Soluble triggering receptor expressed on myeloid cells-1 in acute respiratory infections.

Levels of the soluble form of the triggering receptor expressed on myeloid cells (sTREM)-1 are elevated in severe sepsis. However, it is not known whether sTREM-1 measurements can distinguish milder bacterial infections from noninfectious inflammation. The present authors studied whether serum sTREM-1 levels differ in community-acquired pneumonia, exacerbations of chronic obstructive pulmonary disease (COPD), asthma and controls, and whether sTREM-1 may be used as a surrogate marker for the need for antibiotics. Serum sTREM-1 levels in 150 patients with pneumonia, COPD and asthma exacerbations and 62 healthy controls were measured. Serum sTREM-1 levels were significantly elevated in pneumonia (median 295.2 ng x mL(-1)), COPD (280.3 ng x mL(-1)) and asthma exacerbations (184.0 ng x mL(-1)) compared with controls (83.1 ng x mL(-1)). Levels were higher in pneumonia and Anthonisen type 1 COPD exacerbations than in type 2 and 3 COPD and asthma exacerbations. The area under the receiver operating characteristics curve for sTREM-1 as a surrogate marker for the need for antibiotics was 0.77. Serum levels of the soluble form of the triggering receptor expressed on myeloid cells-1 were elevated predominantly in pneumonia and Anthonisen type 1 COPD exacerbations versus type 2 and 3 chronic obstructive pulmonary disease exacerbations, asthma and controls. Serum levels of the soluble form of the triggering receptor expressed on myeloid cells-1 has moderate but insufficient accuracy as a surrogate marker for the need for antibiotics in lower respiratory tract infections.     

Predicting the dynamic effects of rubella vaccination programmes

In the Netherlands, prepubertal girls have been vaccinated against rubella since 1974 (the UK strategy). Recently the Dutch Health Council advocated the introduction of an elimination strategy: vaccination of 1- and 9-year-old children. Dynamic effects of both strategies are studied using deterministic and stochastic models. Estimates of several epidemiological parameters are given. All computations and simulations were performed using as much field data as possible. Under the old strategy a new equilibrium is expected around the years 1995 to 2000; the new strategy is estimated to eliminate rubella (CRS) in large parts of the population 3 to 5 years after its initiation. Possible consequences of the new strategy on a cluster of people who refuse vaccination are investigated.     

The vibratory innocent heart murmur in schoolchildren: A case-control Doppler echocardiographic study

Summary In 810 schoolchildren (aged 5–14 years) the prevalence of a grade 1–3/6 vibratory innocent heart murmur (VIHM) is 41%. Restricted to a grade 2 or 3 VIHM, the prevalence is 14%, decreasing from 21% in the age-class 5–6 years to 8% for children 13–14 years of age. The prevalence of a grade 3 VIHM is 1%. Together with a matched control, 84 children with a grade 2 or 3 VIHM underwent further cardiologic examination including electrocardiography, phonocardiography, and Doppler echocardiography. A positive correlation was found between the presence of a VIHM and higher left ventricular voltages on the ECG, but within the normal range; lower heart rate; smaller diameter of the ascending aorta (AAO); and higher blood flow velocity and higher maximal acceleration of the blood flow in the LVOT and the AAO. In 40% of the children with a VIHM, a systolic aortic valve vibration was seen with a frequency 100 Hz and an amplitude 1 mm, whereas this type of vibration was present in only one case control. No significant difference was found concerning the prevalence of false tendons in the left ventricle, systolic and diastolic diameter of the left ventricle, systolic time intervals, and shortening fraction of the left ventricle. The VIHM is strongly associated with a smaller AAO, with higher velocity and acceleration of the blood flow in the LVOT and AAO, and with a vibratory phenomenon of the aortic valve, pointing towards the LVOT-aortic valve region as the site of origin of the VIHM.     

Memory and learning are not impaired in presymptomatic individuals with an increased risk of Huntington's disease

Retrieval from long-term memory in patients with brain injuries was investigated with a memory scanning paradigm (Conway & Engle, 1994), that allows dissociation of scanning processes within short-term memory and memory retrieval processes from long-term memory. The study focused on the influence of brain injury on memory retrieval processes that are assumed to be automatic. Thirteen patients with memory impairment and 13 healthy matched control subjects were tested. In general, patients showed increased reaction times, but they showed set size independent retrieval from long-term memory indicating preserved automatic retrieval processes. In a subgroup of patients with more severe memory deficits, however, automatic retrieval processes appeared not to be intact. Learning profiles of the patients were characterized by smaller item chunks, indicating differences in the process of information acquisition.     

Surfactant protein A and stable microbubble formation in tracheal aspirates

This study aimed to determine the role of surfactant protein A (SP-A) in the formation of stable microbubble in tracheal aspirates. Our results showed that as the concentration of anti SP-A antibodies added to tracheal aspirate specimens increased, the number of stable microbubble formed in the specimen decreased. The correlation between stable microbubble counts and the SP-A levels in the tracheal aspirates was good, r = 0.85, p < 0.05. This study suggests that SP-A plays an important role in stable microbubble formation. Measurement of small stable microbubbles is thus a useful bedside test for predicting the SP-A activity in the tracheal aspirates and in indirect measurement of lung maturity.     

Severe malabsorption in autoimmune polyendocrinopathy-candidosis-ectodermal dystrophy syndrome successfully treated with immunosuppression

A 15 year old boy with autoimmune polyendocrinopathy-candidosis-ectodermal dystrophy syndrome suffered recurrent episodes of severe intractable diarrhoea, steatorrhoea, and hypocalcaemia. The only treatment modality, which controlled the malabsorption syndrome, was immunosuppression with intravenous high dose methylprednisolone and oral methotrexate maintenance therapy.     

Adjuvant capecitabine-containing chemotherapy benefit and homologous recombination deficiency in early-stage triple-negative breast cancer patients

Background The addition of adjuvant capecitabine to standard chemotherapy of early-stage triple-negative breast cancer (TNBC) patients has improved survival in a few randomised trials and in meta-analyses. However, many patients did not benefit. We evaluated the BRCA1-like DNA copy number signature, indicative of homologous recombination deficiency, as a predictive biomarker for capecitabine benefit in the TNBC subgroup of the FinXX trial.Methods Early-stage TNBC patients were randomised between adjuvant capecitabine-containing (TX + CEX: capecitabine-docetaxel, followed by cyclophosphamide-epirubicin-capecitabine) and conventional chemotherapy (T + CEF: docetaxel, followed by cyclophosphamide-epirubicin-fluorouracil). Tumour BRCA1-like status was determined on low-coverage, whole genome next-generation sequencing data using an established DNA comparative genomic hybridisation algorithm.Results For 129/202 (63.9%) patients the BRCA1-like status could be determined, mostly due to lack of tissue. During a median follow-up of 10.7 years, 35 recurrences and 32 deaths occurred. Addition of capecitabine appears to improve recurrence-free survival more among 61 (47.3%) patients with non-BRCA1-like tumours (HR 0.23, 95% CI 0.08–0.70) compared to 68 (52.7%) patients with BRCA1-like tumours (HR 0.66, 95% CI 0.24–1.81) (P-interaction = 0.17).Conclusion Based on our data, patients with non-BRCA1-like TNBC appear to benefit from the addition of capecitabine to adjuvant chemotherapy. Patients with BRCA1-like TNBC may also benefit. Additional research is needed to define the subgroup within BRCA1-like TNBC patients who may not benefit from adjuvant capecitabine.Subject terms: Breast cancer, Translational research, Predictive markers, Breast cancer     

Human acute leukemia cell line with the t(4;11) chromosomal rearrangement exhibits B lineage and monocytic characteristics

A cell line, designated RS4;11, was established from the bone marrow of a patient in relapse with an acute leukemia that was characterized by the t(4;11) chromosomal abnormality. The cell line and the patient's fresh leukemic cells both had the t(4;11)(q21;q23) and an isochromosome for the long arm of No. 7. Morphologically, all cells were lymphoid in appearance. Ultrastructurally and cytochemically, approximately 30% of the cells possessed myeloid features. The cells were strongly positive for terminal deoxynucleotidyl transferase. They were HLA-DR positive and expressed surface antigens characteristic for B lineage cells, including those detected by anti-B4, BA-1, BA-2, and PI153/3. Immunoglobulin gene analysis revealed rearrangements of the heavy chain and kappa chain genes. The cells lacked the common acute lymphoblastic leukemia antigen and antigenic markers characteristic of T lineage cells. The cells reacted with the myeloid antibody 1G10 but not with other myeloid monoclonal antibodies. Treatment with 12-O-tetradecanoyl- phorbol-13-acetate induced a monocyte-like phenotype demonstrated by cytochemical, functional, immunologic, and electron microscopic studies. The expression of markers of both early lymphoid and early myeloid cells represents an unusual phenotype and suggests that RS4;11 represents a cell with dual lineage capabilities. To our knowledge, RS4;11 is the first cell line established from t(4;11)-associated acute leukemia.     

Use of multiple T cell-directed intact ricin immunotoxins for autologous bone marrow transplantation

The monoclonal antibodies (MoAb) T101, G3.7, 35.1, and TA-1 were conjugated to intact ricin using a thioether linkage. These MoAb detect, respectively, the CD5[gp67], CD7[p41], CD2[p50], and [gp95, 170] determinants that are found in the vast majority of cases of T cell acute lymphocytic leukemia (T-ALL). The resulting immunotoxins (ITs) and an equimolar mixture of these ITs were evaluated as potential purgative reagents for autologous transplantation in T-ALL. Leukemic cell lines were used to compare the kinetics of protein synthesis inactivation mediated by each IT. The cells were treated with IT in the presence of lactose in order to block the native binding of ricin. The observed rates of protein synthesis inactivation correlated with target antigen expression detected by fluorescence-activated cell sorter analysis. Of the four ITs, T101-ricin (T101-R) exhibited the fastest rate of inactivation, followed in order by G3.7-ricin, TA-1-ricin, and 35.1-ricin. At concentrations greater than 300 ng/mL, a cocktail containing an equimolar amount of all four ITs (referred to as the four- IT cocktail) exhibited kinetics that were as fast or faster than those of T101-R. The long-term cytotoxic effects of individual ITs and the four-IT cocktail were evaluated using a sensitive clonogenic assay. Each IT was specifically cytotoxic and inhibited 1 to 4 logs of clonogenic leukemic cells at doses (300 to 600 ng/mL) that can be used clinically. The four-IT cocktail was highly cytotoxic; a concentration of 300 ng/mL inhibited greater than 4 logs of leukemic cells while sparing the majority of committed (CFU-GM, CFU-E) and pluripotent (CFU- GEMM) hematopoietic stem cells. The determination of both short-term kinetics of protein synthesis inactivation and longer-term inhibition of clonogenic growth allowed new insight into cell killing by IT. Our results suggest that ITs continue to act on clonogenic target cells for a period of three to five days. Interestingly, the four-IT cocktail was not as potent against clonogenic leukemic cells as T101-R alone, although it exhibited kinetics of protein synthesis inhibition that were as fast as those of T101-R alone. This finding suggests that internalized ITs may differ in the length of time they remain active within the cell. Our results also demonstrate the importance of using several different assays to evaluate IT reagents.