RETRACTED ARTICLE: The porphyrias: pathophysiology

Porphyrias are a group of inherited and acquired metabolic disorders due to a defect in haem biosynthesis. An enzymatic defect at different steps of haem synthesis leads to tissue accumulation and excessive excretion of porphyrins and/or their toxic precursors. The specific patterns of accumulation determine the variety of clinical manifestations, ranging from acute neurovisceral attacks to skin lesions and liver disease. Most enzyme defects represent partial deficiencies, while familial cases are linked to autosomal or recessive traits. The incomplete penetrance of the genetic defects often requires the triggering or aggravating effect of host-related or environmental factors. While genetics has a role in confirming clinical suspicion and in family screening, biochemical and clinical studies are still central in the diagnosis.     

Spirituality:

This article addresses the use of spirituality in the assessment and treatment of Black alcoholics and their families who are known to health and human services agencies, including alcoholism-specific treatment centers. Common expressions relating to spiritual beliefs are identified and attention is given to the knowledge needed to formulate an assessment and to make a treatment plan. These include sources of hope and strength, the concept of God and Diety, and the relationship between spiritual beliefs and health. Guidelines for therapists are recommended.     

Leisure:

Leisure represents the freedom to make quality of life choices. For the alcoholic, drinking represents total enslavement and results in a deprivation of all freedoms, including the ability to make valid leisure choices. This article presents a programmatic scheme for the assessment of leisure and lifestyle changes necessary to encourage sobriety. The relationships among leisure and lifestyle issues and the clinical process for the recovering alcoholic are explored. Development of a leisure service model for clinical service to the alcoholic is presented.     

Diabetic cardiomyopathy: a controversial entity: reply

We are most grateful to Dr Karamitsos et al. for showing suchan avid interest in our paper.¹ Upon its submission, we wereacutely aware that we might well shake things up, as prior toconfronting the actual study results we also used to supportthe notion of diabetic     

State-of-the-Art: Pharmacologic-Therapecitic Update: Theophyllines-A Review

Management of asthma in emergency departments (ED) has been well documented to be deficient over many years, despite national and international guidelines. This review summarizes the effect of ED protocols aimed at improving the assessment and treatment of asthma in the ED. We performed a PubMed search of the English literature for ED asthma protocols published from 1986 to 2006 and identified 11 studies. Protocols were effective in improving at least some areas of management, including use of appropriate patient assessment, drug therapy per national guidelines, and patient education. A small number of protocols with the specific aims of reducing the length of stay in the ED as well as rates of hospital admission and return visits were effective. Persistent education of ED staff regarding protocols based on current management guidelines and adoption of easy-to-use forms can facilitate improved care of patients with asthma in the ED.     

Cryoablation:

The use of cryoablation in the electrophysiology lab provides some distinct advantages not seen with conventional radiofrequency ablation. Ice mapping allows a functional assessment of a putative ablation site prior to the formation of a permanent lesion. This provides a distinct advantage adjacent to the AV node for para-hisian pathways and difficult cases of AVNRT. Cryoablation also produces minimal endothelial disruption and thrombus formation and causes no collagen shrinkage. This is likely advantageous when ablation is required within venous structures. There is also mounting experimental evidence that cryoablation is safe adjacent to the arterial system, especially within the middle cardiac vein or distal coronary sinus. As the technology evolves and further iterations of the catheter proceed, the role for this new but well-established technology is likely to grow.     

Minireview: GNAS: normal and abnormal functions

GNAS is a complex imprinted gene that uses multiple promoters to generate several gene products, including the G protein alpha-subunit (G(s)alpha) that couples seven-transmembrane receptors to the cAMP-generating enzyme adenylyl cyclase. Somatic activating G(s)alpha mutations, which alter key residues required for the GTPase turn-off reaction, are present in various endocrine tumors and fibrous dysplasia of bone, and in a more widespread distribution in patients with McCune- Albright syndrome. Heterozygous inactivating G(s)alpha mutations lead to Albright hereditary osteodystrophy. G(s)alpha is imprinted in a tissue-specific manner, being primarily expressed from the maternal allele in renal proximal tubules, thyroid, pituitary, and ovary. Maternally inherited mutations lead to Albright hereditary osteodystrophy (AHO) plus PTH, TSH, and gonadotropin resistance (pseudohypoparathyroidism type 1A), whereas paternally inherited mutations lead to AHO alone. Pseudohypoparathyroidism type 1B, in which patients develop PTH resistance without AHO, is almost always associated with a GNAS imprinting defect in which both alleles have a paternal-specific imprinting pattern on both parental alleles. Familial forms of the disease are associated with a mutation within a closely linked gene that deletes a region that is presumably required for establishing the maternal imprint, and therefore maternal inheritance of the mutation results in the GNAS imprinting defect. Imprinting of one differentially methylated region within GNAS is virtually always lost in pseudohypoparathyroidism type 1B, and this region is probably responsible for tissue-specific G(s)alpha imprinting. Mouse knockout models show that G(s)alpha and the alternative G(s)alpha isoform XLalphas that is expressed from the paternal GNAS allele may have opposite effects on energy metabolism in mice.     

21st Century: Review: Ageing and medicine

Throughout the world, populations are ageing. The response of the health services needs to be based on a knowledge of the nature of human ageing and the principles of rational health care for older people. Ageing comes about from interactions between intrinsic (genetic) and extrinsic (environment and lifestyle) factors. Health care has to be responsive to the general needs of older people, but also to recognize the heterogeneity produced by different rates and patterns of individual ageing. There are now real possibilities of improving the course of human ageing through modulation of both intrinsic and extrinsic processes. There is also a need to adapt social institutions to what is a permanent change in demography.     

Role of genetic analyses in cardiology: part I: mendelian diseases: cardiac channelopathies

Genetic analysis can be performed to identify the molecular substrate of inherited arrhythmogenic diseases; however, the role of this information in helping the management of patients is still debated. Here, we support the view that the practical value of genetic analysis is different in the various inherited conditions and that it is strongly influenced by the amount of information available in each disease about genotype-phenotype correlations. In some diseases, clinical management of patients is profoundly affected by the type of the underlying genetic defect; therefore, in these conditions, there is a high priority to introduce genetic analysis into clinical practice. In the absence of genotype-phenotype correlations, genetic testing still can be very useful when there is a clinical advantage in establishing presymptomatic diagnosis or when screening of family members may point to reproductive counseling. Finally, there is a high priority for introducing genetic testing for those genetic diseases in which a limited number of genes allow a high yield of successfully genotyped patients. We have developed a "score" to compare the value of genetic testing in arrhythmogenic diseases and to convey our view that the clinical role of genetic analysis is different in the various inherited cardiomyopathies and channelopathies. Healthcare authorities should become responsive to the advancement of knowledge in this field and should help facilitate access to genotyping for families affected by those conditions in which genetic analysis provides useful information for clinical management.     

Review: Gene Therapy for Cancer:

Gene therapy is a new form of therapeutic intervention with applications in many areas of medical treatment. There are still many technical difficulties to be overcome, but recent advances in the molecular and cellular biology of gene transfer have made it likely that gene therapy will soon start to play an increasing role in clinical practice and particularly in the treatment of cancer. The first clinical gene transfer in an approved protocol took place exactly 10 years ago, and it was for the transfer of gene-marked immune cells into patients with advanced cancer. Now there are 218 active clinical protocols in the United States, and they have involved over 2000 patients worldwide. Among the conditions and diseases for which gene transfer is being tried as treatment, cancer comes first with 130 clinical trials. Fundamental research in the mechanisms of cancer and the development of molecular biology tools are crucial for the success of the treatments in the future. The identification of tumor rejection antigens from a variety of cancers and the immune response that is defective in cancer patients are important topics for future studies. The evaluation of gene therapy combinations involving use of tumor suppressor genes and constructs that inactivate oncogenes is also another important area for future research. The future improvement of present viruses as well as the use of new viral vectors will likely expand the applicability and efficacy of gene therapy. During the next decade technological developments, particularly in the areas of gene delivery and cell transplantation, will be critical for the successful clinical practice of gene therapy.     

Depression and somatization: a review: Part I

The authors describe the relationship between the major depressive disorder and somatization. A literature review documenting the incidence and prevalence of depression in primary care and the rate of misdiagnosis is presented. Evidence is collated that points to several factors in misdiagnosis. The patient often selectively complains about the somatic manifestations of depression, minimizes the affective and cognitive components and is treated symptomatically. This is due to the physician's lack of recognition that the patient may have major depressive disorder and yet not recognize and report the mood component. The authors develop a conceptual model that elucidates the mechanism behind the selective perception and focus by the patient on the somatic manifestations of depression. In this first part, the influence of sociocultural and childhood experience on the ability of the patient to recognize and report mood changes is delineated. Understanding this model is crucial in preventing misdiagnosis and potential iatrogenic harm to the patient.     

Minireview: RET: normal and abnormal functions

The RET gene encodes a single-pass transmembrane receptor tyrosine kinase. RET is the oncogene that causes papillary thyroid carcinoma and medullary thyroid carcinoma. The latter may arise as a component of multiple endocrine neoplasia type 2 syndromes; germline mutations in RET are responsible for multiple endocrine neoplasia type 2 inheritance. In this report we review data on the mechanisms leading to RET oncogenic conversion and on RET targeting as a strategy in thyroid cancer treatment.     

REVIEW: The Zero-Stress State of the Gastrointestinal Tract:

The stresses and strains that remain in an organ when the external load is removed (the no-load state) are called residual stresses and strains. They can be relieved by cutting up the organ to obtain the zero-stress configuration. This phenomenon was demonstrated more than 15 years ago in cardiovascular research but until recently it was not realized by the gastrointestinal research community. The function of the gastrointestinal tract is to propel food by peristaltic motion, which is a result of the interaction of the tissue forces in the wall and the hydrodynamic forces in the food bolus. To understand the tissue forces, it is necessary to know the stress–strain relationships of the tissues that must be measured in reference to the zero-stress state. It has become clear that the zero-stress configuration of the gastrointestinal tract is very different from that of the no-load condition and that the zero-stress state is sensitive to structural and mechanical remodeling. The purpose of this review is to describe the basic theory and experiments of residual stress and to explore its physiological and pathophysiological implications in the gastrointestinal system.     

Acromégalie : améliorer la prise en charge: Acromegaly: improving care

Acromegaly is characterized by increased release of growth hormone (GH) and, consequently, Insulin-Like Growth Factor I (IGF-I), most often by a pituitary adenoma. Prolonged exposure to excess hormone leads to progressive somatic disfigurement and a wide range of systemic manifestations that are associated with increased mortality. Transsphenoidal adenomectomy is the treatment of choice of GH-secreting pituitary tumors but surgical cure is not achieved in around 50% of patients, then adjuvant treatment is necessary. Mortality in acromegaly is normalized with biochemical control and has decreased in the last decade with the increased use of adjuvant therapy. Both GH and IGF-I are currently biomarkers for assessing disease activity in patients with acromegaly. However, discordance between GH and IGF-I results is encountered in a quarter of treated patients. The impacts of such a discrepancy over mortality and morbidity and the risk of biochemical and/or clinical recurrence are unclear. Moreover, despite a good biochemical control, some symptoms persist, leading to a decreased quality of life. Back pain due to vertebral fractures seem to be frequent in these patients and underdiagnosed. In patients with acromegaly, bone mineral density is not a reliable predictor of fracture risk. A more accurate evaluation of bone microstructural alterations associated with GH hypersecretion and vertebral fractures may be provided by new radiological devices analyzing alteration of trabecular microarchitecture, leading to a better prevention.© 2019 Published by Elsevier Masson SAS. All rights reserved.Cet article fait partie du numéro supplément Les Must de l’Endocrinologie 2019 réalisé avec le soutien institutionnel de Ipsen-Pharma.     

REVIEW: Management of gout: beyond allopurinol

The basic concepts of the pathogenesis and management of gout have not altered for many years. Monosodium urate monohydrate crystals drive the disease and identification of these crystals is required for certain diagnosis. In contrast, our understanding of the mediators of gouty inflammation, the appropriate target serum urate concentration during treatment, the drugs available and the best ways to use those drugs have all advanced in recent years and will be the focus of this review.     

Homelessness:

This article provides a background on homelessness that is relevant to gerontological education and training. The variety of homeless subgroups and the problems of definition and enumeration are discussed before focusing on issues concerning the homeless elderly. All levels of human service providers need education and training for meeting the multiplicity of needs of this population. Gerontological and geriatric educators must be informed about the many issues involved in serving the homeless elderly and include these topics in their training programs.     

Vaccines: countering anthrax: vaccines and immunoglobulins.

Anthrax spores rank as the leading threat among bioweapons. This article reviews the accumulated evidence for immunization, either active or passive, to counter the malicious release of anthrax spores. The key protective factor in current anthrax vaccines for humans is a protein called protective antigen, which allows ingress of toxins into cells. The US vaccine is licensed to prevent anthrax, regardless of the route of exposure. Its dosing schedule is cumbersome and somewhat painful (shortcomings that may be resolved by ongoing clinical studies). It can be prescribed with the confidence commensurate with dozens of human safety studies and experience in 1.8 million recent vaccinees. For post-exposure prophylaxis, combining antibiotic prophylaxis and active immunization before illness onset may offer the best combination of prompt and sustained protection, especially for people who inhale large doses of spores. To treat anthrax infection, passive immunization using a polyclonal or monoclonal antibody product may offer important clinical benefit, especially if the anthrax bacteria are resistant to multiple antibiotics.