Reaching Out, Helping Hands Helping Minds: A Hawai'ian Model for Aiding Friends Coping With Dementia.

Reaching a certain age places one in a particular landscape in which dementia may be part of the scenery. This costly public health problem is personally devastating not only for dementia sufferers but for their surrounding interpersonal circle, which is not limited to immediate family. Indeed, friends often become the family you choose; their issues become, at some level, shared issues. In this setting the impulse of a life scientist to offer knowledgeable assistance to a friend fits naturally into a cornerstone of culture in present-day Hawai'i for mobilizing relevant aid from all corners. This model, called "forming a hui", comprises a network of not only formal professional relationships but potentially even more importantly, the informal ones: friendships, serendipitous contacts, someone who knows someone who knows someone, the essence of connectedness on behalf of friends coping with dementia. Storytelling as a means of communication holds a place of prominence in Hawai'ian culture; exchange of ideas, as well as reminiscence, is called "talk story." In this article, lives now built around coping with dementia are woven into a story fabric as into a Hawai'ian quilt.

Keeping Abreast of Developments in the Cancer Wars: A View From the Front.

Cancer somehow lends itself to military analogies, perhaps because of its status as a threat to life itself. We've declared war on cancer over several decades, viewing cancer as a cell going rogue, dividing uncontrollably, and ultimately breaking through local boundaries to spread. Less well known, but critically relevant to the health care impact of questioning authority, is the war within the breast cancer management community, among those studying molecular and cellular targets in breast cancer biology and those managing the human targets that represent cancer's toll. This article outlines current concepts and controversies about breast cancer, presenting a bio/sociological basis and a mental toolkit for thinking about and coping with this conflict.

The glycan-specific sulfotransferase (R77W)GalNAc-4-ST1 putatively responsible for peeling skin syndrome has normal properties consistent with a simple sequence polymorphisim.

Expanded access to DNA sequencing now fosters ready detection of site-specific human genome alterations whose actual significance requires in-depth functional study to rule in or out disease-causing mutations. This is a particular concern for genomic sequence differences in glycosyltransferases, whose implications are often difficult to assess. A recent whole-exome sequencing study identifies (c.229 C > T) in the GalNAc-4-ST1 glycosyltransferase (CHST8) as a disease-causing missense R77W mutation yielding the genodermatosis peeling skin syndrome (PSS) when homozygous. Cabral et al. (Genomics. 2012;99:202-208) cite this sequence change as reducing keratinocyte GalNAc-4-ST1 activity, thus decreasing glycosaminoglycan sulfation, as the mechanism for this blistering disorder. Such an identification could point toward potential clinical and/or prenatal diagnosis of a harmful medical condition. However, GalNAc-4-ST1 has minimal activity toward glycosaminoglycans, instead modifying terminal ß1,4-linked GalNAc on N- and O-linked oligosaccharides on specific glycoproteins. We find expression, processing and catalytic activity of GalNAc-4-ST1 completely equivalent between wild type and (R77W) sulfotransferases. Moreover, keratinocytes have little or no GalNAc-4-ST1 mRNA, indicating that they do not express GalNAc-4-ST1. In addition, loss-of-function of GalNAc-4-ST1 primarily presents as reproductive system aberrations rather than skin effects. These findings, an allele frequency of 0.004357, and a 10-fold difference in prevalence of CHST8 (c.299 C > T, R77W) across different ethnic groups, suggest that this sequence represents a "passenger" distributed polymorphism, a simple sequence variant form of the enzyme having normal activity, rather than a "driver" disease-causing mutation that accounts for PSS. This study presents an example for guiding biomedical research initiatives, as well as medical and personal/family perspectives, regarding newly-identified genomic sequence differences.

Painful Reality: Inappropriate Provider Management of Pain as a Determinant of Health Care Avoidance.

Although pain is often characterized as a subjective, highly individualized phenomenon, in fact, numerous elements which are simply biological in nature underlie interpersonal differences in pain experience that influence the effectiveness of provider pain management. Elements acting at the level of tissues and cells include signal-transmitting molecules in pain pathways; elements acting at the level of the whole person comprise entire brain networks and anatomic elements fostering pain vulnerability. However, knowledge of these elements and translation of such knowledge into practical means for relieving patient pain is dismayingly sparse across the total spectrum of health care professionals. A serious consequence of this knowledge and action gap is that isolated, or worse yet, repeated, pain experiences may lead to profound mistrust of the health care system and its providers and to health care avoidance (e.g., mammography). This article outlines a biologic knowledge base and proposed remedies to improve pain management across the entire domain of health care. Key components of this approach include enhanced education for providers and informational outreach to health care consumers, clarifying pain mechanisms to both constituencies. Moreover, increased accountability within the health care system is needed, both in knowing and applying well-established biomedical knowledge and in best using technical and interpersonal skills necessary for effective pain management.

Mountains, Melting Pot, and Microcosm: Health Care Delay and Dengue/Zika Interplay on Hawaii Island.

Human history in the Hawaiian Islands offers a sobering study in the population dynamics of infectious disease. The indigenous population numbering an estimated half million people prior to Western contact in 1778 was reduced to less than 24,000 by 1920. Much of the decline occurred in the earliest decades after contact with Western diseases including measles, chicken pox, polio, tuberculosis, and venereal disease. A recent outbreak on the Island of Hawaii (also called the Big Island) of imported dengue fever, an illness endemic in 100 countries affecting an estimated 100-400 million people worldwide, provides insights into the problems and prospects for health care policy in managing mosquito-borne disease in a multicultural setting of geographic isolation and health care provider shortage. This incident represents in microcosm a practice run, applicable in many contexts, for an initial localized appearance of Zika virus infection, with important lessons for effective health care management in a rapidly moving and fluid arena.

Molecular profiling reveals diversity of stress signal transduction cascades in highly penetrant Alzheimer's disease human skin fibroblasts.

The serious and growing impact of the neurodegenerative disorder Alzheimer's disease (AD) as an individual and societal burden raises a number of key questions: Can a blanket test for Alzheimer's disease be devised forecasting long-term risk for acquiring this disorder? Can a unified therapy be devised to forestall the development of AD as well as improve the lot of present sufferers? Inflammatory and oxidative stresses are associated with enhanced risk for AD. Can an AD molecular signature be identified in signaling pathways for communication within and among cells during inflammatory and oxidative stress, suggesting possible biomarkers and therapeutic avenues? We postulated a unique molecular signature of dysfunctional activity profiles in AD-relevant signaling pathways in peripheral tissues, based on a gain of function in G-protein-coupled bradykinin B2 receptor (BKB2R) inflammatory stress signaling in skin fibroblasts from AD patients that results in tau protein Ser hyperphosphorylation. Such a signaling profile, routed through both phosphorylation and proteolytic cascades activated by inflammatory and oxidative stresses in highly penetrant familial monogenic forms of AD, could be informative for pathogenesis of the complex multigenic sporadic form of AD. Comparing stimulus-specific cascades of signal transduction revealed a striking diversity of molecular signaling profiles in AD human skin fibroblasts that express endogenous levels of mutant presenilins PS-1 or PS-2 or the Trisomy 21 proteome. AD fibroblasts bearing the PS-1 M146L mutation associated with highly aggressive AD displayed persistent BKB2R signaling plus decreased ERK activation by BK, correctible by gamma-secretase inhibitor Compound E. Lack of these effects in the homologous PS-2 mutant cells indicates specificity of presenilin gamma-secretase catalytic components in BK signaling biology directed toward MAPK activation. Oxidative stress revealed a JNK-dependent survival pathway in normal fibroblasts lost in PS-1 M146L fibroblasts. Complex molecular profiles of signaling dysfunction in the most putatively straightforward human cellular models of AD suggest that risk ascertainment and therapeutic interventions in AD as a whole will likely demand complex solutions.