Generation of cytotoxic T cell responses directed to human leucocyte antigen Class I restricted epitopes from the Aspergillus f16 allergen

Invasive aspergillosis (IA) is a major cause of infection-related mortality in patients with haematological malignancies, especially in recipients of haematopoietic stem cell transplants. We have prepared overlapping pentadecapeptides (11-aa overlap with previous peptide) spanning the entire 427-aa coding region of the Aspergillus allergen, Asp f16 shown previously in mice to induce Th1-type cell responses in vivo and in humans to induce proliferative and cytotoxic CD4(+) T cell responses. Mature dendritic cells (DC) pulsed with a complete pool of peptides were used to generate T cell lines. Two lines from HLA-B*3501(+) donors were found to be strongly cytotoxic to autologous Asp f16-peptide pool- and Aspergillus culture extract-pulsed targets after 4-5 weekly primings. Cytotoxic T lymphocyte (CTL) culture supernatant killed Aspergillus conidia, and cells directly killed Aspergillus hyphae. Cytotoxic activity and interferon (IFN)-gamma production were mediated exclusively by CD8(+) T cells in response to pool-pulsed targets. Interleukin (IL)-4 production was not detected. CTL activity was restricted by HLA-B*3501 and based on peptide prediction programmes was most probably directed to YFKYTAAAL (YFK), LPLCSAQTW (LPL) and GTRFPQTPM (GTR) in one donor, while only LPL was recognized by CTL from the second donor. Pool-pulsed B*3503(+) BLCL but not B*3502(+) or B*3508(+) BLCL presented peptide to donor no. 1. B*3503(+) BLCL presented YFK and to a lesser extent GTR, but not peptide LPL. Our data show that in addition to our previously identified Class II restricted peptide response, DC pulsed with a pentadecapeptide pool from Asp f16 are capable of inducing polyclonal, HLA-Class I-restricted, Aspergillus-specific T cells that may be capable of conferring immunity to IA.     

Urgent desensitization in patients bridged to heart transplantation under extracorporeal membrane oxygenation support: A preliminary experience

Antihuman leukocyte antigen (HLA) antibodies restrict the access to cardiac allografts. Desensitization therapy is a major challenge in patients with cardiogenic shock waiting for urgent heart transplantation (HT). We retrospectively reviewed six patients (mean age of 37.5 years [16–70]) who underwent plasmapheresis (PP) under extracorporeal membrane oxygenation (ECMO) before transplant between January 2017 and September 2018. The average duration of follow‐up was 25 months [20–32]. Mean fluorescence intensity (MFI) of HLA‐specific antibodies was reported as follows: score 4 for MFI < 1000, score 6 for 1000 < MFI < 3000 and score 8 for MFI > 3000. The mean duration of ECMO support was 29 days [1–74] and 6.8 [1–29] PP sessions were performed per patient before transplant. The mean number of HLA‐specific antibodies before HT was 9.6 for score 6 [4–13] and 5.8 for score 8 [1–12]. Four patients had major complications after transplantation (2 hemorrhagic shocks, 5 infectious events). Mean MFI reduction rate was 94% [79–100] for Class I and 44.2% for Class II [0–83]. Hospital survival was 100%, and early antibody‐mediated rejection was diagnosed in one patient at 7 days after HT. Plasmapheresis under ECMO support was associated with favorable early outcomes in highly sensitized candidates for urgent heart transplantation.     

Some peculiar aspects of monoamine oxidase inhibition

CN- ions enhance the inhibition of monoamine oxidase by the hydrazine derivatives, phenelzine [2-phenylethylhydrazine] and pheniprazine [(1-methyl-2-phenylethyl)hydrazine]. This involves partial competitive activation of the initial noncovalent enzyme-inhibitor complex with no significant effect on the subsequent reaction to give the irreversibly inhibited species. Whereas the maximum effects on pheniprazine inhibition of rat liver MAO-B occurred at about 5 microM cyanide, concentrations of 5 mM were necessary for maximum stimulation of MAO-A inhibition. A comparison of the behaviour of rat and ox MAO revealed considerable differences in their sensitivities to pheniprazine and the potentiating effects of cyanide. Species differences were also evident in the interactions derivatives of milacemide [2-n-pentylaminoacetamide] as substrates and mechanism-based inhibitors of MAO-B. In one case there was evidence for apparently large difference in inhibitor sensitivities between human brain MAO-B from different individuals.     

Outcome of Silicone Ring Vertical Gastroplasty in Patients Aged 50 Years and Older

Background: The authors studied the results of silicone ring vertical gastroplasty (SRVG) in patients aged 50 years and older. Methods: The early and late postoperative results in 28 patients aged 50 years or older undergoing SRVG were reviewed retrospectively. The results were compared to those of 370 patients younger than 50 years operated during the same period. Results: There was no postoperative mortality among patients aged 50 years and older. There was a significantly higher incidence of pulmonary embolus and wound infection among patients aged 50 years and older (p < 0.05). The weight loss did not differ significantly between the two studied age groups. Conclusion: SRVG may be performed on patients aged 50 years or older with acceptable complication rate and favourable postoperative results.     

Brain neurosteroid changes after paroxetine administration in mice.

Although it is known that selective serotonin reuptake inhibitors (SSRIs), as other antidepressants, elevate mood only after 3-4 weeks of treatment, the mechanism responsible for this delay is not understood. SSRIs have been demonstrated to alter the levels of neurosteroids such as allopregnanolone (THP) which possess anxiolytic and mood-elevating properties. We compared the effect of 9 and 21 days i.p. administration of paroxetine, a potent SSRI, on the synthesis of THP and its precursor, 5alpha-dihydroprogesterone (DHP), in the mouse cortex, hypothalamus and olfactory bulb. Cortex, olfactory bulb and hypothalamus synthesized levels of DHP were significantly raised after 9 days of paroxetine administration, whereas a significant rise in the THP synthesized level was observed only after 21 days of treatment. Peripheral synthesis of DHP, measured by the level in serum, significantly increased after 9 days, but reverted to normal values after 21 days. No increase was detected in serum THP levels either after 9 or 21 days treatment. Differences in peripheral and brain synthesis indicates independence in brain synthesis. The data indicate that paroxetine administration differentially increases [3H]DHP and [3H]THP content, depending on the duration of the treatment. Our results suggest that brain THP may be involved in the antidepressive and anxiolytic activity of paroxetine.     

Different patterns of esophageal motility disorders among patients with dysphagia and normal endoscopy: A 2-center experience

Esophageal motility disorders (EMDs) are the main etiology of nonobstructive dysphagia (NOD), but they are underestimated in Egypt. High-resolution manometry (HRM) with Chicago Classification version 3.0 (CC v3.0) is the current gold standard diagnostic modality to assess EMD in patients with NOD. In this HRM-based study, we aimed to classify EMD among Egyptian patients and explore the relationship between the severity of symptoms and the various groups of EMD. From January 2020 to January 2021, patients with dysphagia were subjected to diagnostic workup, which included symptom questionnaire for Eckardt score, esophagogastroduodenoscopy, barium esophagogram, and HRM. All patients were categorized based on the HRM results using CC version 3.0 after exclusion of those with obstructive esophageal lesions. Of 252 patients with dysphagia, 55 patients with NOD were analyzed according to CC version 3.0. Achalasia was diagnosed in 31 patients (56.4%) (type I: 18 [58.06%]; type II: 9 [29.03%], and type III: 4 [12.9%]), 3 patients (5.5%) with esophagogastric junction outflow obstruction, 2 patients (3.6%) with absent contractility, 4 patients (7.3%) with distal esophageal spasm, 7 patients (12.7%) with ineffective esophageal motility, and 8 patients (14.5%) with normal manometry. Patients with achalasia experienced significantly high regurgitation (96.8% vs 70.8%; P = .016) compared with those without achalasia. Achalasia was the most common EMD in Egyptian patients with NOD. Eckardt score was higher in patients with outflow obstruction and major motor disorder, but it could not differentiate different categories of CC of EMD. HRM is effective in characterization of EMD.