Loss of p300 accelerates MDS-associated leukemogenesis.

The role that changes in DNA methylation and histone modifications have in human malignancies is poorly understood. p300 and CREB-binding protein (CBP), two distinct but highly homologous lysine acetyltransferases, are mutated in several cancers, suggesting their role as tumor suppressors. In the current study, we found that deletion of p300, but not CBP, markedly accelerated the leukemogenesis ofNup98-HoxD13 (NHD13) transgenic mice, an animal model that phenotypically copies human myelodysplastic syndrome (MDS). p300 deletion restored the ability of NHD13 expressing hematopoietic stem and progenitor cells (HSPCs) to self-renew in vitro, and to expand in vivo, with an increase in stem cell symmetric self-renewal divisions and a decrease in apoptosis. Furthermore, loss of p300, but not CBP, promoted cytokine signaling, including enhanced activation of the MAPK and JAK/STAT pathways in the HSPC compartment. Altogether, our data indicate that p300 has a pivotal role in blocking the transformation of MDS to acute myeloid leukemia, a role distinct from that of CBP.

Chromatin modifiers and the promise of epigenetic therapy in acute leukemia.

Hematopoiesis is a tightly regulated process involving the control of gene expression that directs the transition from hematopoietic stem and progenitor cells to terminally differentiated blood cells. In leukemia, the processes directing self-renewal, differentiation and progenitor cell expansion are disrupted, leading to the accumulation of immature, non-functioning malignant cells. Insights into these processes have come in stages, based on technological advances in genetic analyses, bioinformatics and biological sciences. The first cytogenetic studies of leukemic cells identified chromosomal translocations that generate oncogenic fusion proteins and most commonly affect regulators of transcription. This was followed by the discovery of recurrent somatic mutations in genes encoding regulators of the signal transduction pathways that control cell proliferation and survival. Recently, studies of global changes in methylation and gene expression have led to the understanding that the output of transcriptional regulators and the proliferative signaling pathways are ultimately influenced by chromatin structure. Candidate gene, whole-genome and whole-exome sequencing studies have identified recurrent somatic mutations in genes encoding epigenetic modifiers in both acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL). In contrast to the two-hit model of leukemogenesis, emerging evidence suggests that these epigenetic modifiers represent a class of mutations that are critical to the development of leukemia and affect the regulation of various other oncogenic pathways. In this review, we discuss the range of recurrent, somatic mutations in epigenetic modifiers found in leukemia and how these modifiers relate to the classical leukemogenic pathways that lead to impaired cell differentiation and aberrant self-renewal and proliferation.

John Hughlings Jackson and the conceptual foundations of the neurosciences.

Cerebral localization, including hierarchical organization of the nervous system, was the critical conceptual advance that made possible the development of modern neuroscience in the nineteenth century. Some of our most basic ideas about neural organization were contributed by Hughlings Jackson. In the early twentieth century, Charles Sherrington combined localization with the neurone theory to create the paradigm of neurophysiological integration. Because Sherrington was educated in the Jacksonian tradition of British neurology, Sherringtonian integration contains ideas that are derived from Jackson and from Herbert Spencer.

The crucial decade: modern neurosurgery's definitive development in Harvey Cushing's early research and practice, 1900 to 1910.

When Harvey Cushing announced his full-time commitment to neurological surgery in 1904, it was a discouraging and discouraged enterprise. Other surgeons' mortality rates for patients with brain tumors were 30 to 50%. By 1910 Cushing had operated on 180 tumors; he had a thriving practice, with a patient mortality rate of less than 13%. The three essential ingredients of his success were: 1) a new surgical conceptualization of intracranial pressure (ICP); 2) technical innovations for controlling ICP; and 3) establishment of a large referral base. In the years 1901 through 1905, the implications of his research on the "Cushing reflex" were quickly translated into surgical techniques for controlling ICP. In the period between 1906 and 1910, Cushing built up his referral practice by publishing widely, and especially by lecturing to medical audiences throughout the United States and Canada. His scientific work on ICP was essential to his clinical success, but without his professional and social ability to build a thriving practice, there would have been insufficient material for him to use to improve his approaches.

Incidence of seizures after surgery for supratentorial meningiomas: a modern analysis.

The authors have assessed the incidence of postoperative seizures in 158 patients with supratentorial meningiomas diagnosed by computerized tomography (CT) and/or magnetic resonance (MR) imaging, which theoretically should lead to early diagnosis and treatment and the potential for improved seizure outcome. Univariate chi-square and logistic regression analyses were performed 24 independent variables against the outcome variable of occurrence of a postoperative seizure. The median duration of preoperative seizures was 1 month, considerably shorter than that found in studies conducted prior to the advent of CT and MR imaging. Of 63 patients with a history of preoperative seizures, 40 (63.5%) had complete cessation of seizures after surgery. Twelve (92.3%) of 13 patients with one to three postoperative seizures eventually achieved complete seizure control, whereas only four (40%) of 10 patients with more than three postoperative seizures achieved this result. Overall 88.9% of patients with preoperative seizures achieved complete seizure control postoperatively. Multivariate analysis was used to identify six variables that were predictive of the occurrence of postoperative seizures: preoperative seizure history preoperative language disturbance, extent of tumor removal, parietal location of tumor, postoperative anticonvulsant medication status, and postoperative hydrocephalus. These variables were incorporated into a diagnostic model designed to predict the risk of a postoperative seizure following meningioma surgery. On the basis of their findings, the authors conclude that earlier detection and treatment of supratentorial meningiomas improve seizure outcome in patients with preoperative epilepsy. Furthermore an assessment of the risk of postoperative seizures may help guide decisions concerning weaning patients from anticonvulsant medications postoperatively.

Phrenology in the science and culture of the 19th century.

In the last decade of the 18th century, Franz Joseph Gall of Vienna invented a combination of physiognomy and brain localization that he originally called "craniology" (the science of the head) and later called "organology" (the science of the organs of the brain). Between 1800 and 1812, he worked with Johann Christoph Spurzheim on a variety of important neuroanatomic studies to support this new science. By 1812, when they parted company in Paris, Spurzheim had become intrigued with the psychosocial potential of the undertaking, which he renamed "phrenology" (the science of the mind). Because a phrenological examination (palpation of skull prominences) could provide an analysis of a person's strengths and weaknesses, Spurzheim thought that his system could lead to personal improvement for everyone, including the laboring classes. He was thus a 19th century reformer, generally on the liberal side of the political and social spectrum. Spurzheim spread his gospel to Britain through several long lecture tours, and phrenology became briefly popular through the efforts of other British reformers, especially George Combe. In 1832, Spurzheim came to the United States. Three months later, he died in Boston, a martyr to his cause. Phrenology then spread widely into American popular culture, encouraged by the entrepreneurial efforts of "the phrenological Fowlers" and others like them. By 1843, the entire Western scientific community rejected organology and phrenology. All forms of cerebral localization were lumped with phrenology and similarly repudiated. Nonetheless, Gall's organology was the first comprehensive, premodern statement of a theory of cerebral localization. The early pioneers of modern localization, especially Paul Broca and David Ferrier, were careful to define how their theories differed from phrenology, even as they provided the clinical and scientific data that confirmed some of its basic tenets.

Internal carotid artery thrombosis after cervical corpectomy.

SUMMARY OF BACKGROUND DATA: A 74-year-old man suffered an extensive right hemispheric infarct 72 hours after undergoing anterior corpectomies of the C4 and C5 vertebrae for cervical myelopathy resulting from ossification of the posterior longitudinal ligament. RESULTS: Angiography revealed proximal right internal carotid artery thrombosis with atherosclerosis and a normal left internal carotid artery. The thrombosis may have been due to stasis during lengthy retraction of an atherosclerotic carotid artery. CONCLUSIONS: Preoperative screening of internal carotid artery blood flow with Doppler ultrasonography is recommended before contemplating extensive anterior cervical surgery in middle-aged and elderly patients at significant risk for atherosclerotic disease.

Housing emergencies and the etiology of homelessness among the urban elderly.

This research examined factors that lead to homelessness and shelter placement of seniors. A purposive sample of 475 aged clients was selected randomly from the files of a citywide emergency service program, 45% of whom were found to have had serious housing-related problems. A subsample of 115 housing problem cases was investigated, including persons who had needed emergency shelter or temporary housing or been living in deteriorated housing. Assessment data from the OARS instrument and open-ended housing history questions were analyzed. Homelessness was found to be significantly associated with low income, dementia, living alone, and an unstable residential history.

The image of the "brain surgeon" in American culture: the influence of Harvey Cushing.

In contemporary American culture, the term "brain surgeon" conjures up the image of an intensely single-minded professional, who deals with terribly complex matters of life and death. These descriptors find their personification in Harvey Cushing, because they are derived directly from him. This hypothesis was tested by a complete search of the New York Times Index and the Reader's Guide to Periodical Literature for the years 1919 to 1942. All entries for Harvey Cushing were reviewed in the original sources. In the New York Times, Cushing's first significant exposure was in response to his winning a Pulitzer Prize in 1925. Major editorial coverage began in 1934, and was especially prominent with the publication of From a Surgeon's Journal in 1936. The process of lionizing Cushing by creating an overdrawn caricature reached its apotheosis in Time magazine in 1939. The Time article was actually a report of Cushing's 70th birthday party. It expounded all of the descriptors that are now associated with "brain surgeon". Thus, it was Cushing's literary skills that initially brought him recognition from editors who were arbiters of public opinion. This attention seems to have been the conduit to his mythologization by the larger public. Although unnamed, it is really Cushing's image that still persists as the prototypical "brain surgeon" in the collective American consciousness.

Clinical clerkships in neurosurgery and neurology at United States medical schools.

The neurology and neurosurgery clinical clerkship experience (excluding lectures and conferences) of the students in U.S. allopathic medical schools during one of the academic years 1986 to 1987 or 1987 to 1988 was surveyed. Almost all schools have at least some students taking these clerkships. The majority of students (78%) have clinical exposure to neurology, but only a minority (28%) take a neurosurgical clerkship; however, far more schools require their students to take neurology clerkships (54%) than neurosurgical clerkships (12%). A few require that either be taken. Overall, 81% of schools require all students to take at least one of these clerkships. For the most part, students taking a clerkship in either specialty do not do so again. The initial and usually unique exposure averages 3.5 weeks in neurology and 2.4 weeks in neurosurgery. For each specialty, required clerkships tended to be shorter than selective clerkships, which in turn were shorter than elective ones. Furthermore, first clerkships offered in the fourth year, whether they were required, selective, or elective, tended to be longer than the corresponding third-year first clerkships at other schools. Whereas the average length of a first clinical clerkship in neurology is almost as long for schools requiring it (3.4 wk) as for those that offer it as an elective or selective (4.0 wk), required neurosurgical clerkships are much shorter (1.5 wk) than elective or selective rotations (3.1 wk). Schools with residency training programs more frequently required students to a clerkship and, consequently, had greater numbers of students taking a clerkship in the corresponding specialty.(ABSTRACT TRUNCATED AT 250 WORDS)

Left occipital lobectomy and the preangular anatomy of reading.

Two patients had alexias after left occipital lobectomies. Case 1 was a 55-year-old man with a glioblastoma. At 4 months after surgery he could read slowly, but reading was neither efficient nor pleasant. Case 2 was a 19-year-old male who had a more restricted, medial occipital lobectomy for an encapsulated mesenchymal chondrosarcoma. The tumor did not invade brain initially, and the patient recovered efficient reading after 15 months. It is postulated that Case 2 was able to recover efficient reading because he still had a field of left ventrolateral occipitotemporal cortex connected to homologous cortex on the right.

Training ophthalmology residents to treat patients with vision loss. Results of a demonstration program.

Ophthalmology residents attended a day-long training program designed to teach them about the rehabilitation needs of visually impaired and blind patients. A pretest measuring the participants' knowledge of rehabilitation services and their rehabilitation-oriented activities was administered before the training program and a posttest measuring the same items was administered 6 months after the program. Several of the rehabilitation-oriented measures that participants themselves take with visually impaired and blind patients increased substantially during the 6-month period as did their knowledge of rehabilitation services available in the community. The referrals made for these rehabilitation services and the participants' interactions with allied health professionals who serve visually impaired and blind patients increased only slightly. These findings suggest the need to institutionalize training for residents in the topic of rehabilitation and to allocate time within their schedules for making referrals and working cooperatively with allied health professionals.

Catabolic effect of dexamethasone in patients with major head injuries.

In the records of our extensive metabolic studies on trauma victims, we found 16 head injured patients who had no other major injuries. Among them, nine had been given dexamethasone for at least 6 days. The other seven had not received any corticosteroids. There was no significant difference in the Glasgow Coma Scales of the treated and untreated groups. Metabolic balance studies were carried out for at least 3 days, including the periods when the treated patients were receiving dexamethasone. Mean nitrogen balance was -0.296 +/- 0.03 g/kg/day for the treated group and -0.182 +/- 0.03 g/kg/day for the untreated group. This difference was significant (p = 0.02, t-test). Our metabolic data are also consistent with those of other published studies, which used other corticosteroids and somewhat different methodologies. Thus, it is clearly established that corticosteroids cause significant degrees of catabolism in head injured patients, beyond what would "normally" be expected in such patients if they did not receive these drugs.