Characterization of the dominant autoreactive T-cell epitope in spontaneous autoimmune haemolytic anaemia of the NZB mouse

NZB mice spontaneously develop autoimmune haemolytic anaemia (AIHA) due to a T helper-dependent autoantibody response against the erythrocyte anion channel protein, Band 3. Here, we characterize the recognition of the Band 3 sequence 861-874, which carries the dominant, I-E(d)-restricted T cell epitope. The ability of N and C-terminal truncated versions of peptide 861-874 to elicit NZB splenic T-cell proliferation indicated that the core epitope spans residues 862-870. Next, a set of alanine substitution analogues was tested to determine which residues functioned either as MHC anchor or TCR contact residues. A combination of proliferation and MHC:peptide binding assays identified residues 862(L), 864(V), 865(L), and 869(K) as I-E(d) anchor residues, and 868(V) as the only TCR contact residue. The ability of the wild-type sequence 861-874 to compete with a high affinity reference peptide for binding to I-E(d) indicates that the escape of pathogenic NZB T cells from purging of the autoreactive repertoire cannot be attributed to ineffective presentation of peptide 861-874 by its restricting element. It will now be possible to design altered peptide ligands of Band 3 861-874, in order to further dissect the mechanisms responsible for the maintenance and loss of T cell tolerance to RBC autoantigens, and to modulate the immune response in AIHA.     

A survey of bacterial diversity in ticks,lice and fleas from Australia

We isolated bacteria from ticks, lice and fleas. Partial small subunit rRNA sequences were obtained for each isolate and the closest matches in the FastA database were determined. These bacteria were mostly Gram-positive (Firmicutes), although representatives from the Proteobacteria (alpha, beta, gamma subdivisions) and CFB group were also isolated. Most of the isolates we found were from genera that were present in most of the ectoparasites studied, but a few genera were restricted to one species of ectoparasite. The most commonly isolated genera were Stenotrophomonas, Staphylococcus, Pseudomonas, Acinetobacter and Bacillus. Species of Bacillus and Proteus, which have biopesticide potential, were found in some of these ectoparasites. Overall, the communities of bacteria were similar to those found in other studies of parasitic arthropods.     

Staphylococcal toxin-induced T cell proliferation in atopic eczema correlates with increased use of superantigen-reactive Vbeta-chains in cutaneous lymphocyte-associated antigen (CLA)-positive lymphocytes

Staphylococcal superantigens have been implicated in the pathogenesis of atopic dermatitis (AD). This may occur through superantigenic activation of T lymphocytes and their subsequent induction of the skin homing receptor CLA on activated cells. We investigated the proliferative responses of peripheral blood mononuclear cells (PBMC) from 10 patients with an infective exacerbation of AD and six normal controls to the staphylococcal superantigens, staphylococcal enterotoxin A and B (SEA, SEB) and toxic shock syndrome toxin-1 (TSST-1), and the mitogens phytohaemagglutinin (PHA) and concanavalin A (Con A). We also assessed CLA and T cell receptor (TCR) Vbeta-chain expression by immunofluorescence and flow cytometry before and after stimulation. PBMC from AD patients showed two-fold increased proliferation to SEA and SEB (P < 0.01) compared with normals, whereas the response to mitogenic stimulation was identical. Analysis of (TCR) Vbeta-chain expression demonstrated increased use of superantigen-reactive Vbeta families in freshly isolated PBMC in AD patients compared with controls. This pattern of Vbeta-chain expression was only observed in the CLA+ but not the total population of T cells. Furthermore, there was a positive correlation between the enhanced PBMC proliferative response and increased expression of superantigen-reactive Vbeta families in atopic patients. These data support the concept that superantigens are important in the pathogenesis of this common condition, and also provide evidence that the increased use of certain Vbeta families in circulating, CLA+, skin homing lymphocytes is of functional significance.     

The development ofAmblyomma americanum andDermacentor variabilis (Acari: Ixodidae) fed on rabbits immunized with tick hemolymph

The possibility of interfering with the normal function of tick hemolymph using antihemolymph antibodies taken in with the bloodmeal, was investigated. Cell free hemolymph from repleteAmblyomma americanum andDermacentor variabilis ticks was used to immunize rabbits. Immunized rabbits developed high antihemolymph antibody titers (ca. 10⁵) and had no ill side effects. Rabbits were simultaneously infested with larvae, nymphs, and adult ticks. The biological performance of ticks fed on immunized rabbits was virtually identical to that of ticks fed on nonimmunized rabbits. Usually, the mean engorgement weights of nymphs and females and the weights of the egg masses of both species were slightly higher for ticks fed on the nonimmunized rabbits but differences were not significant (P>0.05) due to a large standard deviation. The possibility of deactivating a single hemolymph component with specific antibodies is discussed.Journal article 4979 of the Agricultural Experiment Station, Oklahoma State University, Stillwater, OK, USA     

Atmungserregung und zentrale Erregbarkeit bei Ventilationsstörungen der Lunge und bei respiratorischer Acidose

Zusammenfassung Atemphysiologische Untersuchungen an 19 Patienten mit Ventilationsstörungen der Lunge mit dem Atmungsanalepticum Micoren ergeben eine Ventilationssteigerung um 60% des Ausgangswertes, eine Abnahme der arteriellen CO₂-Spannung und eine Zunahme des Blut-p_H, somit eine ventilationsbedingte Verschiebung der Blutgase in Richtung einer relativen respiratorischen Alkalose. Im Mittelpunkt der Untersuchung steht die Frage einer über die Atmungserregung hinaus bei der respiratorischen Acidose und Atemdepression erzielbaren Erregbarkeitsänderung der Zentren. Im Gegensatz zu Patienten ohne respiratorische Acidose läßt sich bei Kranken mit respiratorischer Acidose eine Steigerung der Erregbarkeit auf CO₂-Reiz und eine wahrscheinlich begrenzte Verzögerung der unter O₂-Atmung drohenden zentralen Depression nachweisen. Indikationen und klinische Gesichtspunkte einer medikamentösen Atmungserregung werden unter besonderer Berücksichtigung der respiratorischen Acidose besprochen.Mit freundlicher Unterstützung der Deutschen Forschungsgemeinschaft.     

Ileal bypass for hyperlipidemia

Partial ileal bypass (PIB) is a safe, effective, and lasting therapy for the reduction of lipids and lipoproteins in patients with hyperlipidemia. Following PIB, circulating plasma and low-density lipoprotein (LDL) cholesterol fall markedly, while high-density lipoprotein (HDL) cholesterol rises. The average plasma cholesterol lowering is 25% after diet, with a 40% reduction in the LDL-cholesterol fraction; concurrently, the HDL-cholesterol rises about 8%. These effects have been demonstrated to be maintained for up to 20 years. Currently, PIB is being used in the Program on the Surgical Control of the Hyperlipidemias (POSCH), a randomized controlled clinical trial designed to assess the effects of lipid reduction on mortality and morbidity in a postmyocardial infarction population with arteriographically demonstrated coronary atherosclerosis.

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Resumen La derivación (bypass) ileal parcial (DIP) es una modalidad terapéutica segura, efectiva y durable para la reducción de los lípidos y lipoproteínas en pacientes con hiperlipidemia. Después de la DIP, los niveles de colesterol plasmático y de colesterol de baja densidad descienden en forma marcada, en tanto que los de colesterol de alta densidad ascienden. El promedio de reducción del colesterol plasmático es de 25% después de dieta, con una reducción de 40% de la fracción del colesterol de baja densidad; al mismo tiempo, el colesterol de alta densidad asciende alrededor de un 8%. Se ha demostrado que tales efectos perduran hasta por 20 años. Actualmente se utiliza la DIP en el Programa de Control QuirÚrgico de la Hiperlipidemia (POSCH), un ensayo interinstitucional prospectivo y aleatorizado diseñado para evaluar los efectos de la reducción de los niveles de lípidos sobre la mortalidad y la morbilidad en la población que ha sufrido infarto miocárdico con arteriosclerosis coronaria arteriograficamente demostrada.

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Résumé L'opération décrite par l'auteur en 1963, le courtcircuit partiel d l'iléon représente une méthode thérapeutique dénuée de danger, efficace et durable pour obtenir la réduction des lipides et des lipoprotéines chez les malades qui présentent une hyperlipidémie. A la suite de l'intervention la fraction du cholestérol lipoprotéique de haute densité s'élève. La chute moyenne du cholestérol plasmatique est de l'ordre de 25%: la réduction est de 40% en ce qui concerne la fraction LDL du cholestérol (la fraction athérogène) alors que la fraction HDL (la fraction protectrice) s'élève environ de 8%. Ces effets se maintiennent depuis plus de 20 ans. Actuellement, le court-circuit iléal partiel est soumis à un essai clinique randomisé de contrôle destiné à apprécier les effets de la réduction des lipides sur la morbidité et la mortalité chez des malades qui ont subi un infarctus et chez qui l'artériographie a démontré une athérosclérose coronarienne.

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Supported in part by National Heart, Lung, and Blood Institute, NIH, grant #R10 HL15265.     

Anabolic actions of PTH in murine models: two decades of insights

Parathyroid hormone (PTH) is produced by the parathyroid glands in response to low serum calcium concentrations where it targets bones, kidneys, and indirectly, intestines. The N-terminus of PTH has been investigated for decades for its ability to stimulate bone formation when administered intermittently (iPTH) and is used clinically as an effective anabolic agent for the treatment of osteoporosis. Despite great interest in iPTH and its clinical use, the mechanisms of PTH action remain complicated and not fully defined. More than 70 gene targets in more than 90 murine models have been utilized to better understand PTH anabolic actions. Because murine studies utilized wild-type mice as positive controls, a variety of variables were analyzed to better understand the optimal conditions under which iPTH functions. The greatest responses to iPTH were in male mice, with treatment starting later than 12 weeks of age, a treatment duration lasting 5–6 weeks, and a PTH dose of 30–60 μg/kg/day. This comprehensive study also evaluated these genetic models relative to the bone formative actions with a primary focus on the trabecular compartment revealing trends in critical genes and gene families relevant for PTH anabolic actions. The summation of these data revealed the gene deletions with the greatest increase in trabecular bone volume in response to iPTH. These included PTH and 1-α-hydroxylase (Pth;1α(OH)ase, 62-fold), amphiregulin (Areg, 15.8-fold), and PTH related protein (Pthrp, 10.2-fold). The deletions with the greatest inhibition of the anabolic response include deletions of: proteoglycan 4 (Prg4, −9.7-fold), low-density lipoprotein receptor-related protein 6 (Lrp6, 1.3-fold), and low-density lipoprotein receptor-related protein 5 (Lrp5, −1.0-fold). Anabolic actions of iPTH were broadly affected via multiple and diverse genes. This data provides critical insight for future research and development, as well as application to human therapeutics. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).     

The use of intravenous lidocaine for postoperative pain and recovery: international consensus statement on efficacy and safety

Intravenous lidocaine is used widely for its effect on postoperative pain and recovery but it can be, and has been, fatal when used inappropriately and incorrectly. The risk-benefit ratio of i.v. lidocaine varies with type of surgery and with patient factors such as comorbidity (including pre-existing chronic pain). This consensus statement aims to address three questions. First, does i.v. lidocaine effectively reduce postoperative pain and facilitate recovery? Second, is i.v. lidocaine safe? Third, does the fact that i.v. lidocaine is not licensed for this indication affect its use? We suggest that i.v. lidocaine should be regarded as a ‘high-risk’ medicine. Individual anaesthetists may feel that, in selected patients, i.v. lidocaine may be beneficial as part of a multimodal peri-operative pain management strategy. This approach should be approved by hospital medication governance systems, and the individual clinical decision should be made with properly informed consent from the patient concerned. If i.v. lidocaine is used, we recommend an initial dose of no more than 1.5 mg.kg^-1, calculated using the patient’s ideal body weight and given as an infusion over 10 min. Thereafter, an infusion of no more than 1.5 mg.kg^-1.h^-1 for no longer than 24 h is recommended, subject to review and re-assessment. Intravenous lidocaine should not be used at the same time as, or within the period of action of, other local anaesthetic interventions. This includes not starting i.v. lidocaine within 4 h after any nerve block, and not performing any nerve block until 4 h after discontinuing an i.v. lidocaine infusion.