Finding Milner? The Biographical Search

The essay starts from Milner's wish to be intensely private, ‘illegible’, and poses the question as to how such a subject may be ‘found’ by a biographer, considering aspects of the search for Milner such as parallel process in the work; ethical dilemmas of confidentiality in writing about a psychoanalyst and the effects on the transference for patients reading about their analyst. Finding Milner involved not only the usual biographic tools (interviews with colleagues and descendants, attention to her books, her habits with documents and texts, her images and objects) but also a kind of unconscious knowing of which certain aspects are discussed. The process also had certain effects on the author's clinical practice. As biographic companion Milner brings with her the ‘riches of world culture’. The author suggests that there is further fruitful work to be undertaken on the subject of biography and psychoanalysis.     

Using therapeutic cloning to fight human disease: a conundrum or reality?

The development and transplantation of autologous cells derived from nuclear transfer embryonic stem cell (NT-ESC) lines to treat patients suffering from disease has been termed therapeutic cloning. Human NT is still a developing field, with further research required to improve somatic cell NT and human embryonic stem cell differentiation to deliver safe and effective cell replacement therapies. Furthermore, the implications of transferring mitochondrial heteroplasmic cells, which may harbor aberrant epigenetic gene expression profiles, are of concern. The production of human NT-ESC lines also remains plagued by ethical dilemmas, societal concerns, and controversies. Recently, a number of alternate therapeutic strategies have been proposed to circumvent the moral implications surrounding human nuclear transfer. It will be critical to overcome these biological, legislative, and moral restraints to maximize the potential of this therapeutic strategy and to alleviate human disease.     

Myelolipoma: A New Adrenal Finding in Carney's Complex?

Pigmented nodular cortical hyperplasia, a rare cause of Cushing’s syndrome, is characterized by resistance to inhibition with dexamethasone and normal sized adrenal glands with multiple, small pigmented nodules. The disorder may be a component of a syndrome inherited as an autosomal dominant pattern that includes intra- and extracardiac myxomas, lentiginous lesions, blue nevi, other functional endocrine tumors, and peripheral nerve tumors (Carney’s complex). We report a patient in whom bilateral myelolipomas were found, in addition to the usual features of this complex. A 29-yr-old man was admitted to the hospital for Cushing’s syndrome of probably more than 15 yr duration. Physical examination showed diffuse facial hyperchromatic macules, 0.2–0.5 cm, predominantly around the lips and on the palmar surfaces of the fingers. Results with dexamethasone suppression nocturnal testing (1 and 8 mg) were compatible with an adrenal adenoma. The computed tomography (CT) of the sella turcica was normal. Adrenal CT showed a tumor in the left gland with a double component: one solid and another suggestive of fat, consistent with an angiomyelolipoma. Following 5 wk treatment with ketoconazole, 800 mg per day po, serum cortisol decreased to 5.9 μg/dL, morning and evening, respectively. Bilateral adrenalectomy was performed. Pathologic examination revealed pigmented nodular cortical hypersplasia and a dominant myelolipoma in the left adrenal. A microscopic myelolipoma was identified in the right adrenal. An echocardiogram showed a mass on the posterior wall of the left ventricle which was a myxoma. Study of the patient's family disclosed two sisters with facial lentigines. Echocardiograms were performed on all available first degree relatives: all were normal. Nocturnal inhibition with dexamethasone revealed that one of the patient’s sisters with lentigines also had hypercortisolism. Myelolipoma has been reported in association to Cushing syndrome in humans and experimentally after pituitary extracts in animals. The relationship between this finding and the Carney’s complex remain elusive.     

Using induced pluripotent stem cells (iPSC) to model human neuromuscular connectivity: promise or reality?

Motor neuron diseases (MND) such as amyotrophic lateral sclerosis and spinal muscular atrophy are devastating, progressive and ultimately fatal diseases for which there are no effective treatments. Recent evidence from systematic studies of animal models and human patients suggests that the neuromuscular junction (NMJ) is an important early target in MND, demonstrating functional and structural abnormalities in advance of pathological changes occurring in the motor neuron cell body. The ability to study pathological changes occurring at the NMJ in humans is therefore likely to be important for furthering our understanding of disease pathogenesis, and also for designing and testing new therapeutics. However, there are many practical and technical reasons why it is not possible to visualise or record from NMJs in pre- and early-symptomatic MND patients in vivo. Other approaches are therefore required. The development of stem cell technologies has opened up the possibility of creating human NMJs in vitro, using pluripotent cells generated from healthy individuals and patients with MND. This review covers historical attempts to develop mature and functional NMJs in vitro, using co-cultures of muscle and nerve from animals, and discusses how recent developments in the generation and specification of human induced pluripotent stem cells provides an opportunity to build on these previous successes to recapitulate human neuromuscular connectivity in vitro.     

Finding cancer stem cells: are aldehyde dehydrogenases fit for purpose?

Despite many years of intensive effort, there is surprisingly little consensus on the most suitable markers with which to locate and isolate stem cells from adult tissues. By comparison, the study of cancer stem cells is still in its infancy; so, unsurprisingly, there is great uncertainty as to the identity of these cells. Stem cell markers can be broadly categorized into molecular determinants of self‐renewal, clonogenicity, multipotentiality, adherence to the niche, and longevity. This review assesses the utility of recognizing cancer stem cells by virtue of high expression of aldehyde dehydrogenases (ALDHs), probably significant determinants of cell survival through their ability to detoxify many potentially cytotoxic molecules, and contributing to drug resistance. Antibodies are available against the ALDH enzyme family, but the vast majority of studies have used cell sorting techniques to enrich for cells expressing these enzymes. Live cells expressing high ALDH activity are usually identified by the ALDEFLUOR kit and sorted by fluorescence activated cell sorting (FACS). For many human tumours, but notably breast cancer, cell selection based upon ALDH activity appears to be a useful marker for enriching for cells with tumour‐initiating activity (presumed cancer stem cells) in immunodeficient mice, and indeed the frequency of so‐called ALDH^bri cells in many tumours can be an independent prognostic indicator. Copyright © 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Boom or bubble? Is medical research thriving or about to crash?

A recent issue of JAMA (2005; vol. 294) presented a portrait of medical research as a booming enterprise. By contrast I have suggested that medical research is a speculative bubble due to burst. How can two such different predictions be compatible? From inside the expanding world of medical research everything seems fine and getting better. But to people outside the system, it seems like there is an awful lot of money going in, and not much coming out. Professional criteria of success (publications, impact factors, citations, grant income, large teams, etc.) are not the same as the outsider's view of success. Outsiders want the medical research system to generate therapeutic progress as efficiently as possible: the most progress for the least resources. Medical research is not the only good way of spending money and is in competition with other social systems. As funding increases, diminishing returns will set-in, opportunity costs will begin to bite, and there will be more and more social benefit to be gained from spending the extra research money on something else. Therefore, future cuts in medical research will happen because of pressure from outside the system - specifically pressure from other powerful social systems which will press their alternative claims for funding. In the short term, there will be a quantitative decline of research production. But in the longer term the medical research system will re-grow in a more efficient form. After a 'golden age of therapeutic progress in the mid-20th century, recent decades have seen a 'silver age' of scholasticism which is due to end soon. Perhaps a renaissance of medical research lies not too many years in the future.     

B-cell or T-cell immunity?

The influenza virus behaves unpredictably and can cause devastating pandemics. Nearly 50 years after its first isolation it is probably the most infectious agent known that we cannot yet control. Why? The answer lies in the virus's unique capacity to alter antigenically and in the inability of the host's immune system to respond satisfactorily to the vaccines currently available. What follows is a record, prepared exclusively for Immunology Today, of a conference held in Oxford on March 21–24 this year, to discuss problems relating to protection against influenza.