Biomedical subjects

Daniel H Lowenstein

Publications and source records attributed to Daniel H Lowenstein.

12 recordsLinked to original sources

PubMed2005

Treatment options for status epilepticus.

Status epilepticus is a neurological emergency requiring prompt pharmacological intervention. Recent advances in the treatment of this condition include the introduction of treatment algorithms that are tailored more specifically to clinical situations, a trend towards more aggressive therapies if initial treatment with front-line agents fail, and a better understanding of the role of treatment for patients in status epilepticus in the out-of-hospital setting.

Adult↗

PubMed2004

Laminar organization of the mouse dentate gyrus: insights from BETA2/Neuro D mutant mice.

The dentate gyrus of rodents is characterized by a highly laminar organization: above a compact granule cell layer, commissural/associational (C/A) fibers terminate on proximal granule cell dendrites and entorhinal fibers terminate on distal granule cell dendrites in a nonoverlapping manner. To gain insights into mechanisms that underlie the formation of this laminar structure, we studied mice deficient for BETA2/NeuroD, a basic helix-loop-helix transcription factor essential for granule cell differentiation. Anterograde tracing was used to label C/A and entorhinal fibers and combined with confocal double immunofluorescence for calbindin, calretinin, parvalbumin, and reelin to visualize putative target cells. The dentate gyrus of mutant mice contained only few granule cells, which formed a cap-like structure adjacent to area CA3. Despite the severe hypoplasia of the dentate gyrus, the remaining BETA2/NeuroD-deficient granule cells expressed mature markers, extended dendrites into the molecular layer, and extended mossy fibers into area CA3. Entorhinal and C/A fibers terminated in a nonoverlapping manner in the dendritic field overlying the rudiment. Entorhinal fibers terminated in the outermost portion of the dentate gyrus where they surrounded reelin-positive Cajal-Retzius cells, and C/A fibers terminated above and within the dentate rudiment. The laminar termination of C/A fibers was closest to normal in zones of the rudiment in which granule cells were densely packed. These data indicate that granule cells are able to differentiate in the absence of BETA2/NeuroD and suggest that the signals underlying the laminar anatomy of the dentate gyrus are present in the absence of most target cells.

Animals↗

PubMed2004

Gene expression profiling of seizure disorders.

Seizure disorders affect a significant percentage of the population, and researchers worldwide continue to work toward a better understanding of what initiates, propagates, and results from aberrant and excessive neuronal excitation. During the past two decades, one aspect of this research effort has been to describe the effects of seizure activity upon neuronal gene expression, with hopes of identifying the molecular mechanisms that underlie subsequent changes in cell function and survival. Here we review this body of work from the perspective of how these gene profiling efforts have evolved, starting with one-by-one analyses of specific gene targets to the more recent use of DNA microarrays to survey literally thousands of genes simultaneously. With regard to the latter, we present some of our own work that suggests that molecular mechanisms contributing to normal brain development are reiterated during seizure-induced network reorganization.

Animals↗

PubMed2004

A web-based federated neuroinformatics model for surgical planning and clinical research applications in epilepsy.

There is an increasing need to efficiently share diverse clinical and image data among different clinics, labs, and departments of a medical center enterprise to facilitate better quality care and more effective clinical research. In this paper, we describe a web-based, federated information model as a viable technical solution with applications in medical refractory epilepsy and other neurological disorders. We describe four such online applications developed in a federated system prototype: surgical planning, image analysis, statistical data analysis, and dynamic extraction, transforming, and loading (ETL) of data from a heterogeneous collection of data sources into an epilepsy multimedia data warehouse (EMDW). The federated information system adopts a three-tiered architecture, consisting of a user-interface layer, an application logic layer, and a data service layer. We implemented two complementary federated information technologies, i.e., XML (eXtensible Markup Language) and CORBA (Common Object Request Broker Architecture), in the prototype to enable multimedia data exchange and brain images transmission. The preliminary results show that the federated prototype system provides a uniform interface, heterogeneous information integration and efficient data sharing for users in our institution who are concerned with the care of patients with epilepsy and who pursue research in this area.

Animals↗

PubMed2003

Epilepsy.

Explore the source record for details and available documents.

Cerebral Cortex↗

PubMed2003

Overlapping microarray profiles of dentate gyrus gene expression during development- and epilepsy-associated neurogenesis and axon outgrowth.

Neurogenesis and axon outgrowth are features shared by normal nervous system development and certain forms of epileptogenesis. This observation has led to the hypothesis that some aspects of normal development and epileptogenesis have common molecular mechanisms. To test this hypothesis, we have used DNA microarray analysis to characterize gene expression in the dentate gyrus and identify genes exhibiting similar patterns of regulation during development and epileptogenesis. Of more than 8000 sequences surveyed, over 600 were regulated during development or epileptogenesis, and 37 of these were either upregulated or downregulated during both processes. In situ hybridization analysis of a subset of these "commonality genes" confirmed the patterns of regulation predicted by the microarray data in most cases and demonstrated various spatial and temporal patterns of commonality gene expression. Of the 25 named commonality genes in which some functional characteristics are known, 11 have been implicated in cell morphology and axon outgrowth or cellular proliferation and fate determination. This enrichment for candidate plasticity-related genes supports the concept that developmental mechanisms contribute to network alterations associated with epileptogenesis and offers a useful strategy for identifying molecules that may play a role in both of these processes.

Analysis of Variance↗

PubMed2003

Practice parameter: antiepileptic drug prophylaxis in severe traumatic brain injury: report of the Quality Standards Subcommittee of the American Academy of Neurology.

OBJECTIVE: To review the evidence regarding antiepileptic drug (AED) prophylaxis in patients with severe traumatic brain injury (TBI) in order to make practice recommendations. METHODS: The authors identified relevant studies by searching multiple databases and reviewing reference lists of other sources. They included studies that prospectively compared post-traumatic seizure rates in patients given AED prophylaxis vs controls. Each study was graded (class I to IV) according to a standard classification-of-evidence scheme and results were analyzed and pooled. RESULTS: Pooled class I studies demonstrated a significantly lower risk of early post-traumatic seizures (those occurring within 7 days after injury) in patients given phenytoin prophylaxis compared to controls (relative risk 0.37, 95% CI 0.18 to 0.74). Pooled class I and class II studies demonstrated no significant difference in the risk of late post-traumatic seizures (those occurring beyond 7 days after injury) in patients given AED prophylaxis compared to controls (relative risk 1.05, 95% CI 0.82 to 1.35). Serum AED levels were suboptimal in these studies and adverse effects were mild but frequent. CONCLUSIONS: For adult patients with severe TBI, prophylaxis with phenytoin is effective in decreasing the risk of early post-traumatic seizures. AED prophylaxis is probably not effective in decreasing the risk of late post-traumatic seizures. Further studies addressing milder forms of TBI, the use of newer AEDs, the utility of EEG, and the applicability of these findings to children are recommended.

Acute Disease↗

PubMed2003

Treatment options for status epilepticus.

Ambulatory Care↗

PubMed2003

The Academy at Harvard Medical School: nurturing teaching and stimulating innovation.

The Academy at Harvard Medical School, established in 2001, was formed at a critical moment for medical schools in this country. Several decades of enormous growth in the biomedical research and clinical care activities of medical school faculty have resulted in great societal benefit. The unintended consequence has been a decline in faculty time and reward for the educational mission that is unique to a medical school. The impact of this decline is particularly felt now because the explosive growth in the science and technology relevant to medical practice, coupled with dramatic changes in the health care delivery system, calls for new models for the education of the next generation of physicians. The mission of the academy is to renew and reinvigorate the educational mission of Harvard Medical School (HMS). By bringing together a select group of some of the school's most talented and dedicated faculty and providing direct support for their work related to education, the academy has created a unique mechanism for increasing the recognition of teaching contributions of both academy members and the teaching faculty at large, fostering educational innovation, and providing a forum for the exchange of ideas related to medical education that cross departmental and institutional lines. The authors describe the academy's membership criteria, structure, governance, activities, institutional impact, and plans for long-term evaluation, and indicate challenges the academy will face in the future.

Curriculum↗

PubMed2002

Prolonged seizures increase proliferating neuroblasts in the adult rat subventricular zone-olfactory bulb pathway.

Neuronal precursors in the adult rodent forebrain subventricular zone (SVZ) proliferate, migrate to the olfactory bulb in a restricted pathway known as the rostral migratory stream (RMS), and differentiate into neurons. The effects of injury on this neurogenic region of the mature brain are poorly understood. To determine whether seizure-induced injury modulates SVZ neurogenesis, we induced status epilepticus (SE) in adult rats by systemic chemoconvulsant administration and examined patterns of neuronal precursor proliferation and migration in the SVZ-olfactory bulb pathway. Within 1-2 weeks after pilocarpine-induced SE, bromodeoxyuridine (BrdU) labeling and Nissl staining increased in the rostral forebrain SVZ. These changes were associated with an increase in cells expressing antigenic markers of SVZ neuroblasts 2-3 weeks after prolonged seizures. At these same time points the RMS expanded and contained more proliferating cells and immature neurons. BrdU labeling and stereotactic injections of retroviral reporters into the SVZ showed that prolonged seizures also increased neuroblast migration to the olfactory bulb and induced a portion of the neuronal precursors to exit the RMS prematurely. These findings indicate that SE expands the SVZ neuroblast population and alters neuronal precursor migration in the adult rat forebrain. Identification of the mechanisms underlying the response of neural progenitors to seizure-induced injury may help to advance brain regenerative therapies by using either transplanted or endogenous neural precursor cells.

Animals↗

PubMed2002

Seizure-induced neurogenesis: are more new neurons good for an adult brain?

The idea that neural stem cells may play a role in the pathophysiology or potential treatment of specific epilepsy syndromes is relatively new. This notion relates directly to advances in the field of stem cell biology over the past decade, which have confirmed prior theories that both neural stem cells and neurogenesis, the birth of new neurons, persist in specific regions of the adult mammalian brain. The physiological role of persistent neurogenesis is not known, although recent work implicates this process in specific learning and memory tasks. Knowledge of the normal neurogenic pathways in the mature brain has led to recent studies of neurogenesis in rodent models of acute seizures or epileptogenesis. Most of these studies have examined neurogenesis in the adult rodent dentate gyrus, and current evidence indicates that single brief or prolonged seizures, as well as repeated kindled seizures, increase dentate granule cell (DGC) neurogenesis. The models studied to date include pilocarpine and kainic acid models of temporal lobe epilepsy, limbic kindling, and intermittent perforant path stimulation. Recent work also suggests that pilocarpine-induced status epilepticus increases rostral forebrain subventricular zone (SVZ) neurogenesis and caudal SVZ gliogenesis. Several lines of evidence implicate newly generated neurons in structural and functional network abnormalities in the epileptic hippocampal formation of adult rodents. These abnormalities include aberrant mossy fiber reorganization, persistence of immature DGC structure (e.g. basal dendrites), and the abnormal migration of newborn neurons to ectopic sites in the dentate gyrus. Taken together, these findings suggest a pro-epileptogenic role of seizure- or injury-induced neurogenesis in the epileptic hippocampal formation. However, the induction of forebrain SVZ neurogenesis and directed migration to injury after seizures and other brain insults underscores the potential therapeutic use of neural stem cells as a source for neuronal replacement after injury.

Animals↗

PubMed2002

Models for epilepsy and epileptogenesis: report from the NIH workshop, Bethesda, Maryland.

PURPOSE: The workshop explored the current problems, needs, and potential usefulness of existing methods of discovery of new therapies to treat epilepsy patients. Resistance to medical therapy (pharmacoresistance) and the development of epilepsy (epileptogenesis) are recognized as two of the major problems in epilepsy treatment today. At the same time, there is growing awareness that the development of new therapies has slowed, a trend that has economic and scientific roots. To move toward new and more effective therapies, novel approaches to therapy discovery are needed. METHODS: A workshop was held in March 2001 with the charge to develop a plan to move the exploration and discovery process forward. Participants from academia, government, and industry reviewed the current status of epilepsy therapy and explored the identification of potential new therapies. RESULTS: At the end of the 2-day meeting, the panel made a series of recommendations. The two major recommendations were (a) to establish a means for continuing the examination of new approaches to therapy discovery, and (b) to identify models and approaches to therapy discovery that may identify treatments that are more successful than those available. Further recommendations were made to support the development of technology (miniaturization, computerization, video monitoring, etc.) to facilitate the use of the new models and to identify the mechanisms of therapy success and failure. CONCLUSIONS: Understanding the epidemiology of therapy resistance and providing support for new approaches to therapy development were identified as key issues for introduction of new and more effective treatments.

Animals↗