Sodium chloride or plasmalyte-148 for patients presenting to emergency departments with diabetic ketoacidosis: A nested cohort study within a multicentre,cluster, crossover,randomised, controlled trial

Objective

To test the hypothesis that fluid resuscitation in the ED with plasmalyte-148 (PL) compared with 0.9% sodium chloride (SC) would result in a lower proportion of patients with diabetic ketoacidosis (DKA) requiring intensive care unit (ICU) admission.

Methods

We performed a prespecified nested cohort study at two hospitals within a cluster, crossover, open label, randomised, controlled trial comparing the effects of PL versus SC as fluid therapy for patients who presented to the ED with DKA. All patients presenting within a fixed recruitment period were included. The primary outcome was the proportion of patients admitted to ICU.

Results

Eighty-four patients were enrolled (SC n = 38, PL n = 46). The SC group had a lower median pH on admission (SC: 7.09 [interquartile range (IQR) 7.01–7.21], PL: 7.17 [IQR 6.99–7.26]). The median volume of intravenous fluids administered in ED was 2150 mL (IQR 2000–3200 mL; SC) and 2200 mL (IQR 2000–3450; PL); respectively. A higher proportion of patients in the SC group, 19 (50%), was admitted to ICU compared with PL group, 18 (39.1%); however, after adjustment for pH at presentation and diabetes type in a multivariable logistic regression model, the PL group did not have a significantly different rate of ICU admission compared with the SC group (odds ratio for ICU admission 0.73, 95% confidence interval 0.13–3.97, P = 0.71).

Conclusion

Patients with DKA treated with PL compared with SC in the EDs had similar rates of requiring ICU admission.     

Proliferation and cytogenetic analysis of hairy cell leukemia upon stimulation via the CD40 antigen

Using the CD40 system, in vitro proliferation of hairy cell leukemia (HCL) was examined in 43 patients. In this culture system, cells were stimulated by interleukin-4 (IL-4) and anti-CD40 monoclonal antibodies (MoAbs) that were added in soluble form or were cross-linked via their Fc part using Fc gamma RII-transfected mouse fibroblast cells. Proliferation was induced and confirmed by 3H-thymidine incorporation in 14 cases and by the presence of metaphases in 42 cases. 3H-thymidine incorporation showed a heterogeneous pattern: cross-linking of anti- CD40 gave the highest proliferation in 8 cases; in 11 cases, stimulation with anti-CD40 MoAbs alone, without cross-linking also resulted in proliferation; the addition of IL-4 further enhanced 3H- thymidine incorporation in 5 cases, but suppressed this phenomenon in 5 other cases. The CD40 system proved to be very effective in obtaining cytogenetic data. With a success rate of 42 of 43 patients tested, we found clonal abnormalities in 8 cases (19%) and nonclonal abnormalities with involvement of one or two abnormal metaphases in another 7 cases. The chromosomes most frequently involved in the abnormal karyotypes, both structurally and numerically, were chromosomes 5, 7, and 14. By fluorescence-activated cell-sorting analysis of the cultured cells, and by immunophenotypic analysis of metaphase spreads, T-cell growth could be excluded and the HCL-lineage confirmed. Stimulation via the CD40 antigen is an excellent tool for growing hairy cell leukemia cells.     

Activation of erythropoietin receptors by Friend viral gp55 and by erythropoietin and down-modulation by the murine Fv-2r resistance gene.

The leukemogenic membrane glycoprotein (gp55) encoded by Friend spleen focus-forming virus appears to bind to erythropoietin receptors (EpoR) sto stimulate erythroblastosis [Li, J.-P., D'Andrea, A.D., Lodish, H.F. & Baltimore, D. (1990) Nature (London) 343, 762-764]. To directly compare the effects of gp55 with erythropoietin (Epo), we produced retrovirions that encode either gp55, Epo, or EpoR. After infection with EpoR virus, interleukin 3-dependent DA-3 cells bound 125I-labeled Epo and grew without interleukin 3 in the presence of Epo. These latter cells, but not parental DA-3 cells, became factor-independent after superinfection either with Epo virus or with Friend spleen focus-forming virus. In addition, Epo virus caused a disease in mice that mimicked Friend erythroleukemia. Although Fv-2r homozygotes are susceptible to all other retroviral diseases, they are resistant to both Epo viral and Friend viral erythroleukemias. These results indicate that both gp55 and Epo stimulate EpoR and that the Fv-2 gene encodes a protein that controls response to these ligands. However, the Fv-2 protein is not EpoR because the corresponding genes map to opposite ends of mouse chromosome 9. These results have important implications for understanding signal transduction by EpoR and the role of host genetic variation in controlling susceptibility to an oncogenic protein.     

Effects of monoclonal antibody therapy in patients with chronic lymphocytic leukemia

A phase I clinical trial was initiated to treat patients with stage IV B-derived chronic lymphocytic leukemia (CLL) with the IgG2a murine monoclonal antibody T101. This antibody binds to a 65,000-mol wt (T65) antigen found on normal T lymphocytes, malignant T lymphocytes, and B- derived CLL cells. All of the patients had a histologically confirmed diagnosis of advanced B-derived CLL and were refractory to standard therapy, and more than 50% of their leukemia cells reacted with the T101 antibody in vitro. The patients received T101 antibody two times per week, over two to 50 hours by intravenous administration in 100 mL of normal saline containing 5% human albumin. Twelve patients were treated with a fixed dosage of 1, 10, 50, or 100 mg, and one patient was treated with 140 mg of antibody. It was demonstrated that patients given two-hour infusions of 50 mg developed pulmonary toxicity, with shortness of breath and chest tightness. This toxicity was eliminated when infusions of 50 or 100 mg of T101 were prolonged to 50 hours. All dose levels caused a rapid but transient decrease in circulating leukemia cell counts. In vivo binding to circulating and bone marrow leukemia cells was demonstrated at all dose levels with increased binding at higher dosages. Antimurine antibody responses were not demonstrated in any patients at any time during treatment. Circulating free murine antibody was demonstrated in the serum of only the two patients treated with 100 mg of antibody as a 50-hour infusion and the patient treated with 140 mg of antibody over 30 hours. Antigenic modulation was demonstrated in patients treated at all dose levels but was particularly apparent in patients treated with prolonged infusions of 50 and 100 mg of antibody. We were also able to demonstrate antigenic modulation in lymph node cells, which strongly suggests in vivo labeling of these cells. Overall, T101 antibody alone appears to have a very limited therapeutic value for patients with CLL. The observations of in vivo labeling of tumor cells, antigenic modulation, antibody pharmacokinetics, toxicity, and antimurine antibody formation may be used in the future for more effective therapy when drugs or toxins are conjugated to the antibody.     

Some correlations between specificity and sequence of the first complementarity-determining segments of human kappa light chains.

Examination of the sequences of the first complementarity-determining segments of the light chains of two IgM cold agglutinins agains blood group I, four monoclonal IgM antibodies against IgG proteins, and of three Bence Jones proteins provides clues for predicting which residues contribute to antibody specificity and indicates that these predictions may be tested by evaluating recovery of antibody activity and specificity when various light chains are recombined with homologous and heterologous heavy chains.     

Tumor mutational load predicts time to first treatment in chronic lymphocytic leukemia (CLL) and monoclonal B-cell lymphocytosis beyond the CLL international prognostic index

Next-generation sequencing identified about 60 genes recurrently mutated in chronic lymphocytic leukemia (CLL). We examined the additive prognostic value of the total number of recurrently mutated CLL genes (i.e., tumor mutational load [TML]) or the individually mutated genes beyond the CLL international prognostic index (CLL-IPI) in newly diagnosed CLL and high-count monoclonal B-cell lymphocytosis (HC MBL). We sequenced 59 genes among 557 individuals (112 HC MBL/445 CLL) in a multi-stage design, to estimate hazard ratios (HR) and 95% confidence intervals (CI) for time-to-first treatment (TTT), adjusted for CLL-IPI and sex. TML was associated with shorter TTT in the discovery and validation cohorts, with a combined estimate of continuous HR = 1.27 (CI:1.17-1.39, P = 2.6 × 10⁻⁸; c-statistic = 0.76). When stratified by CLL-IPI, the association of TML with TTT was stronger and validated within low/intermediate risk (combined HR = 1.54, CI:1.37-1.72, P = 7.0 × 10⁻¹⁴). Overall, 80% of low/intermediate CLL-IPI cases with two or more mutated genes progressed to require therapy within 5 years, compared to 24% among those without mutations. TML was also associated with shorter TTT in the HC MBL cohort (HR = 1.53, CI:1.12-2.07, P = .007; c-statistic = 0.71). TML is a strong prognostic factor for TTT independent of CLL-IPI, especially among low/intermediate CLL-IPI risk, and a better predictor than any single gene. Mutational screening at early stages may improve risk stratification and better predict TTT.     

CHEMICAL STUDIES ON BACTERIAL AGGLUTINATION : VII. A QUANTITATIVE STUDY OF THE TYPE SPECIFIC AND GROUP SPECIFIC ANTIBODIES IN ANTIMENINGOCOCCAL SERA OF VARIOUS SPECIES AND THEIR RELATION TO MOUSE PROTECTION

1. The quantitative method for the estimation of agglutinins has been applied to antimeningococcal horse, rabbit, and chicken sera and to the sera of humans convalescing from meningococcus meningitis. The type-specific and group-specific agglutinin N can be measured, using homologous and heterologous suspensions of meningococci. 2. Type I horse, rabbit, and chicken antimeningococcal sera contain considerable amounts of antibody which cannot be removed either by Type II meningococcus suspension or by preparations of the Type I specific polysaccharide. This residual type-specific antibody has marked potency in protecting mice against subsequent infection with meningococci. 3. Most human convalescent sera contain group-specific antibody. Small amounts of protective antibody and of antipolysaccharide are also formed. 4. Type I antisera absorbed with Type I polysaccharide and with Type II meningococci could be used as a guide in the purification of this new antigen.     

A FURTHER STUDY OF THE CROSS REACTION BETWEEN THE SPECIFIC POLYSACCHARIDES OF TYPES III AND VIII PNEUMOCOCCI IN HORSE ANTISERA

1. The cross reaction of the specific polysaccharide of Type VIII pneumococcus with Type III antipneumococcus horse serum has been studied quantitatively and found similar to the S III-anti-S VIII reaction. 2. Contrasted with the general similarity of the two-segment reaction curves were distinct qualitative and quantitative differences in the course and character of the reciprocal reactions with respect to each segment. 3. These differences could be interpreted in terms of the known chemical differences between the specific polysaccharides of the two types. A minimum molecular weight of 62,000 was calculated for S III and 140,000 for S VIII. 4. It was also found possible to fractionate the Type VIII antibody into portions characteristic of each segment of the cross reaction curve. At least three different kinds of Type III and Type VIII anticarbohydrates were identified.     

CHEMICAL AND IMMUNOLOGICAL STUDIES ON THE AGENT PRODUCING LEUKOSIS AND SARCOMA OF FOWLS

The activity of the agent producing sarcoma or leukosis in material deposited by high speed centrifugation is the same as that of the original crude extracts. Material sedimentable at high speed containing approximately 10^–5 mg. N produces tumors at the site of injection. Small quantities of material sedimentable at high speed are present in normal chicken sera, and about twice as much in leukemic sera (strain 1). Normal chicken and mouse spleens and all other human and mouse tissues examined contain large amounts of material sedimentable at high speed. Extraction of leukemic blood cells with saline yields little additional virus. The washed cells readily produce leukosis even after irradiation with amounts of x-rays sufficient to destroy the leukemic cells but not the virus. Freezing at –60°C. preserves the activity of the high speed deposits for at least 6 months. Addition of 5 per cent of saturated Na₂SO₄ solution slightly delays deterioration of high speed deposits in the ice box. Most of the agent measured by inoculation of chickens and the fraction sedimentable at high speed measured by its nitrogen content is precipitated by one-third saturation with sodium sulfate.     

State of the art and recommendationsKangaroo mother care: application in a high‐tech environment

Since Kangaroo Mother Care (KMC) was developed in Colombia in the 1970s, two trends in clinical application emerged. In low income settings, the original KMC model is implemented. This consists of continuous (24 h/day, 7 days/week) and prolonged mother/parent–infant skin‐to‐skin contact; early discharge with the infant in the kangaroo position; (ideally) exclusive breastfeeding; and, adequate follow‐up. In affluent settings, intermittent KMC with sessions of one or a few hours skin‐to‐skin contact for a limited period is common. As a result of the increasing evidence of the benefits of KMC for both infants and families in all intensive care settings, KMC in a high‐tech environment was chosen as the topic for the first European Conference on KMC, and the clinical implementation of the KMC model in all types of settings was discussed at the 7th International Workshop on KMC. Kangaroo Mother Care protocols in high‐tech Neonatal Intensive Care Units (NICU) should specify criteria for initiation, kangaroo position, transfer to/from KMC, transport in kangaroo position, kangaroo nutrition, parents’ role, modification of the NICU environment, performance of care in KMC, and KMC in case of infant instability. Conclusion: Implementation of the original KMC method, with continuous skin‐to‐skin contact whenever possible, is recommended for application in high‐tech environments, although scientific evaluation should continue.