Straight-to-test for the two-week-wait colorectal cancer pathway under the updated NICE guidelines reduces time to cancer diagnosis and treatment.

INTRODUCTION: The 2015 National Institute for Health and Care Excellence guidelines widened the referral criteria for the two-week-wait pathway for suspected lower gastrointestinal cancer. We implemented a straight-to-test protocol to accommodate the anticipated increase in referrals. We evaluated the impact of these changes for relevant pathway metrics and clinical outcomes using a retrospective cohort study with historic controls. MATERIALS AND METHODS: We analysed data from all patients referred to a teaching hospital via the two-week-wait pathway for suspected lower gastrointestinal cancer under the previous guidelines between 1 March and 31 August 2015 compared with the same period in 2016, when the updated guidelines and straight-to-test protocol had been implemented. RESULTS: In the 2015 cohort, there were 64 cancer diagnoses from 664 referrals (9.6% pick-up) compared with 58 cancer diagnoses from 954 referrals in the 2016 cohort (6.1% pick-up). Our straight-to-test protocol reduced the median time to cancer diagnosis by 12.5 days (P < 0.001) and reduced the median time to cancer treatment by 7.5 days (P < 0.05) An increased proportion of non-colorectal cancers were diagnosed in 2016 compared with 2015, (37.9% vs 17.2%, P < 0.05) and more adenomas were removed in 2016 compared with 2015 (377 vs 193). DISCUSSION AND CONCLUSION: Our straight-to-test protocol has resulted in a reduction in times to cancer diagnosis and cancer treatment, despite an increase in the number of referrals. The new referral criteria have considerable resource implications, but their implementation did not result in an increase in the total number of cancers diagnosed.

[New developments in the pharmacotherapy of cocaine dependence]. / Neue Entwicklungen in der Pharmakotherapie der Kokainabhängigkeit.

New possibilities with medications for the treatment of cocaine dependence have begun to emerge. For example, in a randomised controlled study, disulfiram succeeded for the first time in significantly reducing cocaine consumption. In October 2003, a phase IIb study was started in the USA testing active immunisation against cocaine dependence. There is also an ongoing study in Switzerland testing methylphenidate treatment in combination with cognitive behavioural therapy. Pilot studies indicate that vigabatrin, selegiline, and topiramate are promising candidates for further clinical substance testing.

[Cocaine and opiate related disorders]. / Störungen durch Kokain und Opiate.

Cocaine and the opiates are--together with alcohol--involved in the genesis of the "three great addictions". The medical conceptualisation of the dependence phenomenon has evolved on the grounds of a critical observation of different ways of use and treatment endeavours, mainly during the last three centuries. Whereas the prohibitionists favoured (and still favour) total abstinence from all psychotropic drugs, defect theoreticians emphasise analytically-oriented psychotherapeutic procedures aiming at healing a supposed underlying self-defect. Contrarily, proponents of the "Metabolic Theory" of the addictions suggest a mainly medication-based approach in order to normalise a--in their eyes causal--still in some aspects hypothetical metabolic defect. Based on a short survey of recently emerging trends of consumption patterns (speed-balling, chasing, multi-substance-use) in Europe, the most important newer treatment types and forms are presented. Finally, a multimodal, integrated, and individualized approach is recommended.

Frontocortical N-acetylaspartate reduction associated with long-term i.v. heroin use.

To examine possible metabolic frontal lobe alterations in i.v. heroin-dependent patients with different histories of concomitant substance use, N-acetylaspartate (NAA), a putative marker of neuronal viability, was measured by (1)H-MRS. Compared with controls, NAA levels in patients were reduced by 7% in gray matter (p = 0.015) but not in white matter. To what extent comorbid conditions or substance use, including alcohol, contributed to these frontocortical metabolic changes remains to be elucidated.

Novel strategy yields candidate Gsh-1 homeobox gene targets using hypothalamus progenitor cell lines.

We describe the successful application of a strategy that potentially provides for an efficient and universal screen for downstream gene targets. We used the promoter of the Gsh-1 homeobox gene to drive expression of the SV40 T-antigen gene in transgenic mice. We have previously shown that the Gsh-1 homeobox gene is expressed in discrete domains of the ganglionic eminences, diencephalon, and hindbrain during brain development. Gsh-1-SV40 T transgenic mice showed cellular hyperplasia in regions of the brain coincident with Gsh-1 expression. The Gsh-1-SV40 T transgene was introduced, by breeding, into Gsh-1 homozygous mutant mice, and Gsh-1 -/- cell lines were made. Clonal cell lines were generated and analyzed by Northern blot hybridizations and Affymetrix GeneChip probe arrays to determine gene expression profiles. The results indicate that the cell lines remain representative of early developmental stages. Further, immunocytochemistry showed uniformly high levels of nestin expression, typical of central nervous system progenitor cells, and the absence of terminal differentiation markers of neuronal cells. One clonal cell line, No. 14, was then stably transfected with a tet-inducible Gsh-1 expression construct and subcloned. The starting clone 14, together with the uninduced and induced subclones, provided cell populations with varying levels of Gsh-1 expression. Differential display and Affymetrix GeneChip probe arrays were then used to identify transcript differences that represent candidate Gsh-1 target genes. Of particular interest, the drm and gas1 genes, which repress cell proliferation, were observed to be activated in Gsh-1-expressing cells. These observations support models predicting that homeobox genes function in the regulation of cell proliferation.

RecA as a motor protein. Testing models for the role of ATP hydrolysis in DNA strand exchange.

ATP hydrolysis (by RecA protein) fundamentally alters the properties of RecA protein-mediated DNA strand exchange reactions. ATP hydrolysis renders DNA strand exchange unidirectional, greatly increases the lengths of hybrid DNA created, permits the bypass of heterologous DNA insertions in one or both DNA substrates, and is absolutely required for exchange reactions involving four DNA strands. There are at least two viable models to explain how ATP hydrolysis is coupled to DNA strand exchange so as to bring about these effects. The first couples ATP hydrolysis to a redistribution of RecA monomers within a RecA filament. The second couples ATP hydrolysis to a facilitated rotation of the DNA substrates. The RecA monomer redistribution model makes the prediction that heterology bypass should not occur if the single-stranded DNA substrate is linear. The facilitated DNA rotation model predicts that RecA protein should promote the separation of paired DNA strands within a RecA filament if one of them is contiguous with a length of DNA being rotated about the filament exterior. Here, a facile bypass of heterologous insertions with linear DNA substrates is demonstrated, providing evidence against a role for RecA monomer redistribution in heterology bypass. In addition, we demonstrate that following a four-strand DNA exchange reaction, a distal segment of DNA hundreds of base pairs in length can be unwound in a nonreciprocal phase of the reaction, consistent with the direct coupling of an ATP hydrolytic motor to the proposed DNA rotation.