Publications

Molecular targeting of the two receptor interaction domains of the epigenetic repressor silencing mediator of retinoid and thyroid hormone receptors (SMRT(mRID)) produced a transplantable skeletal syndrome that reduced radial bone growth, increased numbers of bone-resorbing periosteal osteoclasts, and increased bone fracture risk. Furthermore, SMRT(mRID) mice develop spontaneous primary myelofibrosis, a chronic, usually idiopathic disorder characterized by progressive bone marrow fibrosis. Frequently linked to polycythemia vera and chronic myeloid leukemia, myelofibrosis displays high patient morbidity and mortality, and current treatment is mostly palliative. To decipher the etiology of this disease, we identified the thrombopoietin (Tpo) gene as a target of the SMRT-retinoic acid receptor signaling pathway in bone marrow stromal cells. Chronic induction of Tpo in SMRT(mRID) mice results in up-regulation of TGF-β and PDGF in megakaryocytes, uncontrolled proliferation of bone marrow reticular cells, and fibrosis of the marrow compartment. Of therapeutic relevance, we show that this syndrome can be rescued by retinoid antagonists, demonstrating that the physical interface between SMRT and retinoic acid receptor can be a potential therapeutic target to block primary myelofibrosis disease progression.

PURPOSE

To elucidate the mechanistic basis for efficacy of intrathecal rituximab. We evaluated complement activation as well as the pharmacokinetics of intraventricular rituximab in patients who participated in two phase 1 multicenter studies.

EXPERIMENTAL DESIGN

We evaluated complement activation as a candidate mediator of rituximab within the central nervous system (CNS). Complement C3 and C5b-9 were quantified by ELISA in serial cerebrospinal fluid (CSF) specimens after intraventricular rituximab administration. We determined rituximab concentration profiles in CSF and serum. A population three- compartment pharmacokinetic model was built to describe the disposition of rituximab following intraventricular administration. The model was derived from results of the first trial and validated with results of the second trial.

RESULTS

Complement C3 and C5b-9 were reproducibly activated in CSF after intraventricular rituximab. Ectopic expression of C3 mRNA and protein within CNS lymphoma lesions was localized to myeloid cells. Constitutive high C3 activation at baseline was associated with adverse prognosis. A pharmacokinetic model was built, which contains three distinct compartments, to describe the distribution of rituximab within the neuroaxis after intraventricular administration.

CONCLUSIONS

We provide the first evidence of C3 activation within the neuroaxis with intraventricular immunotherapy and suggest that complement may contribute to immunotherapeutic responses of rituximab in CNS lymphoma. Penetration of rituximab into neural tissue is supported by this pharmacokinetic model and may contribute to efficacy. These findings have general implications for intraventricular immunotherapy. Our data highlight potential innovations to improve efficacy of intraventricular immunotherapy both via modulation of the innate immune response as well as innovations in drug delivery.

BACKGROUND

Deathbed wills by their nature are susceptible to challenge. Clinicians are frequently invited to give expert opinion about a dying testator's testamentary capacity and/or vulnerability to undue influence either contemporaneously, when the will is made, or retrospectively upon a subsequent challenge, yet there is minimal discourse in this area to assist practice.

METHODS

The IPA Capacity Taskforce explored the issue of deathbed wills to provide clinicians with an approach to the assessment of testamentary capacity at the end of life. A systematic review searching PubMed and Medline using the terms: "deathbed and wills," "deathbed and testamentary capacity," and "dying and testamentary capacity" yielded one English-language paper. A search of the individual terms "testamentary capacity" and "deathbed" yielded one additional relevant paper. A focused selective review was conducted using these papers and related terms such as "delirium and palliative care." We present two cases to illustrate the key issues here.

RESULTS

Dying testators are vulnerable to delirium and other physical and psychological comorbidities. Delirium, highly prevalent amongst terminal patients and manifesting as either a hyperactive or hypoactive state, is commonly missed and poorly documented. Whether the person has testamentary capacity depends on whether they satisfy the Banks v Goodfellow legal criteria and whether they are free from undue influence. Regardless of the clinical diagnosis, the ultimate question is can the testator execute a specific will with due consideration to its complexity and the person's circumstances?

CONCLUSIONS

Dual ethical principles of promoting autonomy of older people with mental disorders whilst protecting them against abuse and exploitation are at stake here. To date, there has been scant discourse in the scientific literature regarding this issue.