The Ionospheric Connection Explorer Mission: Mission Goals and Design.

The Ionospheric Connection Explorer, or ICON, is a new NASA Explorer mission that will explore the boundary between Earth and space to understand the physical connection between our world and our space environment. This connection is made in the ionosphere, which has long been known to exhibit variability associated with the sun and solar wind. However, it has been recognized in the 21st century that equally significant changes in ionospheric conditions are apparently associated with energy and momentum propagating upward from our own atmosphere. ICON's goal is to weigh the competing impacts of these two drivers as they influence our space environment. Here we describe the specific science objectives that address this goal, as well as the means by which they will be achieved. The instruments selected, the overall performance requirements of the science payload and the operational requirements are also described. ICON's development began in 2013 and the mission is on track for launch in 2017. ICON is developed and managed by the Space Sciences Laboratory at the University of California, Berkeley, with key contributions from several partner institutions.

HIF alpha expression in VHL-deficient renal cancer cells is dependent on phospholipase D.

Loss of the von Hippel-Lindau (VHL) tumor suppressor gene contributes to proliferative disorders including renal cell carcinoma. The consequence of VHL loss is increased levels of hypoxia-inducible factor-alpha (HIFalpha), which is targeted for proteolytic degradation by the VHL gene product pVHL. HIF is a transcription factor that increases the expression of factors critical for tumorigenesis in renal cell carcinoma. We report here another regulatory component of HIFalpha expression in renal cancer cells. Phospholipase D (PLD), which is commonly elevated in renal and other cancers, is required for elevated levels of both HIF1alpha and HIF2alpha in VHL-deficient renal cancer cells. The induction of both HIF1alpha and HIF2alpha by hypoxic mimetic conditions was also dependent on PLD in renal cancer cells with restored pVHL expression. The effect of PLD activity upon HIFalpha expression was at the level of translation. PLD activity also provides a survival signal that suppresses apoptosis induced by serum deprivation in the renal cancer cells. Suppression of HIF2alpha has been shown to reverse tumorigenesis with renal cancer cells. The finding here that HIF2alpha expression is dependent on PLD in renal cancer cells suggests that targeting PLD signals may represent an alternative therapeutic strategy for targeting HIF2alpha in renal cancers where HIF2alpha is critical for tumorigenesis and elevated PLD activity is common.

Evaluation of Beauveria bassiana (hyphomycetes) strains as potential agents for control of Triatoma infestans (Hemiptera: Reduviidae).

Chagas disease constitutes a major human health problem in most Latin American countries. This endemic disease is transmitted by several species of triatomine bugs, the most important being Triatoma infestans (Klug). In this article, we report on the selection of strains of the entomopathogenic fungus Beauveria bassiana (Bals.) Vuill. virulent to T. infestans for possible use as bioinsecticides. Four strains of B. hassiana isolated from Argentina (Bb 1, 10, 25, and 65) were evaluated. To calculate mortality and mean lethal time, nymphs and adults of T. infestans were treated with conidia produced on complete agar medium and wheat brain and rice husk medium (WH). The LD50 for nymphs and adults of T. infestans was calculated. The effect of different temperatures (18, 22, 26, 30, and 34 degrees C) and relative humidities (35 and 90% RH) on mortality of nymphs were studied. We evaluated the compatibility of strains with Deltamethrin and Beta-Cypermethrin. Although the strain Bb 25 failed to grow on WH, the other three strains showed similar mortality values independent of the culture medium used to grow the microorganisms. The lowest LD50 values for nymphs were obtained with the strains Bb 10 and 65 and for adults were Bb 1, 10, and 65. The highest mean mortality was obtained with strain Bb 10, and among temperatures the highest mean mortality was observed at 26 degrees C. Relative humidity did not affect the mortality of T. infestans nymphs with all strains and temperatures assayed. Deltamethrin did not affect any of the three strains for the four studied doses, and Beta-Cypermethrin could be used in combination with the fungus only at low doses. The strain Bb 10 was selected for future assays under natural climatic conditions.

Unna and elastic postoperative dressings: comparison of their effects on function of adults with amputation and vascular disease.

OBJECTIVES: To compare the functional outcome associated with the use of Unna semirigid dressings (SRD) and elastic bandage soft dressings (ED) for adults with lower limb amputation. DESIGN: Experimental design. SETTING: Inpatient rehabilitation unit of an urban academic medical center. PARTICIPANTS: A successive series of adults with vascular disease who had lower limb amputation surgery. Subjects were randomly assigned to the SRD (12 patients with 12 recent amputations) or the ED (9 patients with 10 recent amputations) group. Subjects in each group were not significantly different except for age; those in the SRD group were somewhat older. INTERVENTION: Subjects in the SRD group had Unna dressings applied to the amputation limb by physical therapists trained in the technique. Those in the ED group had elastic bandaging by therapists, nurses, family, and themselves, all of whom were trained in the technique. RESULTS: Sixty-seven percent of the SRD group and 20% of those in the ED group were discharged from the rehabilitation unit ambulating with prostheses. Of those who received prostheses, time from admission to the rehabilitation unit to readiness for fitting averaged 20.8 days for the SRD group and 28.7 days for the ED group. Comparison of survival curves shows that the time from surgery to fitting in the SRD group was almost half that of the ED group; 30% of the SRD group was fitted within 34 days, whereas it took 64 days for the same percentage of the ED group to be fitted. CONCLUSIONS: Unna semirigid dressings are more effective in fostering amputation limb wound healing and preparing the amputation limb for prosthetic fitting. Subjects treated with SRDs were more likely to be fitted with prostheses and to return home walking with a prosthesis.

Osteomyocutaneous flap as a preclinical composite tissue allograft: swine model.

Composite tissue allotransplantation (CTA) constitutes one of the last frontiers of microsurgery. Prior to its clinical application, the long-term efficacy of modern immunotherapy must be tested in a pre-clinical CTA model. Based on the concept of osteomyocutaneous forearm flap, we developed a CTA flap model in swine. After identifying the vascular territory of the flaps in six pigs (vascular casting), flaps were transplanted from mismatched donor to recipient pigs (n = 6). Rejection was assessed daily by visual inspection and histopathology of biopsy specimens. Recipient pigs were able to ambulate immediately following surgery. There were no flap failures owing to technical or surgical complications. Rejection occurred over a period of 7 days as manifested by edema, cellular infiltration, epidermalysis, and thrombosis. This pre-clinical flap model is excellent for evaluating the effectiveness of modern immunotherapy because it is anatomically and immunologically relevant and because the minimal morbidity caused to the animal permits long-term studies.

Swine composite tissue allotransplant model for preclinical hand transplant studies.

Our laboratory previously developed and used an orthotopic radial forelimb osteomyocutaneous flap in the pig as a preclinical composite tissue allograft (CTA) model. To ensure that it mimicked the clinical situation as closely as possible we developed this model taking many immunologic and reconstructive considerations into account. While our original pig CTA model was ideal for studying the methods of preventing skin, muscle, bone, vessel and nerve rejection, and systemic toxicity, it did not include specialized tissues/structures of a joint and digit. Therefore, we were unable to evaluate rejection of these specialized tissues and their functional properties. Recognizing the importance of assessing joint rejection and function in hand transplantation research we developed a new swine forelimb CTA model that included the animal's medial digit. The present study describes the anatomy and the transplantation technique used in this new preclinical CTA model. We transplanted a radial osteomyocutaneous flap that included the medial digit between two size- (17-21 kg) and age- (6-8-week) matched farm pigs. We removed the digit from the recipient pig's forelimb in continuity with a section of the radial bone and replaced it with the same structure transplanted from a donor pig. After transplantation, a full-length cast was placed on the recipient pig's operated limb and changes in flap color, temperature and the presence of edema were monitored continuously for 6 h, and then regularly at predetermined intervals over 4 days. No weight bearing restrictions were placed on the animal's operated limb. After 4 days, the animal was euthanized. Direct visual monitoring of the allograft during 4 days revealed it was viable with no signs of graft failure due to technical complications associated with the transplant procedure. Upon waking from anesthesia, the animal stood and wandered freely about its cage with no apparent difficulty. Based on the animal's high level of activity at this time, we concluded that the procedure caused it minimal morbidity. At 4 days after the operation, early signs of rejection (skin erythema and edema) were observed. By incorporating a digit into our original CTA pig forelimb model we have made it a better model for performing preclinical hand transplant studies. The added advantage of being able to assess methods of preventing rejection in the specialized joint/digital tissues (articular cartilage, digital flexor and extensor systems, the nail complex) and assess long-term function of these structures is important. The fact that the procedure does not cause major morbidity to the animal makes it possible to conduct long-term graft survival and functional studies.

Long-term survival of an extremity composite tissue allograft with FK506-mycophenolate mofetil therapy.

BACKGROUND: High-dose tacrolimus (FK506) monotherapy has significantly prolonged rat hindlimb allograft survival. With an eye toward direct clinical application, we used a large-animal extremity composite tissue allograft model to assess the antirejection efficacy and systemic toxicity of combination FK506-mycophenolate mofetil (MMF) treatment. METHODS: Radial forelimb osteomyocutaneous flap transplants were performed between size-matched outbred pigs assigned to one of two groups: 5 control pigs received no immunosuppression and 9 animals received a once-daily oral FK506-MMF-prednisone regimen. Rejection was assessed by visual inspection of flap skin and was correlated with serial histopathologic examination of skin biopsy specimens. RESULTS: In all control pigs the flap was completely rejected on day 7. Of the 9 pigs receiving treatment, 3 died from pneumonia on days 29, 30, and 83 without signs of rejection and another died from gastric rupture on day 42 with persistent mild rejection. The remaining 5 animals were free of rejection at the end of the 90-day follow-up period (P < 0.005 vs controls). Overall, 5 pigs had pneumonia, 4 septic arthritis, 3 toe abscesses, and 5 diarrhea and decreased weight gain. CONCLUSIONS: Combination oral FK506-MMF treatment provided a superior antirejection effect but more produced more toxicity than that previously demonstrated with cyclosporin A-MMF therapy in our model. Our results suggest that reduction of FK506 or MMF doses might decrease both infectious and drug-specific side effects while still providing adequate prophylaxis against rejection.

Scoring of skin rejection in a swine composite tissue allograft model.

BACKGROUND: For the first time, we define and correlate visual and histologic grading systems of composite tissue allograft (CTA) skin rejection in a large-animal model and determine the utility of these grading systems for early diagnosis and monitoring of rejection. MATERIALS AND METHODS: Sixteen pairs of outbred swine underwent transplant of a forelimb osteomyocutaneous free flap. Group I (n = 6) did not receive immunosuppressive therapy. Group II (n = 10) received oral cyclosporin A, mycophenolate mofetil, and prednisone. The flap was visually inspected and protocol skin biopsies were taken at frequent intervals over a 90-day period. Visual Grades 0 (no rejection) to 4 (severe rejection) were assigned based on skin color, bleeding from biopsy site, and blister formation. Histologic Grades 0 to 4 were assigned based on the degree of vasculitis, folliculitis, dermal inflammation, and epidermal degeneration present. RESULTS: All Group I animals progressively rejected their graft by Day 7. Group II grafts survived from 19 and 90 days; 93% of 115 biopsy specimens were read to be within +/-1 histologic score of their assigned flap visual grade. Visual assessment carried an 8% false positive and 39% false negative rate with regard to biopsy-proven rejection. However, 81% of missed rejection specimens were histologic Grade 1. Biopsy, when visually indicated, would detect all rejection episodes when histologically Grade 1 or 2 and still potentially reversible. CONCLUSIONS: Visual scoring of CTA skin serves as a useful tool for initially detecting rejection, but repeated histologic evaluation is necessary for monitoring the subsequent course of the graft.

Pharmacokinetics of intra-arterial delivery of tacrolimus to vascularly isolated rabbit forelimb.

A vascularly isolated rabbit forelimb model simulating conditions of composite tissue allografting was used to determine the regional pharmacokinetic advantage achievable in extremity tissue components during i.a. tacrolimus (FK506) administration. FK506 was infused continuously via osmotic minipump into the right brachial artery of New Zealand rabbits at 0.05, 0.1, and 0.2 mg/kg/day. On day 6, FK506 concentrations were measured in aortic whole blood, heart, lung, liver, kidney, spleen, and fat, as well as in skin, muscle, bone, and bone marrow samples from both right and left forelimbs. The relative tissue concentrations of FK506 in descending order were [spleen approximately lung approximately kidney] > [heart approximately skin approximately muscle] > [fat approximately bone marrow] > [liver approximately bone approximately blood]. In marked contrast to previous results with i.a. cyclosporin A infusion, only a minimal regional advantage of local FK506 delivery (mean right/left concentration ratios 1.0-1.4) was obtained in all forearm tissues over the dose range studied. For each limb tissue, left-sided FK506 concentrations significantly correlated with systemic blood levels, and the left-sided tissue-to-whole-blood concentration ratio did not vary significantly with dose. We conclude that FK506 is pharmacokinetically inferior to cyclosporin A for continuous i.a. administration to the vascularly isolated rabbit forelimb, and hypothesize that this difference is the result of differences in the distribution of each drug within whole blood. Our findings suggest that, despite its demonstrated efficacy in experimental and clinical transplantation, FK506 would not be an appropriate immunosuppressant to deliver via the i.a. route for prevention of limb allograft rejection.

Long-term composite tissue allograft survival in a porcine model with cyclosporine/mycophenolate mofetil therapy.

BACKGROUND: Low-dose cyclosporine (CsA)/mycophenolate mofetil (MMF) therapy has significantly reduced the frequency of rejection and drug-induced side effects in rat hindlimb allograft recipients. With an eye toward direct clinical application, we developed a large-animal extremity composite tissue allograft model to assess the antirejection efficacy and systemic toxicity of combination CsA/MMF treatment. METHODS: Radial forelimb osteomyocutaneous flap transplants were performed between size-matched, outbred pigs assigned to one of two groups: 5 control pigs received no immunosuppression, and 10 pigs received a once-daily oral CsA/MMF/prednisone regimen. Rejection was assessed by visual inspection of flap skin and correlated with serial histopathologic examination of skin biopsies. RESULTS: In all control pigs, the flap was completely rejected on day 7. Of the 10 pigs receiving treatment, one died from pneumonia and an another from an anesthetic complication on days 19 and 30, respectively, without signs of rejection. Two flaps were lost on days 25 and 29 from severe rejection. Three pigs were free of rejection at the end of the 90-day follow-up period, and three had stable mild-to-moderate rejection at 90 days (P= 0.0007 vs. controls). White blood cell and platelet counts, serum creatinine values, and liver function tests remained normal in all animals receiving immunosuppressive therapy. CONCLUSIONS: Our results, to our knowledge, demonstrate for the first time that rejection can be significantly delayed in a large-animal composite tissue allograft model including skin using only orally administered agents dosed according to clinically relevant strategies without significant drug-specific systemic side effects.

Communicating with individuals with Alzheimer's disease: examination of recommended strategies.

Meaningful conversation with individuals in the later stages of Alzheimer's disease (AD) has been considered difficult if not impossible. Limiting communication to simple concrete subjects and closed-ended questions is frequently recommended. Thirty-five 30 minute conversations with individuals with advanced AD (mean Mini-Mental State Examination [MMSE] = 10) were transcribed and the interactions examined. No significant differences in length or relevance of response by type of question was found indicating that subjects were able to respond to open-ended questions. Use of broad opening statements or questions, establishing commonalities, speaking as equals, and sharing of self-facilitated expression of feeling; recognizing themes with salience for the individual helped to maintain the discussion.

Chemical method to increase extreme ultraviolet microchannel-plate quantum efficiency.

The quantum detection efficiency of photon-counting microchannel-plate detector channels can be increased by a factor of 2 in the extreme ultraviolet bandpass, from 256 A to 1024 A, by subjecting the input channel plate to a chemical solution treatment. The efficiency increase has proven to be insensitive to the exposure of laboratory atmosphere and is stable over the extracted charge lifetime equivalent of multiyear astrophysical observations. Chemically treated microchannel plates that are overcoated with opaque photocathodes of KBr and CsI show a factor of 2 quantum detection efficiency increase from 834 A to 1100 A in comparison with previous measurements using conventional untreated microchannel plates.

Reliability of physical performance measures in nursing home residents with Alzheimer's disease.

BACKGROUND: Investigation of the effects of exercise on frail, institutionalized individuals with dementia has been impeded by concerns about the reliability of physical performance measures when used in this population. METHODS: The physical performance of 33 institutionalized subjects with Alzheimer's disease was measured during both the morning and afternoon of day 1 by rater 1 and during both the morning and afternoon of day 2, one week later, by rater 1 and rater 2. Intraclass correlation coefficients (ICCs) were calculated to examine the inter- and intrarater reliability of "sit to stand," "25-foot walk," and "the distance walked in 6 minutes" and walking speed over 25 feet and for 6 minutes. An analysis of variance was performed to determine the components of variance for each test. RESULTS: ICCs for "distance walked in 6 minutes" ranged from .80 to .99 with 77% of the variance explained by inter-subject difference. The ICCs for "time to walk 25 feet" ranged from .57 to .97 with 25% of the variance explained by inter-subject differences. In contrast, the "sit to stand" measure produced ICCs ranging from -.07 to .85 with only 7% of the variance explained by inter-subject differences in this impaired population. CONCLUSION: Our results support the contention that some physical performance measures can be used to test individuals in the later stages of Alzheimer's disease given appropriate modification. Although subjects with Alzheimer's disease may have difficulty following commands and/or require physical assistance, this does not prohibit the reliable assessment of physical performance if measurements are made over longer (6-minute walk) rather than shorter periods (25-foot walk).

Precursors of extracranial carotid atherosclerosis in the Framingham Study.

To investigate cardiovascular risk factors and carotid atherosclerosis, we related previously measured risk factors to carotid atherosclerosis as determined by duplex ultrasonography in the Framingham Study cohort. Risk factors measured prospectively on 1,116 cohort members, ages 66 to 93, were related to the severity of carotid atherosclerosis measured by carotid ultrasonography performed during biennial examination no. 20 (1988 to 1990). The degree of carotid atherosclerosis was expressed as a percent carotid stenosis and, for statistical analysis, subjects were divided into four groups according to percent carotid stenosis. The prevalence of significant carotid stenosis in the general population was low--7% in women and 9% in men. A multivariate logistic regression model showed that age, cigarette smoking, systolic blood pressure, and cholesterol were independently related to carotid atherosclerosis. Alcohol consumption was also significant in men, but not in women. In addition, our results indicate that both current and former smoking in both sexes was related to the degree of carotid atherosclerosis.

Performance comparison among children fitted with myoelectric and body-powered hands.

Seventy-six children with unilateral below-elbow amputation were fitted in random sequence with a myoelectric (MYO) and a body-powered (BP) prosthetic hand of identical size, shape, and glove color. Subjects ranged from six to 17 years, nine months and included 67 children with congenital limb deficiency and nine who sustained traumatic amputation. After training, each child wore each hand for three months. On the form board test requiring only prosthetic use, subjects took 13.7% longer with the MYO and committed more errors with the MYO, specifically in dropping objects and delaying their grasp and release. Object displacement, the most common error, occurred nearly as often with BP as MYO. MYO was minimally faster on a test of ten practical activities designed for bimanual prehension. Card playing was 39.8% faster with BP, whereas donning socks, cutting paper, and bandage application were 27.8%, 12.5%, and 10.9% faster with MYO. Performance with both hands was rated as decidedly poorer than normal quality. No major clinically important differences were found in the comparison of performance.

Ultrasonic-pathological comparison of the human arterial wall. Verification of intima-media thickness.

Recent intravascular ultrasound experience challenges the accuracy of ultrasonic measurement of arterial wall thickness. We reevaluated the correlation between histological and sonographic measurements of intima-media thickness using standard transcutaneous vascular technology. Carotid and femoral arterial segments were imaged before and after fixation using a 7-MHz linear-array vascular transducer. Log compression and beam orientation were varied. Mean intima, media, and adventitia thicknesses were measured and compared with corresponding histological tunica. Tissue processing caused 2.5% shrinkage. Intraobserver reading error was 0.7% for histology and 5.4% for sonography. Ultrasound overestimated the thickness of the intima and adventitia and underestimated the thickness of the media. For combined intima-media thickness, the differences between histology and imaging were insignificant, averaging 4% for the carotid artery and 9% for the femoral artery in the far-wall projection. In the near-wall projection, sonographic intima-media thickness was 20% less than that determined histologically. We conclude that ultrasonography is limited mainly by axial resolution in quantifying the dimensions of individual arterial tunica but is capable of accurately measuring far-wall intima-media thickness.

The wedge punctoplasty for treatment of punctal stenosis.

We describe a new instrument, the Reiss punctal punch, which is specifically designed to performa "wedge" punctoplasty. The Reiss punctal punch was used alone to treat three eyelids of three patients, and in conjunction with horizontal tightening of the eyelid to treat 35 eyelids of 18 patients with symptomatic epiphora related to punctal ectropion with secondary punctal stenosis. After a mean follow up of 12 months, 36/38 (95%) of the eyelids demonstrated a patent punctum, and symptomatic relief was achieved in 35/38 (92%) of the eyes.

Orbitocranial wooden foreign body diagnosed by magnetic resonance imaging. Dry wood can be isodense with air and orbital fat by computed tomography.

In computed tomographic (CT) scans, a wooden foreign body can appear as a lucency with nearly the same density as air or fat, and it can be indistinguishable from orbital adipose tissue. Magnetic resonance imaging (MRI) can localize these wooden foreign bodies in the orbit. We studied a case in which a wooden golf tee lodged in the right optic canal of a nine-year-old boy. The head portion lodged in the orbital apex and the tip entered the interpeduncular fossa. Clinical examination revealed a right paranasal laceration; the right eye had no light perception and a peripapillary hemorrhage, but was otherwise normal. Surgical exploration and evaluation by CT failed to locate the foreign body. However, the golf tee was demonstrated by MRI as a low intensity image. Although it was removed by craniotomy with good neurological results, bacterial panophthalmitis led to enucleation of the eye. This case emphasizes the diagnostic value of MRI and the hazards of retained wooden foreign bodies.