Discussing physician-assisted dying: physicians' experiences in the United States and the Netherlands.

PURPOSE OF THE STUDY: This study aims to further our understanding of the experiences of physicians when discussing physician-assisted dying (PAD) within the context of doctor-patient relationships in various sociolegal settings. Although patients bring up PAD in diverse settings, little is known about how physicians experience these discussions, and such experiences have not been directly compared across countries. DESIGN AND METHODS: A total of 36 physicians in the Netherlands and the United States (including Oregon) were interviewed using individual semistructured interview guides. Interviews were conducted by a single interviewer, audiotaped, and independently transcribed. Inductive qualitative analysis, aided by NVivo7 software, directed purposive sampling of physicians until saturation was met. Multiple coders in a multidisciplinary team analyzed emerging themes and developed theory. RESULTS: PAD discussions, which ranged from theoretical discussions to actual requests, could be gateways to discussions of other end-of-life issues important to patients and could strengthen doctor-patient relationships. Physicians found discussions to be emotionally intense, but often rewarding. Where PAD was legal, physicians utilized existing criteria to guide communication, and discussions were open and honest with patients and colleagues. Where PAD was illegal, conversations were less explicit, and physicians dealt with requests in relative isolation. In addition, physicians' views of their professional role, patients' rights, and religion influenced both their willingness to have and the content of PAD discussions. IMPLICATIONS: Discussion of PAD is an energy-consuming, yet potentially enriching part of the doctor-patient relationship. Legal guidelines may help to provide structure and support for physicians when patients broach the topic of PAD.

Approaches to suffering at the end of life: the use of sedation in the USA and Netherlands.

BACKGROUND: Studies describing physicians' experiences with sedation at the end of life are indispensible for informed palliative care practice, but they are scarce. We describe the accounts of physicians from the USA and the Netherlands, two countries with different regulations on end-of-life decisions regarding their use of sedation. METHODS: Qualitative face-to-face interviews were held in 2007-2008 with 36 physicians (18 from the Netherlands, 18 from the USA), including primary care physicians and specialists. We applied purposive sampling and conducted constant comparative analyses. RESULTS: In both countries, the use of sedation was described in diverse terms, especially in the USA, and was often experienced as emotionally challenging. Respondents stated different and sometimes multiple intentions for their use of sedation. Besides alleviating severe suffering, most Dutch respondents justified its use by stating that it does not hasten death, while most American respondents indicated that it might hasten death but that this was justifiable as long as that was not their primary intention. While many Dutch respondents indicated that they initiated open discussions about sedation proactively to inform patients about their options and to allow planning, the accounts of American respondents showed fewer and less-open discussions, mostly late in the dying process and with the patient's relatives. CONCLUSIONS: The justification for sedation and the openness with which it is discussed were found to differ in the accounts of respondents from the USA and the Netherlands. Further clarification of practices and research into the effect and effectiveness of the use of sedation is recommended to enhance informed reflection and policy making.

A small percentage of family physicians report time devoted to research.

Despite calls by family medicine organizations to build research capacity within the discipline, few family physicians report research activity. Policy that supports efforts in family medicine research and increases awareness of opportunities for primary care research in the practice setting is essential for family medicine to expand its scholarly foundations.

William S. Halsted and Harvey W. Cushing: reflections on their complex association.

William Stewart Halsted, the father of modern surgery, and Harvey Williams Cushing, the father of neurosurgery, are remembered for their countless innovations and contributions to the discipline of surgery. Between 1896 and 1912, they worked together at Johns Hopkins Hospital making many of their respective achievements possible. In the later years, their complex relationship, somewhat strained during Cushing's residency, grew into a mutual respect and deep appreciation for one another. In this offering, the authors attempt to elucidate the evolution of this complex relationship.

Cushing's experience with the surgical treatment of spinal dysraphism.

Although Harvey Cushing is best known for his role in developing surgical treatments for tumors of the central nervous system, he performed diverse neurosurgical procedures throughout his career, both at The Johns Hopkins Hospital (1886--1912) and at the Peter Bent Brigham Hospital (1912--1932). His unique and innovative approach to the treatment of myelomeningoceles associated with hydrocephalus, displayed early in his career, is characteristic of his attempts to circumvent the technical limitations of his time in the management of neurosurgical problems. In this report, the authors discuss the evolution of Cushing's technique in the treatment of myelomeningoceles through two illustrative patient records.

Battling blood loss in neurosurgery: Harvey Cushing's embrace of electrosurgery.

For his pioneering spirit, definitive work, and unparalleled devotion to conquering neurosurgery's toughest obstacles, Harvey Williams Cushing inarguably has earned the title, "The Father of Neurosurgery." His revolutionary incorporation of electrosurgical techniques in neurosurgery was not exceptional, but part of a pattern of recognizing, embracing, and establishing the use of medical technologies with great potential. Until 1910, Cushing had systematically reduced neurosurgery's primary complications--infection and the effects of intracranial pressure--to decrease mortality rates. Hemostasis had always been a concern of William Halsted's surgical protégé, but only after 1910 could Cushing primarily focus on it. In fact, Cushing's crucial collaboration with William T. Bovie and his electrosurgical apparatus conquered this major obstacle in 1926. The nature of their collaboration--two experts in their respective fields who were passionate about their work, working side by side in the operating room--resulted in progress that surpassed all predecessors in the field. Cushing never did learn the physics behind one of the most important advances of his career. Nonetheless, he did know that by greatly reducing blood loss, electrosurgery allowed him to operate in patients whose tumors had been previously deemed inoperable and on the entire spectrum of neurosurgical patients more safely.

Early evolution of neurological surgery: conquering increased intracranial pressure, infection, and blood loss.

At the end of the 19th century, the early evolution of the specialty of neurological surgery was restricted by complications related to infection, increased intracranial pressure, and excessive intraoperative blood loss. These complications often caused mortality rates of 30 to 50%. An improved understanding of pathophysiological factors involved in increased intracranial pressure, along with meticulous surgical techniques learned from William Halsted, allowed Harvey Cushing to increase the safety of neurosurgical procedures that were then in their infancy. Cushing's later development of the "silver clip" and incorporation of electrosurgical techniques facilitated safe resection of brain tumors previously assumed to be inoperable. These pivotal accomplishments paved the way for the establishment of our specialty.

Activation of transcription factor Nrf-2 and its downstream targets in response to moloney murine leukemia virus ts1-induced thiol depletion and oxidative stress in astrocytes.

The neuroimmunodegenerative syndrome that develops in mice infected with ts1, a mutant of Moloney murine leukemia virus, resembles human AIDS. Both ts1 and human immunodeficiency virus type 1 infect astrocytes, microglia, and oligodendrocytes but do not infect neurons. Oxidative stress has been implicated in the neuropathology of AIDS dementia and other neurodegenerative diseases. We report here that ts1 infection of astrocytes (both transformed C1 cells and primary cultures) also induces thiol (i.e., glutathione and cysteine) depletion and reactive oxygen species (ROS) accumulation, events occurring in parallel with viral envelope precursor gPr80(env) accumulation and upregulated expression of endoplasmic reticulum chaperones GRP78 and GRP94. Furthermore, ts1-infected astrocytes mobilize their thiol redox defenses by upregulating levels of the Nrf-2 transcription factor, as well its targets, the xCT cystine/glutamate antiporter, gamma-glutamylcysteine ligase, and glutathione peroxidase. Depleting intracellular thiols by treating uninfected astrocytes with buthionine sulfoximine (BSO), a glutathione synthesis inhibitor, or by culturing in cystine-deficient medium, also induces ROS accumulation, activates Nrf-2, and upregulates Nrf-2 target gene expression in these astrocytes. Overexpression of Nrf-2 in astrocytes specifically increases expression of the above thiol synthesis-related proteins. Further treatment with BSO or N-acetylcysteine in transfected cells modulates this expression. Thiol depletion also accelerates cell death, while thiol supplementation promotes survival of ts1-infected cells. Together, our results indicate that ts1 infection of astrocytes, along with ts1-induced gPr80(env) accumulation, endoplasmic reticulum stress, thiol depletion, and oxidative stress, accelerates cell death; in response to the thiol depletion and oxidative stress, astrocytes activate their Nrf-2-mediated thiol antioxidant defenses, promoting cell survival.

Krev1 interaction trapped-1/cerebral cavernous malformation-1 protein expression during early angiogenesis.

OBJECT: Molecular genetic studies of cerebral cavernous malformation (CCM) have identified three loci, CCM1-3, that can lead to CCM when mutated. Examination of the CCM1 locus established KRIT1 (Krev1 Interaction Trapped genre 1) as the CCM1 gene. Despite the identification of KRIT1 as the gene mutated in CCM1, little has been learned regarding its function. The authors recently demonstrated specific KRIT1 expression in endothelial cells. Based on this result and the fact that the CCM phenotype features defects in microvasculature, we hypothesized that KRIT1 may take an active part in normal angiogenesis. METHODS: In this study, the authors investigated the spatial and temporal expression of KRIT1 during normal vessel development and maturation by examining KRIT1 protein in both in vitro and in vivo angiogenic systems with the use of postconfluent endothelial cell cultures along with placental tissues from different developmental stages. CONCLUSIONS: The results demonstrate that KRIT1 is expressed during capillary-like tube formation in the early stages of angiogenesis in vitro. Histological examination of placental tissue, a well-established in vivo model of angiogenesis, shows KRIT1 expression in active angiogenic and vasculogenic areas of the immature placental villi. As the placenta matures, KRIT1 expression is restricted to microvascular and small arterial endothelial cells with little or no expression seen in the intima of large vessels. It can therefore be concluded that KRIT1 is expressed during early angiogenesis by endothelial cells and may play a key role in vessel formation and/or development.

Mutational analysis of 206 families with cavernous malformations.

OBJECT: A gene contributing to the autosomal-dominant cerebral cavernous malformation (CCM) phenotype, KRIT1 (an acronym for Krev Interaction Trapped 1), has been identified through linkage analysis and mutation screening. The authors collected blood samples from 68 patients with familial CCM and 138 patients with apparently sporadic CCM as well as from their families, in an effort to characterize the prevalence and spectrum of disease-causing sequence variants in the KRIT1 gene. METHODS: The authors used single-strand conformational polymorphism analysis to identify genomic variants in KRIT1, which were sequenced to determine the specific mutation. Among 43 Hispanic-American kindreds who immigrated to the southwestern US from northern Mexico, 31 share an identical founder mutation. This Q455X mutation is found in 18 (86%) of 21 persons with a positive family history and in 13 (59%) of 22 persons with apparently sporadic CCM. This mutation was not found among 13 persons with CCM who were recruited from Mexico. These findings establish the key role of a recent founder mutation in Hispanic persons with CCM who live in the US. Although nearly all Hispanic families in the US in which there are multiple CCM cases linked to the CCM1 locus, only 13 of 25 non-Hispanic CCM-carrying families have displayed evidence of linkage to the CCM1 locus. Among these 13 families, the authors identified eight independent mutations in nine kindreds. They identified four additional mutations among 22 familial CCM kindreds with no linkage information, bringing the total number of independent mutations to 12. Inherited KRIT1 mutations were not detected among 103 non-Hispanic persons in whom a family history of CCM was rigorously excluded. CONCLUSIONS: All mutations were nonsense mutations, frame-shift mutations predicting premature termination, or splice-site mutations located throughout the KRIT1 gene, suggesting that these are genetic loss-of-function mutations. These genetic findings, in conjunction with the clinical phenotype, are consistent with a two-hit model for the occurrence of CCM.