Canine Retina Has a Primate Fovea-Like Bouquet of Cone Photoreceptors Which Is Affected by Inherited Macular Degenerations

Retinal areas of specialization confer vertebrates with the ability to scrutinize corresponding regions of their visual field with greater resolution. A highly specialized area found in haplorhine primates (including humans) is the fovea centralis which is defined by a high density of cone photoreceptors connected individually to interneurons, and retinal ganglion cells (RGCs) that are offset to form a pit lacking retinal capillaries and inner retinal neurons at its center. In dogs, a local increase in RGC density is found in a topographically comparable retinal area defined as the area centralis. While the canine retina is devoid of a foveal pit, no detailed examination of the photoreceptors within the area centralis has been reported. Using both in vivo and ex vivo imaging, we identified a retinal region with a primate fovea-like cone photoreceptor density but without the excavation of the inner retina. Similar anatomical structure observed in rare human subjects has been named fovea-plana. In addition, dogs with mutations in two different genes, that cause macular degeneration in humans, developed earliest disease at the newly-identified canine fovea-like area. Our results challenge the dogma that within the phylogenetic tree of mammals, haplorhine primates with a fovea are the sole lineage in which the retina has a central bouquet of cones. Furthermore, a predilection for naturally-occurring retinal degenerations to alter this cone-enriched area fills the void for a clinically-relevant animal model of human macular degenerations

Pyridoxine for Prevention of Hand-Foot Syndrome Caused by Chemotherapy: A Systematic Review

<div><p>Background</p><p>Hand-foot syndrome (HFS) is a relatively frequent dermatologic toxic reaction to certain anti-cancer chemotherapies. The syndrome can evolve into a distressing condition that limits function and affects quality of life. Pyridoxine (vitamin B6) has been used empirically for the prevention of HFS caused by anti-cancer therapy. However, evidence of its efficacy remains controversial.</p><p>Methodology//Principal Findings</p><p>Systematic literature searches were conducted on the Cochrane Library, PUBMED, EMBASE, LILACS, CBM, CNKI, VIP, WANFANG and the U.S. ClinicalTrials.gov website. We included all related randomized controlled trials (RCTs) irrespective of language. Reviewers from different professions independently assessed all potential studies and extracted data. Subgroup analysis was planned according to dose of pyridoxine. 5 RCTs involving 607 patients were contributed to the meta-analysis. No significant differences were found between patients receiving pyridoxine and placebo for prevention of incidence of HFS and grade 2 or worse HFS (relative risk (RR) 0.96, 95%confidence interval (CI) 0.86–1.06; RR0.95, 95%CI 0.73–1.24, respectively). Similarly, no significant improvement in quality of life was detected among patients. However, significant difference was found for prevention of grade 2 or worse HFS with pyridoxine 400 mg daily compared to 200 mg (RR0.55, 95%CI 0.33–0.92).</p><p>Conclusions/Significance</p><p>There is inadequate evidence to make any recommendation about using pyridoxine for prevention of HFS caused by chemotherapy. However, pyridoxine 400 mg may have some efficacy. Further studies of large sample sizes are needed to evaluate the efficacy and safety of pyridoxine, especially at high dose, in comparison with placebo.</p></div

Forest plot showing the meta-analysis of pyridoxine versus placebo in the incidence of Hand-foot syndrome.

<p>This forest plot is created by the software of RevMan 5.1.0. Horizontal lines indicate 95% CIs. Solid boxes indicate the response rate in each study. Test of heterogeneity (I² = 0%) indicates the absence of substantial heterogeneity. The bottom of diamond indicates the pooled response rate (RR0.96, <i>P</i> = 0.99).</p

Results of Sensitivity Analyses(fixed-effect model).

<p>Abbreviation: NS, not significant.</p

Additional file 1: of The effect of CBT and its modifications for relapse prevention in major depressive disorder: a systematic review and meta-analysis

Results from the systematic search strategy. (DOC 36 kb

Characteristics of the included studies.

<p>Abbreviation: T, treatment group; C, control group; –, no treatment; po. per os.</p><p>Outcomes reported:(1)Incidence of all grades HFS; (2)Incidence of grade 2 or worse HFS; (3)Time to development of grade 2 or worse HFS; (4)Factors affecting development of HFS;(5)Tumor response;(6)Quality of life;(7)Chemotherapy drug dose modification;(8)Progression-free survival;(9)Incidence of Adverse Events excluding HFS.</p

Cost of drugs and hospitalization in the two groups.

<p>Cost of drugs and hospitalization in the two groups.</p

Trial flow chart.

<p>Trial flow chart.</p

<i>In Vivo</i> Generation of Immature Inner Hair Cells in Neonatal Mouse Cochleae by Ectopic Atoh1 Expression

<div><p>Regeneration of auditory hair cells (HCs) is a promising approach to restore hearing. Recent studies have demonstrated that induced pluripotent stem cells/embryonic stem cells or supporting cells (SCs) adjacent to HCs can be converted to adopt the HC fate. However, little is known about whether new HCs are characteristic of outer or inner HCs. Here, we showed <i>in vivo</i> conversion of 2 subtypes of SCs, inner border cells (IBs) and inner phalangeal cells (IPhs), to the inner HC (IHC) fate. This was achieved by ectopically activating Atoh1, a transcription factor necessary for HC fate, in IBs/IPhs at birth. Atoh1+ IBs/IPhs first turned on Pou4f3, another HC transcription factor, before expressing 8 HC markers. The conversion rate gradually increased from ∼2.4% at 1 week of age to ∼17.8% in adult. Interestingly, new HCs exhibited IHC characteristics such as straight line–shaped stereociliary bundles, expression of Fgf8 and otoferlin, and presence of larger outward currents than those of outer HCs. However, new HCs lacked the terminal differentiation IHC marker vGlut3, exhibited reduced density of presynaptic Cbtp2 puncta that had little postsynaptic GluR2 specialization, and displayed immature IHC outward currents. Our results demonstrate that the conversion rate of IBs/IPhs <i>in vivo</i> by Atoh1 ectopic expression into the IHC fate was higher and faster and the conversion was more complete than that of the 2 other SC subtypes underneath the outer HCs; however, these new IHCs are arrested before terminal differentiation. Thus, IBs/IPhs are good candidates to regenerate IHCs <i>in vivo</i>.</p></div