technology can be used to develop an analytical framework for the evaluation and therapeutic manipulation of fundamental disease processes.

Dialkylcarbamoyl chloride (DACC)-coated dressings in the management and prevention of wound infection: a systematic review.

OBJECTIVE: Dialkylcarbomoyl chloride (DACC)-coated dressings (Leukomed Sorbact and Cutimed Sorbact) irreversibly bind bacteria at the wound surface that are then removed when the dressing is changed. They are a recent addition to the wound care professional's armamentarium and have been used in a variety of acute and chronic wounds. This systematic review aims to assess the evidence supporting the use of DACC-coated dressings in the clinical environment. METHOD: We included all reports of the clinical use of DACC-coated dressings in relation to wound infection. Medline, Embase, CENTRAL and CINAHL databases were searched to September 2016 for studies evaluating the role of DACC-coated dressings in preventing or managing wound infections. RESULTS: We identified 17 studies with a total of 3408 patients which were included in this review. The DACC-coating was suggested to reduce postoperative surgical site infection rates and result in chronic wounds that subjectively looked cleaner and had less bacterial load on microbiological assessments. CONCLUSION: Existing evidence for DACC-coated dressings in managing chronic wounds or as a surgical site infection (SSI) prophylaxis is limited but encouraging with evidence in support of DACC-coated dressings preventing and treating infection without adverse effects.

Identification of the sex chromosomes of brown trout (Salmo trutta) and their comparison with the corresponding chromosomes in Atlantic salmon (Salmo salar) and rainbow trout (Oncorhynchus mykiss).

Males are the heterogametic sex in salmonid fishes. In brown trout (Salmo trutta) the sex-determining locus, SEX, has been mapped to the end of linkage group BT-28, which corresponds to linkage group AS-8 and chromosome SSA15 in Atlantic salmon (Salmo salar). We set out to identify the sex chromosomes in brown trout. We isolated Atlantic salmon BAC clones containing microsatellite markers that are on BT-28 and also on AS-8, and used these BACs as probes for fluorescent in situ hybridization (FISH) analysis. SEX is located on the short arm of a small subtelocentric/acrocentric chromosome in brown trout, which is consistent with linkage analysis. The acrocentric chromosome SSA15 in Atlantic salmon appears to have arisen by a centric fusion of 2 small acrocentric chromosomes in the common ancestor of Salmo sp. We speculate that the fusion process that produced Atlantic salmon chromosome SSA15 disrupted the ancestral sex-determining locus in the Atlantic salmon lineage, providing the impetus either for the relocation of SEX or selection pressure for a novel sex-determining gene to arise in this species. Thus, the sex-determining genes may differ in Atlantic salmon and brown trout.

'Super glue'.

Cell--cell adhesion is a significant mechanical component of cell and tissue structure. However, cell contacts are not just static mechanical structures: they are integrated into the cytoskeletal and signalling processes of the cell. The formation and remodelling of cell contacts are basic to both tissue morphogenesis and, after damage, wound repair. Loss of adhesion accompanies tumour metastasis. The interplay between these processes was a major theme of a recent joint meeting of the British Societies of Cell Biology and Developmental Biology on 'Cell and Tissue Morphogenesis' in Brighton, UK (3--6 April 2001).

The Pathfinder image-guided surgical robot.

This paper first describes the workflow of the Pathfinder image-guided surgical robot that has been designed to replace the stereotactic frame in neurosurgery, and then details the calibration stages employed in order to achieve submillimetre positioning accuracy of a tool tip. The process uses non-linear parameter identification techniques in conjunction with some procedures for camera calibration, which exploit the fact that the camera is mounted to a calibrated robot arm that executes precise motions.

Compliance with NICE guidelines when commissioning varicose vein procedures.

BACKGROUND: Varicose veins impair quality of life and can lead to chronic leg ulcers. National Institute for Health and Care Excellence (NICE) guidelines (CG168) set out evidence-based standards for patient management. In England, Clinical Commissioning Groups (CCGs) fund NHS care within their locality. The objective of this study was to evaluate CCGs' commissioning policies and compare them with CG168. METHODS: Searches were made for the published policies of all 206 English CCGs. They were reviewed for compliance with NICE guidelines and the associated quality standard. Areas of disagreement were analysed for themes. RESULTS: Some 203 CCGs (98·5 per cent) had a published policy and 190 (93·6 per cent) of these were published after publication of CG168. Only 73 of the policies (36·0 per cent) were compliant with CG168. Treatment was restricted on the basis of clinical disease severity in 119 CCGs (58·6 per cent); 29 (14·3 per cent) stipulated delay of treatment using a 'trial' of conservative treatment; 22 (10·8 per cent) used lifestyle-related factors such as BMI and smoking status to ration treatment. Treatment was commissioned for uncomplicated symptomatic varicose veins in 87 CCGs (42·9 per cent), but some applied additional rationing mechanisms; 109 CCGs (53·7 per cent) would treat oedema, 183 (90·1 per cent) would treat skin and soft tissue damage, 202 (99·5 per cent) healed ulceration, and all would allow active ulcers to be treated. DISCUSSION: The majority of CCGs in England have commissioning policies that contradict NICE guidelines. Rationing strategies include disease severity, delay and patient lifestyle-related factors, creating unwarranted geographical variation for varicose vein treatment, disregarding the NHS Constitution for England, and perhaps leading to an increase in costly treatment of chronic complications in the long term.

Signal transduction: Life, the universe and ... development.

Glycogen synthase kinase 3 (GSK-3) is a key component of the Wnt signalling pathway, among others, and is known to be regulated by inhibition. Now a novel, dual specificity protein kinase known as Zaphod kinase has been discovered that activates GSK-3 by tyrosine phosphorylation.

Quality of life in patients with intermittent claudication.

BACKGROUND: Intermittent claudication (IC) is a common condition that causes pain in the lower limbs when walking and has been shown to severely impact the quality of life (QoL) of patients. The QoL is therefore often regarded as an important measure in clinical trials investigating intermittent claudication. To date, no consensus exits on the type of life questionnaire to be used. This review aims to examine the QoL questionnaires used in trials investigating peripheral arterial disease (PAD). MATERIAL AND METHODS: A systematic review of randomised clinical trials including a primary analysis of QoL via questionnaire was performed. Trials involving patients with diagnosed PAD were included (either clinically or by questionnaire). Any trial which had QoL as the primary outcome data was included with no limit being placed on the type of questionnaire used. RESULTS: The search yielded a total of 1845 articles of which 31 were deemed appropriate for inclusion in the review. In total, 14 different QoL questionnaires were used across 31 studies. Of the questionnaires 24.06% were missing at least one domain when reported in the results of the study. Mean standard deviation varied widely based on the domain reported, particularly within the SF36. DISCUSSION: Despite previous recommendations for Europewide standardisation of quality of life assessment, to date no such tool exists. This review demonstrated that a number of different questionnaires remain in use, that their completion is often inadequate and that further evidence-based guidelines on QoL assessment are required to guide future research.

Comparison of extramedullary plasmacytomas with solitary and multiple plasma cell tumors of bone.

Patients with solitary osseous plasmacytomas (SOP) differ from those with extramedullary plasmacytomas (EMP) in that they are younger and the proportion of males is smaller. The median survival of the two groups is similar: 86.4 mo for SOP, and 100.8 mo for EMP. Progression-free survival, however, is much better for EMP. Only five EMP patients have progressed following initial radiation therapy: one developed a single bony lesion, two progressed to multiple myeloma, and two developed multiple EMP. Thus, 71% of EMP patients are progression free at 10 yr, and most deaths do not result from plasma cell neoplasia. In contrast, 13 SOP patients have progressed to develop additional osteolytic lesions, so that only 16% of SOP patients are progression free at 10 yr; death resulted from progression to multiple myeloma in most of these patients. In EMP patients the occurrence of involved lymph nodes at the time of diagnosis in seven, and initial relapse in regional nodes in three, suggest that consideration should be given to including regional lymph nodes in the radiation fields used to treat these patients.

Lithium therapy and signal transduction.

Lithium is the simplest therapeutic agent available for the treatment of depression and has been used for over 100 years, yet no definitive mechanism for its effect has been established. Among the proposed mechanisms, two lithium-sensitive signal transduction pathways are active in the brain; these are mediated by glycogen synthase kinase 3beta (GSK-3beta) and inositol (1,4,5)-trisphosphate [Ins(1,4,5)P3] signalling. This article describes recent experiments in cell and developmental biology that advance our understanding of how lithium works and it presents new directions for the study of both depression and Alzheimer's disease (AD).

Neurodevelopment and mood stabilizers.

Mood disorders and schizophrenia share a number of common properties, including: genetic susceptibility; differences in brain structure and drug based therapy. Some genetic loci may even confer susceptibility for bipolar mood disorder and schizophrenia, and some atypical antipsychotic drugs are used as mood stabilizers. As schizophrenia is associated with aberrant neurodevelopment, could this also be true for mood disorders? Such changes could arise pre- or post-natal, however the recent interest in neurogenesis in the adult brain has suggested involvement of these later processes in the origins of mood disorders. Interestingly, the common mood stabilizing drugs, lithium, valproic acid (VPA) and carbamazepine, are teratogens, affecting a number of aspects of animal development. Recent work has shown that lithium and VPA interfere with normal cell development, and all three drugs affect neuronal morphology. The molecular basis for mood stabilizer action in the treatment of mood is unknown, however these studies have suggested both targets and potential mechanisms. Lithium directly inhibits two evolutionarily conserved signal transduction pathways: the protein kinase Glycogen Synthase Kinase-3 (GSK-3) and inositol signaling. VPA can up-regulate gene expression through inhibition of histone deacetylase (HDAC) and indirectly reduce GSK-3 activity. VPA effects are not conserved between cell types, and carbamazepine has no effect on the GSK-3 pathway. All three mood stabilizers suppress inositol signaling, results further supported by studies on the enzyme prolyl oligopeptidase (PO) and the sodium myo-inositol transporter (SMIT). Despite these intriguing observations, it remains unclear whether GSK-3, inositol signaling or both underlie the origins of bipolar disorder.

Construction of a neo fusion gene for expression in both prokaryotic and eukaryotic cells.

A high-copy-number plasmid, pLink, was constructed to allow the direct selection in Escherichia coli of a neo fusion gene capable of conferring Geneticin (G418) resistance on mouse L cells. pLink was derived from pdMmtneo by insertion of a KpnI linker within the 5'-coding region of the neo gene. This created a minus-one frameshift mutation resulting in a translational termination within the N-terminal region of the protein. The Neo activity was restored by insertion into the modified neo gene of a piece of coding sequence derived from human HPRT cDNA. The resulting plasmid, pAH, was microinjected into mouse A9 cells and shown to confer resistance to G418.

A novel, negative selectable marker for gene disruption in Dictyostelium.

The expression of an ochre suppressor mutant of the GluII(UUA) tRNA appears to be lethal to Dictyostelium, and offers a novel 'positive negative' strategy to select for targeted gene disruption by homologous recombination. Inclusion of the suppressor tRNA gene decreases the overall transformation frequency by approximately 20-fold. This increases the proportion of targeted gene disruptions to over 90%.

Optimization and in situ detection of Escherichia coli beta-galactosidase gene expression in Dictyostelium discoideum.

We show that a fusion gene, containing the promoter and 5'-noncoding region of a Dictyostelium discoideum actin 6 gene linked to the Escherichia coli beta-galactosidase (beta Gal) gene (lacZ), directs the production of functionally active beta Gal in D. discoideum and that the enzyme can be detected by staining in situ; a procedure which will be of great value in analyzing cell-type-specific gene expression. We illustrate this by fusing lacZ to the promoter of the prespore-specific gene, D19, and localizing expressing cells in migrating slugs. Optimal expression requires the inclusion of termination and polyadenylylation signals and we describe pDDlac, a vector containing a multiple cloning site upstream from a lacZ-Dictyostelium terminator fusion, which can be used to analyze regulated promoters.

Conventional fractionated radiotherapy for 51 patients with lentigo maligna and lentigo maligna melanoma.

Lentigo maligna (LM) and lentigo maligna melanoma (LMM) are distinct entities from other forms of melanoma, occurring predominantly on the skin of the head and neck in elderly people, having a slow growth rate and a low metastatic potential (10%). Twenty-three patients with LM were treated with conventional fractionated irradiation, 18 were locally controlled and two failed locally both of whom, however, were salvaged with further treatment. Three patients are not evaluable because of short follow-up time. Median time to complete regression of the lesion is seven months. Twenty-eight patients with LMM have been irradiated, 23 are locally controlled, two locally recurred (both retrieved with subsequent treatment), and three are inevaluable because of short follow-up time. One patient with a level 5 LMM has developed regional and distant metastases. It is concluded that irradiation is a simple effective method of treatment for this form of melanoma.

The quality of life of patients following treatment for laryngeal cancer.

One hundred and twenty-nine patients have been interviewed 9 to 15 months following treatment for laryngeal cancer to determine the post treatment quality of voice and life. The patients were subdivided into 3 groups, successfully irradiated T1 and T2 patients, (89 patients), successfully irradiated T3 and T4 patients (24 patients) and those treated by surgery (16 patients). Ninety-three percent of T1 and T2 patients and 79% of T3 and T4 patients are working following treatment as compared to 44% of the surgery patients. Ninety-eight percent of the T1 and T2 and 87.5% of the T3 and T4 patients were able to use the telephone normally as compared to 12% of the surgery patients. Similarly major differences between the successfully irradiated patients and the surgically treated patients in terms of ability to live a normal social life have been noted. The patients also rated their voice in terms of volume, pitch, ability to communicate, quality, rate of speech, flow of speech and dry throat. In every parameter of rating of the voice, with the exception of dryness of the throat, the successfully irradiated patients in all stage groupings had better ratings than the surgery group. Since, in Toronto, survival in advanced glottic and supraglottic cancer is the same using radical radiation with surgery in reserve as survival with primary surgery, it is concluded in view of the superior quality of voice and life in the successfully irradiated patients that irradiation with surgery in reserve is the optimal treatment for these patients. We also conclude that the measurement of quality of life in patients with cancer of the larynx is of vital importance in determining optimal treatment and that further studies in this area are indicated.