Peritoneal Dialysis for AKI in Cameroon: Commercial vs Locally-Made Solutions.

BACKGROUND: Acute kidney injury (AKI) is common in low- and middle-income countries, and is associated with a high mortality. The high mortality rate is in large part due to the inability to perform dialysis in resource-limited settings. Due to significant cost advantages, peritoneal dialysis (PD) has been used to treat AKI in these settings. The costs, however, remain high when commercial solutions are used. METHODS: This is a retrospective cohort study of the outcome, and of the peritonitis rates, of patients with AKI treated with either commercially manufactured PD solutions or locally-made PD solutions. A program to treat AKI with PD was started at Mbingo Baptist Hospital in Cameroon. Between May 2013 and January 2015, solutions and connection sets were provided by the Saving Young Lives Program. From January 2015 through March 2017, solutions were locally produced and available tubing was used. RESULTS: Mortality in hospitalized AKI patients was 28% during the period when commercial solutions and tubing were utilized, and 33% when locally produced solutions and available tubing were utilized. In both groups, peritonitis occurred in 16% of treatment courses. CONCLUSIONS: Locally produced PD solutions, used with locally available tubing, were used to treat AKI with PD. The mortality and peritonitis rates were similar whether locally produced or commercial supplies were used.

Comment on "Broken translational and rotational symmetry via charge stripe order in underdoped YBa2Cu3O6+y".

Comin et al. (Reports, 20 March 2015, p. 1335) have interpreted their resonant x-ray scattering experiment as indicating that charge inhomogeneities in the family of high-temperature superconductors YBa2Cu3O6+y (YBCO) have the character of one-dimensional stripes rather than two-dimensional checkerboards. The present Comment shows that one cannot distinguish between stripes and checkerboards on the basis of the above experiment.

Chaotic properties of spin lattices near second-order phase transitions.

We perform a numerical investigation of the Lyapunov spectra of chaotic dynamics in lattices of classical spins in the vicinity of second-order ferromagnetic and antiferromagnetic phase transitions. On the basis of this investigation, we identify a characteristic of the shape of the Lyapunov spectra, the "G-index," which exhibits a sharp peak as a function of temperature at the phase transition, provided the order parameter is capable of sufficiently strong dynamic fluctuations. As part of this work, we also propose a general numerical algorithm for determining the temperature in many-particle systems, where kinetic energy is not defined.

Absence of exponential sensitivity to small perturbations in nonintegrable systems of spins 1/2.

We show that macroscopic nonintegrable lattices of spins 1/2, which are often considered to be chaotic, do not exhibit the basic property of classical chaotic systems, namely, exponential sensitivity to small perturbations. We compare chaotic lattices of classical spins and nonintegrable lattices of spins 1/2 in terms of their magnetization responses to an imperfect reversal of spin dynamics known as Loschmidt echo. In the classical case, magnetization is exponentially sensitive to small perturbations with a characteristic exponent equal to twice the value of the largest Lyapunov exponent of the system. In the case of spins 1/2, magnetization is only power-law sensitive to small perturbations.

Largest Lyapunov exponents for lattices of interacting classical spins.

We investigate how generic the onset of chaos in interacting many-body classical systems is in the context of lattices of classical spins with nearest-neighbor anisotropic couplings. Seven large lattices in different spatial dimensions were considered. For each lattice, more than 2000 largest Lyapunov exponents for randomly sampled Hamiltonians were numerically computed. Our results strongly suggest the absence of integrable nearest-neighbor Hamiltonians for the infinite lattices except for the trivial Ising case. In the vicinity of the Ising case, the largest Lyapunov exponents exhibit a power-law growth, while further away they become rather weakly sensitive to the Hamiltonian anisotropy. We also provide an analytical derivation of these results.

Universal long-time behavior of nuclear spin decays in a solid.

Magnetic resonance studies of nuclear spins in solids are exceptionally well suited to probe the limits of statistical physics. We report experimental results indicating that isolated macroscopic systems of interacting nuclear spins possess the following fundamental property: spin decays that start from different initial configurations quickly evolve towards the same long-time behavior. This long-time behavior is characterized by the shortest ballistic microscopic time scale of the system and therefore falls outside of the validity range for conventional approximations of statistical physics. We find that the nuclear free-induction decay and different solid echoes in hyperpolarized solid xenon all exhibit sinusoidally modulated exponential long-time behavior characterized by identical time constants. This universality was previously predicted on the basis of analogy with resonances in classical chaotic systems.

Allogeneic stem cell transplantation corrects biochemical derangements in MNGIE.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a multisystemic autosomal recessive disease due to primary thymidine phosphorylase (TP) deficiency. To restore TP activity, we performed reduced intensity allogeneic stem cell transplantations (alloSCTs) in two patients. In the first, alloSCT failed to engraft, but the second achieved mixed donor chimerism, which partially restored buffy coat TP activity and lowered plasma nucleosides. Thus, alloSCT can correct biochemical abnormalities in the blood of patients with MNGIE, but clinical efficacy remains unproven.

Evaluation of alternative computer input devices used by people with disabilities.

The aim of this study was to evaluate a range of alternative computer input devices suitable for people with disabilities and to provide comparative data that will enable health care professionals and users to make informed choices when selecting products. Our focus was on the potential advantages and disadvantages of individual product features as they related to the abilities and needs of different users. A sample of 14 alternative keyboards and pointing devices commonly used by people with disabilities were appraised by 35 disabled adults. A multi-disciplinary panel of independent assessors also appraised the products. We identified key factors regarding the set-up, personal acceptability, ease of use, design features, compatibility and potential limitations of each device. We found that difficulties in accessing computers could sometimes be reduced or overcome by adjusting the existing workstation and customizing computer settings rather than through additional technology. However, successful computer access often requires a combined approach, as a single piece of equipment will rarely provide a complete solution. If alternative computer input devices are necessary, it is likely that the hardware settings will need customizing.

Temperature dependence of the superconducting gap in high-Tc cuprates.

It is proposed that the temperature dependence of the superconducting gap Delta(T) in high-T(c) cuprates can be predicted just from the knowledge of Delta(0) and the critical temperature T(c), and, in particular, Delta(0)/T(c)>4 implies that Delta(T(c)) not equal 0, while Delta(0)/T(c)

T cell recognition of the A2 domain of coagulation factor VIII in hemophilia patients and healthy subjects.

Hemophilia A patients treated with coagulation factor VIII (FVIII), and also some healthy subjects, may develop anti-FVIII antibodies (Ab), whose synthesis is driven by FVIII-specific CD4+ T cells. Some Ab block the procoagulant function of FVIII (inhibitors). Many inhibitors recognize epitopes on the FVIII A2 domain. Here, we have sought to identify A2 epitopes recognized by CD4+ T cells. We tested the proliferative response of CD4+ blood lymphocytes (BL) from hemophilia patients and healthy subjects, to overlapping synthetic peptides spanning the A2 domain sequence. Many A2 peptides induced proliferative responses of CD4+ BL from one or more subjects. The peptide-induced responses were strongest in hemophilia patients with inhibitors, weakest in healthy subjects. A2 peptides comprising residues 371-400, 621-650 and 671-690 elicited frequent and strong responses in hemophilia A patients, and especially in those with inhibitors. Healthy subjects recognized frequently only the sequence 371-400. A three-dimensional model of the A2 domain suggests that these CD4+ epitope sequences have structural features typical of 'universal' CD4+ T epitopes.

Epitope repertoire of human CD4(+) T cells on the A3 domain of coagulation factor VIII.

Severe hemophilia A patients treated with factor (F)VIII may develop antibodies (Ab) that block FVIII function (inhibitors). Autoimmune inhibitors may develop in subjects without congenital hemophilia, and cause acquired hemophilia. Hemophiliacs without inhibitors and healthy subjects may also have small amounts of antiFVIII Ab. FVIII-specific CD4(+) T cells induce antiFVIII Ab synthesis. Here, we have examined their epitope repertoire in hemophilia patients and healthy subjects. We used overlapping synthetic peptides, spanning the sequence of the FVIII A3 domain, to challenge blood CD4(+) T cells in proliferation assays. The epitopes recognized in hemophilia A patients with or without inhibitors, acquired hemophilia patients, or healthy subjects overlapped, yet had characteristic differences. Most members of one or more study groups recognized the sequence regions 1691-1710, 1801-1820, 1831-1850, and 1941-60. In the proposed three-dimensional structure of the A3 domain, these sequences are largely exposed to the solvent and flanked by flexible sequence loops: these are structural features characteristic of 'universal' CD4(+) T epitopes. Hemophilia A patients with inhibitors recognized prominently only the sequence 1801-1820, which overlaps a known inhibitor binding site. This is consistent with the possibility that CD4(+) T cells recognizing epitopes within residues 1801-1820 have a role in inducing inhibitor synthesis. In contrast, CD4(+) T cells sensitized to sequences 1691-1710 and 1941-60, which are recognized by healthy subjects and hemophilia A patients without inhibitors, might curb inhibitor synthesis.

Characterization of human hybridoma clones isolated from hemophilia patients with specificity for different domains of coagulating factor VIII.

Hemophilia A patients treated with human coagulating factor VIII (FVIII) may develop inhibitory antibodies (inhibitors). Characterization of the inhibitors at the clonal level may help exploring new therapeutic strategies. We have generated lymphoblastoid cell lines (LCLs) producing anti-FVIII antibodies from peripheral blood lymphocytes of hemophilia A patients with high inhibitor titers. We fused the anti-FVIII-positive LCLs with a heteromyeloma, to produce FVIII specific hybridomas. We determined the specificity, isotype, idiotypic and immunoglobulin (Ig) variable region heavy (VH) chain gene family profiles of the secreted antibodies (Ab) by ELISA, immunoblotting and RT-PCR. We established eight hybridomas which produced high titers of anti-FVIII Ab. All hybridomas secreted IgM Ab, associated with either kappa(5/8) or lambda(3/8) light chain. Analysis of the expressed VH genes by RT-PCR revealed that the hybridomas utilized only the VH1 (63%) or the VH3 (37%) gene families. Among the cross-reactive idiotypes (CRIs) we tested, only the VH1 and VK3b-associated CRIs were expressed by 3 hybridomas. Immunoblotting of thrombin-digested FVIII demonstrated distinct patterns of reactivity of the monoclonal Ab (MAb) secreted by the hybridomas, which recognized either the A2 domain of the Fvm heavy chain, or the light chain, or both. Our findings suggest that: a) the isotype of the anti-FVIII Ab secreted by LCLs and hybridoma clones (IgM) differs from that of anti-FVIII Ab in vivo, which are predominantly IgG4: this suggests a negative selection of the isotype-switched FVIII-specific B-cells in the periphery of these patients; b) the anti-FVIII Ab have a biased representation of the VH1 gene family, and c) somatic mutations in the VH genes coding for FVIII specificity occur in the anti-FVIII Ab response, as evidenced by lack of expression of the VH-associated CRI.

Recognition of coagulation factor VIII by CD4+ T cells of healthy humans.

Hemophilia A patients treated with coagulation factor (F)VIII may develop an anti-FVIII immune response. Anti-FVIII antibodies may occur also in healthy subjects. To understand the extent to which an immune response to FVIII occurs in healthy subjects, we investigated the proliferative response of blood CD4+ T cells from 90 blood donors to FVIII and to pools of overlapping synthetic peptides spanning the sequences of individual FVIII domains (A1-A3, C1-C2). Most subjects responded to FVIII and several FVIII domains. Men had stronger responses to FVIII than women, and older subjects than younger subjects. The domain-induced responses were weaker than the FVIII-induced responses, yet their intensity in individual subjects correlated with that of the response to FVIII. We examined whether Th1 and/or Th2 cells responded to FVIII in 68 subjects, by determining the CD4+ T cells that secreted interferon-gamma (IFN-gamma) or interleukin (IL)-5 after stimulation with FVIII: 25 subjects had FVIII-specific IFN-gamma-secreting cells, and seven of them had also FVIII-specific IL-5-secreting cells. None had only IL-5-secreting cells. Thus, a CD4+ T cell response to FVIII, which first involves Th1 cells, is common among subjects with a normal procoagulant function.

Human CD4+ T-cell epitope repertoire on the C2 domain of coagulation factor VIII.

Approximately 25% of severe hemophilia A patients develop antibodies (Ab) that neutralize the procoagulant function of factor (F)VIII (inhibitors). Autoimmune FVIII inhibitors may develop in individuals without congenital FVIII deficiency and cause acquired hemophilia. Low titers of anti-FVIII Ab may be present in hemophilia A patients without inhibitors and in healthy blood donors. FVIII-specific CD4+ T-cells drive the synthesis of anti-FVIII Ab. We examined the epitope repertoire of CD4+ T-cells from 15 healthy subjects, 10 hemophilia A patients without inhibitors, 11 hemophilia A patients with inhibitors, and six acquired hemophilia patients. Blood CD4+ T-cells were challenged in proliferation assays with a panel 16 overlapping synthetic peptides, spanning the sequence of the FVIII C2 domain. The sequence region 2291-2330 contained the most frequently and strongly recognized peptides in each of the four subject groups. Crystallographic B factor data and the location of these peptides within the three-dimensional structure of the C2 domain confirm that this region has a high degree of solvent exposure and flexibility within the peptide backbone, which are structural features typical of immunodominant universal CD4+ epitopes. Furthermore, this sequence region overlaps inhibitor-binding sites, suggesting that CD4+ T-cells recognizing peptide sequences within this region might be involved in inhibitor synthesis. The sequence regions 2191-2210 (recognized strongly by each study group except hemophilia A patients with inhibitors) and 2241-2290 (recognized primarily by acquired hemophilia patients and healthy subjects) share the same structural features, and also overlap inhibitor-binding sites. Although similar, there appear to be important differences in the CD4+ epitope repertoires of congenital and acquired hemophilia patients.

Human bronchial epithelial and endothelial cells express alpha7 nicotinic acetylcholine receptors.

The epithelial or endothelial cells that line the human bronchi and the aorta express nicotinic acetylcholine receptors (nAChRs) of alpha3 subtypes. We report here that human bronchial epithelial cells (BEC) and aortic endothelial cells (AEC) express also the nAChR alpha7 subunit, which forms functional nAChRs. Polymerase chain reaction and in situ hybridization experiments detected alpha7 subunit mRNA in cultured human BEC and AEC and in sections of rat trachea. The binding of radiolabeled alpha-bungarotoxin revealed a few thousand binding sites per cell in cultured human BEC and human and bovine AEC. Western blot and immunohistochemistry experiments demonstrated that cultured BEC and AEC express a protein(s) recognized by anti-alpha7 antibodies. Whole-cell patch-clamp studies of cultured human BEC demonstrated the presence of fast-desensitizing currents activated by choline and nicotine that were blocked reversibly by methyllycaconitine (1 nM) and irreversibly by alpha-bungarotoxin (100 nM), consistent with the expression of functional alpha7 nAChRs. In some cells, choline activated also slowly decaying currents, confirming previous reports that BEC express functional alpha3beta4 nAChRs. Exposure of cultured BEC to nicotine (1 microM) for 3 days up-regulated functional alpha7 and alpha3 nAChRs, as indicated by the increased number of cells responding to acetylcholine and choline, with both fast-desensitizing currents, which were blocked irreversibly by alpha-bungarotoxin, and with slowly desensitizing currents, which are alpha-bungarotoxin-insensitive currents. The presence of alpha7 nAChRs in BEC and AEC suggests that some toxic effects of tobacco smoke could be mediated through these nicotine-sensitive receptors.

CD4+ T cells specific for factor VIII as a target for specific suppression of inhibitor production.

The studies we reviewed here have begun to clarify the complex cellular mechanisms involved in the immune response to fVIII, and the circumstances under which fVIII inhibitors develop. Further characterization and comparison of the immune response to fVIII in both hemophilia patients and healthy subjects will help to further elucidate these mechanisms. The murine hemophilia model will hopefully provide further insights into the mechanisms of inhibitor formation, and prove to be a suitable tool for the design and testing of therapeutic strategies aimed at preventing the development of fVIII inhibitors.

Transgenic expression of IL-10 in T cells facilitates development of experimental myasthenia gravis.

Ab to the acetylcholine receptor (AChR) cause experimental myasthenia gravis (EMG). Th1 cytokines facilitate EMG, whereas Th2 cytokines might be protective. IL-10 inhibits Th1 responses but facilitates B cell proliferation and Ig production. We examined the role of IL-10 in EMG by using wild-type (WT) C57BL/6 mice and transgenic (TG) C57BL/6 mice that express IL-10 under control of the IL-2 promoter. We immunized the mice with doses of AChR that cause EMG in WT mice or with low doses ineffective at causing EMG in WT mice. After low-dose AChR immunization, WT mice did not develop EMG and had very little anti-AChR serum Ab, which were mainly IgG1, whereas TG mice developed EMG and had higher levels of anti-AChR serum Ab, which were mainly IgG2, in addition to IgG1. At the higher doses, TG mice developed EMG earlier and more frequently than WT mice and had more serum anti-AChR Ab. Both strains had similar relative serum concentrations of anti-AChR IgG subclasses and IgG and complement at the muscle synapses. CD8(+)-depleted splenocytes from all AChR-immunized mice proliferated in the presence of AChR and recognized a similar epitope repertoire. CD8(+)-depleted splenocytes from AChR-immunized TG mice stimulated in vitro with AChR secreted significantly more IL-10, but less of the prototypic Th1 cytokine IFN-gamma, than those from WT mice. They secreted comparable amounts of IL-4 and slightly but not significantly reduced amounts of IL-2. This suggests that TG mice had reduced activation of anti-Torpedo AChR Th1 cells, but increased anti-AChR Ab synthesis, that likely resulted from IL-10-mediated stimulation of anti-AChR B cells. Thus, EMG development is not strictly dependent on Th1 cell activity.

Primary medical management of recurrent aggressive angiomyxoma of the vulva with a gonadotropin-releasing hormone agonist.

BACKGROUND: An aggressive angiomyxoma of the pelvis is a locally infiltrative lesion treated with wide local excision. Recurrence is common. A potential medical treatment alternative is reported. CASE: A 34-year-old woman presented with her second recurrence of a vulvar angiomyxoma following two prior surgical excisions. Analysis of the recurrent tumor for estrogen and progesterone receptors was strongly positive. The patient was treated with 3 months of a gonadotropin-releasing hormone (GnRH) agonist. Comparison of pre- and posttreatment magnetic resonance imaging scans showed complete radiographic resolution of the tumor. Physical examination confirmed these findings. CONCLUSION: Medical management with a GnRH agonist may obviate the need for radical exenterative surgery for a recurrent aggressive angiomyxoma of the vulva.