Contemporary management of drug-packers

Experience with management of drug-packers (mules) is variable among different centres. However, despite a recorded increase in drug trafficking in general, as yet, no unified, clear guidelines exist to guide the medical management of those who only occasionally encounter these individuals. We describe our recent experience with this growing problem and discuss the most salient points concerning the contemporary management of body packers. Our recent experience demonstrates that type IV packages may now be managed conservatively for the most part

Post-traumatic tension faecopneumothorax in a young male: case report

Diaphragmatic rupture due to trauma is both well recognised and uncommon. The difficulties in diagnosing traumatic diaphragmatic rupture at the first admission are the most common causes of latent morbidity and mortality. Herniation of the abdominal viscera is the most common sequel with strangulation and perforation the most serious complication. This case outlines the delayed presentation of diaphragmatic rupture and herniation presenting as an acute tension faecopneumothorax. We review the relevant literature, with particular emphasis on the difficulties in diagnosis at presentation

Pyrimidine biosynthesis is not an essential function for trypanosoma brucei bloodstream forms

<p>Background: African trypanosomes are capable of both pyrimidine biosynthesis and salvage of preformed pyrimidines from the host, but it is unknown whether either process is essential to the parasite.</p> <p>Methodology/Principal Findings: Pyrimidine requirements for growth were investigated using strictly pyrimidine-free media, with or without single added pyrimidine sources. Growth rates of wild-type bloodstream form Trypanosoma brucei brucei were unchanged in pyrimidine-free medium. The essentiality of the de novo pyrimidine biosynthesis pathway was studied by knocking out the PYR6-5 locus that produces a fusion product of orotate phosphoribosyltransferase (OPRT) and Orotidine Monophosphate Decarboxylase (OMPDCase). The pyrimidine auxotroph was dependent on a suitable extracellular pyrimidine source. Pyrimidine starvation was rapidly lethal and non-reversible, causing incomplete DNA content in new cells. The phenotype could be rescued by addition of uracil; supplementation with uridine, 2′deoxyuridine, and cytidine allowed a diminished growth rate and density. PYR6-5−/− trypanosomes were more sensitive to pyrimidine antimetabolites and displayed increased uracil transport rates and uridine phosphorylase activity. Pyrimidine auxotrophs were able to infect mice although the infection developed much more slowly than infection with the parental, prototrophic trypanosome line.</p> <p>Conclusions/Significance: Pyrimidine salvage was not an essential function for bloodstream T. b. brucei. However, trypanosomes lacking de novo pyrimidine biosynthesis are completely dependent on an extracellular pyrimidine source, strongly preferring uracil, and display reduced infectivity. As T. brucei are able to salvage sufficient pyrimidines from the host environment, the pyrimidine biosynthesis pathway is not a viable drug target, although any interruption of pyrimidine supply was lethal.</p&gt

The ideal healthcare: priorities of people with chronic conditions and their carers

Background It is well established that health consumer opinions should be considered in the design, delivery, and evaluation of health services. However, the opinions of people with chronic conditions and their carers and what they actually consider as ideal healthcare is limited. The aim of this study is to investigate the healthcare priorities of consumers with chronic conditions and their carers, if there are differences between these two groups, and if priorities differ depending on geographical location. Methods The nominal group technique was used as a method to identify what is currently important to, or valued by, participants. This method was also particularly suited to learning about healthcare problems and generating important solutions, thereby helping to bridge the gap between research and policy. Recruitment was carried out via purposive sampling, with the assistance of community pharmacies, general practices, various health agencies, government and non-government organisations. A total of 11 nominal groups were conducted; five groups consisted predominantly of consumers (n = 33 participants), two groups consisted predominantly of carers (n = 12 participants) and four were mixed groups, i.e. consumers, carers, and both (n = 26 participants). Results The findings suggested that to create a model of ideal healthcare for people with chronic conditions and their carers, appropriate and timely healthcare access was of paramount importance. Continuity and coordinated care, patient-centred care and affordability were equally the second most important healthcare priorities for all groups. When compared with other groups, access was discussed more frequently among participants residing in the rural area of Mount Isa. Compared to consumers, carers also discussed priorities that were more reminiscent with their caring roles, such as increased access and continuity and coordinated care. Conclusions Access to healthcare is the most important priority for people with chronic conditions and their carers. In the event of inappropriate access for certain groups, all other efforts to increase the quality of healthcare delivery, e.g. patient-centred care, may be pointless. However, health professionals alone may be limited in their ability to address the concerns related to healthcare access; structural changes by health policy makers may be needed

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Incidence of first stroke and ethnic differences in stroke pattern in Bradford, UK: Bradford Stroke Study

Background: Information on ethnic disparities in stroke between White and Pakistani population in Europe is scarce. Bradford District has the largest proportion of Pakistani people in England; this provides a unique opportunity to study the difference in stroke between the two major ethnic groups. Aim: To determine the first-ever-stroke incidence and examine the disparities in stroke patterns between Whites and Pakistanis in Bradford. Methods: Prospective 12 months study consisting of 273,327 adults (≥18 years) residents. Stroke cases were identified by multiple overlapping approaches. Results: In the study period, 541 first-ever-strokes were recorded. The crude incidence rate was 198 per 100,000 person-years. Age adjusted-standardized rate to the World Health Organization world population of first-ever-stroke is 155 and 101 per 100,000 person-years in Pakistanis and Whites respectively. Four hundred and thirty-eight patients (81%) were Whites, 83 (15.3%) were Pakistanis, 11 (2%) were Indian and Bangladeshis, and 9 (1.7%) were of other ethnic origin. Pakistanis were significantly younger and had more obesity (p = 0.049), and diabetes mellitus (DM) (p = <0.001). They were less likely to suffer from atrial fibrillation (p = <0.001), be ex- or current smokers (p = <0.001), and drink alcohol above the recommended level (p = 0.007) compared with Whites. In comparison with Whites, higher rates of age-adjusted stroke (1.5-fold), lacunar infarction (threefold), and ischemic infarction due to large artery disease (twofold) were found in the Pakistanis. Conclusions: The incidence of first-ever-stroke is higher in the Pakistanis compared with the Whites in Bradford, UK. Etiology and vascular risk factors vary between the ethnic groups. This information should be considered when investigating stroke etiology, and when planning prevention and care provision to improve outcomes after stroke

Discovery of Genes Activated by the Mitochondrial Unfolded Protein Response (mtUPR) and Cognate Promoter Elements

In an accompanying paper, we show that the mitochondrial Unfolded Protein Response or mtUPR is initiated by the activation of transcription of chop through an AP-1 element in the chop promoter. Further, we show that the c/ebpβ gene is similarly activated and CHOP and C/EBPβ subsequently hetero-dimerise to activate transcription of mtUPR responsive genes. Here, we report the discovery of six additional mtUPR responsive genes. We found that these genes encoding mitochondrial proteases YME1L1 and MPPβ, import component Tim17A and enzymes NDUFB2, endonuclease G and thioredoxin 2, all contain a CHOP element in their promoters. In contrast, genes encoding mitochondrial proteins Afg3L2, Paraplegin, Lon and SAM 50, which do not have a CHOP element, were not up-regulated. Conversely, genes with CHOP elements encoding cytosolic proteins were not induced by the accumulation of unfolded proteins in mitochondria. These results indicate that mtUPR responsive genes appear to share a requirement for a CHOP element, but that this is not sufficient for the regulation of the mtUPR. A more detailed analysis of promoters of mtUPR responsive genes revealed at least two additional highly conserved, putative regulatory sites either side of the CHOP element, one a motif of 12 bp which lies 14 bp upstream of the CHOP site and another 9 bp element, 2 bp downstream of the CHOP site. Both of these additional elements are conserved in the promoters of 9 of the ten mtUPR responsive genes we have identified so far, the exception being the Cpn60/10 bidirectional promoter. Mutation of each of these elements substantially reduced the mtUPR responsiveness of the promoters suggesting that these elements coordinately regulate mtUPR

Piperidinols that show anti-tubercular activity as inhibitors of arylamine N-acetyltransferase: an essential enzyme for mycobacterial survival inside macrophages

Latent M. tuberculosis infection presents one of the major obstacles in the global eradication of tuberculosis (TB). Cholesterol plays a critical role in the persistence of M. tuberculosis within the macrophage during latent infection. Catabolism of cholesterol contributes to the pool of propionyl-CoA, a precursor that is incorporated into cell-wall lipids. Arylamine N-acetyltransferase (NAT) is encoded within a gene cluster that is involved in the cholesterol sterol-ring degradation and is essential for intracellular survival. The ability of the NAT from M. tuberculosis (TBNAT) to utilise propionyl-CoA links it to the cholesterol-catabolism pathway. Deleting the nat gene or inhibiting the NAT enzyme prevents intracellular survival and results in depletion of cell-wall lipids. TBNAT has been investigated as a potential target for TB therapies. From a previous high-throughput screen, 3-benzoyl-4-phenyl-1-methylpiperidinol was identified as a selective inhibitor of prokaryotic NAT that exhibited antimycobacterial activity. The compound resulted in time-dependent irreversible inhibition of the NAT activity when tested against NAT from M. marinum (MMNAT). To further evaluate the antimycobacterial activity and the NAT inhibition of this compound, four piperidinol analogues were tested. All five compounds exert potent antimycobacterial activity against M. tuberculosis with MIC values of 2.3-16.9 µM. Treatment of the MMNAT enzyme with this set of inhibitors resulted in an irreversible time-dependent inhibition of NAT activity. Here we investigate the mechanism of NAT inhibition by studying protein-ligand interactions using mass spectrometry in combination with enzyme analysis and structure determination. We propose a covalent mechanism of NAT inhibition that involves the formation of a reactive intermediate and selective cysteine residue modification. These piperidinols present a unique class of antimycobacterial compounds that have a novel mode of action different from known anti-tubercular drugs

Cytokinesis in bloodstream stage Trypanosoma brucei requires a family of katanins and spastin

Microtubule severing enzymes regulate microtubule dynamics in a wide range of organisms and are implicated in important cell cycle processes such as mitotic spindle assembly and disassembly, chromosome movement and cytokinesis. Here we explore the function of several microtubule severing enzyme homologues, the katanins (KAT80, KAT60a, KAT60b and KAT60c), spastin (SPA) and fidgetin (FID) in the bloodstream stage of the African trypanosome parasite, Trypanosoma brucei. The trypanosome cytoskeleton is microtubule based and remains assembled throughout the cell cycle, necessitating its remodelling during cytokinesis. Using RNA interference to deplete individual proteins, we show that the trypanosome katanin and spastin homologues are non-redundant and essential for bloodstream form proliferation. Further, cell cycle analysis revealed that these proteins play essential but discrete roles in cytokinesis. The KAT60 proteins each appear to be important during the early stages of cytokinesis, while downregulation of KAT80 specifically inhibited furrow ingression and SPA depletion prevented completion of abscission. In contrast, RNA interference of FID did not result in any discernible effects. We propose that the stable microtubule cytoskeleton of T. brucei necessitates the coordinated action of a family of katanins and spastin to bring about the cytoskeletal remodelling necessary to complete cell divisio