Evaluation of a radioimmunoassay for plasma adrenocorticotrophin.

A radioimmunoassay for plasma ACTH has been described and evaluated. Rabbit antiserum produced by immunization with [Asp25, Ala26, Gly27,]-alphah-corticotrophin-(1--28)-octacosa-peptide (a sequence analogue of alphah1--28-ACTH) bovine gamma globulin conjugate was used. The antiserum is specific for the NH2-terminal portion of the ACTH molecule and cross-reactivity of human, porcine and rat ACTH in the system has been demonstrated. Reasonable agreement was found between estimates obtained by bioassay and radio-immunoassay of the ACTH content of rat pituitary gland incubation media, indicating a close relationship between the sequence of ACTH recognized by the antibodies and the sequence possessing the steroidogenic activity. Measurement of the amount of ACTH in the plasma required the preliminary extraction and concentration of the hormone. Over a range of concentrations between 3.5 and 3600 pg/ml, extraction recovery was independent of the initial concentration of ACTH in the plasma. Extraction gave rise to no changes in the immunological properties of standard ACTH. The concentration of immunoreactive ACTH in rat plasma was 48 +/- 3.6 (S.E.M.) pg/ml in the morning and 106 +/- 9.9 pg/ml in the afternoon. Exposure to either for 5 min and subsequent laparotomy gave rise to a significant increase in the concentration of immunoreactive ACTH in the plasma. The resting level of ACTH and the ACTH response to stress were both significantly higher 1 and 7 days after adrenalectomy. Intravenous injection of a hypothalamic extract elicited a considerable rise in the concentration of immunoreactive ACTH in the plasma, but no response was seen after oral administration of this partially purified extract. The sensitivity, precision and specificity of this ACTH radioimmunoassay make it a useful tool for studying pituitary--adrenal physiology.     

Impaired T-lymphocyte function in B-chronic lymphocytic leukaemia as measured by the local xenogeneic graft-versus-host reaction

The immunological dysfunction observed in B-chronic lymphocytic leukaemia (B-CLL) is often related to T-lymphocyte incompetence. The local xenogeneic graft-vs.-host reaction (XGVHR), an assay to evaluate T-lymphocyte function, was performed in 112 untreated B-CLL patients. The XGVHR results significantly correlated with clinical parameters: 37.1% of the patients in the stable phase (Rai stage 0–1–2) and only 13.3% of the patients in the progressive phase (Rai stage 3–4) had positive XGVHR results. Patients with negative results had a higher number and percentage of lymphocytes (25 247 vs. 17 071/μl and 75.9% vs. 65.6%, respectively), much lower T/B lymphocyte ratio (0.37 vs. 0.93), higher WBC count (30 977 vs. 23 458/μl), lower platelet count (158 068 vs. 181 684/μl) and lower levels of IgA and IgM (115.6 vs. 200.5 mg/dl and 80.4 vs. 124.3 mg/dl, respectively) compared to those with positive results. Among those with negative XGVHR results, a higher mortality rate was found in those who had infections compared with those who did not (73.7% vs. 9.1%). In conclusion, the XGVHR assay significantly correlates with important characteristics of B-CLL and may be useful in the clinical evaluation of B-CLL patients.     

Diagnostic and prognostic factors in acute monocytic leukaemia: an analysis of 51 cases

Diagnostic features (cytochemistry, immunophenotyping and serum biochemistry) were examined in 51 cases of acute monocytic leukaemia (AMoL). Peroxidase, Sudan black B and alpha naphthyl acetate esterase (ANAE) cytochemical reactions were unrelated to morphological (FAB groups M5a and M5b) or immunological subtype. ANAE cytochemistry, however, indicated that AMoL cases could be subdivided into those with typical (M-type) reactions and those with insignificant staining or monocytic ANAE isoenzymes (defined by IEF). All cases were phenotypically CD13/CD33 positive and, with one exception, had greater than 30% HLA-DR positive cells. Membrane CD14 expression was insignificant or variable in 33% of M5a cases in contrast to 23/24 M5b cases which showed high proportions of CD14-staining cells with at least two monoclonal antibodies. Serum lysozyme, LDH and beta-2 microglobulin (beta 2m) were increased in 88%, 68% and 81% of cases respectively but, with the exception of statistically higher lysozyme levels in CD14+ cases, were unrelated to the morphological, cytochemical or immunological diagnostic subgroups. Clinical and diagnostic features were also examined as possible prognostic indicators. The morphological, cytochemical and immunological subgroups of AMoL were not found to be of prognostic relevance but age (P = 0.004), renal failure (P = 0.005) and serum beta 2m levels (P = 0.002) were related to patient survival. Moreover, renal failure and serum beta 2m remained significant (P = 0.012 respectively) when age was taken into account and were shown to be independent prognostic variables.     

Prostanoids cytoprotection for maintaining remission in ulcerative colitis failure of 15(R), 15-methylprostaglandin E2

To establish whether the cytoprotective properties of prostanoids can be used for maintaining remission in ulcerative colitis, 24 patients with ulcerative colitis in remission were randomly assigned to receive either 15(R), 15-methyl-PGE2 (200 micrograms/day) or to continue with sulfasalazine (2.0 g/day) for up to 28 weeks. All patients included were symptom free and sigmoidoscopy and rectal biopsy performed upon entering the trial did not reveal any signs of disease activity. Of the 12 patients who discontinued sulfasalazine and were allocated to receive 15(R), 15-methyl-PGE2, five flared up within the first four weeks and three others had to stop the trial because of severe diarrhea. Because of the high incidence of side effects and flare-up, the other four patients were instructed to stop the trial. In contrast, only two of the 12 sulfasalazine-treated patients flared-up and the other 10 concluded the 28 weeks of the trial symptom free. These results indicate that 15(R), 15-methyl-PGE2 cannot be used to control and support remission in ulcerative colitis patients.     

Efficient maternal to neonatal transfer of antibodies against SARS-CoV-2 and BNT162b2 mRNA COVID-19 vaccine

BACKGROUNDThe significant risks posed to mothers and fetuses by COVID-19 in pregnancy have sparked a worldwide debate surrounding the pros and cons of antenatal SARS-CoV-2 inoculation, as we lack sufficient evidence regarding vaccine effectiveness in pregnant women and their offspring. We aimed to provide substantial evidence for the effect of the BNT162b2 mRNA vaccine versus native infection on maternal humoral, as well as transplacentally acquired fetal immune response, potentially providing newborn protection.METHODSA multicenter study where parturients presenting for delivery were recruited at 8 medical centers across Israel and assigned to 3 study groups: vaccinated (n = 86); PCR-confirmed SARS-CoV-2 infected during pregnancy (n = 65), and unvaccinated noninfected controls (n = 62). Maternal and fetal blood samples were collected from parturients prior to delivery and from the umbilical cord following delivery, respectively. Sera IgG and IgM titers were measured using the Milliplex MAP SARS-CoV-2 Antigen Panel (for S1, S2, RBD, and N).RESULTSThe BNT162b2 mRNA vaccine elicits strong maternal humoral IgG response (anti-S and RBD) that crosses the placenta barrier and approaches maternal titers in the fetus within 15 days following the first dose. Maternal to neonatal anti-COVID-19 antibodies ratio did not differ when comparing sensitization (vaccine vs. infection). IgG transfer ratio at birth was significantly lower for third-trimester as compared with second trimester infection. Lastly, fetal IgM response was detected in 5 neonates, all in the infected group.CONCLUSIONAntenatal BNT162b2 mRNA vaccination induces a robust maternal humoral response that effectively transfers to the fetus, supporting the role of vaccination during pregnancy.FUNDINGIsrael Science Foundation and the Weizmann Institute Fondazione Henry Krenter.     

Phages and their potential to modulate the microbiome and immunity

Bacteriophages (hence termed phages) are viruses that target bacteria and have long been considered as potential future treatments against antibiotic-resistant bacterial infection. However, the molecular nature of phage interactions with bacteria and the human host has remained elusive for decades, limiting their therapeutic application. While many phages and their functional repertoires remain unknown, the advent of next-generation sequencing has increasingly enabled researchers to decode new lytic and lysogenic mechanisms by which they attack and destroy bacteria. Furthermore, the last decade has witnessed a renewed interest in the utilization of phages as therapeutic vectors and as a means of targeting pathogenic or commensal bacteria or inducing immunomodulation. Importantly, the narrow host range, immense antibacterial repertoire, and ease of manipulating phages may potentially allow for their use as targeted modulators of pathogenic, commensal and pathobiont members of the microbiome, thereby impacting mammalian physiology and immunity along mucosal surfaces in health and in microbiome-associated diseases. In this review, we aim to highlight recent advances in phage biology and how a mechanistic understanding of phage–bacteria–host interactions may facilitate the development of novel phage-based therapeutics. We provide an overview of the challenges of the therapeutic use of phages and how these could be addressed for future use of phages as specific modulators of the human microbiome in a variety of infectious and noncommunicable human diseases.     

Recommendations for Responsible Development and Application of Neurotechnologies

Advancements in novel neurotechnologies, such as brain computer interfaces (BCI) and neuromodulatory devices such as deep brain stimulators (DBS), will have profound implications for society and human rights. While these technologies are improving the diagnosis and treatment of mental and neurological diseases, they can also alter individual agency and estrange those using neurotechnologies from their sense of self, challenging basic notions of what it means to be human. As an international coalition of interdisciplinary scholars and practitioners, we examine these challenges and make recommendations to mitigate negative consequences that could arise from the unregulated development or application of novel neurotechnologies. We explore potential ethical challenges in four key areas: identity and agency, privacy, bias, and enhancement. To address them, we propose (1) democratic and inclusive summits to establish globally-coordinated ethical and societal guidelines for neurotechnology development and application, (2) new measures, including “Neurorights,” for data privacy, security, and consent to empower neurotechnology users’ control over their data, (3) new methods of identifying and preventing bias, and (4) the adoption of public guidelines for safe and equitable distribution of neurotechnological devices.