Update in carcinoid heart disease - the heart of the matter

Carcinoid heart disease (CHD) is a paraneoplastic cardiac manifestation occurring in patients with carcinoid syndrome (CS) and advanced neuroendocrine malignancy. In about 20–40% of patients with CS, chronic exposure to tumor-released circulating vasoactive peptides typically results in right-sided valvular fibrosis leading to valve dysfunction and right heart failure. CHD remains a significant cause of morbidity and mortality. The management of patients with CHD is complex, as both the systemic malignant disease and the heart involvement have to be addressed. Early diagnosis and timely surgical intervention in selected patients are of utmost importance and offer a survival benefit. In patients with advanced carcinoid heart disease, valve replacement surgery is the most effective option to alleviate cardiac symptoms and contribute to survival outcomes. A collaboration of a multidisciplinary team in centers with experience is required to provide optimal patient management. Here, we review the current literature regarding CHD presentation, pathophysiology, diagnostic tools, and available treatment strategies.

     

Atopy and neural damage

The occurrence of myelitis with atopic diathesis (atopic myelitis) affecting young adults has recently been noted in Japan. The disease preferentially affects the posterior column of the cervical spinal cord, as shown clinically and by MRI. It is characterized by hyperIgEaemia and the presence of mite antigen-specific IgE. The spinal cord lesions have been shown to be eosinophilic inflammation on biopsy and thus an allergic mechanism is thought to be operative in this condition. In addition, we also found that Hirayama disease, juvenile muscular atrophy of the distal upper extremity, is also associated with airway allergy such as allergic rhinitis and atopic asthma. In children, poliomyelitislike illness after acute asthma attacks is well known as Hopkins syndrome. Moreover, by the prospective study of the history of allergic disorders in common neurologic diseases, an association between spinal progressive muscular atrophy (SPMA) and asthma as well as between myelitis and atopic dermatitis has been demonstrated. These observations strongly suggest a link between atopic diathesis and spinal cord damage. Central nervous system damage associated with atopic diathesis may be classified into two types; eosinophilic myelitis preferentially affecting the cervical spinal cord and lower motor neuron damage, such as Hopkins syndrome, Hirayama disease and SPMA. The former is typically associated with atopic dermatitis while the latter, with airway allergy.     

Combination therapy of established cancer using a histone deacetylase inhibitor and a TRAIL receptor agonist

Histone deacetylase inhibitors (HDACi) and agents such as recombinant tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and agonistic anti-TRAIL receptor (TRAIL-R) antibodies are anticancer agents that have shown promise in preclinical settings and in early phase clinical trials as monotherapies. Although HDACi and activators of the TRAIL pathway have different molecular targets and mechanisms of action, they share the ability to induce tumor cell-selective apoptosis. The ability of HDACi to induce expression of TRAIL-R death receptors 4 and 5 (DR4/DR5), and induce tumor cell death via the intrinsic apoptotic pathway provides a molecular rationale to combine these agents with activators of the TRAIL pathway that activate the alternative (death receptor) apoptotic pathway. Herein, we demonstrate that the HDACi vorinostat synergizes with the mouse DR5-specific monoclonal antibody MD5-1 to induce rapid and robust tumor cell apoptosis in vitro and in vivo. Importantly, using a preclinical mouse breast cancer model, we show that the combination of vorinostat and MD5-1 is safe and induces regression of established tumors, whereas single agent treatment had little or no effect. Functional analyses revealed that rather than mediating enhanced tumor cell apoptosis via the simultaneous activation of the intrinsic and extrinsic apoptotic pathways, vorinostat augmented MD5-1-induced apoptosis concomitant with down-regulation of the intracellular apoptosis inhibitor cellular-FLIP (c-FLIP). These data demonstrate that combination therapies involving HDACi and activators of the TRAIL pathway can be efficacious for the treatment of cancer in experimental mouse models.     

A comparison of symptoms and intra-arterial ambulatory blood pressure during long term dual chamber atrioventricular synchronous (DDD) and ventricular demand (VVI) pacing.

Fifteen patients with dual chamber pacemakers implanted for atrioventricular block (11) or sinoatrial disease (4) completed a single blind within-patient comparison of symptoms and 24 hour intra-arterial blood pressure during long term atrioventricular synchronous (DDD) pacing and long term ventricular demand (VVI) pacing. The patients reported significantly less breathlessness, fatigue, and dizziness and a significantly greater sense of general well-being during DDD pacing than during VVI pacing. Twelve of the fifteen patients expressed a strong preference for DDD pacing. Systolic blood pressure tended to be lower and was significantly more variable during VVI pacing than during DDD pacing (mean (SD) daytime systolic blood pressure 132.4 (17.1) and 140.4 (13.1) mm Hg respectively). Accordingly, episodes of hypotension were more common during VVI pacing, which may partly explain why the patients reported more symptoms during this mode of pacing.     

Molecular and cellular analyses of HLA class II-associated susceptibility to autoimmune diseases in the Japanese population

It is well known that individuals who are positive for particular HLA class II alleles show a high risk of developing autoimmune diseases. HLA class II molecules expressed on antigen-presenting cells present antigenic peptides to CD4⁺ T cells. Their extensive polymorphism affects the structures of peptides bound to HLA class II molecules to create individual differences in immune responses to antigenic peptides. In order to gain a better understanding of mechanisms of the association between HLA class II alleles and susceptibility to autoimmune diseases, it is important to identify self-peptides presented by disease-susceptible HLA class II molecules and triggering disease-causative T cells. Many of the autoimmune diseases are observed in all ethnic groups, whereas the incidence of diseases, clinical manifestations and disease-susceptible HLA class II alleles are different among various ethnic groups for some autoimmune diseases. These phenomena suggest that differences in autoimmune self-peptide(s) in the context of disease-susceptible HLA class II molecules may cause these differences. Therefore, comparisons among disease-susceptible HLA class II alleles, autoantigenic peptides, and clinical manifestations of autoimmune diseases in different ethnic groups would be helpful in elucidating the pathogenesis of the diseases. In this review, we describe our recent findings on (1) the uniqueness of both clinical manifestations and the HLA-linked genetic background of Asian-type (opticospinal form) multiple sclerosis, (2) the characteristics of glutamic acid decarboxylase 65 (GAD65) or β₂-glycoprotein I (β₂-GPI) autoreactive T cells in Japanese patients with insulin-dependent diabetes mellitus (IDDM) or anti-β₂-GPI antibody-associated autoimmunity, respectively, and (3) the generation of an efficient delivery system of peptides to the HLA class II-restricted antigen presentation path-way by utilizing a class II-associated invariant chain peptide (CLIP)-substituted invariant chain, which may be applicable to an evaluation of the "molecular mimicry hypothesis" for the activation of autoreactive T cells.     

Socioecological and message framing factors influencing maternal influenza immunization among minority women

Objective

A suboptimal level of seasonal influenza vaccination among pregnant minority women is an intractable public health problem, requiring effective message resonance with this population. We evaluated the effects of randomized exposure to messages which emphasize positive outcomes of vaccination (“gain-frame”), or messages which emphasize negative outcomes of forgoing vaccination (“loss-frame”). We also assessed multilevel social and community factors that influence maternal immunization among racially and ethnically diverse populations.

Study design

Minority pregnant women in metropolitan Atlanta were enrolled in the longitudinal study and randomized to receive intervention or control messages. A postpartum questionnaire administered 30 days postpartum evaluated immunization outcomes following baseline message exposure among the study population. We evaluated key outcomes using bivariate and multivariate analyses.

Results

Neither gain- [OR = 0.5176, (95% CI: 0.203,1.322)] nor loss-framed [OR = 0.5000, 95% CI: (0.192,1.304)] messages were significantly associated with increased likelihood of immunization during pregnancy. Significant correlates of seasonal influenza immunization during pregnancy included healthcare provider recommendation [OR = 3.934, 95% CI: (1.331,11.627)], use of hospital-based practices as primary source of prenatal care [OR = 2.584, 95% CI: (1.091,6.122)], and perceived interpersonal support for influenza immunization [OR = 3.405, 95% CI: (1.412,8.212)].

Conclusion

Dissemination of vaccine education messages via healthcare providers, and cultivating support from social networks, will improve seasonal influenza immunization among pregnant minority women.