Trypanosoma cruzi Infection in Tumor Necrosis Factor Receptor p55-Deficient Mice

Tumor necrosis factor receptor p55 (TNFRp55) mediates host resistance to several pathogens by allowing microbicidal activities of phagocytes. In the studies reported here, TNFRp55^−/− mice infected with the intracellular parasite Trypanosoma cruzi showed clearly higher parasitemia and cumulative mortality than wild-type (WT) controls did. However, gamma interferon (IFN-γ)-activated macrophages from TNFRp55^−/− mice produced control levels of nitric oxide and killed the parasite efficiently in vitro. Trypanocidal mechanisms of nonphagocytic cells (myocardial fibroblasts) from both TNFRp55^−/− and WT mice were also activated by IFN-γ in a dose-dependent way. However, IFN-γ-activated TNFRp55^−/− nonphagocytes showed less effective killing of T. cruzi than WT control nonphagocytes, even when interleukin 1β (IL-1β) was added as a costimulator. In vivo, T. cruzi-infected TNFRp55^−/− mice and WT mice released similar levels of NO and showed similar levels of IFN-γ mRNA and inducible nitric oxide synthase mRNA in their tissues. Instead, increased susceptibility to T. cruzi of TNFRp55^−/− mice was associated with reduced levels of parasite-specific immunoglobulin G (IgG) (but not IgM) antibodies during infection, which is probably linked to abnormal B-cell differentiation in secondary lymphoid tissues of the mutant mice. Surprisingly, T. cruzi-infected TNFRp55^−/− mice showed increased inflammatory and necrotic lesions in several tissues, especially in skeletal muscles, indicating that TNFRp55 plays an important role in controlling the inflammatory process. Accordingly, levels of Mn²⁺ superoxide dismutase mRNA, a TNF-induced enzyme which protects the cell from the toxic effects of superoxide, were lower in mutant than in WT infected mice.     

Relevance of individual characteristics for human heat stress response is dependent on exercise intensity and climate type

Multiple heterogeneous groups of subjects (both sexes and a wide range of maximal oxygen uptake V˙O_{2 max} , body mass, body surface area (A _D),% body fat, and A _D/mass coefficient) exercised on a cycle ergometer at a relative (%V˙O_2max, REL) or an absolute (60?W) exercise intensity in a cool (CO 21°C, 50% relative humidity), warm humid (WH 35°C, 80%) and a hot dry (HD 45°C, 20%) environment. Rectal temperature (T _re) responses were analysed for the influence of the individual's characteristics, environment and exercise intensity. Exposures consisted of 30-min rest, followed by 60-min exercise. The T _re was negatively correlated with mass in all conditions. Body mass acted as a passive heat sink in all the conditions tested. While negatively correlated with V˙O_{2 max} and V˙O_{2 max} per kilogram body mass in most climates, T _re was positively correlated with V˙O_{2 max} and V˙O_{2 max} per kilogram body mass in the WH/REL condition. Thus, when evaporative heat loss was limited as in WH, the higher heat production of the fitter subjects in the REL trials determined T _re and not the greater efficiency for heat loss associated with high V˙O_{2 max} . Body fatness significantly affected T _re only in the CO condition, where, with low skin blood flows (measured as increases in forearm blood flow), the insulative effect of fat was pronounced. In the warmer environments, high skin blood flows offset the resistance offered by peripheral adipose tissue. Contrary to other studies, T _re was positively correlated with A _D/mass coefficient for all conditions tested. For both exercise types used, being big (a high heat loss area and heat capacity) was apparently more beneficial from a heat strain standpoint than having a favourable A _D/mass coefficient (high in small subjects). The total amount of variance in T _re responses which could be attributed to individual characteristics was dependent on the climate and the type of exercise. Though substantial for absolute exercise intensities (52%–58%) the variance explained in T _re differed markedly for relative intensities: 72% for the WH climate with its limited evaporative capacity, and only 10%–26% for the HD and CO climates. The results showed that individual characteristics play a significant role in determining the responses of body core temperature in all conditions tested, but their contribution was low for relative exercise intensities when evaporative heat loss was not restricted. This study demonstrated that effects of individual characteristics on human responses to heat stress cannot be interpreted without taking into consideration both the heat transfer properties of the environment and the metabolic heat production resulting from the exercise type and intensity chosen. Their impact varies substantially among conditions.     

Apoptosis in B-chronic lymphocytic leukaemia

B-chronic lymphocytic leukaemia (B-CLL) is characterised by the progressive accumulation of monoclonal B cells, which may be the result of several factors leading to extended B-CLL cell lifespan, increased proliferative capacity and diminished cell death. Here we review the implications of several signals mediated by receptors, such as surface IgM, CD6 and CD40, for the B-CLL cell survival, together with data on gene modulation in relation to the apoptosis process in B-CLL cells. We also describe some features of the Fas/FasL system in B-CLL that hypothetically might contribute to the accumulation of leukaemic cells and the progressions of the disease, by downregulating the apoptotic response or avoiding the autologous immune response.     

A strategy to improve treatment‐related mortality and abandonment of therapy for childhood ALL in a developing country reveals the impact of treatment delays

Background

Treatment‐related mortality and abandonment of therapy are major barriers to successful treatment of childhood acute lymphoblastic leukemia (ALL) in the developing world.

Procedure

A collaboration was undertaken between Instituto Nacional de Cancerologia (Bogota, Colombia), which serves a poor patient population in an upper‐middle income country, and Dana‐Farber/Boston Children's Cancer and Blood Disorders Center (Boston, USA). Several interventions aimed at reducing toxic deaths and abandonment were implemented, including a reduced‐intensity treatment regimen and a psychosocial effort targeting abandonment. We performed a cohort study to assess impact.

Results

The Study Population comprised 99 children with ALL diagnosed between 2007 and 2010, and the Historic Cohort comprised 181 children treated prior to the study interventions (1995–2004). Significant improvements were achieved in the rate of deaths in complete remission (13% to 3%; P = 0.005), abandonment (32% to 9%; P < 0.001), and event‐free survival with abandonment considered an event (47% to 65% at 2 years; P = 0.016). However, relapse rate did not improve. Medically unnecessary treatment delays were common, and landmark analysis revealed that initiating the PIII phase of therapy ≥4 weeks delayed predicted markedly inferior disease‐free survival (P = 0.016). Conversely, patients who received therapy without excessive delays had outcomes approaching those achieved in high‐income countries.

Conclusions

Implementation of a twinning program was followed by reductions in abandonment and toxic deaths, but relapse rate did not improve. Inappropriate treatment delays were common and strongly predicted treatment failure. These findings highlight the importance of adherence to treatment schedule for effective therapy of ALL. Pediatr Blood Cancer 2015;62:1395–1402. © 2015 Wiley Periodicals, Inc.     

The effects of exercise type and elbow angle on vertical ground reaction force and muscle activity during a push-up plus exercise

Background

Proper alignment of the scapula during upper extremity motion is important in maintaining shoulder joint function and health. Push-up plus exercise is considered as one of the best exercise to strengthen the muscles that stabilize the scapula. The purpose of the study is to examine the effects of push-up plus variants and elbow position on vertical ground reaction force and electromyographical activity of four shoulder muscles during concentric contraction.

Methods

A total of 22 healthy subjects volunteered for the study. Each of the subjects performed both modified and traditional push-up plus. Modified push-up plus was performed with both knees and hands touching the ground while the traditional push-up plus was executed with hands and feet contacting the ground. Electromyography (EMG) of the upper trapezius (UT), lower trapezius (LT), infraspinatus (INFRA), and serratus anterior (SA), and vertical ground reaction forces (vGRF) were collected.

Results

The traditional push-up plus exhibited higher EMG activity in all muscles tested (P < .05) and vertical ground reaction force (P < .001) compared to modified push-up plus. The highest difference in EMG activity between the two exercises was observed with the Serratus Anterior muscle (22%). Additionally, the traditional push-up plus presented a higher vGRF compared to the modified push-up plus (P < .001) by 17%. The SA had the greatest EMG activity compared to the other muscles tested during the concentric phase of the traditional push-up plus, and this did not occur during the plus phase of the exercise.

Conclusion

The highest activity of the serratus anterior occurred at 55° of elbow extension during the concentric phase of the traditional PUP and not at the plus phase of the exercise. This suggests that when prescribing an exercise to target the serratus anterior, a traditional push-up is adequate and the plus-phase is not necessary. However, for patients that cannot perform a traditional push-up, the modified push-up plus would be a great alternative to strengthen their serratus anterior.     

Effect of cyclosporin A on glomerular filtration rate in children with minimal change nephrotic syndrome

Cyclosporin A (CyA) is now commonly used in the management of children with steroid-dependent nephrotic syndrome. In order to assess nephrotoxicity related to CyA therapy, we measured glomerular filtration rate (GFR) on 123 occasions in 24 children with minimal change nephrotic syndrome receiving CyA. GFR was estimated from the plasma clearance of⁵¹chromium-EDTA every 3 months during CyA therapy of up to 27 months duration. There was a significant reduction in GFR after 3 months of CyA therapy [118±33 (SD) to 93±24 ml/min per 1.73 m²] but no further fall thereafter, although the reduction in GFR was sustained for the duration of CyA therapy. This reduction in GFR appeared to be reversible upon cessation of CyA, but careful monitoring of renal function is necessary in such patients to prevent the development of longer term nephrotoxic sequelae.     

IGHV3‐21 gene usage is associated with high TCL1 expression in chronic lymphocytic leukemia

T‐cell leukemia/lymphoma protein 1 (TCL1) was recently shown to display an expression pattern in chronic lymphocytic leukemia (CLL) corresponding to molecular subtypes, where poor‐risk patients demonstrated higher expression levels. Here, we examined the mRNA expression pattern of TCL1 in 144 patients with CLL, including 67 immunoglobulin heavy‐chain variable (IGHV) mutated, 58 IGHV unmutated and 19 patients with IGHV3‐21 usage. A higher TCL1 expression level was detected in patients with CLL with unmutated vs. mutated IGHV genes (P < 0.001), whereas no difference was demonstrated within the IGHV3‐21 cohort (i.e., mutated vs. unmutated and stereotyped vs. non‐stereotyped complementarity determining region 3). The IGHV3‐21 subgroup displayed high TCL1 mRNA expression, differing significantly from other IGHV mutated cases (P < 0.001), although 11/19 had mutated IGHV genes. Furthermore, high TCL1 expression levels were associated with significantly shorter overall survival (P < 0.001). Altogether, we show that TCL1 mRNA expression may predict clinical outcome in CLL and that the IGHV3‐21 subset, regardless of mutational status, displays high TCL1 expression.     

Invited review Psychiatric aspects of hyperthyroidism

This article reviews the psychiatric aspects of hyperthyroidism. The psychosomatic theory in the aetiology of thyrotoxicosis is first reviewed in relation to pre-morbid personality and stress. The nature of hyperthyroidism is briefly analysed, as it has direct relevance to the integral psychiatric manifestations of the disorder. Psychiatric manifestations are then described: firstly, those that are an integral part of hyperthyroidism and; secondly, those which have been reported to occur in association with hyperthyroidism. The psychosocial impact of the disease is also considered. There follows a discussion of the antecedents of psychiatric disorder in relation to mediating psychological and biological factors. The article reviews past and present evidence concerning the nature of the association between hyperthyroidism and other psychiatric disorders. Course and outcome of psychiatric disorder in hyperthyroidism are reviewed and, lastly, an appraisal is made of implications for management.