Miracle-dz/UniFAR-FTUs huggingface dataset:
Targeting an Aromatic Hotspot in Plasmodium falciparum 1‐Deoxy‐d‐xylulose‐5‐phosphate Reductoisomerase with β‐Arylpropyl Analogues of Fosmidomycin

Blocking the 2‐C‐methyl‐d‐erythrithol‐4‐phosphate pathway for isoprenoid biosynthesis offers new ways to inhibit the growth of Plasmodium spp. Fosmidomycin [(3‐(N‐hydroxyformamido)propyl)phosphonic acid, 1] and its acetyl homologue FR‐900098 [(3‐(N‐hydroxyacetamido)propyl)phosphonic acid, 2] potently inhibit 1‐deoxy‐d‐xylulose‐5‐phosphate reductoisomerase (Dxr), a key enzyme in this biosynthetic pathway. Arylpropyl substituents were introduced at the β‐position of the hydroxamate analogue of 2 to study changes in lipophilicity, as well as electronic and steric properties. The potency of several new compounds on the P. falciparum enzyme approaches that of 1 and 2. Activities against the enzyme and parasite correlate well, supporting the mode of action. Seven X‐ray structures show that all of the new arylpropyl substituents displace a key tryptophan residue of the active‐site flap, which had made favorable interactions with 1 and 2. Plasticity of the flap allows substituents to be accommodated in many ways; in most cases, the flap is largely disordered. Compounds can be separated into two classes based on whether the substituent on the aromatic ring is at the meta or para position. Generally, meta‐substituted compounds are better inhibitors, and in both classes, smaller size is linked to better potency.
The coat protein of Alternanthera mosaic virus is the elicitor of a temperature-sensitive systemic necrosis in Nicotiana benthamiana , and interacts with a host boron transporter protein

Different isolates of Alternanthera mosaic virus (AltMV; Potexvirus), including four infectious clones derived from AltMV-SP, induce distinct systemic symptoms in Nicotiana benthamiana. Virus accumulation was enhanced at 15 1C compared to 25 1C; severe clone AltMV 3-7 induced systemic necrosis (SN) and plant death at 15 1C. No interaction with potexvirus resistance gene Rx was detected, although SN was ablated by silencing of SGT1, as for other cases of potexvirus-induced necrosis. Substitution of AltMV 3-7 coat protein (CPSP) with that from AltMV-Po (CPPo) eliminated SN at 15 1C, and ameliorated symptoms in Alternanthera dentata and soybean. Substitution of only two residues from CPPo [either MN(13,14)ID or LA(76,77)IS] efficiently ablated SN in N. benthamiana. CPSP but not CPPo interacted with Arabidopsis boron transporter protein AtBOR1 by yeast two-hybrid assay; N. benthamiana homolog NbBOR1 interacted more strongly with CPSP than CPPo in bimolecular fluorescence complementation, and may affect recognition of CP as an elicitor of SN. Published by Elsevier Inc.
Neuropsychological Management of Mild Traumatic Brain Injury

Despite the importance of the problem, strikingly little has been written about effective approaches to the treatment of individuals with mild to moderate brain injury. This book provides a context for understanding and evaluating the common consequences of such injuries and offers both theoretical perspectives and practical suggestions for helping individuals to adjust to and compensate for residual difficulties.
A systematic review of outcomes in patients undergoing liver surgery in an enhanced recovery after surgery pathways.

OBJECTIVES Enhanced recovery after surgery (ERAS) or fast-track protocols have been implemented in different fields of surgery to attenuate the surgical stress response and accelerate recovery. The objective of this study was to systematically review the literature on outcomes of ERAS protocols applied in liver surgery. METHODS The MEDLINE, EMBASE, PubMed and Cochrane Library databases were searched for randomized controlled trials (RCTs), case-control studies and case series published between January 1966 and October 2011 comparing adult patients undergoing elective liver surgery in an ERAS programme with those treated in a conventional manner. The primary outcome measure was hospital length of stay (LoS). Secondary outcome measures were time to functional recovery, and complication, readmission and mortality rates. RESULTS A total of 307 articles were found, six of which were included in the review. These comprised two RCTs, three case-control studies and one retrospective case series. Median LoS ranged from 4 days in an ERAS group to 11 days in a control group. Morbidity, mortality and readmission rates did not differ significantly between the groups. Only two studies assessed time to functional recovery. Functional recovery in these studies was reached 2 days before discharge. CONCLUSIONS This systematic review suggests that ERAS protocols can be successfully implemented in liver surgery. Length of stay is reduced without compromising morbidity, mortality or readmission rates.
CONTRAST RADIOGRAPHY OF THE OVINE GASTROINTESTINAL TRACT

Contrast radiography of the alimentary canal was conducted in six adult sheep with barium sulfate (70% W/V, 25–30 ml/kg). A period of 12 hours was adequate for opacification of most parts of the gastrointestinal tract. The presence of contrast medium in different parts of the alimentary canal was noted for as long as 60 hours. The right lateral view was adequate for visualization of most structures, but the typical laminar mucosal pattern of the omasum and the spiral mucosal folds of the abomasum were demonstrated better on the ventrodorsal view.
Synthesis and Biological Evaluation of Novel 2‐Aminonicotinamide Derivatives as Antifungal Agents

Based on the structures of the reported compounds G884 [N‐(3‐(pentan‐2‐yloxy)phenyl)nicotinamide], E1210 [3‐(3‐(4‐((pyridin‐2‐yloxy)methyl)benzyl)isoxazol‐5‐yl)pyridin‐2‐amine], and 10 b [2‐amino‐N‐((5‐(3‐fluorophenoxy)thiophen‐2‐yl)methyl)nicotinamide], which inhibit the biosynthesis of glycosylphosphatidylinositol (GPI)‐anchored proteins in fungi, a series of novel 2‐aminonicotinamide derivatives were designed, synthesized, and evaluated for in vitro antifungal activity. Most of these compounds were found to exhibit potent in vitro antifungal activity against Candida albicans, with MIC80 values ranging from 0.0313 to 4.0 μg mL−1. In particular, compounds 11 g [2‐amino‐N‐((5‐(((2‐fluorophenyl)amino)methyl)thiophen‐2‐yl)methyl)nicotinamide] and 11 h [2‐amino‐N‐((5‐(((3‐fluorophenyl)amino)methyl)thiophen‐2‐yl)methyl)nicotinamide] displayed excellent activity against C. albicans, with MIC80 values of 0.0313 μg mL−1, and exhibited broad‐spectrum antifungal activity against fluconazole‐resistant C. albicans, C. parapsilosis, C. glabrata, and Cryptococcus neoformans, with a MIC80 range of 0.0313–2.0 μg mL−1. Further studies by electron microscopy and laser confocal microscopy indicated that compound 11 g targets the cell wall and decreases GPI anchor content on the cell surface of C. albicans.
THE OPTICAL COHERENCE TOMOGRAPHY–OPHTHALMOSCOPE FOR EXAMINATION OF CENTRAL SEROUS CHORIORETINOPATHY WITH PRECIPITATES

Purpose: To report the exact location of multiple yellowish dot-like precipitates in central serous chorioretinopathy (CSC) with the Optical Coherence Tomography (OCT)–Ophthalmoscope (Nidek-OTI, Gamagori, Japan). Design: Retrospective, observational study. Methods: Twenty eyes of 18 patients (average age, 53 years) with CSC were examined by the OCT-Ophthalmoscope. Multiple yellowish dot-like precipitates were seen in all eyes by biomicroscopic examination. Results: Multiple highly reflective dots (bright dots) were seen by the OCT-Ophthalmoscope in all 20 eyes. The bright dots were observed on the posterior surface of the detached neurosensory retina by cross-sectional B-scan OCT in all eyes and in the detached neurosensory retina in 14 eyes. The bright dots were preferentially located in the outer retinal layer. Transverse C-scan OCT confirmed that the location of the bright dots coincided with that of the precipitates. Conclusions: Both cross-sectional B-scan and transverse C-scan images obtained with the OCT-Ophthalmoscope showed subretinal and intraretinal bright dots in eyes with CSC, which may indicate that the yellowish dot-like precipitates are not only on the posterior surface of the detached retina but also in the detached neurosensory retina. Intraretinal precipitates in eyes with CSC may result from the accumulation of proteins or macrophages with the phagocytized photoreceptor outer segments.
Effects of salinity on performance and microbial community structure of an anoxic-aerobic sequencing batch reactor

The effects of salinity on the performance and microbial community structure of activated sludge were investigated in an anoxic-aerobic sequencing batch reactor (SBR). The removal efficiencies of chemical oxygen demand (COD) and -N decreased as the influent salinity increased from 0.5% to 6%. The specific oxygen utilization rate of activated sludge increased from 22.47 to 43.16 mg O2 g−1 mixed liquid suspended solids (MLSS) h−1 with the increase in salinity from 0.5% to 4% and subsequently decreased to 18.3 mg O2 g−1 MLSS h−1 at 6% salinity. The specific ammonium oxidation rate (SAOR) and specific nitrite oxidation rate (SNOR) decreased slowly at 0.5–1% salinity and then decreased rapidly with the increase in salinity from 1% to 6%. The SNOR diminished at a faster rate than the SAOR with the increase in salinity from 0.5% to 6%. The specific nitrate reduction rate (SNRR) decreased with the increase in salinity, whereas the SNRR was higher than the sum of SAOR and SNOR at 0.5–6% salinity. The denaturing gradient gel electrophoresis profiles revealed obvious changes in microbial community structure at different salinities. Some microbes were capable of tolerating up to 6% salinity in the SBR, such as Planomonospora sphaerica, Nitrosomonas sp. Is32, and Denitromonas sp. D2–1.
Sialoadenectomy enhances hepatic injury induced by lipopolysaccharide/galactosamine in mice

Background: Submandibular salivary glands (SMGs) synthesize, accumulate and secrete a large amount of epidermal growth factor (EGF) in mice. It is known that surgical removal of SMG (sialoadenectomy) alters cell turnover in the liver and exacerbates liver injury induced by lipopolysaccharide/galactosamine (LPS/GalN).
The role of rosuvastatin in the treatment of pediatric homozygous familial hypercholesterolemia

Introduction: Homozygous familial hypercholesterolemia (HoFH) is a rare disorder characterized by severely increased cholesterol levels that lead to an extremely high risk of premature cardiovascular disease (CVD). Aggressive lipid-lowering therapy should be started at an early age with highly potent statins. Rosuvastatin is such a highly efficacious statin with a favorable safety profile that might be advantageous in pediatric HoFH. Areas covered: The authors conducted a PubMed search for rosuvastatin papers and papers on statin use in HoFH published in English. This review describes the pharmacology, safety and efficacy of rosuvastatin and discusses its use in pediatric HoFH. Expert opinion: To date, there is very little evidence on the efficacy and safety of rosuvastatin in pediatric HoFH. Sufficient clinical evidence has proven the lipid-lowering capacity and subsequent CVD prevention of rosuvastatin in hypercholesterolemic adults. Furthermore, clinical studies in children heterozygous familial hypercholesterolemia aged 6 years and older revealed no untoward safety concerns. Rosuvastatin is, therefore, a promising agent in the treatment of pediatric HoFH.
TACHYPHYLAXIS AFTER INTRAVITREAL BEVACIZUMAB FOR EXUDATIVE AGE-RELATED MACULAR DEGENERATION

Purpose: To describe tachyphylaxis to intravitreal bevacizumab (IVB) in patients with exudative age-related macular degeneration (AMD). Methods: We retrospectively reviewed the records of 59 consecutive patients treated with IVB at the National Eye Institute over a 14-month period and identified cases demonstrating loss of treatment efficacy as revealed by spectral domain optical coherence tomography. We defined tachyphylaxis as a loss of therapeutic response to IVB 28 ± 7 days after administration in an eye that had previously demonstrated a therapeutic response in the same time interval. Results: Five patients (six eyes) were identified as developing tachyphylaxis after repeated treatment with IVB. High-dose IVB (2.50 mg) did not restore therapeutic response in these patients. Bilateral tachyphylaxis to IVB was seen after an episode of unilateral postinjection anterior uveitis. After the first treatment of IVB, the median time taken to develop tachyphylaxis was 100 weeks (range: 31–128 weeks), and the median number of IVB treatments to the development of tachyphylaxis was 8 treatments (range: 5–10 treatments). Conclusion: Tachyphylaxis can occur after long-term intravitreal use of bevacizumab in patients with AMD. The precise mechanism of tachyphylaxis is unclear, but both local and/or systemic factors may be involved.
The history of the “natural history” of hepatitis C (1968–2009)

In the late 1960's, only types A and B hepatitis were believed to exist, distinguished by circumstances of exposure and incubation periods. In the early 1970's, studies of transfusion recipients were begun with the belief that hepatitis B would be responsible should transfusion‐associated hepatitis develop. After discovery of the viruses of hepatitis A and B, neither agent was found responsible, hence non‐A, non‐B (NANB) hepatitis. Initial follow‐up of these cases showed that ∼ 50% developed chronic hepatitis based on persistence of serum enzymes for at least 6 months. Approximately 15 years later, after the hepatitis C virus had been identified as the cause for NANB hepatitis, chronic hepatitis was found to develop more frequently as indicated by persistent viral infection in over 80% of infected adults but in only about 50% of infected children or young women. Follow‐up over 2 to 4 decades indicated that many infected persons developed progressive hepatic fibrosis, sometimes culminating in cirrhosis and/or liver cancer. Long‐term natural history studies have proved to be challenging because disease onset is often silent and progression extremely slow. Differing strategies have been used to determine the natural history, the descriptions and results of which are presented in this review.
Relaxometric studies of gadolinium-functionalized perfluorocarbon nanoparticles for MR imaging.

Fluorine MRI ((19) F MRI) is receiving an increasing attention as a viable alternative to proton-based MRI ((1) H MRI) for dedicated application in molecular imaging. The (19) F nucleus has a high gyromagnetic ratio, a 100% natural abundance and is furthermore hardly present in human tissues allowing for hot spot MR imaging. The applicability of (19) F MRI as a molecular and cellular imaging technique has been exploited, ranging from cell tracking to detection and imaging of tumors in preclinical studies. In addition to applications, developing new contrast materials with improved relaxation properties has also been a core research topic in the field, since the inherently low longitudinal relaxation rates of perfluorocarbon compounds result in relatively low imaging efficiency. Borrowed from (1) H MRI, the incorporation of lanthanides, specifically Gd(III) complexes, as signal modulating ingredients in the nanoparticle formulation has emerged as a promising approach to improvement of the fluorine signal. Three different perfluorocarbon emulsions were investigated at five different magnetic field strengths. Perfluoro-15-crown-5-ether was used as the core material and Gd(III)DOTA-DSPE, Gd(III)DOTA-C6-DSPE and Gd(III)DTPA-BSA as the relaxation altering components. While Gd(III)DOTA-DSPE and Gd(III)DOTA-C6-DSPE were favorable constructs for (1) H NMR, Gd(III)DTPA-BSA showed the strongest increase in (19F) R(1). These results show the potential of the use of paramagnetic lipids to increase (19F) R(1) at clinical field strengths (1.5-3 T). At higher field strengths (6.3-14 T), gadolinium does not lead to an increase in (19F) R(1) compared with emulsions without gadolinium, but leads to an significant increase in (19F) R(2). Our data therefore suggest that the most favorable situation for fluorine measurements is at high magnetic fields without the inclusion of gadolinium constructs.
Liver cancer stem cells: implications for a new therapeutic target

Hepatocellular carcinoma (HCC) is an aggressive tumour with a poor prognosis. Current therapeutic strategies against this disease target mostly rapidly growing differentiated tumour cells. However, the result is often dismal due to the chemoresistant nature of this tumour type. Recent research efforts on stem cells and cancer biology have shed light on new directions for the eradication of cancer stem cells (CSCs) in HCC. The liver is a distinctive organ with the ability of tissue renewal in response to injury. Based on the hypothesis that cancer development is derived from the hierarchy of the stem cell system, we will briefly discuss the origin of liver stem cells and its relation to HCC development. We will also summarize the current CSC markers in HCC and discuss their relevance to the treatment of this deadly disease.
Re: Retinal functional changes measured by microperimetry in neovascular age-related macular degeneration patients treated with ranibizumab.

To the Editor: Tsang et al1 presented some interesting data regarding the use of primary 23-gauge transconjunctival sutureless vitrectomy for rhegmatogenous retinal detachment. We have read with interest the comments provided by the author.1 We are interested in emphasizing the complications that can arise from the use of perfluorcarbon liquids (PFCLs) during 23-gauge transconjunctival sutureless vitrectomy for rhegmatogenous retinal detachment. The authors reported that perfluorodecalin (Bausch & Lomb, Waterford, Ireland) was used to flatten the posterior retina up to the most anterior tear.1 The PFCLs, such as perfluorodecaline, have an intermediate interfacial tension against water of 50 mN/m and a dynamic viscosity of 5.10 mPa s.2 The high specific gravity, transparency, and low viscosity of PFCL makes it a very effective surgical tool. The retina, being hydrophilic, prefers to be in contact with water rather than with PFCL, thereby forming a meniscus that is convex upward. Moreover, the PFCL bubble tends to remain rounded because the interfacial energy creates a net attraction inward. These findings prevent the PFCL from reaching the subretinal space. We would like to indicate the possible risk of subretinal PFCL retention as a significant complication associated to 23-gauge transconjunctival sutureless vitrectomy. To optimize the cutting and the speed of the vitrectomy through a small-gauge system, we need to use a higher vacuum setting and higher bottle infusion. Tsang et al1 reported that the vacuum was set at 400 mmHg to 500 mmHg, with a bottle height of 50 cm. These settings can generate high turbulence if the level of PFCL filling is too anterior and close to the fluid infusion line. The low viscosity of PFCL, together with the high current of fluid, can produce the formation of small bubbles of PFCL, which are able to easily reach the subretinal space. In a series of 26 eyes treated by 23-gauge transconjunctival sutureless vitrectomy for rhegmatogenous retinal detachment with multiple retinal breaks, including at least 1 break bigger than 2-clock hours, we report 2 cases (7.6%) of subretinal PFCL retention that led to disruption of the retinal pigment epithelium and progressive photoreceptor atrophy. This kind of complication could be related to the smaller size of the trocars, combined with the higher intraocular pressure used during surgery with a smallgauge system. We would like to report this significant complication encountered using PFCL as a surgical tool during 23-gauge vitrectomy.
Effect of magnetic field and iron content on NMR proton relaxation of liver, spleen and brain tissues.

Iron accumulation is observed in liver and spleen during hemochromatosis and important neurodegenerative diseases involve iron overload in brain. Storage of iron is ensured by ferritin, which contains a magnetic core. It causes a darkening on T2 -weighted MR images. This work aims at improving the understanding of the NMR relaxation of iron-loaded human tissues, which is necessary to develop protocols of iron content measurements by MRI. Relaxation times measurements on brain, liver and spleen samples were realized at different magnetic fields. Iron content was determined by atomic emission spectroscopy. For all samples, the longitudinal relaxation rate (1/T1 ) of tissue protons decreases with the magnetic field up to 1 T, independently of iron content, while their transverse relaxation rate (1/T2 ) strongly increases with the field, either linearly or quadratically, or a combination thereof. The extent of the inter-echo time dependence of 1/T2 also varies according to the sample. A combination of theoretical models is necessary to describe the relaxation of iron-containing tissues. This can be due to the presence, inside tissues, of ferritin clusters of different sizes and densities. When considering all samples, a correlation (r(2) = 0.6) between 1/T1 and iron concentration is observed at 7.0 T. In contrast the correlation between 1/T2 and iron content is poor, even at high field (r(2) = 0.14 at 7.0 T). Our results show that MRI methods based on T1 or T2 measurements will easily detect an iron overloading at high magnetic field, but will not provide an accurate quantification of tissue iron content at low iron concentrations.
Inter-rater reliability of preventable death judgments

This study examined the inter-rater reliability of preventable death judgments for trauma. A total of 130 deaths were reviewed for potential preventability by multiple panels of nationally chosen experts. Deaths involving a central nervous system (CNS) injury were reviewed by three panels, each consisting of a trauma surgeon, a neurosurgeon, and an emergency physician. Deaths not involving the CNS were reviewed by three panels, each consisting of two trauma surgeons and an emergency physician. Cases for review were sampled from all hospital trauma deaths occurring in Maryland during 1986. Panels were given prehospital and hospital records, medical examiner reports, and autopsy reports, and asked to independently classify deaths as not preventable (NP), possibly preventable (POSS), probably preventable (PROB), or definitely preventable (DEF). Cases in which there was disagreement about preventability were discussed by the panel as a group (via conference call). Results indicated that overall reliability was low. All three panels reviewing non-CNS deaths agreed in only 36% of the cases (kappa = 0.21). Agreement among panels reviewing CNS deaths was somewhat higher at 56% (kappa = 0.40). Most of the disagreements, however, were in judging whether deaths were NP or POSS. Agreement was higher for early deaths and less severely injured patients. For non-CNS deaths agreement was also higher for younger patients. When both autopsy results and prehospital care reports were available reliability increased across panels. A variety of approaches have been used to elicit judgments of preventability. This study provides information to guide recommendations for future studies involving implicit judgments of preventable death.
Diabetes mellitus as an independent prognostic predictor and its association with renal dysfunction in patients with hepatocellular carcinoma

Background: Patients with hepatocellular carcinoma (HCC) often have coexisting cirrhosis, which may predispose to the development of diabetes mellitus (DM). Diabetic HCC patients may have renal insufficiency and a subsequent worse outcome. This study investigated the interaction between DM, cirrhosis and renal dysfunction and the impact of these factors on HCC.