Structure-activity relationships and mechanism of action of tetragomycin derivatives as inhibitors of Staphylococcus aureus staphyloxanthin biosynthesis.

Despite the main strategy to overcome bacterial resistance has focused on the development of more potent antimicrobial agents, the evolutionary pressure caused by such drugs makes this strategy limited. Molecules that interfere with virulence factors appear as a promising alternative though, as they cause reduced selective pressure. As a matter of fact, staphyloxanthin biosynthesis inhibition (STXBI) has been pursued as promising strategy to reduce S. aureus virulence. Herein, we report the inhibitory profile of 27 tetrangomycin derivatives over staphyloxanthin production. The experimental result showed that naphthoquinone dehydro-α-lapachone (25 - EC50 = 57.29 ± 1.15 µM) and 2-Isopropylnaphtho[2,3-b]furan-4,9-dione (26 EC50 = 82.10 ± 1.09 µM) are the most potent compounds and suggest that hydrogen acceptor groups and lipophilic moieties decorating the naphthoquinone ring are crucial for STXBI. In addition, we present an in situ analysis, through RAMAN spectroscopy, that is inexpensive and might be employed to probe the mechanism of action of staphyloxanthin biosynthesis inhibitors. Therefore, our molecular simplification strategies afforded promising lead compounds for the development of drugs that modulate S. aureus staphyloxanthin biosynthesis.

Lives and Economic Loss in Brazil due to Lack of Radiotherapy Access in Cervical Cancer: A Cost-Effectiveness Analysis.

AIMS: Among all malignancies, the use of radiotherapy incurs the highest survival benefit within cervical cancers. Radiotherapy, however, remains underutilised for cervical cancers within the Brazilian public health system (BPHS). The objective of this study was to estimate the potential health and monetary benefits for universal access to radiotherapy and chemoradiotherapy (CRT) for untreated cervical cancer patients in the BPHS. MATERIALS AND METHODS: Using 2016 data on Brazilian cervical cancer incidence and availability of radiotherapy/CRT in the BPHS, the number of cancer deaths due to radiotherapy/CRT underutilisation was estimated. The incremental effectiveness was calculated by life-year gain. The indirect costs from mortality-related productivity loss (MRPL) were estimated based on life expectancy, wage and labour force participation rate. MRPL was compared with direct medical costs after being adjusted to 2016 US dollars. This study was conducted from the payer's perspective; both costs and effectiveness were discounted at a rate of 3%. The incremental cost-effectiveness ratio (ICER) was calculated to determine the cost-effectiveness of radiotherapy for cervical cancer in Brazil. One-way sensitivity analyses were carried out to assess the robustness of the model. RESULTS: The total number of life-years lost due to lack of universal access to radiotherapy and CRT per year were 27 199 and 31 627, respectively. The annual cost to match the radiotherapy gap was $10.5 million, with an additional cost of $3 million to close the CRT gap. The mean years of potential life lost per death was 20.5. The cost per life saved was $7942 for radiotherapy alone (ICER $388/life-year) and $8774 for CRT (ICER $429/life-year). MRPL due to shortage of radiotherapy and CRT were $59 million and $69 million, respectively. CONCLUSION: Providing universal access to radiotherapy/CRT for cervical cancer patients in the BPHS is highly cost-effective and should be prioritised as an impactful public health initiative.

Avaliação psicométrica em português do indicador de dor crônica de Helsinki em cães com sinais crônicos de osteoartrite / Psychometric testing in Portuguese of Helsinki's chronic pain index for dogs with chronic signs of osteoarthritis

Objetivou-se determinar a validade, a confiabilidade e a sensibilidade do indicador de dor crônica de Helsinki (IDCH) em português, além de estabelecer correlação entre a plataforma de pressão em cães com displasia coxofemoral (DCF). O questionário foi preenchido por tutores de 40 animais com DCF e por 16 tutores de cães saudáveis. Os animais com DCF foram tratados com carprofeno 4,4mg/kg (GT= 21) ou placebo (GP= 19), administrados uma vez ao dia, durante quatro semanas. A avaliação consistiu no preenchimento do questionário (IDCH), na escala analógica visual de dor (EAVdor) e na escala analógica visual de locomoção (EAVloc) com duas semanas (A1) e imediatamente antes do tratamento (A2), duas (S2) e quatro (S4) semanas de tratamento e após duas semanas do término do tratamento (S6). A consistência interna dos dados foi considerada excelente (alfa de Cronbach = 0,89). Houve correlação moderada entre o IDCH e a EAVdor e boa entre o IDCH e a EAVloc, porém não houve diferença entre o grupo tratado com carprofeno e placebo no IDCH. Não houve correlação entre os dados da plataforma de pressão e o IDCH. O questionário apresentou validade de constructo, critério e fidedignidade e pode-se empregá-lo em países de língua portuguesa em cães com osteoartrite.(AU)

We aimed to determine validity, reliability, and sensitivity of Helsinki's chronic pain index (HCPI) and stablish a correlation between HCPI in dogs with hip dysplasia (HD) using pressure sensitive walkway. Forty-owners of dogs with HD and 16 owners of health dogs filled a questionnaire. Dogs with HD were treated with carprofen 4.4mg/kg (GT n= 21) or with placebo (GP n= 19), both were administered once a day for 4 weeks. Evaluation was performed by the owners using the questionnaire (HCPI), the Visual Analogue Scale for pain (VASpain) and the VAS for locomotion (VASloc). The evaluation was performed 2 weeks before the treatment began (A1), immediately after treatment (A2), two (S2), four (S4) and two weeks after the end of treatment (S6) and the lameness was evaluated by pressure sensitive walkway. The internal consistency of the data was considered excellent (Cronbach´α coefficient= 0.89). There was a moderate correlation between the HCPI and VASpain. For VASloc the correlation was good. However, there was no difference between treatments, indicating low sensibility. No correlation was observed between pressure sensitive walkway and HCPI. We concluded that the questionnaire has construct and criterion validity, reliability and can be applied in dogs with osteoarthritis in Portuguese-speaking countries.(AU)

Radiographic measurements of the hindlimbs in crab-eating foxes (Cerdocyon thous, Linnaeus, 1766).

Life expectancy of crab-eating foxes in captivity is approximately 11 years, which favours the development of diseases including orthopaedic disorders. However, to understand disorders that may affect these animals, it is worth determining a normal range of measurements. Therefore, this study aimed to evaluate radiographic measurements of joint angles of the hindlimbs and the ratio of patellar ligament length to patellar length in healthy crab-eating foxes. Fifteen captive crab-eating foxes (Cerdocyon thous), eight males and seven females, aged more than 1 year old, weighing 5.5-7.9 kg were used. Anatomic and mechanical femoral joint angles were assessed in ventrodorsal radiographic views, and mediolateral views were taken to measure patellar ligament length and patellar length, and the tibial plateau angle. The right and left hindlimbs were evaluated. All measurements were conducted in triplicate by the same investigator. No statistically significant differences were observed between sides in the radiographic measurements. The anatomic lateral proximal femoral angle and the anatomic lateral distal femoral angle recorded mean values of 95.43° and 92.75°, respectively. The mechanical lateral proximal femoral angle and the mechanical lateral distal femoral angle recorded mean values of 93.39° and 96.75°, respectively. Inclination angles measured according to the Tomlinson, Hauptman A and Hauptman B methods were 133.80°, 147.32° and 128.63°, respectively. The tibial plateau recorded 18.77°, and the ratio of the patellar ligament length to the patellar length was 1.99. In conclusion, the collected data are important to characterize the normal values of crab-eating fox limbs.

Osteology and radiology of the Maned Wolf (Chrysocyon brachyurus) pelvic limb.

This study describes the osteology and radiology of the pelvic limb in maned wolves. Ten (five live and five dead) maned wolves (Chrysocyon brachyurus), five males and five females, aged from 2 to 7 years old were used. Digital radiographs were taken and recorded for both pelvic limbs in all animals. Osteology was correlated with the radiographic images. The pelvis had a rectangular shape, and the obturator foramen (foramen obturatum) was oval. The femoral neck (collum femoris) was short and thick. The greater trochanter (trochanter major) extended proximally to near the dorsum of the femoral head (caput ossis femoris). The lateral femoral condyle (condylus lateralis) was larger than the medial condyle (condylus medialis), and the intercondylar fossa (fossa intercondylaris) had a slightly oblique orientation. The proximal tibia displayed medial and lateral condyles with the medial larger. The femur was slightly shorter than the tibia. Seven tarsal bones (ossa tarsi) were present, four long metatarsal bones (ossa metatarsalia II - V) and a short first metatarsal bone (os metatarsal I).

Structure of Trypanosoma cruzi glycosomal glyceraldehyde-3-phosphate dehydrogenase complexed with chalepin, a natural product inhibitor, at 1.95 A resolution.

The structure of the glycosomal glyceraldehyde-3-phosphate dehydrogenase (gGAPDH) from Trypanosoma cruzi complexed with chalepin, a natural product from Pilocarpus spicatus, has been determined by X-ray crystallography to 1.95 A resolution. The structure is in the apo form without cofactors in the subunits of the tetrameric gGAPDH in the asymmetric unit. Unequivocal density corresponding to the inhibitor was clearly identified in one monomer. The final refined model of the complex shows extensive conformational changes when compared with the native structure. The mode of binding of chalepin to gGAPDH and its implications for inhibitor design are discussed.

Production of the rotifer Brachionus plicatilis (Ploimida: Brachionidae) in a Brazilian coastal lagoon.

Secondary production, density and biomass fluctuations, and some reproductive aspects of the rotifer Brachionus plicatilis were studied weekly for two years in a Brazilian coastal lagoon. Food (and secondarily temperature) seemed to be the main factor involved in the summer increments. In the first summer, a mass mortality of fish caused changes in the phytoplankton, which switched from the dominance of Cyanophyceae to Chlorophyceae and other groups. For two months, production, density and biomass were relatively high until the recovery of the Cyanophyceae dominance. In the second summer, peaks of shorter duration and higher values of production, in comparison to the first one, were found. The contribution of resting eggs hatching, in the first summer, and the increment in parthenogenetic reproduction, in the second summer, would account for the population increases observed. Males and mictic females occurred when densities were high.