Inequalities in full immunization coverage: trends in low- and middle-income countries

ObjectiveTo investigate disparities in full immunization coverage across and within 86 low- and middle-income countries.MethodsIn May 2015, using data from the most recent Demographic and Health Surveys and Multiple Indicator Cluster Surveys, we investigated inequalities in full immunization coverage – i.e. one dose of bacille Calmette-Guérin vaccine, one dose of measles vaccine, three doses of vaccine against diphtheria, pertussis and tetanus and three doses of polio vaccine – in 86 low- or middle-income countries. We then investigated temporal trends in the level and inequality of such coverage in eight of the countries.FindingsIn each of the World Health Organization’s regions, it appeared that about 56–69% of eligible children in the low- and middle-income countries had received full immunization. However, within each region, the mean recorded level of such coverage varied greatly. In the African Region, for example, it varied from 11.4% in Chad to 90.3% in Rwanda. We detected pro-rich inequality in such coverage in 45 of the 83 countries for which the relevant data were available and pro-urban inequality in 35 of the 86 study countries. Among the countries in which we investigated coverage trends, Madagascar and Mozambique appeared to have made the greatest progress in improving levels of full immunization coverage over the last two decades, particularly among the poorest quintiles of their populations.ConclusionMost low- and middle-income countries are affected by pro-rich and pro-urban inequalities in full immunization coverage that are not apparent when only national mean values of such coverage are reported.     

AUTOSOMAL RECESSIVE INHERITANCE OF HYPOHIDROTIC ECTODERMAL DYSPLASIA

Letters to the Editor are welcomed for publication (subject to editing). Letters must be signed by all autliors, typewritten double spaced, and must not exceed two pages of text including references. Two copies of all letters should be submitted. Letters should not duplicate material submitted or published in other journals. Prepublication proofs will not be provided.     

Cell-surface residence of sphingosine 1-phosphate receptor 1 on lymphocytes determines lymphocyte egress kinetics

The sphingosine 1-phosphate receptor 1 (S1P₁) promotes lymphocyte egress from lymphoid organs. Previous work showed that agonist-induced internalization of this G protein–coupled receptor correlates with inhibition of lymphocyte egress and results in lymphopenia. However, it is unclear if S1P₁ internalization is necessary for this effect. We characterize a knockin mouse (S1p1r^S5A/S5A) in which the C-terminal serine-rich S1P₁ motif, which is important for S1P₁ internalization but dispensable for S1P₁ signaling, is mutated. T cells expressing the mutant S1P₁ showed delayed S1P₁ internalization and defective desensitization after agonist stimulation. Mutant mice exhibited significantly delayed lymphopenia after S1P₁ agonist administration or disruption of the vascular S1P gradient. Adoptive transfer experiments demonstrated that mutant S1P₁ expression in lymphocytes, rather than endothelial cells, facilitated this delay in lymphopenia. Thus, cell-surface residency of S1P₁ on T cells is a primary determinant of lymphocyte egress kinetics in vivo.Sphingosine 1-phosphate (S1P), a multifunctional lipid mediator that signals via five G protein–coupled receptors (GPCRs), regulates vascular maturation, permeability, and angiogenesis (Hla, 2004; Cyster, 2005). Recently, interest in the roles of S1P and its receptors in the immune system has been prompted in part by the identification of the immunomodulator FTY720 (Brinkmann et al., 2002; Mandala et al., 2002; Chiba, 2005), which upon phosphorylation by Sphk2 to FTY720-P (Sanchez et al., 2003; Zemann et al., 2006) acts as a strong agonist for four out of five S1P receptors (Brinkmann et al., 2004). FTY720 induces profound lymphopenia by inhibiting the egress of lymphocytes from the thymus, peripheral lymph nodes, and Peyer’s patches (Chiba, 2005). Indeed, it is now appreciated that S1P signaling modulates the trafficking of not only naive and central memory T cells, but also B cells, dendritic cells, NK cells, osteoclasts, and hematopoietic progenitor cells (Allende and Proia, 2002; Kabashima et al., 2006; Massberg et al., 2007; Schwab and Cyster, 2007; Walzer et al., 2007; Ledgerwood et al., 2008; Rivera et al., 2008; Sebzda et al., 2008; Ishii et al., 2009). These studies suggest that S1P regulates hematopoietic and immune cell trafficking under homeostatic and disease conditions; however, it is unclear precisely how S1P receptor signaling modulates cellular responses to egress cues.The mechanism of how S1P regulates T cell trafficking has been intensively investigated; T cell–specific deletion of S1p1r or hematopoietic reconstitution using S1p1r^−/− fetal liver cells resulted in profound lymphopenia, suggesting that the T cell–intrinsic S1P receptor 1 (S1P₁) is essential for their egress from the thymus and secondary lymph nodes (Allende et al., 2004; Matloubian et al., 2004). This observation, coupled with the finding that FTY720-P induces the loss of cell-surface S1P₁ from lymphocytes in an irreversible manner (Gräler and Goetzl, 2004; Matloubian et al., 2004), suggests that functional antagonism of S1P₁ in the lymphocyte compartment is essential for the inhibition of T cell egress.However, other studies have led to the proposal of an alternative mechanism by which S1P₁ regulates lymphocyte egress. Immunofluorescence microscopy demonstrated high expression levels of S1P₁ in endothelial cells, whereas staining of lymphocytes was weaker (Singer et al., 2005; Sinha et al., 2009). Moreover, administration of SEW2971, a selective S1P₁ agonist, does not induce irreversible receptor loss from the cell surface but causes significant lymphopenia in vivo (Jo et al., 2005). Two-photon microscopy of explanted lymph nodes containing labeled lymphocytes suggested that S1P₁ agonists may modulate barrier function and closure of vascular portals in the medulla, through which T cells egress into efferent lymphatics (Wei et al., 2005). Thus, this alternative proposal favors endothelial cells as the primary target cell type for S1P₁ agonists to inhibit lymphocyte egress (Rosen et al., 2008).Close interactions between immune and vascular cells may underlie the ability of S1P₁ to promote lymphocyte egress. In lymph node cortical sinuses, egress of T and B cells required S1P₁-dependent transendothelial traverse (Grigorova et al., 2009; Sinha et al., 2009). Indeed, competing chemotactic signaling between the egress-promoting S1P–S1P₁ system and the retention-promoting CXCL21–CCR7 chemokine receptor system of T cells appears to determine the rate and extent of their egress from secondary lymphoid organs (Pham et al., 2008). Whether S1P₁ signaling in lymphocytes, endothelial compartments, or both is important in the process of egress is not known.S1P₁ is a type I GPCR that is rapidly phosphorylated upon agonist stimulation. Although several protein kinases are involved in the phosphorylation of S1P₁ (Lee et al., 2001), phosphorylation at the C-terminal domain is particularly relevant to receptor desensitization and internalization (Hla, 2001). Because FTY720-P is degraded less efficiently than S1P by S1P lyase and S1P phosphatases (Bandhuvula et al., 2005; Mechtcheriakova et al., 2007; Yamanaka et al., 2008), its ligation likely induces sustained receptor activation kinetics. Presumably, this underlies the FTY720-P–induced irreversible internalization and proteosomal degradation of S1P₁ and resultant lymphopenia (Oo et al., 2007). The GRK-2 enzyme is capable of phosphorylating the serine-rich motif in the C-terminal tail of S1P₁ (Watterson et al., 2002), and we recently demonstrated that mutation of the five serines in the C terminus of S1P₁ to nonphosphorylatable alanines inhibited S1P- and FTY720-P–induced receptor internalization in transfected HEK293 cells (Oo et al., 2007). Although previous studies of GPCR signaling and chemotaxis have provided some insights into the role of internalization in these processes, the results appear to be receptor specific. For example, a CXCR4 superagonist induced greater chemotaxis than the native ligand stromal cell–derived factor–1α (SDF-1α) with no perceptible receptor internalization (Sachpatzidis et al., 2003). Conversely, mutations in the C terminus of CXCR2 resulted in defective receptor internalization concomitant with impaired chemotaxis (Sachpatzidis et al., 2003). In the case of S1P₁, it is unknown whether internalization is required for lymphocyte egress and recirculation.To address the role of S1P₁ internalization in the control of lymphocyte egress during homeostasis and FTY720 treatment, we developed a mouse model in which WT S1P₁ is replaced by the internalization-deficient mutant (S5A-S1P₁). We show that although T cell trafficking under homeostasis is unaltered, S1p1r^S5A/S5A mice display kinetic resistance to lymphopenia induced by the S1P₁ modulator (FTY720-P) or disruption of the S1P gradient. Adoptive transfer of S1p1r^WT/WT and S1p1r^S5A/S5A lymphocytes and S1P₁ surface staining of lymph node endothelial cells demonstrate that the T cell S1P₁, and not endothelial cell S1P₁ expression, regulates the rate of lymphocyte egress in vivo. These data support a T cell–intrinsic model of S1P₁ signaling in egress kinetics wherein the internalization of S1P₁ is a crucial modulator of the cues for T cell migration.     

Mutation of the protein tyrosine kinase consensus site in the herpes simplex virus 1 alpha22 gene alters ICP22 posttranslational modification

We previously reported that at least eight HSV-1 and five HSV-2 proteins were tyrosine phosphorylated in infected human and mouse cells and the first phosphotyrosine-modified gene product identified was the ICP22 regulatory protein (Blaho, J. A., Zong, C. S., and Mortimer, K. A., 1997, J. Virol. 71, 9828-9832). All electrophoretic forms of ICP22 are tyrosine phosphorylated with the exception of the fastest migrating (unmodified) isoform. We now report the following. (i) ICP22 that reacted with a specific anti-phosphotyrosine antibody contained a significant amount of phosphotyrosine based on phospho-amino acid analysis. These results validate the discovery of ICP22 tyrosine phosphorylation. (ii) Wild-type ICP22 extracted from infected HEp-2 cells migrated as at least seven isoforms, termed ICP22a-g, in denaturing gels. (iii) The primary structure of ICP22 possesses a sequence that is homologous to protein tyrosine kinase recognition sites. A virus, termed RF141, was generated in which ICP22 tyrosine(193) in the kinase target site was mutated to an alanine. (iv) Biochemical analyses of infected HEp-2 and primary HFF cells indicated that the distributions of ICP22 isoforms differed between RF141 and control HSV-1(F). (v) The accumulations of representative viral polypeptides in RF141-infected HEp-2 cells appeared similar to wild-type virus. (vi) RF141 had reduced efficiencies of plating in HFF cells compared to control Vero cells. These differences increased as the multiplicity of infection decreased. Based on these results, we conclude (vii) that ICP22 tyrosine(193) is required for optimal posttranslational modification of the protein in HSV-1 infected human epithelial HEp-2 and primary human fibroblast cells.     

Evidence-based paediatrics

Evidence-based medicine is practised widely in some specialties and is now part of many undergraduate and graduate medical curricula. However, the extent to which it is used in clinical paediatric practice is not known and its expansion remains a major challenge. Access to technology which facilitates literature searching, and development of journals addressing specific paediatric problems, will encourage the use of evidence-based medicine by the busy paediatrician. Informed practice of evidence-based medicine will ensure that clinical expertise is complemented by a thorough search, evaluation and judicious application of relevant information from the medical literature.     

Hypoxaemia in infants with respiratory tract infections

Nineteen infants who were graduates from special care baby units underwent two overnight tape recordings of oxygen saturation (SaO2) and breathing movements; one during an upper (n = 12) or lower (n = 7) respiratory tract infection and the other when free of infection. Baseline SaO2 was lower during infection (median 99.6 vs 100%, p less than 0.01), with four patients having values (84.3-95.5%) below the normal lower limit for full-term infants (97%). The median number of apnoeic pauses was also lower during respiratory tract infection (4.7 vs 15.7/h, p less than 0.02). The median number of episodic desaturations (SaO2 less than or equal to 80%) did not change significantly (1.3 vs 1.9/h, p greater than 0.05), with the exception of one patient who had extremely increased values during infection for both apnoeic pauses (63/h) and desaturations (112/h). No infant, however, was considered clinically hypoxaemic. Clinically unsuspected hypoxaemia may thus occur during respiratory tract infection in a proportion of infants graduating from special care baby units. Such hypoxaemia may have potentially deleterious effects.