Third, fourth, and sixth cranial nerve palsies following closed head injury.

BACKGROUND: The relationship between the circumstances and severity of closed head injury (CHI) and the clinical and imaging features of cranial nerve 3, 4, and 6 palsies has not been rigorously addressed in a large study. METHODS: Retrospective chart review of 210 consecutive patients with CHI examined at a single tertiary care center from 1987 to 2002. Patients were located by searching the ophthalmology inpatient consultation and neuro-ophthalmology outpatient databases and hospital emergency room billing codes for a diagnosis of traumatic 3, 4, or 6 cranial nerve palsy (Cranial Nerve Injury Group) and a diagnosis of CHI without traumatic 3, 4, or 6 nerve palsy (Control Group). The Cranial Nerve Injury Group was then subdivided into two groups: those with injuries to an individual cranial nerve and those with multiple (including bilateral) cranial nerve injuries. Comparisons between groups were based on age, gender, type of accident, Glasgow Coma Scale (GCS), documented loss of consciousness (LOC), type of ocular injury, presence of systemic injury, need for rehabilitation, physical therapy and cognitive scores, and imaging features. RESULTS: The Cranial Nerve Injury Group had a significantly higher severity of head injury, more CT abnormalities, and worse short-term neurologic outcomes as compared with the Control Group. These trends were also found when each cranial nerve injury subgroup was compared with the Control Group. Those with cranial nerve 3 palsy had the most severe head injury; those with cranial nerve 4 palsy had an intermediate level of head injury; and those with cranial nerve 6 palsy had the lowest level of head injury. There were no consistent associations between the location of the imaging abnormalities and which cranial nerve was damaged. CONCLUSIONS: CHI with palsy of an ocular motor nerve was more severe than CHI without ocular motor nerve palsy, as measured by the GCS, intracranial and skull imaging abnormalities, and a greater frequency of inpatient rehabilitation. Palsy of cranial nerve 3 was associated with relatively more severe CHI than was palsy of cranial nerves 4 or 6. The location of the imaging abnormalities did not correlate with a particular cranial nerve injury.     

Cortical plasticity: effect of high and low intensity conditioning electrical stimulations (100 Hz) on SEPs to painful finger stimulation.

OBJECTIVE: To study the effect of high-frequency (100 Hz) repetitive conditioning electrical stimulation (CES, 10 min) on human somatosensory evoked potentials (SEPs) to evaluate if short-term cortical plasticity could be induced. METHODS: Painful electrical stimulations were applied to thumb (D1) and little finger (D5) fingertips, respectively. The 124-channel EEG was recorded from 10 healthy male volunteers. Peak stages around 34, 45, 212, 331 ms were analyzed with focal maximum amplitude (FA) and area magnitude (AM) of scalp field potential, topography, and equivalent current dipole source localisation, comparing before and after two-level CES (high- vs. low-level) applied to the He-Gu acupoint. RESULTS: After a high-level CES, the positive FA and AM of the current efflux showed a significant increase at the early phase 34 ms, and significantly decreased at 45 ms in D1 SEPs. The negative FA and AM of the current influx were significantly increased at late phase 350 ms of the D5 SEPs. Only 36 ms, the z-axis position of dipole was significantly changed from (x: -15.9 mm, y: 29.6 mm, z: 43.9 mm) to (x: -12.9 mm, y: 29.4mm, z: 51.5mm) for the D5 SEPs. CONCLUSIONS: The high-level CES significantly attenuated the subsequent cortical activation (45 ms peak for D1 stimulation). Both low- and high-level CES significantly enhanced the late activities (226, 350 ms) in D5 stimulation. This may be explained by pain sensation change at the level of subcortical cingulate cortex induced by the site-dependent post-effect of CES. SIGNIFICANCE: This study showed cortical plasticity induced by conditioning somatosensory stimulation.     

Early, but not late therapy with a vasopressin V1a-antagonist ameliorates the development of renal damage after 5/6 nephrectomy.

INTRODUCTION: Vasopressin, mainly through the V1a-receptor, is thought to be a major player in the maintenance of hyperfiltration. Its inhibition could therefore lead to a decrease in progression of chronic renal failure. To this end, the effect of the vasopressin V1a-receptor-selective antagonist, YM218, was studied on proteinuria and focal glomerulosclerosis in early and late intervention after 5/6 nephrectomy in rats, and compared with an angiotensin-converting enzyme inhibitor (ACE-I). MATERIALS AND METHODS: After 5/6 nephrectomy, early intervention was performed between week 2 and 10 thereafter with the V1a-receptor-selective antagonist (VRA, 10 mg/kg/day, n=10), enalapril (ACE-I, 10 mg/kg/day, n=9), or vehicle (n=8). Late intervention was performed in another group between week 6 and 12 with VRA (10 mg/kg/day, n=7), lisinopril (ACE-I, 5 mg/kg/day, n=7), or vehicle (n=7). RESULTS: In early intervention, proteinuria and focal glomerulosclerosis were significantly decreased by VRA compared to vehicle (44+7% and 59+8% respectively). ACE-I significantly decreased proteinuria (67+7%) and a trend towards a decrease in focal glomerulosclerosis was observed (30+18%). In late intervention, VRA did not decrease proteinuria and focal glomerulosclerosis compared to vehicle (21+20% and 0%, respectively), ACE-I significantly lowered proteinuria (92+2%) and a focal glomerulosclerosis (69+1%) lowering trend was observed. CONCLUSION: These results indicate that VRA may protect against early progression of renal injury after 5/6 nephrectomy, whereas its effectiveness seems limited in established renal damage.     

Design of noninflammatory synthetic siRNA mediating potent gene silencing in vivo.

Targeted silencing of disease-associated genes by synthetic short interfering RNA (siRNA) holds considerable promise as a novel therapeutic strategy. However, unmodified siRNA can be potent triggers of the innate immune response, particularly when associated with delivery vehicles that facilitate intracellular uptake. This represents a significant barrier to the therapeutic development of siRNA due to toxicity and off-target gene effects associated with this inflammatory response. Here we show that immune stimulation by synthetic siRNA can be completely abrogated by selective incorporation of 2'-O-methyl (2'OMe) uridine or guanosine nucleosides into one strand of the siRNA duplex. These noninflammatory siRNA, containing less than 20% modified nucleotides, can be readily generated without disrupting their gene-silencing activity. We show that, coupled with an effective systemic delivery vehicle, 2'OMe-modified siRNA targeting apolipoprotein B (apoB) can mediate potent silencing of its target mRNA, causing significant decreases in serum apoB and cholesterol. This is achieved at therapeutically viable siRNA doses without cytokine induction, toxicity, or off-target effects associated with the use of unmodified siRNA. This approach to siRNA design and delivery should prove widely applicable and represents an important step in advancing synthetic siRNA into a broad range of therapeutic areas.     

Relationship between insulin-like growth factor I, dehydroepiandrosterone sulfate and proresorptive cytokines and bone density in cystic fibrosis

Introduction Patients with cystic fibrosis (CF) are known to be at risk for early osteoporosis, and the mechanisms that mediate bone loss are still being delineated. The aim of the present investigation was to investigate if a correlation exists in these patients between skeletal measurements by dual-energy x-ray absorptiometry (DXA) and two anabolic factors, dehydroepiandrosterone (DHEA) and insulin-like growth factor I (IGF-I), and proresorptive factors such as the cytokines interleukin-1β, tumor necrosis factor α, and interleukin-6. Methods We studied 32 outpatients (18 females; mean age: 26.2 ± 7.9 years) at a tertiary care medical center. The subjects had venous samples obtained, underwent anthropometric and bone mineral density (BMD) measurements, and completed a health survey. Serum IGF-I concentrations were below the age-adjusted mean in 78% of the participants, and DHEA sulfate (DHEAS) concentrations were low in 72%. Serum concentrations of all cytokines were on the low side of normal; nonetheless, there was a modest inverse correlation between IL-1β and BMD at all sites. Results In univariate analyses, IGF-I and DHEAS were significant correlates of BMD or bone mineral content. In final multivariate models controlling for anthropometric and other variables of relevance to bone density, only IGF-I was identified as a significant independent skeletal predictor. While alterations in DHEAS, IGF-I, and specific cytokines may contribute to skeletal deficits in patients with CF, of these factors a low IGF-I concentration appears to be most strongly correlated with BMD. Conclusions These findings may have therapeutic implications for enhancing bone density in these patients.     

Academic Degrees and Clinical Practice Characteristics: The University of Washington Physician Assistant Program: 1969-2000

CONTEXT: The physician assistant profession has been moving toward requiring master's degrees for new practitioners, but some argue this could change the face of the discipline. PURPOSE: To see if there is an association between physician assistants' academic degrees and practice in primary care, in rural areas, and with the medically underserved. METHODS: Surveys were sent to 880 graduates of the first 32 University of Washington physician assistant classes through 2000. Respondents noted their academic degree at program entry and the highest degree attained at any time up to the time of survey. Relationships between practice characteristics and academic degree levels were tested by unadjusted odds ratios and logistic regression after controlling for year of graduation and sex. RESULTS: Of the 478 respondents, 54% worked in primary care, about 30% practiced in nonmetropolitan communities, and 42% reported providing care for the medically underserved. Respondents with no degree (33% of total at entry, 24% at survey) were significantly more likely than degree holders to work in primary care and nonmetropolitan areas. Respondents with no degree at program entry were significantly more likely, and those with no degree at the time of the survey were marginally more likely, to self-report work with the medically underserved. CONCLUSION: Respondents with no academic degree are significantly more likely to demonstrate a commitment to primary, rural, and underserved health care. These findings may inform the national debate about the impact of required advanced degrees on the practice patterns of nonphysician providers.