Early microvascular damage in diabetes (e.g. capillary nonperfusion and ischemia) can now be assessed and quantified with optical coherence tomography-angiography (OCT-A). The morphology of vascular tissue is indeed affected by different factors; however, there is a paucity of data examining whether OCT-A metrics are influenced by ocular, systemic and demographic variables in subjects with diabetes. We conducted an observational cross-sectional study and included 434 eyes from 286 patients with diabetes. Foveal avascular zone (FAZ) area, FAZ circularity, total and parafoveal vessel density (VD), fractal dimension (FD), and vessel diameter index (VDI) from the superficial capillary plexus OCT-angiogram were measured by a customized automated image analysis program. We found that diabetic retinopathy (DR) severity was associated with increased FAZ area, decreased FAZ circularity, lower VD, lower FD, and increased VDI. Enlarged FAZ area was correlated with shorter axial length and thinner central subfield macular thickness. Decreased FAZ circularity was correlated with a reduction in visual function. Decreased VD was correlated with thinner macular ganglion-cell inner plexiform layer. Increased VDI was correlated with higher fasting glucose level. We concluded that the effects of ocular and systemic factors in diabetics should be taken into consideration when assessing microvascular alterations via OCT-A.

A total of 88 salmonella isolates (72 clinical isolates for which the ciprofloxacin MIC was >0.06 g/ml, 15 isolates for which the ciprofloxacin MIC was <0.06 g/ml, and Salmonella enterica serotype Typhimurium ATCC 13311) were studied for the presence of genetic alterations in four quinolone resistance genes, gyrA, gyrB, parC, and parE, by multiplex PCR amplimer conformation analysis. The genetic alterations were confirmed by direct nucleotide sequencing. A considerable number of strains had a mutation in parC, the first to be reported in salmonellae. Seven of the isolates sensitive to 0.06 g of ciprofloxacin per ml had a novel mutation at codon 57 of parC (Tyr573Ser) which was also found in 29 isolates for which ciprofloxacin MICs were >0.06 g/ml. Thirty-two isolates had a single gyrA mutation (Ser833Phe, Ser833Tyr, Asp873Asn, Asp873Tyr, or Asp873 Gly), 34 had both a gyrA mutation and a parC mutation (29 isolates with a parC mutation of Tyr573Ser and 5 isolates with a parC mutation of Ser803Arg). Six isolates which were isolated recently (from 1998 to 2001) were resistant to 4 g of ciprofloxacin per ml. Two of these isolates had double gyrA mutations (Ser833Phe and Asp873Asn) and a parC mutation (Ser803Arg) (MICs, 8 to 32 g/ml), and four of these isolates had double gyrA mutations (Ser833Phe and Asp873Gly), one parC mutation (Ser803Arg), and one parE mutation (Ser4583Pro) (MICs, 16 to 64 g/ml). All six of these isolates and those with a Ser803Arg parC mutation were S. enterica serotype Typhimurium. One S. enterica serotype Typhi isolate harbored a single gyrA mutation (Ser833Phe), and an S. enterica serotype Paratyphi A isolate harbored a gyrA mutation (Ser833Tyr) and a parC mutation (Tyr573Ser); both of these isolates had decreased susceptibilities to the fluoroquinolones. The MICs of ciprofloxacin, levofloxacin, and sparfloxacin were in general the lowest of those of the six fluoroquinolones tested. Isolates with a single gyrA mutation were less resistant to fluoroquinolones than those with an additional parC mutation (Tyr573Ser or Ser803Arg), while those with double gyrA mutations were more resistant.Salmonellosis remains a major public health problem worldwide. In contrast to gastroenteritis caused by salmonellae, invasive salmonellosis requires prompt antibiotic therapy. The antibiotics used for the treatment of salmonellosis have traditionally been chloramphenicol, sulfamethoxazole-trimethoprim, and ampicillin. However, with the development of resistance to these drugs, fluoroquinolones have been used and have been successful in treating many clinical cases. Unfortunately, fluoroquinolone-resistant strains have rapidly developed in recent years, and treatment failures have been reported (2,8,13,20,37,44,47).Resistance to the fluoroquinolones in salmonellae has mainly been attributed to mutations in the gyrA gene. Mutations have rarely been reported in the gyrB gene, and none have been reported in the parC gene (7,12,36,48,51). Other resistance mechanisms such as efflux and reduced uptake of drugs have also...

Our findings provides new information on baseline morphology of retinal microvasculature and its associated factors in school children, which will be useful for interpreting OCT-A metrics and for identifying and characterising pathological changes in retinal microvasculature.

Orthotropic liver transplantation is the only established treatment for end-stage liver diseases. Utilization of hepatocyte transplantation and bio-artificial liver devices as alternative therapeutic approaches requires an unlimited source of hepatocytes. Stem cells, especially embryonic stem cells, possessing the ability to produce functional hepatocytes for clinical applications and drug development, may provide the answer to this problem. New discoveries in the mechanisms of liver development and the emergence of induced pluripotent stem cells in 2006 have provided novel insights into hepatocyte differentiation and the use of stem cells for therapeutic applications. This review is aimed towards providing scientists and physicians with the latest advancements in this rapidly progressing field.

Background: To test clinically relevant factors associated with quantitative artifact-free deep capillary plexus (DCP) metrics in patients with diabetes mellitus (DM). Methods: 563 eligible eyes (221 with no diabetic retinopathy [DR], 135 with mild DR, 130 with moderate DR, and 77 with severe DR) from 334 subjects underwent optical coherence tomography-angiography (OCT-A) with a swept-source OCT (Triton DRI-OCT, Topcon, Inc., Tokyo, Japan). Strict criteria were applied to exclude from analysis those DCP images with artifacts and of poor quality, including projection artifacts, motion artifacts, blurriness, signal loss, B-scan segmentation error, or low-quality score. A customized MATLAB program was then used to quantify DCP morphology from the artifact-free DCP images by calculating three metrics: foveal avascular zone (FAZ), vessel density (VD), and fractal dimension (FD). Results: 166 (29.5%) eyes were excluded after quality control, leaving in the analysis 397 eyes (170 with no DR, 101 with mild DR, 90 with moderate DR, 36 with severe DR) from 250 subjects. In the multiple regression models, larger FAZ area was associated with more severe DR (β = 0.687; p = 0.037), shorter axial length (AL) (β = − 0.171; p = 0.003), thinner subfoveal choroid thickness (β = − 0.122; p = 0.031), and lower body mass index (BMI) (β = − 0.090; p = 0.047). Lower VD was associated with more severe DR (β = − 0.842; p = 0.001), shorter AL (β = 0.107; p = 0.039), and poorer visual acuity (VA) (β = − 0.133; p = 0.021). Lower FD was associated with more severe DR (β = − 0.891; p < 0.001) and with older age (β = − 0.142; p = 0.004). Conclusions: Quantitative artifact-free DCP metrics are associated with VA, DR severity, AL, subfoveal choroidal thickness, age, and BMI in diabetic patients. The effects of ocular and systemic factors should be considered for meaningful interpretations of DCP changes in DM patients.

We recently reported the isolation of a scorpion toxin named U 1 -liotoxin-Lw1a (U 1 -LITX-Lw1a) that adopts an unusual 3D fold termed the disulfide-directed hairpin (DDH) motif, which is the proposed evolutionary structural precursor of the three-disulfide-containing inhibitor cystine knot (ICK) motif found widely in animals and plants.Here we reveal that U 1 -LITX-Lw1a targets and activates the mammalian ryanodine receptor intracellular calcium release channel (RyR) with high (fM) potency and provides a functional link between DDH and ICK scorpion toxins. Moreover, U 1 -LITX-Lw1a, now described as φ-liotoxin-Lw1a (φ-LITX-Lw1a), has a similar mode of action on RyRs as scorpion calcines, although with significantly greater potency, inducing full channel openings at lower (fM) toxin concentrations whereas at higher pM concentrations increasing the frequency and duration of channel openings to a submaximal state. In addition, we show that the C-terminal residue of φ-LITX-Lw1a is crucial for the increase in full receptor openings but not for the increase in receptor subconductance opening, thereby supporting the two-binding-site hypothesis of scorpion toxins on RyRs. φ-LITX-Lw1a has potential both as a pharmacological tool and as a lead molecule for the treatment of human diseases that involve RyRs, such as malignant hyperthermia and polymorphic ventricular tachycardia.

IMPORTANCE Whether optical coherence tomography angiography (OCT-A) outperforms OCT to detect glaucoma remains inconclusive. OBJECTIVE To compare (1) the diagnostic performance for detection of glaucoma and (2) the structure-function association between inner macular vessel density and inner macular thickness. DESIGN, SETTING, AND PARTICIPANTSThis cross-sectional study included 115 patients with glaucoma and 35 healthy individuals for measurements of retinal thickness and retinal vessel density, segmented between the anterior boundary of internal limiting membrane and the posterior boundary of the inner plexiform layer, over the 3 × 3-mm 2 macula using swept-source OCT. All participants were Chinese. Visual sensitivity corresponding to the 3 × 3-mm 2 macular region was expressed in unlogged 1/lambert for investigation of the structure-function associations. Diagnostic performance was evaluated with area under the receiver operating characteristic curves (AUCs). The study was conducted between January 12, 2016, and December 12, 2016. MAIN OUTCOMES AND MEASURESArea under the receiver operating characteristic curve and R 2 analysis. RESULTSOf the 115 patients with glaucoma, 42 (36.5%) were women (mean [SD] age, 53.5 [13.4] years); of the 35 individuals with healthy eyes, 25 (71.4%) were women (age, 60.6 [5.9] years). Inner macular vessel density and thickness were 4.3% (95% CI, 2.4%-6.1%) and 21.1 μm (95% CI, 17.4-24.9 μm) smaller, respectively, in eyes with glaucoma compared with healthy eyes. The AUC of mean inner macular thickness for glaucoma detection was greater than that of mean inner macular vessel density (difference, 0.17; 95% CI, 0.01-0.31; P = .03). At 90% specificity, the sensitivity of mean inner macular thicknesses for detection of glaucoma was greater than that of mean inner macular vessel densities (difference, 29.2%; 95% CI, 11.5%-64.6%; P = .02). The strength of the structure-function association was stronger for mean inner macular thickness than mean inner macular vessel density in the linear (difference in R 2 = 0.38; 95% CI, 0.22-0.54; P < .001) and nonlinear (difference in R 2 = 0.36; 95% CI, 0.21-0.51; P < .001) regression models.CONCLUSIONS AND RELEVANCE In this study, OCT measurement of inner macular thickness shows a higher diagnostic performance to detect glaucoma and a stronger structure-function association than the currently used OCT-A measurement of inner macular vessel density. These findings may suggest that OCT-A of the macula has a limited role in the diagnostic evaluation of glaucoma.

SUMMARYThe neural network of the temporal lobe is thought to provide a cognitive map of our surroundings. Functional analysis of this network has been hampered by coarse tools that often result in collateral damage to other circuits. We developed a chemogenetic system to temporally control electrical input into the hippocampus. When entorhinal input to the perforant path was acutely silenced, hippocampal firing patterns became destabilized and underwent extensive remapping. We also found that spatial memory acquired prior to neural silencing was impaired by loss of input through the perforant path. Together, our experiments show that manipulation of entorhinal activity destabilizes spatial coding and disrupts spatial memory. Moreover, we introduce a chemogenetic model for non-invasive neuronal silencing that offers multiple advantages over existing strategies in this setting.