Adherence intervention research: what have we learned and what do we do next?

Although there is general agreement from studies demonstrating that adherence to inhaled corticosteroid therapy is often inadequate to establish consistent control, relatively little concurrence exists in reports of interventions to correct the problem. Half of the studies reviewed found that the experimental intervention did not change adherence, and behavior change reported by patients was often not accompanied by changes in treatment success. Studies used a variety of methods that differed in quality with findings that were often contradictory. Key limitations in many studies included reliance on inadequate adherence measures, inclusion of convenience samples of well-motivated patients, and assessments of intervention outcomes artificially boosted by attrition of least adherent participants. Research is encouraged into innovative interventions that are brief, easily implemented, and can be tailored to individual patients and diverse clinical settings. Of particular importance is inclusion of hard-to-reach patients, including urban and rural poor and the use of valid measures of adherence at intervals sufficient to establish enduring benefit.     

Twenty-five years of fiber analysis: what have we learned?

Asbestos exposure has resulted in a variety of diseases, including asbestosis, carcinoma of the lung (LC), pleural plaques, and malignant mesothelioma (MM). We hypothesized that there have been significant changes in the mineral fiber content of lung tissue from individuals with these diseases over the past 25 years. Asbestos content was measured in lung tissue samples from 819 individuals using light microscopy (to measure asbestos body concentrations) and scanning electron microscopy (to measure types and concentrations of mineral fibers). Cases were divided chronologically according to those occurring in the first half (group 1) versus those occurring in the second half (group 2). The study included 419 cases of MM, 206 cases of asbestosis, and 340 cases of LC. The median asbestos body count (in asbestos bodies per gram) decreased from group 1 to group 2 for each disease: MM, 480 to 350; asbestosis, 24700 to 19200; and LC, 1600 to 174 (reference range, 0-20). A similar trend was observed for fiber counts by scanning electron microscopy. Amosite was the most frequently detected asbestos fiber type and decreased in frequency of detection and median concentration from group 1 to group 2. Crocidolite showed an increased detection frequency from group 1 to group 2 across all 3 disease categories. The decrease in asbestos body and amosite concentrations over time is consistent with the banning of asbestos from insulation products in 1972. The source for the increased detection of crocidolite was not identified and needs further investigation.     

Mouse models of global airway allergy: what have we learned and what should we do next?

Recent epidemiological and clinical data indicate that allergic rhinitis and asthma coexist and should be considered as one airway allergy syndrome. In spite of the importance of this new concept of global airway allergy, it has not fundamentally changed our daily diagnostic and therapeutic strategies so far because of the lack of essential clues to understand the correlation between allergic inflammation in upper and lower airways. Because of the resemblance of experimentally induced allergic airway inflammation in mice to inflamed airways of allergic patients, mouse models can enhance our insight into mechanisms underlying the global airway allergy syndrome. We here review data generated in mice that are relevant for understanding the development of airway allergy and provide new options for research on the so-called 'united airway disease'.     

Biology and grading of pleomorphic xanthoastrocytoma—what have we learned about it?

Pleomorphic xanthoastrocytoma (PXA) is a rare astrocytoma predominantly affecting children and young adults. We performed comprehensive genomic characterization on a cohort of 67 patients with histologically defined PXA (n = 53, 79%) or anaplastic PXA (A‐PXA, n = 14, 21%), including copy number analysis (ThermoFisher Oncoscan, n = 67), methylation profiling (Illumina EPIC array, n = 43) and targeted next generation sequencing (n = 32). The most frequent alterations were CDKN2A/B deletion (n = 63; 94%) and BRAF p.V600E (n = 51, 76.1%). In 7 BRAF p.V600 wild‐type cases, alternative driver alterations were identified involving BRAF, RAF1 and NF1. Downstream phosphorylation of ERK kinase was uniformly present. Additional pathogenic alterations were rare, with TERT, ATRX and TP53 mutations identified in a small number of tumors, predominantly A‐PXA. Methylation‐based classification of 46 cases utilizing a comprehensive reference tumor allowed assignment to the PXA methylation class in 40 cases. A minority grouped with the methylation classes of ganglioglioma or pilocytic astrocytoma (n = 2), anaplastic pilocytic astrocytoma (n = 2) or control tissues (n = 2). In 9 cases, tissue was available from matched primary and recurrent tumors, including 8 with anaplastic transformation. At recurrence, two tumors acquired TERT promoter mutations and the majority demonstrated additional non‐recurrent copy number alterations. Methylation class was preserved at recurrence. For 62 patients (92.5%), clinical follow‐up data were available (median follow‐up, 5.4 years). Overall survival was significantly different between PXA and A‐PXA (5‐year OS 80.8% vs. 47.6%; P = 0.0009) but not progression‐free survival (5‐year PFS 59.9% vs. 39.8%; P = 0.05). WHO grade remained a strong predictor of overall survival when limited to 38 cases defined as PXA by methylation‐based classification. Our data confirm the importance of WHO grading in histologically and epigenetically defined PXA. Methylation‐based classification may be helpful in cases with ambiguous morphology, but is largely confirmatory in PXA with well‐defined morphology.     

Hematopoietic stem cell transplantation for autoimmune diseases: what have we learned?

Numerous individuals and institutions throughout the world have contributed to the development of hematopoietic stem cell transplantation (HSCT) for autoimmune diseases. In this review, we will summarize what we have learned at our own institution (Northwestern University), and how it has guided our therapy. An emphasis will be placed on both the scientific basis for the development of autologous hematopoietic stem cell transplantation and a summary of the data in a variety of human diseases.     

Occupational asthma: What have we learned?

Occupational asthma is one of the most frequent work-related diseases and may represent between 2% and 6% of all cases of asthma. It is defined as asthma causally and specifically related to exposure to airborne dusts, gases, vapors, or fumes in the working environment. Because it may cause long-lasting disability, it is important to properly identify affected workers and to withdraw them from exposure to the sensitizing agent as soon as possible. Although the history is the clue to the diagnosis, it is not sensitive or specific. The diagnosis should be confirmed by objective means, essentially by monitoring of peak expiratory flow and nonallergic bronchial responsiveness or by specific inhalation challenges. In this article the author reviews the investigation of occupational asthma. (J Allergy Clin Immunol 1998;102:S90-5.)     

Bone bioelectricity: what have we learned in the past 160 years?

The direct relationship between bone strain and electric fields has spurred continual interest in the field of bioelectricity over the past 160 years. It has been reported that stress-generated potentials alter cell proliferation and extracellular matrix secretion. The observation that endogenous electrical signals facilitate osteoinduction has lead to high production of electrical stimulation devices to fix bone defects. Despite the reported 100,000 nonunions healed as of 1990 with electrical stimulation, skepticism due to lack of homogeneity with trial design and dosage still exists within the scientific community. It is the purpose of this review to assess the bioelectric phenomenon of bone as it applies to piezoelectricity, fracture healing, and overall changes in bone metabolism which occur with controlled electrical stimulation.     

Vaccination of travelers: how far have we come and where are we going?

Vaccine recommendations are a prominent part of health preparations before international travel. We review progress made in the past decade regarding vaccines used primarily by persons traveling from high-income countries to low- and middle-income countries. The combined hepatitis A-B vaccine, the recently licensed Vero cell-derived Japanese encephalitis vaccine and conjugated quadrivalent meningococcal vaccines are discussed. This article provides updates on yellow fever vaccine-associated visceral and neurologic adverse events, indications for influenza vaccine in travelers, the rapid immunization schedule for tick-borne encephalitis vaccine, schedules for postexposure rabies prophylaxis, and new insights about oral cholera vaccines following the outbreak in Haiti. The future should bring vaccines for serogroup B Neiserria meningitidis, dengue and malaria, as well as an inactivated yellow fever vaccine.     

The (pro)renin receptor. A decade of research: what have we learned?

The discovery of a (pro)renin receptor ((P)RR) in 2002 provided a long-sought explanation for tissue renin–angiotensin system (RAS) activity and a function for circulating prorenin, the inactive precursor of renin, in end-organ damage. Binding of renin and prorenin (referred to as (pro)renin) to the (P)RR increases angiotensin I formation and induces intracellular signalling, resulting in the production of profibrotic factors. However, the (pro)renin concentrations required for intracellular signalling in vitro are several orders of magnitude above (patho)physiological plasma levels. Moreover, the phenotype of prorenin-overexpressing animals could be completely attributed to angiotensin generation, possibly even without the need for a receptor. The efficacy of the only available putative (pro)renin receptor blocker handle region peptide remains doubtful, leading to inconclusive results. The fact that, in contrast to other RAS components, (P)RR knock-outs, even tissue-specific, are lethal, points to an important, (pro)renin-independent, function of the (P)RR. Indeed, recent research has highlighted ancillary functions of the (P)RR as an essential accessory protein of the vacuolar-type H⁺-ATPase (V-ATPase), and in this role, it acts as an intermediate in Wnt signalling independent of (pro)renin. In conclusion, (pro)renin-dependent signalling is unlikely in non-(pro)renin synthesizing organs, and the (P)RR role in V-ATPase integrity and Wnt signalling may explain some, if not all of the phenotypes previously associated with (pro)renin-(P)RR interaction.     

Virus‐based immunotherapy of cancer: what do we know and where are we going?

Raising an efficient and sustained immune response to a growing tumour is extremely challenging, as tumours not only lack the capacity to induce an environment optimal for induction of the relevant immune response, but also tend to promote the development of very efficient immunosuppressive mechanisms. This review aims to evaluate selected cancer vaccination approaches using virus-based cancer vaccines. These seem promising based on their capacity to mimic natural infection and hence to efficiently trigger the innate immune system and in turn a potent cellular immune response towards the tumours. However, even when a potent immune response has been induced, this is often not sufficient to eliminate the tumour completely before the cancer cells have had time to evolve new escape mechanisms as a result of the selection pressure from the initial immune response directed towards them. Therefore, it is very likely that it is necessary to combine a therapeutic tumour vaccine with immunomodulating strategies in order to accomplish effective tumour degradation or at least to hinder metastasis. Some of the immunosuppressive mechanisms worth trying to manipulate will be discussed in this review.