The role of eosinophils in airway tissue remodelling in asthma

There is an increasing evidence that airway structural change (termed remodelling) is associated with the severity and chronicity of asthma. Recent studies support an important role for eosinophils in the remodelling process. In particular eosinophil depletion studies have demonstrated that several aspects of remodelling are attenuated. Eosinophils have been confirmed as an important source of TGF-beta(1) as well as other important cytokines that can lead to the direct activation of epithelium and mesenchymal cells that are considered to drive airway remodelling. The current studies that support a role for eosinophils in airway remodelling are reviewed in article.     

Communicating critical values in anatomic pathology

Critical values in anatomic pathology are usually information sensitive, whereas most such values in laboratory medicine are time sensitive. However, there is an important time element in anatomic pathology as well. Pathologists should be aware that many medicolegal actions against radiologists are based on failure to communicate "abnormal" results in a timely manner. Are pathologists the next group that will be targeted? Pathologists can spend much time trying to communicate important data that will affect patient care to someone who will accept the information. This is not an efficient use of pathologists' professional time. Most important, what are our obligations to patients to communicate "critical" abnormal results to the treating physician? What results need to be so communicated? Are pathologists obliged to contact the patient directly if there is a failure to communicate the critical results to a clinician? We explore these questions to promote discussion of these important issues as they relate to pathologists' liability and to patient care.     

Attributing death to cancer: cause-specific survival estimation

Cancer survival estimation is an important part of assessing the overall strength of cancer care in a region. Generally, the death of a patient is taken as the end point in estimation of overall survival. When calculating the overall survival, the cause of death is not taken into account. With increasing demand for better survival of cancer patients it is important for clinicians and researchers to know about survival statistics due to disease of interest, i.e. net survival. It is also important to choose the best method for estimating net survival. Increase in the use of computer programmes has made it possible to carry out statistical analysis without guidance from a bio-statistician. This is of prime importance in third- world countries as there are a few trained bio-statisticians to guide clinicians and researchers. The present communication describes current methods used to estimate net survival such as cause-specific survival and relative survival. The limitation of estimation of cause-specific survival particularly in India and the usefulness of relative survival are discussed. The various sources for estimating cancer survival are also discussed. As survival-estimates are to be projected on to the population at large, it becomes important to measure the variation of the estimates, and thus confidence intervals are used. Rothman's confidence interval gives the most satisfactory result for survival estimate.     

Impact of comorbidities on asthma

Asthma is a common and serious illness with suboptimal outcomes of care. Epidemiological studies show certain comorbidities occurring more frequently than expected with asthma, with some being associated with poor control and a differential response to therapy options. This review summarizes the evidence of clinically important comorbidities, focusing on the best-explored conditions, including rhinitis and rhinosinusitis, anxiety and depression, obesity, gastroesophageal reflux, smoking and dysfunctional breathing. The evidence of epidemiological and pathophysiological associations for these comorbidities is explored, and the practical therapeutic implications are considered. Comorbidities are important for clinicians treating asthma as they may be markers of patients at risk of poor outcomes, they may point to specific effective treatment options and they are important to researchers as possible confounding factors in clinical trials.     

Integration of feeding and spontaneous physical activity: role for orexin

Spontaneous physical activity is activity that is non-volitional, or subconscious, such as fidgeting and shifting in one's seat, and time spent moving (standing and ambulating). Recent evidence indicates that spontaneous physical activity, and the resulting thermogenesis (non-exercise activity thermogenesis) may be regulated by brain systems. A large number of brain areas, with their associated neurotransmitter populations and connectivity, participate in the regulation of feeding behavior by acting as energy sensing and modulating centers. Although less well characterized, it is likely that a multitude of neurotransmitters and brain areas act to mediate spontaneous physical activity. These two behaviors, feeding and spontaneous physical activity, affect energy intake and expenditure and thus are important to body weight. Interestingly, often the two behaviors are affected simultaneously; when feeding is affected, so too is spontaneous physical activity, and both food intake and physical activity (whether spontaneous or volitional) influence activity of brain areas important to both. Several brain areas and neuropeptides are important to feeding and spontaneous physical activity. The lateral hypothalamus is one area that appears important to both behaviors, as stimulation or lesion of this region produces alterations in feeding behavior and spontaneous physical activity. Orexin neurons, with their central location in the lateral hypothalamus, widespread projections and connectivity to other brain areas important to energy homeostasis, are well situated to perform an integrative function. This review focuses on how hypothalamic orexins participate in both feeding and spontaneous physical activity, and provides potential models for the integration of signals important to both.     

Ethanol and NMDA receptor signaling

NMDA receptors are a multi-subunit family of ionotropic receptors activated by the neurotransmitter glutamate. Localized primarily postsynaptically in neurons, they play an important role in mediating excitatory synaptic neurotransmission and are implicated in a wide variety of important calcium-dependent neuronal processes. Experimental animals expressing mutant forms of NMDA subunits display abnormal behaviors and locomotor and cognitive impairments. Over the last 10 years, a wealth of studies has indicated that NMDA receptors are an important site of action for ethanol in the brain. The effects of acute ethanol on NMDA receptor function is discussed herein, with particular focus on efforts to define a molecular site of action of ethanol on the receptor. While it is clear that the ethanol sensitivity of NMDA receptors is influenced by subunit composition, it is also apparent that posttranslational factors such as phosphorylation and protein-protein interactions are important in modulating this sensitivity.     

Specific and nonspecific immune responses to Marek's disease virus

Marek's disease (MD) virus (MDV) has provided an important model to study immune responses against a lymphoma-inducing herpesvirus in its natural host. Infection in chickens starts with a lytic infection in B cells, followed by a latent infection in T cells and, in susceptible birds, T cell lymphomas develop. Non-specific and specific immune responses are important for the control of virus infection and subsequent tumor development. Interferon-gamma and nitric oxide are important for the control of virus replication during the lytic phase of infection and are also important to prevent reactivation of MDV replication in latently infected and transformed cells. Cytotoxic T cells (CTLs) are the most important of the specific immune responses in MDV. In addition to antigen-specific CTL against MDV proteins pp38, glycoprotein B (gB), Meq, and ICP4, ICP27-specific CTL can also be detected as early as 6 to 7 days post infection. The epitope for gB recognized by CTLs from P2a (MHC: B(19)B(19)) chickens has been localized to the Eco47III-BamHI (nucleotides 1515-1800) fragment. A proposed model for the interactions of cytokines and immune responses as part of the pathogenesis of MD is discussed.     

The journals of importance to UK clinicians: a questionnaire survey of surgeons

Background  

Peer-reviewed journals are seen as a major vehicle in the transmission of research findings to clinicians. Perspectives on the importance of individual journals vary and the use of impact factors to assess research is criticised. Other surveys of clinicians suggest a few key journals within a specialty, and sub-specialties, are widely read. Journals with high impact factors are not always widely read or perceived as important. In order to determine whether UK surgeons consider peer-reviewed journals to be important information sources and which journals they read and consider important to inform their clinical practice, we conducted a postal questionnaire survey and then compared the findings with those from a survey of US surgeons.     

Atherosclerosis in Indians and lipoprotein (a)

Indians, both immigrant or native, are predisposed to develop a cluster of risk factors, and consequently are more prone to manifest CAD as compared to several other ethnic groups. Lipid profile in them is not characterised by hypercholesterolemia, instead the atherogenic profile is denoted by high TG and low HDL-c levels. Lp(a), is a recently discovered important independent and inheritable risk factor for atherosclerosis. It plays an important role in atherogenesis, and acts as a prothrombotic agent as well. Levels of Lp(a) are significantly higher in Indians subjects as well as their offsprings. Thus, Lp(a) is likely to have substantial role in development of early and extensive atherosclerosis in Indians. It is essential to include Lp(a) in battery of tests for evaluation of coronary risk especially in Indians. Further studies shall unravel the full ramifications of adverse effects of this lipoprotein.     

Men considering a hypothetical treatment for prostate cancer: a comparison to patients

BACKGROUND: In facilitating informed decision making about PSA screening, men are often asked to consider the potential consequences of the test, including a diagnosis of prostate cancer and how they would want to be treated. However, there is no empirical evidence thus far demonstrating that men are able to consider this hypothetical situation in a realistic manner. PURPOSE: To compare the features (attributes) of treatments that are important to non-patient men considering a hypothetical diagnosis of prostate cancer with those deemed important to men actually diagnosed with early-stage disease. METHODS: Two groups of men went through a decision aid interview to help them choose between treatment options for early-stage prostate cancer: non-patient men who imagined themselves to be diagnosed with the disease, and newly diagnosed patients. During the interview participants identified features of the treatment and disease that were important to their decisions. RESULTS: The percentage of non-patients and patients that thought particular attributes were important was correlated: r (33) = 0.77, p < 0.01. The effects on bladder and bowel functioning were considered important to >or=50% of each group. In addition to the 22 attributes initially presented, 49% of non-patients and 67% of patients identified additional attributes as being important to their decision. Eight (42%) of the 19 additional attributes were identified by non-patients and patients alike. CONCLUSIONS: The group of non-patient men provided a close approximation to the group of newly diagnosed men with respect to the attributes identified as being important to their treatment decisions for early-stage prostate cancer, suggesting that the consideration of what is important to the decision by non-patient men is realistic.     

Item analysis as a basis for weighting examination questions

Not all tost questions are of equal importance and, therefore, should not be weighted equally. To determine weight, a method has been used in which the weight of each question is based on what the class as a whole learned from what was presented in lectures, laboratories, and assigned reading material. Multiple choice written tests are machine-graded and the percentage of students correctly answering each question is used as the weighting factor. Important basic material that is emphasized in lecture or that can readily be recognized by the students as important will be weighted high if most students learn it. Questions about small details that are not stressed will be weighted low if few students learn that detail. However, questions on poorly taught material will be weighted low if the students do riot learn it, even if material is important. Students who just memorize detail but do not understand what is important will not gain from this method. Since the methods weights the question based on what the class as a whole learned, the students think it is fair. Students are more willing to learn when they believe trey are being treated fairly. © 1994 Wiley-Liss, Inc.     

Clarification of the pathogenesis and development of clinical examination for allergic diseases

The incidence of allergic diseases has dramatically increased in recent decades in Japan; therefore, it is important to establish ways to diagnose allergic patients based on their pathogenesis and to treat them. Allergic diseases are complicated and diverse disorders in which various cells and mediators are involved; however, it is widely accepted that they are Th2-type inflammations triggered by the invasion of allergens. It is known that either IL-4 or IL-13, particularly the latter, has an important role in the pathogenesis of bronchial asthma among Th-2 type cytokines; however, it is unclear how IL-4 or IL-13 causes asthmatic phenotypes. We have been trying to address this question by using microarray analysis. We have recently found that periostin, identified as an IL-4/IL-13-inducible gene by microarray analysis, is a novel component of subepithelial fibrosis of bronchial asthma. This finding is important to demonstrate the significance of IL-4 and/or IL-13 as a therapeutic target to inhibit fibrosis in bronchial asthma. Furthermore, it is also important to establish a way to diagnose allergic patients in which IL-4 or IL-13 is dominantly involved, and to apply the developing IL-4/IL-13 inhibitors to these patients. In this article, we show how we are addressing this issue.     

Isolation of vascular smooth muscle cells from a single murine aorta

The vascular smooth muscle cell plays a significant role in many important cardiovascular disorders, and smooth muscle biology is therefore important to cardiovascular research. The mouse is critical to basic cardiovascular research, largely because techniques for genetic manipulation are more fully developed in the mouse than in any othermammalian species. We describe here a technique for isolating smooth muscle cells from a single mouse aorta. This technique is particularly useful when material is limiting, as is frequently the case when genetically modified animals are being characterized.     

The emerging functions of UCP2 in health, disease, and therapeutics

The uncoupling proteins (UCPs) are attracting an increased interest as potential therapeutic targets in a number of important diseases. UCP2 is expressed in several tissues, but its physiological functions as well as potential therapeutic applications are still unclear. Unlike UCP1, UCP2 does not seem to be important to thermogenesis or weight control, but appears to have an important role in the regulation of production of reactive oxygen species, inhibition of inflammation, and inhibition of cell death. These are central features in, for example, neurodegenerative and cardiovascular disease, and experimental evidence suggests that an increased expression and activity of UCP2 in models of these diseases has a beneficial effect on disease progression, implicating a potential therapeutic role for UCP2. UCP2 has an important role in the pathogenesis of type 2 diabetes by inhibiting insulin secretion in islet beta cells. At the same time, type 2 diabetes is associated with increased risk of cardiovascular disease and atherosclerosis where an increased expression of UCP2 appears to be beneficial. This illustrates that therapeutic applications involving UCP2 likely will have to regulate expression and activity in a tissue-specific manner.     

Biodegradable polymeric scaffolds for musculoskeletal tissue engineering

Biodegradable scaffolds have played an important role in a number of tissue engineering attempts over the past decade. The goal of this review article is to provide a brief overview of some of the important issues related to scaffolds fabricated from synthetic biodegradable polymers. Various types of such materials are available; some are commercialized and others are still in the laboratories. The properties of the most common of these polymers are discussed here. A variety of fabrication techniques were developed to fashion polymeric materials into porous scaffolds, and a selection of these is presented. The very important issue of scaffold architecture, including the topic of porosity and permeability, is discussed. Other areas such as cell growth on scaffolds, surface modification, scaffold mechanics, and the release of growths factors are also reviewed. A summary outlining the common themes in scaffold-related science that are found in the literature is presented.     

Steroid phobia and adherence--problems, solutions, impact on benefit/risk profile

Adherence is important with all medications. It can be more difficult with inhaled steroids in light of concern about adverse effects. Although the degree of fear regarding inhaled steroids is difficult to quantify, it appears to be an important factor in adherence. These fears exist for several reasons, including misinformation obtained from such sources as the Internet. To improve adherence and decrease morbidity and mortality, it is vital that health care providers are aware of potential barriers to adherence. Measures such as simplifying and properly explaining medication regimens are helpful. Just as important is the establishment of a strong patient-provider relationship. This makes it easier to convince patients of the need for recommended medications. If the provider is able to effectively communicate and convince the patient of the benefit/risk ratio of steroids, improved patient outcomes can be achieved.     

Kidney transplant pathology

Biopsy of the transplanted kidney plays an important role in the care and treatment of patients after kidney transplantation. Today the renal biopsy is a standard procedure which is performed early after renal transplantation in the case of a primary non-functioning graft or a significant rise in serum creatinine. On the other hand, a kidney biopsy is performed if an acute or creeping rise in serum creatinine or acute onset of proteinuria or erythrocyturia is observed during follow-up. Furthermore, zero biopsies or intraoperative biopsies of the graft are important in order to obtain information about the initial quality of the graft. This is particularly important in view of the shortage of donor organs and the resulting necessity to accept increasingly marginal organs, such as for example in the ESP program. In addition, an increasing number of transplant centres perform protocol biopsies, i.e. biopsies that are not based on clinical indication, but are performed at a certain time point after transplantation to detect subclinical rejections as well as histological alterations pointing to chronic allograft damage. Additionally, there is much scientific interest in protocol biopsies.     

MicroRNAs: potential therapeutic targets in diabetic complications of the cardiovascular and renal systems

Diabetes mellitus is a serious health problem that can lead to several pathological complications in numerous organs and tissues. The most important and most prevalent organs affected by this disease are the heart and the kidneys, and these complications are the major causes of death in patients with diabetes. MicroRNAs (miRNAs), short non‐coding RNAs, have been found to be functionally important in the regulation of several pathological processes, and they are emerging as an important therapeutic tool to avoid the complications of diabetes mellitus. This review summarizes the knowledge on the effects of miRNAs in diabetes. The use of miRNAs in diabetes from a clinical perspective is also discussed, focusing on their potential role to repair cardiovascular and renal complications.     

Glioma-specific antigens for immune tumor therapy

This review describes glioma-specific antigens important in immunotherapy of glioma tumors. The structure and function of these antigens and recent immunotherapy data are summarized. Also, some important aspects of tumor formation are outlined. The roles of neuronal precursor cells and tumor stroma cells are discussed. The stroma cells of the tumor may be of interest as a target for tumor therapy, especially since they are less heterogeneous than the tumor cells. To date, the clinical benefit of immunotherapy has been very limited. Immunotherapy is, however, still an extremely promising approach to tumor therapy and it will most likely be implemented as a future treatment option for many types of tumors. The current shortcomings of immunotherapy will probably diminish as we start to understand and are able to modulate tumor-induced immunosuppression. There is also a need for a continued search for new tumor-specific antigens and to optimize protocols for vaccine administration.