Environmental radioactivity assessment of the Brunei Darussalam coastline of the South China Sea.

Radioactivity levels of naturally occurring radionuclides at the coast of Brunei Darussalam were evaluated along with their dose rates. Twenty-six berm and intertidal sediment samples were measured using gamma-ray spectrometry. The mean activity concentrations of 226Ra, 232Th and 40K in berm sediments were 10.07 ± 1.02 Bq/kg, below the minimum detectable activity, and 21.44 ± 1.23 Bq/kg, respectively, whereas for intertidal sediments they were 7.01 ± 0.87, 1.67 ± 0.15 and 4.99 ± 0.42 Bq/kg, respectively. With respect to the radiological health risk, the average hazard indices, absorbed gamma dose rate, effective dose equivalent, and excess lifetime cancer risk were found to be less than the global average. Calculation of the activity ratio showed that 40K is the main source of radiation in the coastal sediments. Furthermore, the difference in radioactivity levels between the berm sediments and intertidal sediments collected at the same location was investigated. Finally, a standard geological terminology of the littoral zone profile is proposed for describing coastal samples for universal communication among researchers.

Assessment of radioactivity concentration in intertidal sediments from coastal provinces in Oman and estimation of hazard and radiation indices.

The natural radioactivity of intertidal sediment samples collected from the beaches of Oman was investigated. Using gamma ray spectrometry, the activity concentrations of 226Ra, 232Th and 40K in the sediment samples were measured to have average values of 20.49 ± 3.50, 2.26 ± 0.60 and 44.83 ± 4.60 Bq kg-1 respectively. The activity levels reported are considerably lower than the worldwide average. The annual effective dose rate was estimated to be 0.015 mSv yr-1 on average. Additionally, the mean radium equivalent, external and internal indices were 26.89, 0.07 and 0.13 Bq kg-1 respectively which were well below the risk limits. Gamma and alpha radiation indices were computed to be less than unity and show no exceedance beyond the recommended level. Our results provide baseline data for radioactivity in intertidal sediment samples of Oman and show that intertidal beach sand does not pose significant radiological risk to human health.

Functional and genetic evidence that nucleoside transport is highly conserved in Leishmania species: Implications for pyrimidine-based chemotherapy.

Leishmania pyrimidine salvage is replete with opportunities for therapeutic intervention with enzyme inhibitors or antimetabolites. Their uptake into cells depends upon specific transporters; therefore it is essential to establish whether various Leishmania species possess similar pyrimidine transporters capable of drug uptake. Here, we report a comprehensive characterization of pyrimidine transport in L. major and L. mexicana. In both species, two transporters for uridine/adenosine were detected, one of which also transported uracil and the antimetabolites 5-fluoruracil (5-FU) and 5F,2'deoxyuridine (5F,2'dUrd), and was designated uridine-uracil transporter 1 (UUT1); the other transporter mediated uptake of adenosine, uridine, 5F,2'dUrd and thymidine and was designated Nucleoside Transporter 1 (NT1). To verify the reported L. donovani model of two NT1-like genes encoding uridine/adenosine transporters, and an NT2 gene encoding an inosine transporter, we cloned the corresponding L. major and L. mexicana genes, expressing each in T. brucei. Consistent with the L. donovani reports, the NT1-like genes of either species mediated the adenosine-sensitive uptake of [3H]-uridine but not of [3H]-inosine. Conversely, the NT2-like genes mediated uptake of [3H]-inosine but not [3H]-uridine. Among pyrimidine antimetabolites tested, 5-FU and 5F,2'dUrd were the most effective antileishmanials; resistance to both analogs was induced in L. major and L. mexicana. In each case it was found that the resistant cells had lost the transport capacity for the inducing drug. Metabolomics analysis found that the mechanism of action of 5-FU and 5F-2'dUrd was similar in both Leishmania species, with major changes in deoxynucleotide metabolism. We conclude that the pyrimidine salvage system is highly conserved in Leishmania species - essential information for the development of pyrimidine-based chemotherapy.

Controlled human malaria infection of Tanzanians by intradermal injection of aseptic, purified, cryopreserved Plasmodium falciparum sporozoites.

Controlled human malaria infection (CHMI) by mosquito bite has been used to assess anti-malaria interventions in > 1,500 volunteers since development of methods for infecting mosquitoes by feeding on Plasmodium falciparum (Pf) gametocyte cultures. Such CHMIs have never been used in Africa. Aseptic, purified, cryopreserved Pf sporozoites, PfSPZ Challenge, were used to infect Dutch volunteers by intradermal injection. We conducted a double-blind, placebo-controlled trial to assess safety and infectivity of PfSPZ Challenge in adult male Tanzanians. Volunteers were injected intradermally with 10,000 (N = 12) or 25,000 (N = 12) PfSPZ or normal saline (N = 6). PfSPZ Challenge was well tolerated and safe. Eleven of 12 and 10 of 11 subjects, who received 10,000 and 25,000 PfSPZ respectively, developed parasitemia. In 10,000 versus 25,000 PfSPZ groups geometric mean days from injection to Pf positivity by thick blood film was 15.4 versus 13.5 (P = 0.023). Alpha-thalassemia heterozygosity had no apparent effect on infectivity. PfSPZ Challenge was safe, well tolerated, and infectious.

When Are Circular Lesions Square? A National Clinical Education Skin Lesion Audit and Study

BACKGROUND: Skin cancer is the most prevalent cancer by organ type and referral accuracy is vital for diagnosis and management. The British Association of Dermatologists (BAD) and literature highlight the importance of accurate skin lesion examination, diagnosis and educationally-relevant studies. METHODS: We undertook a review of the relevant literature, a national audit of skin lesion description standards and a study of speciality training influences on these descriptions. Questionnaires (n=200), with pictures of a circular and an oval lesion, were distributed to UK dermatology/plastic surgery consultants and speciality trainees (ST), general practitioners (GP), and medical students (MS). The following variables were analysed against a pre-defined 95% inclusion accuracy standard: site, shape, size, skin/colour, and presence of associated scars. RESULTS: There were 250 lesion descriptions provided by 125 consultants, STs, GPs, and MSs. Inclusion accuracy was greatest for consultants over STs (80% vs. 68%; P<0.001), GPs (57%) and MSs (46%) (P<0.0001), for STs over GPs (P<0.010) and MSs (P<0.0001) and for GPs over MSs (P<0.010), all falling below audit standard. Size description accuracy sub-analysis according to circular/oval dimensions was as follows: consultants (94%), GPs (80%), STs (73%), MSs (37%), with the most common error implying a quadrilateral shape (66%). Addressing BAD guidelines and published requirements for more empirical performance data to improve teaching methods, we performed a national audit and studied skin lesion descriptions. To improve diagnostic and referral accuracy for patients, healthcare professionals must strive towards accuracy (a circle is not a square). CONCLUSIONS: We provide supportive evidence that increased speciality training improves this process and propose that greater focus is placed on such training early on during medical training, and maintained throughout clinical practice.

Cyclic AMP effectors in African trypanosomes revealed by genome-scale RNA interference library screening for resistance to the phosphodiesterase inhibitor CpdA.

One of the most promising new targets for trypanocidal drugs to emerge in recent years is the cyclic AMP (cAMP) phosphodiesterase (PDE) activity encoded by TbrPDEB1 and TbrPDEB2. These genes were genetically confirmed as essential, and a high-affinity inhibitor, CpdA, displays potent antitrypanosomal activity. To identify effectors of the elevated cAMP levels resulting from CpdA action and, consequently, potential sites for adaptations giving resistance to PDE inhibitors, resistance to the drug was induced. Selection of mutagenized trypanosomes resulted in resistance to CpdA as well as cross-resistance to membrane-permeable cAMP analogues but not to currently used trypanocidal drugs. Resistance was not due to changes in cAMP levels or in PDEB genes. A second approach, a genome-wide RNA interference (RNAi) library screen, returned four genes giving resistance to CpdA upon knockdown. Validation by independent RNAi strategies confirmed resistance to CpdA and suggested a role for the identified cAMP Response Proteins (CARPs) in cAMP action. CARP1 is unique to kinetoplastid parasites and has predicted cyclic nucleotide binding-like domains, and RNAi repression resulted in >100-fold resistance. CARP2 and CARP4 are hypothetical conserved proteins associated with the eukaryotic flagellar proteome or with flagellar function, with an orthologue of CARP4 implicated in human disease. CARP3 is a hypothetical protein, unique to Trypanosoma. CARP1 to CARP4 likely represent components of a novel cAMP signaling pathway in the parasite. As cAMP metabolism is validated as a drug target in Trypanosoma brucei, cAMP effectors highly divergent from the mammalian host, such as CARP1, lend themselves to further pharmacological development.

Pyrimidine biosynthesis is not an essential function for Trypanosoma brucei bloodstream forms.

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. 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. 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.

Pyrimidine salvage in Trypanosoma brucei bloodstream forms and the trypanocidal action of halogenated pyrimidines.

African trypanosomes are capable of both pyrimidine biosynthesis and salvage of preformed pyrimidines from the host. However, uptake of pyrimidines in bloodstream form trypanosomes has not been investigated, making it difficult to judge the relative importance of salvage and synthesis or to design a pyrimidine-based chemotherapy. Detailed characterization of pyrimidine transport activities in bloodstream form Trypanosoma brucei brucei found that these cells express a high-affinity uracil transporter (designated TbU3) that is clearly distinct from the procyclic pyrimidine transporters. This transporter had low affinity for uridine and 2'deoxyuridine and was the sole pyrimidine transporter expressed in these cells. In addition, thymidine was taken up inefficiently through a P1-type nucleoside transporter. Of importance, the anticancer drug 5-fluorouracil was an excellent substrate for TbU3, and several 5-fluoropyrimidine analogs were investigated for uptake and trypanocidal activity; 5F-orotic acid, 5F-2'deoxyuridine displayed activity in the low micromolar range. The metabolism and mode of action of these analogs was determined using metabolomic assessments of T. brucei clonal lines adapted to high levels of these pyrimidine analogs, and of the sensitive parental strains. The analysis showed that 5-fluorouracil is incorporated into a large number of metabolites but likely exerts toxicity through incorporation into RNA. 5F-2'dUrd and 5F-2'dCtd are not incorporated into nucleic acids but act as prodrugs by inhibiting thymidylate synthase as 5F-dUMP. We present the most complete model of pyrimidine salvage in T. brucei to date, supported by genome-wide profiling of the predicted pyrimidine biosynthesis and conversion enzymes.

Synthesis of marine-derived 3-alkylpyridinium alkaloids with potent antiprotozoal activity.

Given the pressing need for new antiprotozoal drugs without cross-resistance with current (failing) chemotherapy, we have explored 3-tridecylpyridinium alkaloids (3TPAs), derivatives of viscosamine, as antiparasitic agents. We have developed a simple synthetic route toward viscosamine and related cyclic and linear monomers and oligomers. Evaluation for cytotoxicity on the protozoan parasites Trypanosoma brucei, Leishmania spp., and Plasmodium falciparum revealed several 3TPAs with antiprotozoal activity in the nanomolar range. Their promising selectivity index in vitro prompted us to study the dynamics of cytotoxicity on trypanosomes in more detail. Parasites were killed relatively slowly at therapeutically safe concentrations, in a process that did not target the cell cycle. Clearance of T. brucei cultures was observed at drug concentrations of 1-10 µM.

Prevalence of body dysmorphic features in patients undergoing cosmetic procedures at the National Skin Centre, Singapore.

BACKGROUND: Body dysmorphic disorder (BDD) is characterised by an obsessive preoccupation with a slight defect in appearance, and recognition is essential. OBJECTIVE: To screen by a previously developed questionnaire the prevalence of BDD in an aesthetics clinic in Singapore. This questionnaire has a positive predictive value of 70% and a negative predictive value of 100%; patients answering that they were preoccupied with their appearance and having answered 'yes' in part A, answered 8 further questions (part B) grading the degree of distress (B4) and impairment (B5) of social functioning. METHODS: The questionnaire was given to 396 patients: 198 attending Mandalay Aesthetics Clinic and 198 controls at a general outpatient clinic. The screen was considered suggestive of BDD if the patients: were preoccupied by their defect (question A) and qualified the degree of stress (question B4) or impairment of functioning (question B5) as moderate to severe. RESULTS: 58.1% of patients undergoing cosmetic procedures answered 'yes' to question A (odds ratio = 18.21, 95% confidence interval = 9.87-33.59). 41.74 and 26.96% of those qualified the distress (question B4) and impairment (question B5) as moderate to severe. CONCLUSION: A calculated prevalence of 29.4% in an aesthetics centre warrants systematic screening for BDD.

Complicação vascular de osteocondroma: relato de caso / Vascular complication of osteochondroma: case report

Osteocondromas ou exostose são os tumores benignos mais comuns do tecido ósseo . Eles surgem durante o período de crescimento e, raramente, são responsáveis por complicações vasculares. No presente relato, reportamos um caso de paciente com osteocondroma no membro inferior e complicação vascular provocada pela compressão da artéria poplítea. O paciente apresentava queixas de dor em membro inferior direito quando foi investigado com angiografia e radiografia, que identificaram a lesão vascular e a tumoração óssea. Os tratamentos cirúrgicos simultâneos de ambas as lesões foram realizados com boa evolução pós-operatória.

Estudo retrospectivo comparativo de algumas técnicas cirúrgicas no tratamento do "hallux valgus" / A comparative retrospective study of some surgical techniques in the treatment of hallux valgus

Em estudo retrospectivo os autores comparam os resultados de 70 pés operados de hallux valgus, com seguimento médio de 58 meses, pelas seguintes técnicas: Hohmann, chevron, tipo Lelièvre-Viladot e osteotomia na base do primeiro metatarsiano. Confrontam-se as variaçöes pré e pós-operatórias, mediante análise dos resultados, que foram obtidos baseados em critérios subjetivos e objetivos. Conclui-se que as variaçöes encontradas nos valores pré e pós-operatórios dos ângulos intermetatársico, de valgismo do hallux e protusäo relativa do primeiro metatarsiano säo fatores fundamentais para obter bons resultados com as diversas técnicas cirúrgicas em estudo. Além disso, a avaliaçäo de cada caso de maneira individual é de suma importância para decidir pelo procedimento ideal a ser feito

Tratamentos das discrepâncias de comprimento dos membros inferiores através da epifisiodese / Treatment of lower limb discrepancies by epiphysiodesis

Foram revistos retrospectivamente 28 pacientes submetidos a epifisiodese para tratamento das discrepâncias de comprimento de membros inferiores, 22 pela técnica percutânea e seis pela de Phemister. O tempo de hospitalizaçÒo pela técnica percutânea foi de um dia. Houve bloqueio de crescimento em todos os pacientes. A única complicaçäo encontrada foi uma sinovite de articulaçäo do joelho, que ocorreu em oito pacientes e se resolveu completamente em um tempo máximo de duas semanas. Devido a sua simplicidade, bom aspecto estético da cicatriz, curto tempo de hospitalizaçäo, baixo custo, efetividade e pequeno índice de complicaçöes, a epifisiodese, especialmente a técnica percutânea, é nosso método de escolha nos pacientes em crescimento com discrepância de comprimento dos membros inferiores final projetada entre 2cm e 5cm.