Role of acyl-coenzyme A: cholesterol transferase 1 (ACAT1) in retinal neovascularization.

BACKGROUND: We have investigated the efficacy of a new strategy to limit pathological retinal neovascularization (RNV) during ischemic retinopathy by targeting the cholesterol metabolizing enzyme acyl-coenzyme A: cholesterol transferase 1 (ACAT1). Dyslipidemia and cholesterol accumulation have been strongly implicated in promoting subretinal NV. However, little is known about the role of cholesterol metabolism in RNV. Here, we tested the effects of inhibiting ACAT1 on pathological RNV in the mouse model of oxygen-induced retinopathy (OIR). METHODS: In vivo studies used knockout mice that lack the receptor for LDL cholesterol (LDLR-/-) and wild-type mice. The wild-type mice were treated with a specific inhibitor of ACAT1, K604 (10 mg/kg, i.p) or vehicle (PBS) during OIR. In vitro studies used human microglia exposed to oxygen-glucose deprivation (OGD) and treated with the ACAT1 inhibitor (1 µM) or PBS. RESULTS: Analysis of OIR retinas showed that increased expression of inflammatory mediators and pathological RNV were associated with significant increases in expression of the LDLR, increased accumulation of neutral lipids, and formation of toxic levels of cholesterol ester (CE). Deletion of the LDLR completely blocked OIR-induced RNV and significantly reduced the AVA. The OIR-induced increase in CE formation was accompanied by significant increases in expression of ACAT1, VEGF and inflammatory factors (TREM1 and MCSF) (p < 0.05). ACAT1 was co-localized with TREM1, MCSF, and macrophage/microglia makers (F4/80 and Iba1) in areas of RNV. Treatment with K604 prevented retinal accumulation of neutral lipids and CE formation, inhibited RNV, and decreased the AVA as compared to controls (p < 0.05). The treatment also blocked upregulation of LDLR, ACAT1, TREM1, MCSF, and inflammatory cytokines but did not alter VEGF expression. K604 treatment of microglia cells also blocked the effects of OGD in increasing expression of ACAT1, TREM1, and MCSF without altering VEGF expression. CONCLUSIONS: OIR-induced RNV is closely associated with increases in lipid accumulation and CE formation along with increased expression of LDLR, ACAT1, TREM1, and MCSF. Inhibiting ACAT1 blocked these effects and limited RNV independently of alterations in VEGF expression. This pathway offers a novel strategy to limit vascular injury during ischemic retinopathy.

Bt-induced hormesis in Bt-resistant insects: Theoretical possibility or factual concern?

The biphasic dose-response of a stressor where low amounts of a toxicant may stimulate some biological processes is a recent focus of attention in insecticide ecotoxicology. Nonetheless, the importance and management consequences of this phenomenon of pesticide-induced hormesis remain largely unrecognized. Curiously, the potential induction of hormesis by insecticidal proteins such as Bacillus thuringiensis toxins (i.e., Bt toxins), a major agriculture pest management tool of widespread use, has been wholly neglected. Thus, we aimed to circumvent this shortcoming while assessing the potential occurrence of hormesis induced by the Bt toxin Cry1Fa in its main target pest species - the fall armyworm Spodoptera frugiperda. Concentration-response bioassays were carried out in a Bt-susceptible and a Bt-resistant population providing the purified Cry1Fa toxin in artificial diet and recording the insect demographic parameters. As significant hormetic effect was detected in both populations with a significant increase in the net reproductive rate and the intrinsic rate of population growth, the potential occurrence of Bt-induced hormesis was subsequently tested providing the insects with leaves from transgenic Bt maize expressing the toxic protein. The performance of the Bt-resistant insects was not different in both maize genotypes, indicating that the leaf expression of the Bt protein did not promote hormesis in the resistant insects. Thus, despite the Bt-induced hormesis detected in the purified protein bioassays, the phenomenon was not detected with current levels of Bt expression in maize minimizing the risk of this additional efficacy constraint besides that of field occurrence of Bt resistance.

Biasing Influence of 'Mental Shortcuts' on Diagnostic Decision-Making: Radiologists Can Overlook Breast Cancer in Mammograms When Prior Diagnostic Information Is Available.

When making decisions under uncertainty, people in all walks of life, including highly trained medical professionals, tend to resort to using 'mental shortcuts', or heuristics. Anchoring-and-adjustment (AAA) is a well-known heuristic in which subjects reach a judgment by starting from an initial internal judgment ('anchored position') based on available external information ('anchoring information') and adjusting it until they are satisfied. We studied the effects of the AAA heuristic during diagnostic decision-making in mammography. We provided practicing radiologists (N = 27 across two studies) a random number that we told them was the estimate of a previous radiologist of the probability that a mammogram they were about to see was positive for breast cancer. We then showed them the actual mammogram. We found that the radiologists' own estimates of cancer in the mammogram reflected the random information they were provided and ignored the actual evidence in the mammogram. However, when the heuristic information was not provided, the same radiologists detected breast cancer in the same set of mammograms highly accurately, indicating that the effect was solely attributable to the availability of heuristic information. Thus, the effects of the AAA heuristic can sometimes be so strong as to override the actual clinical evidence in diagnostic tasks.

How well do practicing radiologists interpret the results of CAD technology? A quantitative characterization.

Many studies have shown that using a computer-aided detection (CAD) system does not significantly improve diagnostic accuracy in radiology, possibly because radiologists fail to interpret the CAD results properly. We tested this possibility using screening mammography as an illustrative example. We carried out two experiments, one using 28 practicing radiologists, and a second one using 25 non-professional subjects. During each trial, subjects were shown the following four pieces of information necessary for evaluating the actual probability of cancer in a given unseen mammogram: the binary decision of the CAD system as to whether the mammogram was positive for cancer, the true-positive and false-positive rates of the system, and the prevalence of breast cancer in the relevant patient population. Based only on this information, the subjects had to estimate the probability that the unseen mammogram in question was positive for cancer. Additionally, the non-professional subjects also had to decide, based on the same information, whether to recall the patients for additional testing. Both groups of subjects similarly (and significantly) overestimated the cancer probability regardless of the categorical CAD decision, suggesting that this effect is not peculiar to either group. The misestimations were not fully attributable to causes well-known in other contexts, such as base rate neglect or inverse fallacy. Non-professional subjects tended to recall the patients at high rates, even when the actual probably of cancer was at or near zero. Moreover, the recall rates closely reflected the subjects' estimations of cancer probability. Together, our results show that subjects interpret CAD system output poorly when only the probabilistic information about the underlying decision parameters is available to them. Our results also highlight the need for making the output of CAD systems more readily interpretable, and for providing training and assistance to radiologists in evaluating the output.

Expert camouflage-breakers can accurately localize search targets.

Camouflage-breaking is a special case of visual search where an object of interest, or target, can be hard to distinguish from the background even when in plain view. We have previously shown that naive, non-professional subjects can be trained using a deep learning paradigm to accurately perform a camouflage-breaking task in which they report whether or not a given camouflage scene contains a target. But it remains unclear whether such expert subjects can actually detect the target in this task, or just vaguely sense that the two classes of images are somehow different, without being able to find the target per se. Here, we show that when subjects break camouflage, they can also localize the camouflaged target accurately, even though they had received no specific training in localizing the target. The localization was significantly accurate when the subjects viewed the scene as briefly as 50 ms, but more so when the subjects were able to freely view the scenes. The accuracy and precision of target localization by expert subjects in the camouflage-breaking task were statistically indistinguishable from the accuracy and precision of target localization by naive subjects during a conventional visual search where the target 'pops out', i.e., is readily visible to the untrained eye. Together, these results indicate that when expert camouflage-breakers detect a camouflaged target, they can also localize it accurately.

Comparative study on epidural administration of dexmedetomidine, dexmedetomidine-lidocaine or lidocaine in conscious rabbits.

The aim of this study was to compare the cardiorespiratory, arterial blood gas and antinociceptive effects of dexmedetomidine (D), dexmedetomidine-lidocaine (DL) or lidocaine (L) administered epidurally on conscious rabbits. Eight six-month-old male New Zealand rabbits were randomly distributed into three treatments: D (2.5 µg/kg); DL (2.5 µg/kg; 2 mg/kg); and L (2 mg/kg). The drugs were injected epidurally via a catheter. Cardiorespiratory, arterial blood gas and antinociceptive variables were recorded before administration, 5 and 10 min after drug administration, then every 10 min until the animals presented a positive response to nociceptive stimulation of perineal dermatomes. Two animals had permanent paralysis after DL treatment due to hemorrhage and congestion with neuron necrosis in spinal cord segments. There was a reduction in mean arterial pressure in treatment L at 5 and 10 min, compared with the baseline, and in treatment DL at 10-30 min. Increases in pH were observed in treatment D at 5 and 10 min, and in DL at all the times evaluated, compared with the baseline. No alterations were observed in other blood gas or electrolyte variables. Antinociceptive effects were evaluated in the perineal, sacral and lumbar regions, and were restricted to the perineal region following D and L treatment. The antinociceptive effects following DL were greater than D and L alone in all of the regions. L and D promotes short-term antinociceptive effects for up to 15 min and, when used in combination with D, increased the duration and extent of sensory block by up to 45 min.

Osteoporotic spine fractures treated with kyphoplasty or vertebroplasty: a meta-analysis / Fraturas osteoporóticas da coluna tratados com cifoplastia ou vertebroplastia: uma metanálise / Fracturas osteoporóticas de la columna vertebral tratadas con cifoplastía o vertebroplastía: un metaanálisis

ABSTRACT Kyphoplasty (KP) and vertebroplasty (VP) are both widely adopted treatments for patients with osteoporotic vertebral fractures (OVF), however, which of these techniques is more effective has not yet been established. We performed a systematic review of articles, followed by meta-analysis, in an attempt to establish the differences between KP and VP. Initially, 187 articles were obtained, 20 of which were systematically reviewed and submitted to meta-analysis. Thus, 2,226 patients comprised the universe of the present article, 1202 of whom underwent KP and 1024 of whom underwent VP. The statistically significant results observed included lower mean bone cement leakage (ml) in the group submitted to kyphoplasty, with OR: 1.50 [CI95%: 1.16 - 1.95], p <0.05; shorter mean surgical time (minutes), 0.45 [CI90% 0.08 - 0.82], p <0.1, for the group submitted to VP as compared to the KP group; and a lower mean postoperative Oswestry Disability Index score in the KP group, OR: −0.14 [CI95%: −0.28 - 0.01], p <0.05. KP was more effective in improving physical function and had a lower frequency of cement leakage when compared to VP, although it requires longer surgical time. Level of evidence III; Systematic review of level III studies.

RESUMO Tanto a cifoplastia (KP) quanto a vertebroplastia (VP) são tratamentos bastante adotados para pacientes com fratura vertebral osteoporótica (FVO), no entanto, ainda não foi estabelecido qual destas é a técnica de maior eficácia. Realizamos uma revisão sistemática de artigos, seguida de metanálise, na tentativa de estabelecer as diferenças entre KP e VP. Foram obtidos inicialmente 187 artigos, sendo que destes, 20 foram revisados sistematicamente e submetidos à metanálise. Assim, 2226 pacientes compuseram o universo do presente artigo, sendo 1202 destes submetidos à KP e 1024 à VP. Entre os resultados estatisticamente significativos, foi observado um menor extravasamento médio de cimento ósseo (ml) no grupo submetido à cifoplastia, OR: 1,50 [IC 95%: 1,16 - 1,95], p < 0,05; o tempo médio de operação (minutos) 0,45 [IC 90%: 0,08 - 0,82], p < 0,1, na comparação entre KP e VP é menor no grupo submetido à vertebroplastia e no pós-cirúrgico, o Índice Médio de Incapacidade de Oswestry foi menor no grupo KP OR: −0,14 [IC 95% −0,28 - 0,01], p < 0,05. A KP foi mais eficaz na melhora da função física e menor frequência de extravasamento de cimento quando comparada à VP embora demande maior tempo cirúrgico. Nível de evidência III; Revisão sistemática de estudos de nível III.

RESUMEN Tanto la cifoplastía (KP) como la vertebroplastía (VP) son tratamientos ampliamente adoptados en pacientes con fractura vertebral osteoporótica (FVO), sin embargo, aún no se ha establecido cuál de ellas es la técnica más eficaz. Se realizó una revisión sistemática de artículos, seguida de un metaanálisis, en un intento de establecer las diferencias entre KP y VP. Inicialmente se obtuvieron 187 artículos, de los cuales 20 fueron revisados sistemáticamente y sometidos a un metaanálisis. Así, 2226 pacientes constituyeron el universo del presente artículo, 1202 de ellos sometidos a KP y 1024 a VP. Entre los resultados estadísticamente significativos, se observó una menor extravasación media de cemento óseo (ml) en el grupo sometido a cifoplastía, OR: 1,50 [IC 95%: 1,16 - 1,95], p <0,05; el tiempo medio de intervención (minutos) 0,45 [IC 90% 0,08 - 0,82], p <0,1, en la comparación entre KP y VP es menor en el grupo sometido a vertebroplastía y en el posquirúrgico, el Índice de Discapacidad de Oswestry promedio fue menor en el grupo KP OR: −0,14 [IC 95 % CI −0,28 - 0,01], p <0,05. La KP fue más eficaz en la mejora de la función física y con menor frecuencia de extravasación de cemento en comparación con la VP, aunque requiere un tiempo quirúrgico más prolongado. Nivel de evidencia III; Revisión sistemática de estudios de nivel III.