The present study was undertaken to test whether inhibition of the proangiogenic inflammatory cytokine tumor necrosis factor (TNF)-alpha can modulate retinal hypoxia and preretinal neovascularization in a murine model of oxygen-induced retinopathy (OIR). OIR was produced in TNF-alpha-/- and wild-type (WT) control C57B6 neonatal mice by exposure to 75% oxygen between postnatal days 7 and 12 (P7 to P12). Half of each WT litter was treated with the cytokine inhibitor semapimod (formerly known as CNI-1493) (5 mg/kg) by daily intraperitoneal injection from the time of reintroduction to room air at P12 until P17. The extent of preretinal neovascularization and intraretinal revascularization was quantified by image analysis of retinal flat-mounts and retinal hypoxia correlated with vascularization by immunofluorescent localization of the hypoxia-sensitive drug pimonidazole (hypoxyprobe, HP). HP adducts were also characterized by Western analysis and quantified by competitive enzyme-linked immunosorbent assay. TNF-alpha-/- and WT mice showed a similar sensitivity to hyperoxia-induced retinal ischemia at P12. At P13 some delay in early reperfusion was evident in TNF-alpha-/- and WT mice treated with semapimod. However, at P17 both these groups had significantly better vascular recovery with less ischemic/hypoxic retina and preretinal neovascularization compared to untreated retinopathy in WT mice. Immunohistochemistry showed deposition of HP in the avascular inner retina but not in areas underlying preretinal neovascularization, indicating that such aberrant vasculature can reduce retinal hypoxia. Inhibition of TNF-alpha significantly improves vascular recovery within ischemic tissue and reduces pathological neovascularization in OIR. HP provides a useful tool for mapping and quantifying tissue hypoxia in experimental ischemic retinopathy.

Loss of the outer retina reduces the severity of diabetic retinopathy in a murine model. Oxygen usage by the photoreceptors during dark adaptation may contribute to retinal hypoxia and exacerbate the progression of diabetic retinopathy.

IMPORTANCE Excessive infant crying is common, distressing, but without proven effective prevention or management options. Probiotics may be a promising solution. OBJECTIVE To examine whether probiotics are effective in the prevention/management of crying ("colic") in infants 3 months or younger. DATA SOURCES A systematic search of MEDLINE, EMBASE, and the Cochrane Library, supplemented by the metaRegister of Controlled Trials. STUDY SELECTION Studies that randomized infants 3 months or younger to oral probiotics vs placebo or no or standard treatment with the outcome of infant crying, measured as the duration or number of episodes of infant crying/distress or diagnosis of "infant colic." Twelve of the 1180 initially identified studies were selected. DATA EXTRACTION AND SYNTHESIS This review/meta-analysis was conducted according to guidelines from the Cochrane Handbook for Systematic Reviews of Interventions, with reporting following the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Data were independently extracted by 3 of us. MAIN OUTCOME(S) AND MEASURE(S) Infant crying, measured as the duration or number of episodes of infant crying/distress, or diagnosis of "infant colic." RESULTS Of the 12 trials (1825 infants) reviewed, 6 suggested probiotics reduced crying, and 6 did not. Three of the 5 management trials concluded probiotics effectively treat colic in breastfed babies; 1 suggested possible effectiveness in formula-fed babies with colic, and 1 suggested ineffectiveness in breastfed babies with colic. Meta-analysis of 3 small trials of breastfed infants with colic found that Lactobacillus reuteri markedly reduced crying time at 21 days (median difference, -65 minutes/d; 95% CI, -86 to -44). However, all trials had potential biases. Meanwhile, of 7 prevention trials, 2 suggested possible benefits. Considerable variability in the study populations, study type, delivery mode/dose of probiotic supplementation, and outcomes precluded meta-analysis. CONCLUSIONS AND RELEVANCE Although L reuteri may be effective as treatment for crying in exclusively breastfed infants with colic, there is still insufficient evidence to support probiotic use to manage colic, especially in formula-fed infants, or to prevent infant crying. Results from larger rigorously designed studies applicable to all crying infants will help draw more definitive conclusions.

Relative hypoxia occurs in the inner retina especially during dark adaptation. Photoreceptor loss reduces retinal oxygen usage and hypoxia which corresponds with attenuation of the retinal microvasculature. These studies suggest that in normal physiological conditions and diurnal cycles the adult retina exists in a state of borderline hypoxia, making this tissue particularly susceptible to even subtle reductions in perfusion.