Abstract

Terminal Care and Death with Dignity

Yutaka Suzuki

Progress in medicine prolongs life, and progress in the field of palliative medicine has improved terminal care for patients with cancer in Japan. But we have made possible a new undesirable state of life in which patients remain “unnaturally alive” instead of dying a natural death. The Ministry of Health, Labor and Welfare has presented guidelines on determining the process of terminal medicine. Both The Japan Society of Intensive Care Medicine and the Japan Association for Acute Medicine have announced official guidelines regarding terminal medicine. Unfortunately, medical students and medical doctors in Japan do not have the chance to undergo training in terminal medicine during formal university courses or post-graduate clinical training courses. Two regrettable “mercy killing” incidents occurred at Tokai University Hospital and Kawasaki-kyodo Hospital. The former is KCL injection to the patient of multiple myeloma, the latter is muscle relaxant injection to the respiratory failure patient of bronchial asthma which resulted murder convictions. These incidents occurred as a result of the absence of training regarding terminal care and death with dignity. It is therefore essential that medical education addresses these important fields. Both the Yokohama and Tokyo district courts have recommended the creation of procedures or laws promoting death with dignity. I feel that it is important for medical doctors to recognize their lack of knowledge regarding terminal medicine.

Predictors of Outcome in Distal Radius Fractures

Ruby Grewal

Distal radius fractures in the elderly tend to be caused by low-energy mechanisms, typically a fall from standing height. These fragility fractures tend to be associated with reduced bone density and are distinct from higher-energy distal radius fractures seen more frequently in physiologically younger, more active patients. Outcomes in older patients are less dependent on restoration of anatomic radiographic parameters than in younger patients, likely due to their lower functional demands. Other factors predictive of outcome include carpal malalignment, other intracarpal pathologies, ulnar-sided wrist pain, and wrist stiffness. For these factors also, advanced age and diminished functional demands reduce their influence on outcome. Fixation options in the older population are the same as those for younger patients; however, older patients are more likely to require an external fixator to supplement K-wire fixation and are more likely to require synthetic bone substitutes to address metaphyseal and epiphyseal bone voids that threaten the stability of internal fixation. Future comparative research would be more conclusive if the distinction between fragility and non-fragility fractures of the distal radius were made consistently in the inclusion criteria of investigations. The use of validated outcomes questionnaires such as DASH and PRWE will also help to refine the answers emerging from new studies.

Pathogenesis of Gastritis in Ileitis-prone SAMP1/Yit Mice

Peter B. Ernst, E.B. Wiznerowicz, S.H. Feldman and K.S. Tung

The gastrointestinal tract faces the unique immunological challenge of coping with a dynamic and vast array of dietary and microbial antigens. Chronic inflammatory disease of the intestine and the stomach arises in genetically susceptible individuals who fail to properly regulate host responses to these luminal antigens. One example of chronic inflammatory diseases of the gut is inflammatory bowel disease, which manifests as ulcerative colitis or Crohn's disease. Crohn's disease tends to affect the terminal ileum, but in humans, the disease can arise in virtually any site from the mouth to the anus. One of the most studied models of spontaneous Crohn's disease is the SAMP1/Yit mouse model. These mice have many manifestations resembling human Crohn's disease, including discontinuous and transmural chronic inflammation of the terminal ileum and, in some cases, perianal fistulae. Other studies have shown that ileitis is associated with pro-inflammatory cytokine production. Although many immunological responses are perturbed, some evidence suggests that the primary defect lies in the epithelial cell barrier. In the process of studying epithelial permeability, we showed that the stomach in SAMP1/Yit mice also has increased permeability. Upon further examination, these mice were shown to have a marked, chronic gastritis with focal to diffuse aggregates of mononuclear cells of different lineages. These aggregates were located predominantly in the oxyntic mucosa with occasional lesions in the forestomach, but only relatively rarely with cellular infiltrates in the antral mucosa. Realtime RT PCR shows an increase in many of the pro-inflammatory Th cell-derived cytokines in the gastric mucosa of SAMP1/Yit mice. The adoptive transfer of T cells into immunodeficient recipients induces ileitis, gastritis and duodenitis; however, many of the cells in the aggregates are B cells. SAMP1/Yit B cells exacerbate ileitis when co-transferred into immunodeficient recipients, possibly by interfering with regulatory Th cell function. Gastritis is also enhanced by B cells. As SAMP1/Yit mice are derived from AKR mice, we examined AKR mice and determined that they too have an increase in the occurrence of gastritis. B cells also contribute to the inflammation. Thus, these data suggest that SAMP1/Yit mice display gastritis as well as ileitis and that B cells play a role in the pathogenesis of the inflammation of both sites.

Non-coding RNAs for Medical Practice

Tetsuro Sotoyama and George A. Calin

Alterations in microRNA and other short or long non-coding RNA are involved in the initiation, progression and metastases of human cancer. The main molecular alterations are represented by variations in gene expression that are usually mild but have consequences for a vast number of target protein coding genes. The causes of the widespread differential expression of non-coding RNAs in malignant compared with normal cells can be explained by the location of these genes in cancer-associated genomic regions, by epigenetic mechanisms and by alterations in the processing machinery. MicroRNA and other short or long non-coding RNA expression profiling of human tumors has identified signatures associated with diagnosis, staging, progression, prognosis and response to treatment. In addition, profiling has been exploited to identify non-coding RNAs that may represent downstream targets of activated oncogenic pathways or that are targeting protein coding genes involved in cancer. Recent studies proved that microRNAs and non-coding ultraconserved genes are main candidates for the elusive class of cancer predisposing genes and that other types of non-coding RNAs participate in the genetic puzzle giving rise to the malignant phenotype. These discoveries could be exploited for the development of useful markers for diagnosis and prognosis, as well as for the development of new RNA-based cancer therapies.

Scar-free Healing - From Embryonic Mechanisms to Potential Adult Human Pharmaceutical Agents

Mark W.J. Ferguson

Embryonic wounds, which heal without a scar, contain high levels of transforming growth factor beta 3 (TGFβ3), a key morphogenetic protein in skin development. Administration of recombinant TGFß3 to adult wounds in mice, rats and pigs results in markedly reduced or absent scarring. We have developed human recombinant TGFβ3 (Juvista, Avotermin) as a potential new pharmaceutical agent for the prevention and reduction of scarring. To date, we have conducted 16 phase I and phase II double-blind, placebo-controlled, randomised clinical trials in subjects with a variety of indications, exploring various aspects of dosing administration and scar measurement, among others. We concluded that injection of 500 ng/100 μL/linear cm wound margin of Juvista, at the time of wound closure and 24 h later, leads to a statistically and clinically significant improvement in scarring. Juvista-treated scars blend in better with the surrounding skin and are less noticeable, being flat and less red compared to placebo-treated scars in the same individual. This has been shown in incisional wounds made under the arms of volunteers and in clinical trials in patients, e.g., following bilateral varicose vein surgery or scar revision surgery. The first EU phase III trial for Juvista in scar revision surgery (Revise) is fully recruited and should report data in H1 2011. These studies demonstrate that knowledge of the cellular and molecular basis of scar-free versus scarring healing can lead to the identification of therapeutic targets from which novel pharmaceutical agents can be developed. Juvista shows promise in clinical trials as a therapy for the reduction of scarring.

Genetic Signature and Epigenetic Markers in Bladder Cancer

Wun-Jae Kim

Transitional cell carcinomas of the urinary bladder have diverse biological and functional characteristics. Many bladder cancer markers have been evaluated for detecting and monitoring tumors using serum, bladder washes, and urinary specimens. However, none of the biomarkers reported to date has shown sufficient sensitivity and specificity to detect the whole spectrum of bladder cancer diseases in routine clinical practice. The limited value of the established prognostic markers requires the analysis of new molecular parameters of interest for predicting the prognosis of bladder cancer patients, particularly with respect to patients who are at high risk of recurrence and progression. Over the past decade, there has been major progress in elucidating the molecular genetic and epigenetic changes that lead to the development of bladder cancer. Because multiple genetic and epigenetic alterations are required for the transformation of a normal cell into a cell with a malignant and ultimately metastatic phenotype, assessment of multiple markers as a whole might better describe the biological phenotype of a particular cancer. For these reasons, the role of multiple biomarkers in regulating tumorigenesis and prognosis is of particular interest. Recently, new high-throughput microarray technology has made it possible to gain comprehensive insight into the molecular basis of human diseases. With this technology, hundreds or even thousands of genetic and epigenetic alterations in a tumor can be surveyed simultaneously. This article focuses on recent advances in the genetic and epigenetic aspects of bladder cancer and emphasizes how molecular biology is likely to affect future research and clinical aspects in this field.

Regulators of Second Heart Field Development

Robert G. Kelly

Rapid extension of the embryonic heart tube during cardiac looping occurs by addition of cells from pharyngeal mesoderm to the elongating poles of the heart tube. These progenitor cells, termed the second heart field, are characterised by properties of elevated proliferation and differentiation delay with respect to the initially contiguous differentiated cells in the cardiac crescent that give rise to the linear heart tube. Progressive addition of second heart field cells to the heart tube is regulated by signals from surrounding pharyngeal epithelia, neural crest cells and pharyngeal mesoderm itself, which together define the niche of these cardiac progenitor cells in the early embryo. Direct or indirect perturbation of second heart field development results in failure to extend the heart tube, leading to cardiac alignment defects at later developmental stages, including a spectrum of conotruncal defects seen in human congenital heart anomalies. Here, data will be presented concerning three transcriptional regulators of murine second heart field development, the DiGeorge syndrome candidate gene Tbx1, Hes1 and Tbx3, loss of function of which impacts on outflow tract morphogenesis leading to congenital heart defects.

Endoscopic Endonasal Skull Base Surgery: The Naples Experience

Paolo Cappabianca

The endoscopic endonasal approach, initially reserved for sellar lesions, requires precise anatomical knowledge, technical skills and an integrated appreciation of the pathology being dealt with. In recent years, the approach has been gaining acceptance thanks to evolving procedures and surgical tools aimed at lowering morbidity and mortality in a safe, feasible and practical way. The process has been evolutionary, rather than revolutionary, as a result of advances in medical sciences, surgical technique, innovations and technological progress. Nowadays, it represents a minimally invasive approach for treating several diseases, mostly those involving the entire skull base, i.e., the suprasellar, retrosellar and parasellar spaces. The panoramic identification of the relevant anatomical landmarks facilitates the surgeon's orientation, despite the lack of 3D vision. Indeed, it offers the surgeon the opportunity to visualize the surgical field safely and effectively, thus providing the possibility to pass through a less complex structure (nasal cavity) in order to reach a more complex one (the brain with its neurovascular structures). We have been employing the endoscopic endonasal technique since 1997 and have treated approximately 900 patients; initially, the aim was to remove different sellar lesions, but recently the extended endonasal approach has been applied to treat lesions involving the surrounding skull base areas. We report our experience with the endoscopic endonasal approach to the skull base through a step-by-step depiction of the technique to access different compartments, detailing the anatomy as seen from the endonasal perspective and describing possible complications and the techniques to manage them.