Abstract Introduction The determination of the groups at risk of death at admission in patients with bacterial infection in the ICU is important. Several prognostic factors have already been identified, however the neutrophil/lymphocyte ratio (NLR) has the advantage of being common and inexpensive. Objective To determine the threshold value of NLR to determine the group at risk of 15-day mortality and the overall survival of patients according to this threshold. Methods This was a retrospective cohort conducted in the intensive care unit of the Ibn Rochd University Hospital in Casablanca over a period of 2 years (January 2019 - January 2021), among hospitalized patients with bacterial infection, acquired or nosocomial. The sample size was calculated a priori and multivariate statistical analyses (multiple logistic regression, Youden index and Kaplan Meier survival estimation and Log Rank) were performed using Rstudio software. The significance level was less than 5%. Results A total of 200 patients were included in the study, 136 patients were alive at 15 days, there were no differences in age between the two groups. Factors associated with patient mortality at 15 days were: gender, use of vasoactive drugs, use of mechanical ventilation, type of sepsis, site of infection, SOFA score (p < 0.000), Apache score (p = 0.009) and NLR at admission (p = 0.001). The cut-off value for NLR was 15.07 with a mean discriminant value of 64.1%. The difference in median overall survival of patients in the two groups according to the threshold value was statistically significant 22 +/- 1.9 days and 11 +/-1.12 days (p = 0.042). Conclusions The NLR appears to be a prognostic factor for 15-day mortality. The knowledge of prognostic factors and threshold values of these indicators allow the prediction of at-risk groups in order to best adapt their management. Key messages The use of common and inexpensive biological prognostic markers are a reliable alternative to identify at-risk patients to optimize their management in developing countries. The RNL is a good biological prognostic markers of mortality of patients infected in ICU.

On behalf of the authors identified below, Itamar Raz, the corresponding author, has formally requested to retract Abstract 453, cited above, which was published in Diabetologia Supplement 1, September 2014—the Abstract Volume of 2014 EASD Annual meeting. The abstract reports on the DIA-AID 1 trial, which examined the safety and efficacy of DiaPep277 to treat type 1 diabetes. The DIA-AID 1 trial was funded by Andromeda Biotech, Ltd. On 8 September 2014, Hyperion Therapeutics, Inc., which acquired Andromeda Biotech in June 2014, announced that it had chosen to terminate the DiaPep277 programme. As stated in the press release issued by Hyperion Therapeutics, ‘The company has uncovered evidence that certain employees of Andromeda Biotech, Ltd ... engaged in serious misconduct, including collusion with a third-party biostatistics firm in Israel to improperly receive un-blinded DIA-AID 1 trial data and to use such data in order to manipulate the analyses to obtain a favorable result’ [1]. The corresponding author writes: ‘In view of the public statements by Hyperion Therapeutics [1] regarding alleged scientific misconduct, we, the authors of this statement, are retracting the above-cited abstract. We wish to emphasize that we were not involved in the assembly of the raw data or the alleged misconduct. ‘The following authors support the decision to retract the article: Itamar Raz, Paolo Pozzilli, Thomas Linn and Francois Bonnici.’ Diabetologia was only able to contact four of the six coauthors who are/were Andromeda Biotech employees—Dana Elias, Merana Tamir, Rachel Eren and Shlomo Dagan. None of these co-authors responded to emails and therefore none of the Andromeda Biotech employees were part of this retraction process.

Background Treatment with DiaPep277 (R), a peptide derived from HSP60, has been shown to preserve beta-cell function in non-obese diabetic mouse (NOD) mice and in a trial with newly diagnosed human patients with type 1 diabetes treated over a 10-month period. This article extends the clinical trial observations to a total of 20 months of treatment to determine the safety and the effects of repeated doses of DiaPep277 on endogenous insulin secretion, metabolic control, and exogenous insulin requirements.Methods Thirty-five male patients (aged 16-58) with a basal C-peptide greater than 0.1 nmol/L were assigned to periodic treatment with DiaPep277 (1 mg) or placebo for a 12-month treatment and 18-month observation protocol, later extended to an additional year of treatment. Stimulated C-peptide, HbA(1c), and an exogenous insulin dose were the clinical endpoints.Results At 18 months, stimulated C-peptide concentrations had fallen in the placebo group (p = 0.0005) but were maintained in the DiaPep277 group. The need for exogenous insulin was higher in the placebo group than in the DiaPep277 group. Mean HbA(1c) concentrations were similar in both groups. After extension of the study, patients continuing treatment with DiaPep277 and those switched from placebo to DiaPep277 manifested a trend towards a greater preservation of beta-cell function compared to patients maintained on or switched to placebo. The safety profile of DiaPep277 was similar between the treatment and placebo groups, and no drug-related adverse events occurred.Conclusions Periodic treatment of subjects with DiaPep277 over 2 years was safe and associated preservation of endogenous insulin secretion up to 18 months was observed. Copyright (C) 2006 John Wiley & Sons, Ltd.

BACKGROUND:Type 1 diabetes mellitus (T1DM) is a T-cell-mediated autoimmune disease that leads to the destruction of insulin-producing beta cells. Treatment with DiaPep277, a peptide derived from heat-shock protein 60 (hsp60), has been found to slow the deterioration of beta-cell function after clinical onset of diabetes in NOD mice and human adults. Our aim was to evaluate the efficacy and safety of DiaPep277 treatment in attenuating beta-cell destruction in children with recent-onset T1DM. METHODS:A prospective, randomized, double-blind, phase II design was used. The sample included 30 children (19 males) aged 7-14 years who had been diagnosed with T1DM from 53 to 116 days previously, and had basal C-peptide concentrations above 0.1 nmol/L. The children were randomized to receive subcutaneous injections of 1 mg DiaPep277 (15 patients) or 40 mg mannitol (placebo) at entry and at 1, 6, and 12 months. The duration of follow-up was 18 months. The groups were compared for stimulated C-peptide level, exogenous insulin dose, and HbA1c concentration. RESULTS:C-peptide levels similarly decreased over time in the DiaPep277- and placebo-treated patients. There was no significant difference in insulin dose or HbA1c concentration between the groups at any time point. No serious drug-related adverse effects were recorded throughout the study period. CONCLUSIONS:One-year treatment with DiaPep277 at a dosage of 1 mg is safe for use and well tolerated in children with recent-onset T1DM. However, it appears to have no beneficial effect in preserving beta-cell function or improving metabolic control.

BACKGROUND:Type 1 diabetes results from autoimmune destruction of insulin-producing pancreatic beta cells. The 60 kDa heat-shock protein (hsp60) is one of the known target self antigens. An immunomodulatory peptide from hsp60, p277, arrested beta-cell destruction and maintained insulin production in newly diabetic NOD mice. We did a randomised, double-blind, phase II study of peptide treatment in patients with newly diagnosed (<6 months) type 1 diabetes.METHODS:35 patients with type 1 diabetes and basal C-peptide concentrations above 0.1 nmol/L were assigned subcutaneous injections of 1 mg p277 and 40 mg mannitol in vegetable oil (DiaPep277; n=18) at entry, 1 month, and 6 months, or three placebo injections (mannitol in vehicle; placebo; n=17). The primary endpoint was glucagon-stimulated C-peptide production. Secondary endpoints were metabolic control and T-cell autoimmunity to hsp60 and to p277 (assayed by cytokine secretion). 31 patients completed 10 months of follow-up and were included in the intention-to-treat analysis.FINDINGS:At 10 months, mean C-peptide concentrations had fallen in the placebo group (n=16) but were maintained in the DiaPep277 group (n=15; 0.26 [SD 0.11] vs 0.93 [0.35] nmol/L; p=0.039). Need for exogenous insulin was higher in the placebo than in the DiaPep277 group (0.67 [0.33] vs 0.43 [0.17] U/kg; p=0.042). Haemoglobin A1c concentrations were low (around 7%) in both groups. T-cell reactivity to hsp60 and p277 in the DiaPep277 group showed an enhanced T-helper-2 cytokine phenotype. No adverse effects were noted.INTERPRETATION:Although this study was small, treatment of newly diagnosed type 1 diabetes with DiaPep277 seems to preserve endogenous insulin production, perhaps through induction of a shift from T-helper-1 to T-helper-2 cytokines produced by the autoimmune T cells.

Functional delta opioid receptors were expressed in Xenopus oocytes following injection of poly(A+)RNA isolated from the mouse neuroblastoma X rat glioma hybrid cell line, NG108-15. Oocytes coinjected with in vitro transcribed beta 2-adrenergic receptor mRNA and NG108-15 cell mRNA had 3-fold elevated cAMP levels following isoproterenol treatment. Application of delta opioids to these oocytes caused dose-dependent inhibition of isoproterenol-induced increase of cAMP, which was antagonized by naltrexone. This is the first demonstration of the expression of opioid receptors in Xenopus oocytes. The ability to assay expression of delta opioid receptors functionally coupled to the inhibition of adenylate cyclase in Xenopus oocytes following injection of exogenous mRNA will provide a system to investigate the relationship of molecular structure to function of opioid receptors.

Thymocytes were propagated in long-term cultures supported by stromal cells of both bone marrow and thymus origin. Interleukin 2 (IL-2) supplementation augmented the cell yield and allowed detailed phenotype analysis. Within 2-3 months of culture a cell population was selected in which the expression of Thy-1 antigen persisted, CD4 and CD8 antigens gradually declined, and Pgp-1 antigen, found on less than 5% of fresh thymocytes, was strongly increased. This cultured cell population (Thy-1.2 origin) contained no detectable spleen colony-forming units (CFU-S) but efficiently repopulated the thymus of Thy-1.1-irradiated congenic mice, indicating the precursor T-cell nature of the population. Upon removal from the stroma, the T cells exhibited poor cytotoxicity towards syngeneic tumor cells. Further propagation with IL-2 in the absence of stroma resulted in the acquisition of cytotoxic ability. Replacement of the horse serum used in the above experiments with fetal calf serum resulted in accumulation of cells expressing B220 antigen. This experimental model provides the means to maintain lymphocyte precursor cells in long-term culture and to further study their differentiation in the absence of stroma, both in vitro and in vivo.

Hemopoiesis is a multistep process involving stem cell renewal, commitment, differentiation, maturation and consequent positioning of the cells within the tissue. Stromal cells are a major component of the hemopoietic microenvironment. The in vitro culture of cloned stromal cells has enabled detailed analysis of their functions and has provided answers relating to the contribution of stromal cells to the control of hemopoiesis. Cultured stromal cells were found to support the renewal of stem cells through a mechanism that did not seem to involve already known cytokines. Cloned stromal cells from both marrow and thymus supported the in vitro accumulation of myeloid as well as T and B lymphoid cells. Thus, cloned stromal cells had the ability to induce multilineage hemopoiesis, irrespective of the organ from which they were derived. Invariably, stromal cells tended to select in culture for hemopoietic cells at early differentiation stages and restricted the accumulation of mature cells. These functions may be part of the mechanism that protects the stem cell pool from excess differentiation.

Long-term hemopoiesis in culture depends upon the presence of an adherent layer composed of a variety of stromal cells. A subtype of endothelial-adipocytes from the bone marrow stroma (clone 14F1.1) was previously shown to induce long-term myelopoiesis and renewal of pluripotent stem cells. One of a series of stromal cell lines and clones from mouse thymus stroma (STAC-1.2) has now been found to support long-term hemopoiesis. These marrow- and thymus-derived stromal cell clones also have lymphopoietic activities: precursor T cells, or pre-B cells accumulated in co-cultures of thymus cells and the stromal clones, as indicated by cell surface markers, T cell receptor and immunoglobulin gene rearrangements. The predominance of a cell type in these cultures depended upon the serum used to supplement the medium. Recombinant interleukin 2 (IL-2) and the 14F1.1 clone synergistically promoted the proliferation of thymocytes, while a thymus hormone, THF-gamma 2, shifted the population to a relatively mature phenotype. It is proposed that one major function of stromal cells, whether from the bone marrow or thymus, is to restrain the maturation flow and preferentially support the accumulation of cells at early differentiation stages.

Hemopoiesis is a sequence of events initiated by the self-renewal of pluripotent stem cells followed by a series of differentiation steps and completed in the formation of distinct tissue patterns. Differentiation and self-renewal are antagonistic processes. A mechanism that attenuates the differentiation flow is obligatory to prevent the exhaustion of the stem cell pool. We suggest that stromal cells from the bone marrow control stem cell renewal through a mechanism that does not require colony-stimulating factors. The organization of cells within the tissue and their specific localization is suggested to be directed by stromal cell activities other than differentiation inducers. These stromal cell activities restrict differentiation or accumulation of mature cells. They are therefore designated as 'Restrictins'.

We derived stromal cell lines from mouse thymus using methods previously established for bone marrow stroma. Two main morphologically distinct groups of cell strains emerged: epithelioid and mixed fibroblast-macrophage. Transmission electron microscopy revealed frequent junctional-complex formations between adjacent cells, a feature that characterized almost all of the thymus stromal lines, but was confined to only one of the five distinct subtypes of cell lines from bone marrow. In contrast to marrow stromal cells, the thymus-derived cell lines were all negative with fat-detecting reagents, had low acid phosphatase and no basic phosphatase activities and were unable to support the in vitro proliferation of myeloid progenitor cells (CFU-gm). Leukemia cell inhibitory activity (LCIA) was detected in one of the thymus stromal cell lines. The differences observed between cell lines derived from the stroma of the thymus and those from bone marrow may relate to the functional specificities of these organs.