Heart transplantation in repaired transposition of the great arteries

Cardiac transplantation was carried out in a 40-year-old man with the diagnosis of repaired transposition of the great arteries and right-sided aortic arch who had end-stage cardiac failure due to myopathy of the ventricles. Because of several previous surgical repairs and the orientation of the great vessels, the operation presented some technical problems. Therefore, modifications of operative procedures were used, including recipient hypothermia, circulatory arrest, and changes in the donor heart implantation. The removal of the donor heart was modified in such a way that the graft included the aortic arch and both pulmonary arteries. With the extra length of ascending aorta and transverse arch, the innominate, left carotid, and left subclavian vessels were excised as a button, thereby leaving the distal orifice of the aorta in the superior portion of the transverse arch. For the recipient, the operation was performed using hypothermic total circulatory arrest to dissect free the huge pulmonary artery and the short right-sided aortic arch to place the clamp. Implantation of the donor heart was modified accordingly. The technical results were confirmed one and a half months later on a control digital angiogram. Thirty-five days postoperatively the patient was discharged. Six months after operation, the patient is doing better than ever before in his life. Our findings suggest that a complicated conotruncal development does not preclude cardiac transplantation.     

Ontogeny of hallucal metatarsal rigidity and shape in the rhesus monkey (Macaca mulatta) and chimpanzee (Pan troglodytes)

Life history variables including the timing of locomotor independence, along with changes in preferred locomotor behaviors and substrate use during development, influence how primates use their feet throughout ontogeny. Changes in foot function during development, in particular the nature of how the hallux is used in grasping, can lead to different structural changes in foot bones. To test this hypothesis, metatarsal midshaft rigidity [estimated from the polar second moment of area (J) scaled to bone length] and cross‐sectional shape (calculated from the ratio of maximum and minimum second moments of area, I_max/I_min) were examined in a cross‐sectional ontogenetic sample of rhesus macaques (Macaca mulatta; n = 73) and common chimpanzees (Pan troglodytes; n = 79). Results show the hallucal metatarsal (Mt1) is relatively more rigid (with higher scaled J‐values) in younger chimpanzees and macaques, with significant decreases in relative rigidity in both taxa until the age of achieving locomotor independence. Within each age group, Mt1 rigidity is always significantly higher in chimpanzees than macaques. When compared with the lateral metatarsals (Mt2–5), the Mt1 is relatively more rigid in both taxa and across all ages; however, this difference is significantly greater in chimpanzees. Length and J scale with negative allometry in all metatarsals and in both species (except the Mt2 of chimpanzees, which scales with positive allometry). Only in macaques does Mt1 midshaft shape significantly change across ontogeny, with older individuals having more elliptical cross‐sections. Different patterns of development in metatarsal diaphyseal rigidity and shape likely reflect the different ways in which the foot, and in particular the hallux, functions across ontogeny in apes and monkeys.     

State of the art: using natriuretic peptide levels in clinical practice

Natriuretic peptide (NP) levels (B-type natriuretic peptide (BNP) and N-terminal proBNP) are now widely used in clinical practice and cardiovascular research throughout the world and have been incorporated into most national and international cardiovascular guidelines for heart failure. The role of NP levels in state-of-the-art clinical practice is evolving rapidly. This paper reviews and highlights ten key messages to clinicians:     

Children with Functional Motor Limitations: The Effects on Family Strengths

Sixty children with functional motor limitations (age range from 15months to 7years 3months) and their parents participated in the study. The objective was to explore the relationship of the severity of their restrictions on family strengths. Functional motor abilities of the children were assessed using Autti-Ramos Scale. Cognitive functions were assessed using the Swedish standardized version of the Griffiths Scales of Mental Development. Family strengths were indexed using the Family Functioning Style Scale. The social-economical status, childrens age and caretakers age were taken into account. Overall, the results indicated that family strengths were rather strong. Only families rearing a child with severe participation limitations (functional motor limitations and cognitive difficulties) showed less strengths concerning family identity and internal coping relative to families with a child with milder participation limitations.This research has been made possible by the grants of theTampere University Foundation and Medical Research Fund of Tampere University Hospital, Finland. We thank Matti Koivikko, MD, PhD, and Markku Ojanen, PhD, for their critical comments.     

Priority actions for the non-communicable disease crisis

The UN High-Level Meeting on Non-Communicable Diseases (NCDs) in September, 2011, is an unprecedented opportunity to create a sustained global movement against premature death and preventable morbidity and disability from NCDs, mainly heart disease, stroke, cancer, diabetes, and chronic respiratory disease. The increasing global crisis in NCDs is a barrier to development goals including poverty reduction, health equity, economic stability, and human security. The Lancet NCD Action Group and the NCD Alliance propose five overarching priority actions for the response to the crisis--leadership, prevention, treatment, international cooperation, and monitoring and accountability--and the delivery of five priority interventions--tobacco control, salt reduction, improved diets and physical activity, reduction in hazardous alcohol intake, and essential drugs and technologies. The priority interventions were chosen for their health effects, cost-effectiveness, low costs of implementation, and political and financial feasibility. The most urgent and immediate priority is tobacco control. We propose as a goal for 2040, a world essentially free from tobacco where less than 5% of people use tobacco. Implementation of the priority interventions, at an estimated global commitment of about US$9 billion per year, will bring enormous benefits to social and economic development and to the health sector. If widely adopted, these interventions will achieve the global goal of reducing NCD death rates by 2% per year, averting tens of millions of premature deaths in this decade.     

N-acetyl-l-cysteine sensitizes pancreatic cancers to gemcitabine by targeting the NFκB pathway

First-line therapy for pancreatic cancer is gemcitabine. Although tumors may initially respond to the gemcitabine treatment, soon tumor resistance develops leading to treatment failure. Previously, we demonstrated in human MIA PaCa-2 pancreatic cancer cells that N-acetyl-l-cysteine (NAC), a glutathione (GSH) precursor, prevents NFκB activation via S-glutathionylation of p65-NFκB, thereby blunting expression of survival genes. In this study, we documented the molecular sites of S-glutathionylation of p65, and we investigated whether NAC can suppress NFκB signaling and augment a therapeutic response to gemcitabine in vivo. Mass spectrometric analysis of S-glutathionylated p65-NFκB protein in vitro showed post-translational modifications of cysteines 38, 105, 120, 160 and 216 following oxidative and nitrosative stress. Circular dichroism revealed that S-glutathionylation of p65-NFκB did not change secondary structure of the protein, but increased tryptophan fluorescence revealed altered tertiary structure. Gemcitabine and NAC individually were not effective in decreasing MIA PaCa-2 tumor growth in vivo. However, combination treatment with NAC and gemcitabine decreased tumor growth by approximately 50%. NAC treatment also markedly enhanced tumor apoptosis in gemcitabine-treated mice. Compared to untreated tumors, gemcitabine treatment alone increased p65-NFκB nuclear translocation (3.7-fold) and DNA binding (2.5-fold), and these effects were blunted by NAC. In addition, NAC plus gemcitabine treatment decreased anti-apoptotic XIAP protein expression compared to gemcitabine alone. None of the treatments, however, affected extent of tumor hypoxia, as assessed by EF5 staining. Together, these results indicate that adjunct therapy with NAC prevents NFκB activation and improves gemcitabine chemotherapeutic efficacy.     

Suboptimal recognition of a T cell epitope of the major dog allergen Can f 1 by human T cells

We have previously proposed that mammalian lipocalin allergens are recognized suboptimally by the human immune system due to their homology with endogenous lipocalins. Here, we have characterized in detail the human T cell recognition of one of the previously identified T cell epitopes of the major dog allergen Can f 1, contained in peptide p105–120. A panel of peptide analogues (altered peptide ligands, APLs) of p105–120 was tested on two specific T cell clones restricted by different human leukocyte antigen (HLA) alleles. Interestingly, we identified for both of the clones several heteroclitic APLs that were capable of stimulating them at 10–30-fold lower concentrations than the natural peptide. Moreover, one of the heteroclitic APLs identified with the T cell clones, L115F, was observed to induce a stronger polyclonal T cell response than the natural allergen peptide from the peripheral blood mononuclear cells (PBMCs) of six Can f 1-allergic subjects studied. The heteroclitic APLs bound with the same affinity as p105–120 to common HLA-DR- and HLA-DP-alleles, suggesting that their improved stimulatory capacity is attributable to a more efficient T cell receptor (TCR) recognition rather than increased HLA binding. Collectively, our data suggest that p105–120 is recognized suboptimally by human T cells. This may contribute to the allergenicity of Can f 1.