Robust spinal motor neuron transduction following intrathecal delivery of AAV9 in pigs.

Adeno-associated viral vector 9 (AAV9) has recently been shown to penetrate the blood-brain barrier via intravascular administration, making it a good candidate for diffuse gene delivery. However, the potential side effects of systemic delivery are unknown. Intrathecal viral vector administration may be more invasive than intravenous injections, but it requires far less vector and it can be performed on an outpatient basis, making it an ideal route of delivery for clinical translation. A total of 12 domestic farm pigs (<20 kg) underwent a single-level lumbar laminectomy with intrathecal catheter placement for AAV9 delivery. Animals were perfused and the tissue was harvested 30 days after treatment. Gene expression was assessed by anti-green fluorescent protein immunohistochemistry. Although a single lumbar injection resulted in gene expression limited to the lumbar segment of the spinal cord, three consecutive boluses via a temporary catheter resulted in diffuse transduction of motor neurons (MNs) throughout the cervical, thoracic and lumbar spinal cords. We now present the first successful robust transduction of MNs in the spinal cord of a large animal via intrathecal gene delivery using a self-complementary AAV9. These promising results can be translated to many MN diseases requiring diffuse gene delivery.

Ipsilateral motor dysfunction from unilateral stroke: implications for the functional neuroanatomy of hemiparesis.

BACKGROUND: Motor dysfunction in the contralateral hand has been well characterised after stroke. The ipsilateral hand has received less attention, yet may provide valuable insights into the structure of the motor system and the nature of the recovery process. By tracking motor function of both hands beginning in the acute stroke period in patients with cortical versus subcortical lesions, we sought to understand the functional anatomy of the ipsilateral deficit. METHODS: We examined 30 patients with first-ever unilateral hemiparetic stroke, 23 with subcortical lesions affecting the corticospinal tract, seven with cortical involvement. Patients performed hand dynamometry and the 9-Hole Peg Test (9HPT) with each hand at 24-48 h, 1 week, 3 months and 1 year after stroke. Linear regression was used to compare the two different motor tasks in each hand. Repeated measures ANOVA was used to compare recovery rates of the two tasks in the first 3 months. RESULTS: Ipsilateral 9HPT scores averaged z = -7.1, -3.6, -2.5 and -2.3 at the four time points whereas grip strength was unaffected. The initial degree of impairment of grip strength in the contralateral hand did not correlate with the degree of impairment of 9HPT in either the contralateral or ipsilateral hand (r = 0.001, p = 0.98), whereas the initial degree of impairment of 9HPT in the contralateral hand correlated with the degree of impairment of 9HPT in the ipsilateral hand (r = 0.79, p = 0.035). The rate of recovery also differed for the two tasks (p = 0.005). CONCLUSION: Ipsilateral motor deficits are demonstrable immediately after stroke and extend into the subacute and chronic recovery period. Dissociation between grip strength and dexterity support the notion that dexterity and grip strength operate as anatomically and functionally distinct entities. Our findings in patients with subcortical lesions suggest that the model of white matter tract injury needs to be refined to reflect the influence of a subcortical lesion on bi-hemispheral cortical networks, rather than as a simple "severed cable" model of disruption of corticofugal fibres. Our data have implications for both stroke clinical trials and the development of new strategies for therapeutic intervention in stroke recovery.

Antioxidants attenuate multiple phases of formalin-induced nociceptive response in mice.

An emerging theme in the study of the pathophysiology of chronic and persistent pain is the role of pro-oxidant substances. Reactive oxygen species (ROS) have been implicated in contributing to and/or maintaining conditions of chronic pain. Recent pre-clinical reports suggest that antioxidants are effective analgesics in neuropathic and inflammatory pain models. The present study extends this work by examining the effect of three antioxidants on tissue injury-induced nociception. C57BL6 mice (20-25 g) were pretreated with either phenyl-N-tert-butylnitrone (PBN; 50 mg/kg, i.p.), 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxy (TEMPOL; 200 or 50 mg/kg, i.p.), N-acetyl-L-cysteine (NAC; 200 or 100mg/kg, i.p.), or vehicle (0.5 ml/100 g), 5 min before intraplantar formalin (10%, 20 microl) injection. Nociceptive responding, indicated by licking or biting the affected hindlimb, was quantified for 30 min after formalin injection. Each drug was effective in attenuating two or more phases (acute, quiescent, and tonic) of the formalin response. To assess putative site of action, intrathecal TEMPOL (380 nmol/5 microl, i.t.) was given 5 min before intraplantar formalin. Intrathecal TEMPOL produced a 83% reduction in nociceptive responding in the tonic phase, but no significant attenuation of the acute phase response. To confirm that the antioxidant property of intrathecal TEMPOL was responsible for its analgesic effect on the formalin-induced pain response, intrathecal TEMPOL was coadministered with the free radical donor tert-butylhydroperoxide (tert-BuOOH). Tert-BuOOH coadminstration reversed the TEMPOL-induced analgesia in the tonic intraplantar formalin response reduction. The data suggest that pro-oxidant species may be important mediators of tissue injury-induced algesia in rodents, and that a spinal site of action is implicated in the tonic response.

On the uniqueness of the surface sources of evoked potentials.

The uniqueness of a surface density of sources localized inside a spatial region R and producing a given electric potential distribution in its boundary B0 is revisited. The situation in which R is filled with various subregions, each one having a definite constant value for the electric conductivity is considered. It is argued that the knowledge of the potential in all B0 fully determines the surface-located sources for a general class of surfaces supporting them and also a wide type of those sources. The class of surfaces can be defined as a union of an arbitrary but finite number of open or closed surfaces. The only restriction upon them is that no one of the closed surfaces contains inside it another (nesting) of the closed or open ones. The types of sources are surface charge densities and double layer (dipolar) densities for the open surfaces and more restrictively, only surface charge densities for the closed ones. A two-dimensional analytically solvable example illustrating the drastic appearance of uniqueness after arbitrarily small holes are opened in nested surfaces is discussed.

Tocqueville revisited. The meaning of American prosperity.

Why is business so admired in the United States and so often denigrated in Europe? How has America created 30 million new jobs in the last 20 years while the European Union, with a bigger population, only managed 5 million? What is feeding America's apparently inexhaustible appetite for growth and its recent dramatic improvements in productivity? In 1831, French philosopher Alexis de Tocqueville came to America to examine its prison system and returned with a vision of democracy so profound it has become part of our cultural heritage. More than a century and a half later, renowned British business philosopher Charles Handy retraces Tocqueville's intellectual journey, this time focusing not on democracy but on capitalism. The result is an eye-opening look at some of the fundamental assumptions underpinning business in America today. It is America's optimism that Handy finds most striking, the unquestioned belief that tomorrow can--and should--be made better than today. He contrasts this with the Spaniards when they came to the New World: No haya novedades, those Spaniards would say, "Let nothing new arise." The energy engendered by American optimism, coupled with the Puritan belief in work and in the nobility of earned wealth (as opposed to Europe's furtive attitude toward its nobility's inherited wealth) lies, in Handy's view, at the heart of America's success. Will American capitalism, born as it was from a property-owning democracy, now adapt to a dematerialized world, where property is intellectual rather than physical? Handy draws no absolute conclusions, but rather lays out the challenges that must be overcome for tomorrow to indeed continue to be better than today in this still-young country.

Through the organizational looking glass: you can't plan tomorrow's organizations with today's assumptions.

It's hard to imagine what our industrial society would be like if, for instance, there were no factories. How would things get produced, how would business survive? But are we, in fact, an industrial society? Are factories going to be the prime production place for a society that is conserving energy and doesn't need to travel to work because the silicon chip makes it more efficient to work at home? Who knows what the impact of energy conservation and women in the work force will be on future organizations? One thing we can be sure of, this author writes, is that whatever tomorrow brings, today's assumptions probably cannot account for it. We are, he asserts, entering a period of discontinuous change where the assumptions we have been working with as a society and in organizations are no longer necessarily true. He discusses three assumptions he sees fading--what causes efficiency, what work is, and what value organizational hierarchy has--and then gives some clues as to what our new assumptions might be. Regardless of what our assumptions actually are, however, our organizations and society will require leaders willing to take enormous risks and try unproved ways to cope with them.

Balancing corporate power: a new Federalist paper.

In an effort to govern their increasingly complex organizations, chief executives in some of today's largest corporations are turning to one of the world's oldest political philosophies-federalism. Given that organizations are seen more and more as minisocieties, the prospect of applying political principles to management makes a great deal of sense. Federalism is particularly appropriate because it offers a well-recognized system for dealing with paradoxes of power and control: the need to make things big by keeping them small; to encourage autonomy but within bounds; and to combine variety and shared purpose, individuality and partnership, local and global. As London Business School professor Charles Handy explains it, federalism responds to these paradoxes by balancing power among those in the center of the organization, those in the centers of expertise, and those in the center of the action--the operating businesses. The centers of federal organizations meet regularly, but they do not need to live together. Doing so would concentrate too much power in one place, whereas federalism gets its strength and energy from spreading responsibility across many decision points. Guided by five principles, federalism avoids the risks of autocracy and the overcontrol of a central bureaucracy. It ensures a measure of democracy and creates a "dispersed center" that is more a network than a place. That's why Asea Brown Boveri CEO Percy Barnevik calls his sprawling "multi-domestic" enterprise of 1,100 separate companies and 210,000 employees a federation. It succeeds because the independent bits, be they individuals, clusters, or business units, know they are part of the greater whole.

Looking ahead: implications of the present.

On its seventy-fifth anniversary, HBR asked five of the business world's most insightful thinkers to comment on the challenges taking shape for executives as they move into the next century. In "The Future That Has Already Happened," Peter Drucker examines the effects of the increasing underpopulation of the world's developed countries. With growing imbalances in labor resources worldwide, he writes, executives in the developed countries will need to improve the productivity of knowledge and of knowledge workers to maintain a competitive advantage. Esther Dyson's article "Mirror, Mirror on the Wall" reveals the mind shift executives will need to make in a networked world, where companies will be known for what they do rather than for what they say. Executives will have to respond openly and intelligently to feedback about their organizations. The old language of property and ownership no longer serves executives, writes Charles Handy in "The Citizen Corporation." The corporation should be thought of no longer as property but as a community, where members are regarded as citizens. Technology has given executives more information than today's machines can help them understand, explains Paul Saffo in "Are You Machine Wise?" Machine-wise executives will know when to turn their computers off and take their own counsel, he writes. Peter Senge's article "Communities of Leaders and Learners" urges executives to reject the myth of leaders as isolated heroes and instead to build a community of leaders. Sustained institutional learning, he writes, requires organizations to reintegrate their typically fragmented learning processes.

Home care of patients with technically complex nursing needs. High-technology home care.

Patients with technically complex nursing needs are being discharged home from the hospital. Home care agencies striving to meet those needs have clinical, administrative, and educational concerns. Careful planning is the key to meeting these concerns.

Cellulitis--an unreported complication of long-term SCI patients.

Major problems for spinal cord injured patients are pressure ulcers, urinary tract infections, and pain management. However, an unreported complication is cellulitis. A retrospective chart review for the calendar year 1993 revealed 312 cases of cellulitis identified as either a primary or secondary diagnosis. Cellulitis was identified more than once for some of the patients in this sample. A review of the literature showed limited citations specific to the spinal cord injured population. This paper analyzes the reported cases for the period of January 1, 1993 through December 31, 1993. The cellulitis diagnosis is examined with the following variables: frequency of occurrence, skin integrity impairment, presence of infection, septicemia, thrombophlebitis, length of hospitalization, rate of recurrence, and area of contact. This data suggest that cellulitis is an important complication to the spinal cord injured patient. However, additional research is needed to provide predictive value. This analysis provides information to SCI nurses to enhance knowledge and understanding of risk factors and develop patient teaching methods for management and prevention.

The new equation.

What the formula doesn't say is what happens to the other half of all workers, the half no longer needed. Nor does it make clear that as well as being paid twice as much, the favored half will also have to work twice as hard. Hence the paradox that half of the people have money but no time, and the other half have time but no money.

Patient-centered high-technology home care.

High-technology home care is a reality in today's health care system. Nurses, as health professionals, will be involved in high-technology home care for many patients, regardless of age or diagnosis. The nurse's involvement may be in the predischarge setting or in the home actually providing care. High-technology home care cannot and should not merely be care of the technology (the "machines and tubes") at home; rather, it should emphasize the care of the patients and families who are receiving technically complex therapies. To provide care for the patient and entire family, all nurses involved with the patient need to be aware of where the patient and family are developmentally, the structure of family relationships, the expectations with regard to home therapy, and the ability of the patient and family to physically or emotionally manage the therapy. Incorporating this information into a care plan for patient and family teaching can enable the nurse to provide care to the patient and family that surpasses that of merely seeing that the high-technology procedure is done safely and correctly.

A protocol for foscarnet administration.

Recently the Food and Drug Administration approved the drug foscarnet for treatment of cytomegalovirus retinitis. As with many other medications, foscarnet has some serious side effects and needs to be administered according to a standardized protocol. This article presents a protocol that was developed for the safe and appropriate delivery of foscarnet.

A protocol for intravenous pentamidine administration.

Pentamidine isethionate has been approved by the Food and Drug Administration as a treatment for Pneumocystis carinii pneumonia, the most common opportunistic infection associated with acquired immunodeficiency syndrome. This article outlines the protocol for intravenous administration of pentamidine isethionate in use at The Mount Sinai Medical Center in New York.