Is age-related failure of metabolic reprogramming a principal mediator in idiopathic Parkinson's disease? Implications for treatment and inverse cancer risk.

Idiopathic Parkinson's disease (IPD) is a neurodegenerative disorder characterized by selective degeneration of the substantia nigra pars compacta (SNc), dorsal motor nucleus of the vagus and other vulnerable nervous system regions characterized by extensive axonal arborization and intense energy requirements. Systemic age-related depression of mitochondrial function, oxidative phosphorylation (OXPHOS) and depressed expression of genes supporting energy homeostasis is more severe in IPD than normal aging such that energy supply may exceed regional demand. In IPD, the overall risk of malignancy is reduced. Cancer is a collection of proliferative diseases marked by malignant transformation, dysregulated mitosis, invasion and metastasis. Many cancers demonstrate normal mitochondrial function, preserved OXPHOS, competent mechanisms of energy homeostasis, and metabolic reprogramming capacities that are lacking in IPD. Metabolic reprogramming adjusts OXPHOS and glycolytic pathways in response to changing metabolic needs. These opposite metabolic features form the basis of a two component hypothesis. First, that depressed mitochondrial function, OXPHOS deficiency and impaired metabolic reprogramming contribute to focal energy failure, neurodegeneration and disease expression in IPD. Second, that the same systemic metabolic deficits inhibit development and proliferation of malignancies in IPD. Studies of mitochondrial aging, familial PD (FPD), the lysosomal storage disorder, Gaucher's disease, Parkinson's disease cybrids, the mitochondrial cytopathies, and disease-related metabolic reprogramming both in IPD and cancer provide support for this model.

The Geriatrics in Primary Care Demonstration: Integrating Comprehensive Geriatric Care into the Medical Home: Preliminary Data.

Three thousand nine hundred thirty-one veterans aged 75 and older receive primary care (PC) in two large practices of the Department of Veterans Affairs (VA) Boston Healthcare System. Cognitive and functional disabilities are endemic in this group, creating needs that predictably exceed available or appropriate resources. To address this problem, Geriatrics in Primary Care (GPC) embeds geriatric services directly into primary care. An on-site consulting geriatrician and geriatric nurse care manager work directly with PC colleagues in medicine, nursing, social work, pharmacy, and mental health within the VA medical home. This design delivers interdisciplinary geriatric care within PC that emphasizes comprehensive evaluations, care management, planned transitions, informed resource use, and a shift in care focus from multiple subspecialties to PC. Four hundred thirty-five veterans enrolled during the project's 4-year course. Complex, fragmented care was evident in a series of 50 individuals (aged 82 ± 7) enrolled during Months 1 to 6. The year before, these individuals made 372 medical or surgical subspecialty clinic visits (7.4 ± 9.8); 34% attended five or more subspecialty clinics, 48% had dementia, and 18% lacked family caregivers. During the first year after enrollment the mean number of subspecialty clinic visits declined significantly (4.7 ± 5.0, P = .01), whereas the number of PC-based visits remained stable (3.1 ± 1.5 and 3.3 ± 1.5, respectively, P = .50). Telephone contact by GPC (2.3 ± 2.0) and collaboration with PC clinicians replaced routine follow-up geriatric care. GPC facilitated planned transitions to rehabilitation centers (n = 5), home hospice (n = 2), dementia units (n = 3), and home care (n = 37). GPC provides efficient, comprehensive geriatric care and case management while preserving established relationships between patients and the PC team. Preliminary results suggest "care defragmentation," as reflected by a significant reduction in subspecialty clinic use. Model simplicity and flexibility facilitated ready implementation.

Does metabolic failure at the synapse cause Alzheimer's disease?

Alzheimer's disease (AD) a neurodegenerative disorder of widely distributed cortical networks evolves over years while A beta (Aß) oligomer neurotoxicity occurs within seconds to minutes. This disparity combined with disappointing outcomes of anti-amyloid clinical trials challenges the centrality of Aß as principal mediator of neurodegeneration. Reconsideration of late life AD as the end-product of intermittent regional failure of the neuronal support system to meet the needs of vulnerable brain areas offers an alternative point of view. This model introduces four ideas: (1) That Aß is a synaptic signaling peptide that becomes toxic in circumstances of metabolic stress. (2) That intense synaptic energy and maintenance requirements of cortical hubs may exceed resources during peak demand initiating a neurotoxic cascade in these selectively vulnerable regions. (3) That axonal transport to and from neuron soma cannot account fully for high mitochondrial densities and other requirements of distant terminal axons. (4) That neurons as specialists in information management, delegate generic support functions to astrocytes and other cell types. Astrocytes use intercellular transport by exosomes and tunneling nanotubes (TNTs) to deliver mitochondria, substrates and protein reprocessing services to axonal sites distant from neuronal soma. This viewpoint implicates the brain's support system and its disruption by various age and disease-related insults as significant mediators of neurodegenerative disease. A better understanding of this system should broaden concepts of neurodegeneration and facilitate development of effective treatments.

Sudden appearance and spontaneous regression of diffuse large B cell lymphoma in a man with a broken arm.

An elderly, demented man with stable κ bi-clonal gammopathy of unknown significance suffered a severe displaced right humeral fracture in a fall. One week later a rapidly enlarging head, neck and axillary adenopathy first appeared, including a 2 cm tonsillar node that partially obstructed the oropharynx. A left cervical node biopsy demonstrated diffuse large B cell lymphoma with CD20+, bcl-2+, κ+, CD3-, Epstein-Barr virus negative malignant cells. During the next month lymphadenopathy regressed more than 90% in the absence of treatment with chemotherapeutic agents, radiation or glucocorticoids. Following 2 months of clinical improvement, he died of pneumonia 95 days after the injury. An autopsy demonstrated residual right hilar and mediastinal malignant lymphadenopathy. These unusual events may be related to immunosuppressive and other systemic effects of acute injury on tumour behaviour.

George L. Engel 1913-1999: remembering his life and work: strengthening a father-son bond in a new time of grief.

OBJECTIVE: This essay reviews George Engel's clinical and scientific contributions within the context of a personal and professional biography. An examination of the response to the abrupt loss of human bonds resulting from the attack on the World Trade Center is used to verify Dr Engel's belief that relationship and communication are central to scientific study in the clinical setting and in the practice of medicine. METHODS: Engel's published autobiographical reports, personal reminiscences, and key scientific publications are reviewed in the light of published or broadcast personal responses to the World Trade Center disaster. RESULTS AND CONCLUSION: Dr Engel recognized the singular importance of human bonds to the work of the physician. He described the unity of complex human experiences and basic biological processes. Public and personal grief evoked by destruction of those bonds on September 11 reflects an implicit, universal understanding of the essential human connections between us all. In the work of the physician, Dr Engel proposed disciplined study of those bonds to enrich personal connections, to promote understanding of patient and illness and to sustain the physician through emotionally and intellectually meaningful work. Herein lies the connection between Engel's contributions and the grief evoked by these events.