Longitudinal Changes in Cerebral Perfusion, Perivascular Space Volume, and Ventricular Volume in a Healthy Cohort Undergoing a Spaceflight Analog.

BACKGROUND AND PURPOSE: A global decrease in brain perfusion has recently been reported during exposure to a ground-based spaceflight analog. Considering that CSF and glymphatic flow are hypothesized to be propelled by arterial pulsations, it is unknown whether a change in perfusion would impact these CSF compartments. The aim of the current study was to evaluate the relationship among changes in cerebral perfusion, ventricular volume, and perivascular space volume before, during, and after a spaceflight analog. MATERIALS AND METHODS: Eleven healthy participants underwent 30 days of bed rest at 6° head-down tilt with 0.5% atmospheric CO2 as a spaceflight analog. For each participant, 6 MR imaging brain scans, including perfusion and anatomic-weighted T1 sequences, were obtained before, during, and after the analog period. Global perfusion, ventricular volume, and perivascular space volume time courses were constructed and evaluated with repeated measures ANOVAs. RESULTS: Global perfusion followed a divergent time trajectory from ventricular and perivascular space volume, with perfusion decreasing during the analog, whereas ventricular and perivascular space volume increased (P < .001). These patterns subsequently reversed during the 2-week recovery period. CONCLUSIONS: The patterns of change in brain physiology observed in healthy participants suggest a relationship between cerebral perfusion and CSF homeostasis. Further study is warranted to determine whether a causal relationship exists and whether similar neurophysiologic responses occur during spaceflight.

Mutation in the Sodium Channel Gene Corresponds With Phenotypic Resistance of Rhipicephalus sanguineus sensu lato (Acari: Ixodidae) to Pyrethroids.

The brown dog tick, Rhipicephalus sanguineus sensu lato (Latreille), is a cosmopolitan ectoparasite and vector of pathogens that kill humans and animals. Pyrethroids represent a class of synthetic acaricides that have been used intensely to try to control the brown dog tick and mitigate the risk of tick-borne disease transmission. However, acaricide resistance is an emerging problem in the management of the brown dog tick. Understanding the mechanism of resistance to acaricides, including pyrethroids, is important to adapt brown dog tick control strategies. The main objective of this study was to determine if target-site mutations associated with pyrethroid resistance in other pests could be associated with phenotypic resistance detected in a brown dog tick population from Florida. We amplified segment 6 of the domain III of the voltage-sensitive sodium channel protein, using cDNAs synthesized from pyrethroid-susceptible and pyrethroid-resistant tick strains. A single nucleotide point mutation (SNP) identified in a highly conserved region of domain III S6 in the resistant ticks resulted in an amino acid change from phenylalanine to leucine. This mutation is characteristic of resistance phenotypes in other tick species, and is the first report of this mutation in R. sanguineus. Molecular assays based on this knowledge could be developed to diagnose the risk for pyrethroid resistance, and to inform decisions on integrated brown dog tick management practices.

Inventions and patents: a practical tutorial.

Patents are designed to protect and encourage creativity and innovation. Patenting a biomedical discovery can be a requirement before a pharmaceutical company or biotech entity will invest in the lengthy and costly clinical testing necessary to achieve patient benefit. Although scientists and clinicians are well versed in research publication requirements, patent descriptions and claims are formatted in a manner quite different from a research paper. Patents require (a) a series of logical statements clearly delineating the boundaries of the novel aspects of the invention and (b) sufficient disclosure of the invention so that it can be reproduced by others. Patents are granted only for inventions that meet three conditions: novelty, nonobviousness, and usefulness. This chapter provides basic guidelines and definitions of technology transfer: inventions, inventorship, and patent filing, which are summarized using a question and answer format.

Activity-based therapies to promote forelimb use after a cervical spinal cord injury.

Significant interest exists in strategies for improving forelimb function following spinal cord injury. We investigated the effect of enriched housing combined with skilled training on the recovery of skilled and automatic forelimb function after a cervical spinal cord injury in adult rats. All animals were pretrained in skilled reaching, gridwalk crossing, and overground locomotion. Some received a cervical over-hemisection lesion at C4-5, interrupting the right side of the spinal cord and dorsal columns bilaterally, and were housed in standard housing alone or enriched environments with daily training. A subset of animals received rolipram to promote neuronal plasticity. Animals were tested weekly for 4 weeks to measure reaching, errors on the gridwalk, locomotion, and vertical exploration. Biotinylated dextran amine was injected into the cortex to label the corticospinal tract. Enriched environments/daily training significantly increased the number and success of left reaches compared to standard housing. Animals also made fewer errors on the gridwalk, a measure of coordinated forelimb function. However, there were no significant improvements in forelimb use during vertical exploration or locomotion. Likewise, rolipram did not improve any of the behaviors tested. Both enriched housing and rolipram increased plasticity of the corticospinal tract rostral to the lesion. These studies indicate that skilled training after a cervical spinal cord injury improves recovery of skilled forelimb use (reaching) and coordinated limb function (gridwalk) but does not improve automatic forelimb function (locomotion and vertical exploration). These studies suggest that rehabilitating forelimb function after spinal cord injury will require separate strategies for descending and segmental pathways.

Extracellular heat shock protein 70: a critical component for motoneuron survival.

The dependence of developing spinal motoneuron survival on a soluble factor(s) from their target, muscle tissue is well established both in vivo and in vitro. Considering this apparent dependence, we examined whether a specific component of the stress response mediates motoneuron survival in trophic factor-deprived environments. We demonstrate that, although endogenous expression of heat shock protein 70 (HSP70) did not change during trophic factor deprivation, application of e-rhHsp70 (exogenous recombinant human Hsp70) promoted motoneuron survival. Conversely, depletion of HSP70 from chick muscle extract (MEx) potently reduces the survival-promoting activity of MEx. Additionally, exogenous treatment with or spinal cord overexpression of Hsp70 enhances motoneuron survival in vivo during the period of naturally occurring cell death [programmed cell death (PCD)]. Hindlimb muscle cells and lumbar spinal astrocytes readily secrete HSP70 in vitro, suggesting potential physiological sources of extracellular Hsp70 for motoneurons. However, in contrast to exogenous treatment with or overexpression of Hsp70 in vivo, muscle-targeted injections of this factor in an ex vivo preparation fail to attenuate motoneuron PCD. These data (1) suggest that motoneuron survival requirements may extend beyond classical trophic factors to include HSP70, (2) indicate that the source of this factor is instrumental in determining its trophic function, and (3) may therefore influence therapeutic strategies designed to increase motoneuron Hsp70 signaling during disease or injury.

Bypassing Bypass Surgery and Other Success Stories from the National Institutes of Health.

After a heart attack, patients often undergo a procedure to open up the clogged artery and install a tiny meshlike device called a stent to keep the artery propped open. In most cases, the body reacts to this foreign object with scar-tissue formation, and the artery narrows again. To combat this re-clogging process, National Institutes of Health inventors developed paclitaxel-coated stents and later licensed it to Angiotech. Approved by the Food and Drug Administration in March 2004, these stents are expected to substantially reduce the use of coronary artery bypass surgery, an expensive operation now performed annually on 350,000-plus Americans. This and three other examples of NIH licensing success stories are described in this paper: (a) Kepivance, which improves the quality of life for cancer patients by eliminating mouth sores, (b) AIDS drug ddI, an important component of many combination drug therapies, and (c) Vitravene, the first and only antisense drug to be approved by FDA. These four examples will illustrate the success not only of the NIH licensing program, but also the innovative approaches taken by NIH inventors and the persistence of its commercial partners. This paper also highlights the business and legal lessons learned from these four cases.

Administration of Hsp70 in vivo inhibits motor and sensory neuron degeneration.

The induction of heat shock proteins (Hsps) serves not only as a marker for cellular stress but also as a promoter of cell survival, which is especially important in the nervous system. We examined the regulation of the constitutive and stress-induced 70-kD Hsps (Hsc70 and Hsp70, respectively) after sciatic nerve (SN) axotomy in the neonatal mouse. Additionally, the prevention of axotomy-induced SN cell death by administration of several preparations of exogenous Hsc70 and Hsp70 was tested. Immunohistochemistry and Western blot analyses showed that endogenous levels of Hsc70 and Hsp70 did not increase significantly in lumbar motor neurons or dorsal root ganglion sensory neurons up to 24 hours after axotomy. When a variety of Hsc70 and Hsp70 preparations at doses ranging from 5 to 75 microg were applied to the SN stump after axotomy, the survival of both motor and sensory neurons was significantly improved. Thus, it appears that motor and sensory neurons in the neonatal mouse do not initiate a typical Hsp70 response after traumatic injury and that administration of exogenous Hsc/Hsp70 can remedy that deficit and reduce the subsequent loss of neurons by apoptosis.

The phosphodiesterase inhibitor rolipram delivered after a spinal cord lesion promotes axonal regeneration and functional recovery.

Although there is no spontaneous regeneration of mammalian spinal axons after injury, they can be enticed to grow if cAMP is elevated in the neuronal cell bodies before the spinal axons are cut. Prophylactic injection of cAMP, however, is useless as therapy for spinal injuries. We now show that the phosphodiesterase 4 (PDE4) inhibitor rolipram (which readily crosses the blood-brain barrier) overcomes inhibitors of regeneration in myelin in culture and promotes regeneration in vivo. Two weeks after a hemisection lesion at C3/4, with embryonic spinal tissue implanted immediately at the lesion site, a 10-day delivery of rolipram results in considerable axon regrowth into the transplant and a significant improvement in motor function. Surprisingly, in rolipram-treated animals, there was also an attenuation of reactive gliosis. Hence, because rolipram promotes axon regeneration, attenuates the formation of the glial scar, and significantly enhances functional recovery, and because it is effective when delivered s.c., as well as post-injury, it is a strong candidate as a useful therapy subsequent to spinal cord injury.

Synthesis and antiviral evaluation of halogenated beta-D- and -L-erythrofuranosylbenzimidazoles.

A series of 2-substituted benzimidazole D- and L-erythrofuranosyl nucleosides were synthesized and tested for activity against herpesviruses and for cytotoxicity. The D-nucleosides 2,5, 6-trichloro-1-(beta-D-erythrofuranosyl)benzimidazole (8a) and 2-bromo-5,6-dichloro-1-(beta-D-erythrofuranosyl)benzimidazole (8b) were prepared by coupling 1,2,3-tri-O-acetyl-beta-D-erythrofuranose (D-6) with the appropriate benzimidazole, followed by removal of the acetyl protecting groups. The 2-isopropylamino (9), 2-cyclopropylamino (10), and 2-mercaptobenzyl (11) derivatives were synthesized by nucleophilic displacements of the C-2 chlorine in the benzimidazole moiety of 8a. The D-nucleoside 4-bromo-5, 6-dichloro-2-isopropylamino-1-(beta-D-erythrofuranosyl)benzimid azo le (17) was prepared by coupling D-6 with the appropriate benzimidazole. The L-erythrofuranosyl derivatives, 5, 6-dichloro-2-isopropylamino-1-(beta-L-erythrofuranosyl)benzimid azo le (21a), its 2-cyclopropylamino analogue (21b), and the 2-isopropylamino analogue (25), were prepared by coupling L-6 with the appropriate benzimidazole. Several of these new derivatives had very good activity against HCMV in plaque and yield reduction assays (IC(50) = 0.05-19 microM against the Towne strain of HCMV) and DNA hybridization assays. Very little activity was observed against other herpesviruses. This pattern is similar to the antiviral activity profile observed for the corresponding ribofuranosides 2,5, 6-trichloro-1-(beta-D-ribofuranosyl)benzimidazole (4a), its 2-bromo analogue (4b), and the 2-cyclopropylamino analogue (4c). In comparison, 8a was 15-fold more active against HCMV than 4a, and 8b was 4-fold more active against HCMV than 4b. The 5, 6-dichloro-2-isopropylamino-1-(beta-L-erythrofuranosyl)benzimid azo le (21a) was less active than 4c, which is now in clinical trials for HCMV infection. Both 8a,b had comparable HCMV activity to 4c. Mode of action studies with the D-erythrose analogues established that 8b acted by inhibition of viral DNA processing whereas 9 and 10 may act via a different mechanism. The lack of a 5'-hydroxymethyl group in all members of this series established that antiviral activity occurred without 5'-phosphorylation, a feature required for the activity of most nucleoside analogues.

Radial keratotomy learning curve using the American technique.

PURPOSE: To delineate the learning curve for a beginning refractive surgeon using the centrifugal (American) technique. SETTING: Naval Medical Center, San Diego, California, USA. METHODS: The first 100 radial keratotomy (RK) cases (51 patients) of one surgeon, divided into five sequential groups of 20, were retrospectively reviewed. All patients had RK using the American technique. Emmetropia was the goal in all patients. Groups were compared with respect to preoperative refractive status, age, sex, and outcome. Outcomes analysis included visual acuity, refractive error, complications, and enhancement rates. Data were reviewed preoperatively and 1 and 3 months postoperatively. RESULTS: All five groups were age and sex matched. There was no difference in preoperative refractive error among the five groups. Sequential improvement in early postoperative refractive error from a mean of -1.73 diopters (D) +/- 1.00 (SD) (first 20) to 0.45 +/- 0.55 D (last 20) (P < .001) and decreased enhancement rates from 50% (first 20) to 0% (last 20) (P = .002) were statistically significant. Visual acuity at 1 month was 20/40 or better in 47% of patients in Group 1 (first 20), whereas all patients in Group 5 (last 20) had an acuity better than 20/40 (P < .001). There was no significant difference in complication rates among the five groups. CONCLUSION: The results of RK using the American technique can improve significantly with surgeon experience. Enhancement rates decreased with experience, and there was no difference in complication rates during the learning period of one surgeon.

Propofol and alfentanil prevent the increase in intraocular pressure caused by succinylcholine and endotracheal intubation during a rapid sequence induction of anesthesia.

The increase in intraocular pressure (IOP) associated with succinylcholine (Sch) has made its use in patients with open globe injuries controversial. Studies that have examined techniques to prevent the increase in IOP due to Sch have shown a larger increase in IOP from the stimulus of laryngoscopy and endotracheal intubation. The purpose of our study was to examine whether the combination of propofol and alfentanil would prevent the increase in IOP due to Sch as well as endotracheal intubation during a rapid sequence induction of anesthesia. Sixty patients were randomized to receive either thiopental 5 mg/kg and Sch 1.5 mg/kg (Group I), propofol 2 mg/kg and Sch 1.5 mg/kg (Group II), or propofol 2 mg/kg, alfentanil 40 micrograms/kg, and Sch 1.5 mg/kg (Group III). The IOP was measured continuously from baseline awake (control) values until 15 s after successful intubation. All three groups had a significant decrease in IOP with the induction of anesthesia. Succinylcholine produced a consistent increase in IOP from the postinduction low in Groups I and II, but this increase was not significantly higher than baseline. The postintubation IOPs in Groups I and II were significantly higher than baseline (P < 0.001). During the entire study period, the IOP in Group III never increased above baseline. The IOP in Groups I and II had already begun to decline by 15 s postintubation, suggesting that laryngoscopy and intubation have the greatest effect on increasing IOP. We conclude that the combination of propofol and alfentanil prevents the increase in IOP from Sch as well as the increase associated with endotracheal intubation during a rapid sequence induction of anesthesia.

A small-incision technique for suturing a posterior chamber intraocular lens.

The authors present a technique of transscleral fixation of a posterior chamber intraocular lens modified to permit a small-incision approach by using a foldable silicone lens. This modification improved intraoperative globe stability and reduced operative time. This procedure also has the potential for expediting postoperative recovery and visual rehabilitation.

Pulmonary management of the ALS patient.

Amyotrophic lateral sclerosis (ALS) is a chronic progressive motor neuron disease with a poor prognosis which eventually weakens and paralyzes the respiratory muscles. ALS is characterized by progressive degeneration of both cortical and alpha motor neurons of the final common pathway. Early symptoms usually begin with alpha motor neuron involvement and then progress to include cortical motor neuron involvement. Degeneration of respiratory nerve centers in the anterior horn at the C3-C5 levels results in respiratory muscle fatigue, respiratory failure and eventually death. Treatment consists of preventing respiratory complications and supporting lung function for as long as possible. One case example of a critically ill patient with ALS highlights nursing concerns. With advanced directives and durable power of attorney, the patient now has better means available for making known the decision of whether to accept or reject mechanical ventilation.

Composite grafting of the maxillary sinus for placement of endosteal implants. A preliminary report of 48 patients.

The maxillary sinuses in 48 patients were grafted with dense, non-resorbable hydroxylapatite (HA) particles combined with autologous, cancellous bone. After 3 months of healing, HA-coated titanium endosteal implants were placed in the maxilla, and following an additional 3-5 month healing period, the dentitions were restored with various prostheses. Of the 267 maxillary implants placed, 18 (6.4%) failed. Thirteen (6.4%) of the 203 implants placed in the grafted floor of the sinus failed, and 5 (7.8%) of the 64 implants placed in the anterior maxilla failed. Simultaneous lateral and anterior onlay grafting of the alveolar process with the same composite graft material was required in 36 (75%) patients because the width of the alveolar process was considered insufficient for placement of endosseous implants. The mean follow-up period was 17 months (range 12-32). Results from this preliminary study indicate that composite grafting of the maxillary sinus with onlay grafting of the alveolar ridge will provide the bony structure necessary for placement of endosseous implants. Further follow-up of these patients is necessary to determine the long-term stability of this technique; however, these results are promising.

Familial clustering of scleroderma spectrum disease.

This is the second case report of familial scleroderma (systemic sclerosis) in South Carolina. The family includes two cases of scleroderma meeting American Rheumatism Association criteria, one of systemic sclerosis sine scleroderma, and two other cases of undifferentiated connective tissue disease with features of scleroderma spectrum disorders; there are also two cases of Raynaud's phenomenon (one associated with rheumatoid arthritis), for a total of seven affected relatives. Evidence of scleroderma spectrum disorders was sought in six siblings of the two co-index cases and in 23 of the 35 offspring. Laboratory studies included antinuclear antibody determinations and typing for the following genetic markers: HLA (A, B, C, DR), complotypes, Gm and Km allotypes, and alpha-1 antitrypsin phenotypes. No common genetic markers restricted to affected members of this family were found, and no environmental exposures were detected that could explain this familial clustering of cases. This report should, however, add to the slowly accumulating information on the genetic characteristics of families at unusually high risk for scleroderma spectrum disorders. Positive antinuclear antibody tests at a titer of 1/40 or higher were present in 57 percent of the first-degree relatives of the affected cases.