The influence of spinal venous blood pressure on cerebrospinal fluid pressure.

In Alligator mississippiensis the spinal dura is surrounded by a venous sinus; pressure waves can propagate in the spinal venous blood, and these spinal venous pressures can be transmitted to the spinal cerebrospinal fluid (CSF). This study was designed to explore pressure transfer between the spinal venous blood and the spinal CSF. At rest the cardiac-related CSF pulsations are attenuated and delayed, while the ventilatory-related pulsations are amplified as they move from the spinal venous blood to the spinal CSF. Orthostatic gradients resulted in significant alterations of both cardiac- and ventilatory-related CSF pulsations. Manual lateral oscillations of the alligator's tail created pressure waves in the spinal CSF that propagated, with slight attenuation but no delay, to the cranial CSF. Oscillatory pressure pulsations in the spinal CSF and venous blood had little influence on the underlying ventilatory pulsations, though the same oscillatory pulsations reduced the ventilatory- and increased the cardiac-related pulsations in the cranial CSF. In Alligator the spinal venous anatomy creates a more complex pressure relationship between the venous and CSF systems than has been described in humans.

Optimization of Time- and Code-Division-Multiplexed Readout for Athena X-IFU.

Readout of a large, spacecraft-based array of superconducting transition-edge sensors (TESs) requires careful management of the layout area and power dissipation of the cryogenic-circuit components. We present three optimizations of our time- (TDM) and code-division-multiplexing (CDM) systems for the X-ray Integral Field Unit (X-IFU), a several-thousand-pixel-TES array for the planned Athena-satellite mission. The first optimization is a new readout scheme that is a hybrid of CDM and TDM. This C/TDM architecture balances CDM's noise advantage with TDM's layout compactness. The second is a redesign of a component: the shunt resistor that provides a dc-voltage bias to the TESs. A new layout and a thicker Pd-Au resistive layer combine to reduce this resistor's area by more than a factor of 5. Third, we have studied the power dissipated by the first-stage SQUIDs (superconducting quantum-interference devices) and the readout noise versus the critical current of the first-stage SqUIDs. As a result, the X-IFU TDM and C/TDM SQUIDs will have a specified junction critical current of 5 µA. Based on these design optimizations and TDM experiments described by Durkin, et al. (these proceedings), TDM meets all requirements to be X-IFU's backup-readout option. Hybrid C/TDM is another viable option that could save spacecraft resources.

Demonstration of Athena X-IFU Compatible 40-Row Time-Division-Multiplexed Readout.

Time-division multiplexing (TDM) is the backup readout technology for the X-ray Integral Field Unit (X-IFU), a 3,168-pixel X-ray transition-edge sensor (TES) array that will provide imaging spectroscopy for ESA's Athena satellite mission. X-0IFU design studies are considering readout with a multiplexing factor of up to 40. We present data showing 40-row TDM readout (32 TES rows + 8 repeats of the last row) of TESs that are of the same type as those being planned for X-IFU, using measurement and analysis parameters within the ranges specified for X-IFU. Singlecolumn TDM measurements have best-fit energy resolution of (1.91 ± 0.01) eV for the Al Kα complex (1.5 keV), (2.10 ± 0.02) eV for Ti Kα (4.5 keV), (2.23 ± 0.02) eV for Mn Kα (5.9 keV), (2.40 ± 0.02) eV for Co Kα (6.9 keV), and (3.44 ± 0.04) eV for Br Kα (11.9 keV). Three-column measurements have best-fit resolution of (2.03 ± 0.01) eV for Ti Kα and (2.40 ± 0.01) eV for Co Kα. The degradation due to the multiplexed readout ranges from 0.1 eV at the lower end of the energy range to 0.5 eV at the higher end. The demonstrated performance meets X-IFU's energy-resolution and energy-range requirements. True 40-row TDM readout, without repeated rows, of kilopixel scale arrays of X-IFU-like TESs is now under development.

How Internally Coupled Ears Generate Temporal and Amplitude Cues for Sound Localization.

In internally coupled ears, displacement of one eardrum creates pressure waves that propagate through air-filled passages in the skull and cause displacement of the opposing eardrum, and conversely. By modeling the membrane, passages, and propagating pressure waves, we show that internally coupled ears generate unique amplitude and temporal cues for sound localization. The magnitudes of both these cues are directionally dependent. The tympanic fundamental frequency segregates a low-frequency regime with constant time-difference magnification from a high-frequency domain with considerable amplitude magnification.

The effects of radiation on antitumor efficacy of an oncolytic adenovirus vector in the Syrian hamster model.

We report that radiation enhances the antitumor efficacy of the oncolytic adenovirus vector VRX-007 in Syrian hamster tumors. We used tumor-specific irradiation of subcutaneous tumors and compared treatment options of radiation alone or combined with VRX-007 and cyclophosphamide (CP). Radiation therapy further augmented the VRX-007-mediated inhibition of tumor growth, in both CP-treated and non-CP-treated hamsters, even though radiation did not lead to increased viral replication in tumors when compared with those treated with VRX-007 alone. Moreover, tumor growth inhibition was similar in tumors irradiated either 1 week before or after injection with VRX-007, which suggests that radiation exerts its antitumor effect independently from vector therapy. Thus, our results demonstrate that these two therapies do not have to be provided simultaneously to enhance their combined effectiveness against subcutaneous hamster tumors.

The role of cyclophosphamide in enhancing antitumor efficacy of an adenovirus oncolytic vector in subcutaneous Syrian hamster tumors.

We have previously reported that intratumoral injection of VRX-007--an Ad5 (a species C adenovirus)-based vector overexpressing adenovirus death protein--can suppress the growth of subcutaneous HaK (hamster renal cancer) tumors. VRX-007 replication and tumor growth inhibition are enhanced when the hamsters are immunosuppressed by a high dose of cyclophosphamide (CP), an immunosuppressive and chemotherapeutic agent. Here, we report that continuous immunosuppression with CP was not required for increased oncolytic activity of VRX-007 because short-term dosing or continuous dosing with the drug yielded similar antitumor results. Prolonged viral replication was found only in animals on continuous CP treatment. We used 007-Luc, a replication-competent, luciferase-expressing vector similar to VRX-007, to investigate the replication of the vector over time. Tumor growth inhibition was similar in hamsters given CP treatment either 1 week before or 1 week after 007-Luc injection, which suggests that CP exerts its antitumor efficacy independently of vector therapy. 007-Luc did not spread far from the inoculation site, even in immunosuppressed, CP-treated animals. Our results indicate that the enhanced effectiveness that is produced by the combination of VRX-007 and CP therapies is due to their two independent mechanisms and that they do not have to be given simultaneously for the improved outcome.

Herpes zoster incidence in a multicenter cohort of solid organ transplant recipients.

BACKGROUND: Immunosuppressed patients are at increased risk for herpes zoster (HZ), but incidence in solid organ transplant (SOT) recipients has varied in multiple studies. To assess incidence of HZ, we examined patients who underwent SOT and received follow-up care within the large multicenter US Department of Veteran's Affairs healthcare system. METHODS: Incident cases of HZ were determined using ICD-9 coding from administrative databases. A multivariable Cox proportional hazards model, adjusted for a priori risk factors, was used to assess demographic factors associated with development of HZ. RESULTS: Among the 1077 eligible SOT recipients, the cohort-specific incidence rate of HZ was 22.2 per 1000 patient-years (95% confidence interval [CI], 18.1-27.4). African Americans (37.6 per 1000 [95% CI, 25.0-56.6]) and heart transplants recipients (40.0 per 1000 [95% CI, 23.2-68.9]) had the highest incidence of HZ. Patients transplanted between 2005 and 2007 had the lowest incidence (15.3 per 1000 [95% CI, 8.2-28.3]). In a multivariable model, African Americans (hazard ratio [HR] 1.88; 95% CI: 1.12, 3.17) and older transplant recipients (HR 1.13; 95% CI: 1.01, 1.27 [per 5-year increment]) had increased relative hazards of HZ. CONCLUSIONS: These data demonstrate that HZ is a common infectious complication following SOT. Future studies focused on HZ prevention are needed in this high-risk population.

Neighborhood poverty and kidney transplantation among US Asians and Pacific Islanders with end-stage renal disease.

The degree to which low transplant rates among Asians and Pacific Islanders in the United States are confounded by poverty and reduced access to care is unknown. We examined the relationship between neighborhood poverty and kidney transplant rates among 22 152 patients initiating dialysis during 1995-2003 within 1800 ZIP codes in California, Hawaii and the US-Pacific Islands. Asians and whites on dialysis were distributed across the spectrum of poverty, while Pacific Islanders were clustered in the poorest areas. Overall, worsening neighborhood poverty was associated with lower relative rates of transplant (adjusted HR [95% CI] for areas with > or =20% vs. <5% residents living in poverty, 0.41 [0.32-0.53], p < 0.001). At every level of poverty, Asians and Pacific Islanders experienced lower transplant rates compared with whites. The degree of disparity increased with worsening neighborhood poverty (adjusted HR [95% CI] for Asians-Pacific Islanders vs. whites, 0.64 [0.51-0.80], p < 0.001 for areas with <5% and 0.30 [0.21-0.44], p < 0.001 for areas with > or =20% residents living in poverty; race-poverty level interaction, p = 0.039). High levels of neighborhood poverty are associated with lower transplant rates among Asians and Pacific Islanders compared with whites. Our findings call for studies to identify cultural and local barriers to transplant among Asians and Pacific Islanders, particularly those residing in resource-poor neighborhoods.

Outcome of cardiac arrests attended by emergency medical services staff at community outpatient dialysis centers.

Cardiac arrest is the leading cause of death among dialysis patients in the United States. We measured the outcome of cardiac arrests attended by Emergency Medical Services (EMS) staff at hemodialysis facilities in a 14-year population-based retrospective study to identify cardiac arrest cases at a dialysis unit. Associated factors were determined using unconditional logistic regression. Of the 102 cardiac arrests identified around the time of dialysis, 10 occurred before, 72 during, and 20 after hemodialysis. The initial measured abnormality was ventricular fibrillation or tachycardia in 72 cases. Of those who survived transportation to a hospital, survival to discharge was 24 with 15% survival at 1 year. Compared to arrests that occurred prior to dialysis, the odds of ventricular fibrillation were 5-fold greater in patients on dialysis but 14-fold greater in those arresting after dialysis. One-third of cases occurred after the introduction of automated external defibrillators, and in half of the cases these devices were attached prior to EMS arrival. Once these devices were attached, most were used for defibrillation. We conclude that ventricular arrhythmias are the predominant features among arrested in-center dialysis patients with most occurrences during dialysis. The role of these devices in dialysis units will need a larger study to evaluate their efficacy.

Substitution of conserved cysteine residues in wheat streak mosaic virus HC-Pro abolishes virus transmission by the wheat curl mite.

Substitutions in the amino-proximal region of wheat streak mosaic virus (WSMV) HC-Pro were evaluated for effects on transmission by the wheat curl mite (Aceria tosichella Keifer). Alanine substitution at cysteine residues 16, 46 and 49 abolished vector transmission. Although alanine substitution at Cys(20) had no effect, substitution with arginine reduced vector transmission efficiency. Random substitutions at other positions (Lys(7) to Asn, Asn(19) to Ile, and Arg(45) to Lys) did not affect vector transmission. These results suggest that a zinc-finger-like motif (His(13)-X2-Cys(16)-X29-Cys(46)-X2-Cys(49)) in WSMV HC-Pro is essential for vector transmission.

Regulation of neuronal pituitary adenylate cyclase-activating polypeptide expression during culture of guinea-pig cardiac ganglia.

The trophic neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) increases in many different neuron types following injury; a response postulated to support cell survival and regeneration. In acutely isolated cardiac ganglia, approximately 1% of the cardiac neurons exhibited PACAP immunoreactivity whereas after 72 h in culture, approximately 25% of the neurons were PACAP immunoreactive. In contrast, there was no increase in vasoactive intestinal polypeptide (VIP)-immunoreactive (IR) cells. Using a combination of immunocytochemical and molecular techniques, we have quantified PACAP expression, during explant culture of guinea-pig cardiac ganglia. Using real time polymerase chain reaction, PACAP transcript levels increased progressively up to 48 h in culture with no further increase after 72 h. PACAP transcript levels were reduced by neurturin at 48 h in culture but not after 24 or 72 h in culture. In addition, neurturin partially suppressed the percentage of PACAP-IR neurons after 72 h in culture, an effect mediated by activation of the phosphatidylinositol 3-kinase and mitogen-activated protein kinase signaling pathways. The addition of different known regulatory molecules, including ciliary neurotrophic factor (CNTF), interleukin-1 beta (Il-1beta), tumor necrosis factor-alpha (TNFalpha), fibroblast growth factor basic (bFGF), transforming growth factor-beta (TGF-beta) and nerve growth factor (NGF) did not increase the percentage of PACAP-IR neurons after 24 h in culture; a result indicating that the generation and secretion of these factors did not stimulate PACAP expression. The presence of 20 nM PACAP or 10 muM forskolin increased the percentage of PACAP-IR cardiac neurons in 24 h cultures, but not in 72 h cultures. Neither treatment enhanced the number of VIP-IR neurons. The addition of the PACAP selective receptor (PAC(1)) receptor antagonist, M65 (100 nM) suppressed the 20 nM PACAP-induced increase in percentage of PACAP-IR cells in 24 h cultures indicating the effect of PACAP was mediated through the PAC(1) receptor. However, 100 nM M65 had no effect on the percentage of PACAP-IR cells in either 24 or 48 h cultures not treated with exogenous PACAP, suggesting that endogenous release of PACAP likely did not contribute to the enhanced peptide expression. We postulate that the enhanced PACAP expression, which occurs in response to injury is facilitated in the explant cultured cardiac ganglia by the loss of a target-derived inhibitory factor, very likely neurturin. In intact tissues the presence of neurturin would normally suppress PACAP expression. Lastly, our results indicate that many common trophic factors do not enhance PACAP expression in the cultured cardiac neurons. However, the stimulatory role of an, as yet, unidentified factor cannot be excluded.

Racial and ethnic differences in incident myocardial infarction in end-stage renal disease patients: The USRDS.

African Americans have a greater risk of cardiovascular disease (CVD) than Caucasians in early chronic kidney disease; however, limited data describe racial and ethnic differences in the risk of incident myocardial infarction (MI) among patients with end-stage renal disease (ESRD). We conducted a prospective, observational cohort study among 271 102 incident dialysis patients receiving renal replacement therapy enrolled in the United States Renal Data System (USRDS) for whom Medicare was the primary insurer between 1995 and 2000. The incidence and risk of any MI (non-fatal or fatal) estimated by Cox proportional hazards models was the primary outcome of interest. Of those with prevalent CVD at baseline (118 708), 14 849 had an incident non-fatal MI compared with 9926 events for those without prevalent CVD (152 394). Patients with prevalent CVD had higher crude rates of combined fatal and non-fatal MI (99.3/1000 person-years vs 42.9/1000 person-years) compared with those without prevalent CVD. Among those with prevalent CVD, African Americans (adjusted relative risk (aRR)=0.65, 95% confidence interval (CI):0.62-0.68), Asian Americans (aRR=0.74, 95% CI: 0.66-0.83), and Hispanics (aRR=0.72, 95% CI: 0.68-0.77) were 26-35% less likely to have an incident MI compared to Caucasians. Similarly, among those without prevalent CVD, racial/ethnic minorities were 26-42% less likely to have an incident MI compared to Caucasians. We conclude that in a national setting where comparable access to dialysis and associated medical care, exist, racial/ethnic minorities were found to have a lower risk of non-fatal and fatal MI than Caucasians.

Trophic factor modulation of cocaine- and amphetamine-regulated transcript peptide expression in explant cultured guinea-pig cardiac neurons.

The present study investigated the influence of trophic factors on the expression of cocaine- and amphetamine-regulated transcript peptide (CARTp) in guinea-pig cardiac ganglia maintained in explant culture. In acutely isolated cardiac ganglia preparations, <1% of the cholinergic cardiac neurons exhibited CARTp immunoreactivity. In contrast, this number increased to >25% of the cardiac neurons after 72 h in explant culture. This increase in the number of CARTp neurons in cultured cardiac ganglia explants was accompanied by an increase in CARTp transcript levels as assessed by real time polymerase chain reaction. Treatment of cardiac ganglia cultures with neurturin or glial-derived trophic factor (both at 10 ng/ml) for 72 h prevented the increase in neurons that exhibited CARTp immunoreactivity. In contrast, treatment with ciliary neurotrophic factor (50 ng/ml) for 72 h produced a small significant increase in the percentage of CARTp-immunoreactive cardiac neurons and treatment with nerve growth factor (100 ng/ml) had no effect. Neurturin treatment also decreased cardiac neuron CARTp levels after 72 h in explant culture. Cardiac neurons exhibited immunoreactivity to the neurturin receptor GFRalpha2 whereas non-neural cells preferentially exhibited immunoreactivity to the glial-derived neurotrophic factor receptor GFRalpha1 and neurturin transcripts were detected in cardiac tissue extracts. We hypothesize that a target-derived inhibitory factor, very likely neurturin, is a critical factor suppressing the expression of CARTp in guinea-pig cardiac neurons. These observations contrast with those reported in sympathetic neurons that suggest up-regulation of trophic factors after axotomy or during explant culture is a key factor contributing to the up-regulation of many neuropeptides.

Audit of specialist registrar training in tympanomastoid surgery for chronic otitis media.

BACKGROUND: A prospective audit of specialist registrars' (SRs') training in tympanomastoid surgery for chronic otitis media within the Anglia Regional Training Scheme is described. This audit recorded the surgical activity of the trainees and their contribution to operative procedures, and assessed the results of the procedures. This type of systematic approach to the audit of surgical training is important in light of the current shortened training programmes and increased accountability of trainers. OBJECTIVES: The study aimed to establish the levels of exposure to, supervision of and outcome of ear operations for chronic otitis media performed by ENT trainees in the East Anglia region. METHOD: A prospective, region-wide, minimum otology dataset-based proforma audit was undertaken, with compulsory SR participation. Proformas were completed at the time of operation (form one) and at a minimum interval of nine months post-operatively (form two). Data on form one included hospital, supervising consultant, name and training year of SR, contribution of SR (based on England Royal College of Surgeons guidelines interpreted by the SR), pre-operative audiology average (air conduction/bone conduction over 0.5, 1, 2 and 4 kHz), the pathology and the state of the ear at the time of surgery, and a breakdown of the procedure(s) undertaken. Form two recorded data relevant to form one as well as information regarding patient satisfaction and the operative result obtained, graded as 'gold' (no disease, dry ear and hearing average < 25 dB), 'silver' (two of these three) and 'bronze' (one of these three). All completed forms were analysed using Microsoft Access software. RESULTS: Completed copies of 409 form ones and 156 form twos were analysed. With advancing years, SRs' contributions to procedures increased without significant effect on the graded outcome, which appeared to be independent of SR year of training. Different regional hospitals were compared. Data collected also provided an otology training portfolio for SRs, forming part of their registrar in-training assessment (RITA). CONCLUSION: The East Anglia SR audit of SRs' training in tympanomastoid surgery for chronic otitis media was a powerful training tool. It demonstrated the safe progression of SR training in supervised ear surgery, with SRs' results being comparable to those for consultant-performed procedures.

Mechanics of venom expulsion in Crotalus, with special reference to the role of the fang sheath.

A combination of anatomical and experimental preparations were used to explore the function of the venom delivery system in rattlesnakes (Crotalus). The distal end of the venom duct is compressed near the point where it empties into the venom chamber, a space surrounding the fang defined by the fang sheath. Within the venom chamber, the inner fang membrane lies obliquely over the base of the fang at least partially occluding the entrance orifice. When the fang is retracted the combination of the compressed venom duct and the spatial position of the inner fang membrane serve to inhibit or block venom flow. As the fang is erected beyond approximately 60 degrees (relative to the roof of the mouth) localized compression of the fang sheath decreases the size of the venom chamber, relieves the compressive force from the venom duct, and displaces the inner fang membrane away from the entrance orifice of the fang. Pressure recordings taken at different locations along the venom delivery system demonstrate that the venom gland produces suction during relaxation of the extrinsic glandular musculature. These findings suggest that the venom delivery system of Crotalus is both more flexible and more regulated than previously assumed.

The cytoplasmic domain of the integrin alpha9 subunit requires the adaptor protein paxillin to inhibit cell spreading but promotes cell migration in a paxillin-independent manner.

The integrin alpha9 subunit forms a single heterodimer, alpha9beta1. The alpha9 subunit is most closely related to the alpha4 subunit, and like alpha4 integrins, alpha9beta1 plays an important role in leukocyte migration. The alpha4 cytoplasmic domain preferentially enhances cell migration and inhibits cell spreading, effects that depend on interaction with the adaptor protein, paxillin. To determine whether the alpha9 cytoplasmic domain has similar effects, a series of chimeric and deleted alpha9 constructs were expressed in Chinese hamster ovary cells and tested for their effects on migration and spreading on an alpha9beta1-specific ligand. Like alpha4, the alpha9 cytoplasmic domain enhanced cell migration and inhibited cell spreading. Paxillin also specifically bound the alpha9 cytoplasmic domain and to a similar level as alpha4. In paxillin(-/-) cells, alpha9 failed to inhibit cell spreading as expected but surprisingly still enhanced cell migration. Further, mutations that abolished the alpha9-paxillin interaction prevented alpha9 from inhibiting cell spreading but had no effect on alpha9-dependent cell migration. These findings suggest that the mechanisms by which the cytoplasmic domains of integrin alpha subunits enhance migration and inhibit cell spreading are distinct and that the alpha9 and alpha4 cytoplasmic domains, despite sequence and functional similarities, enhance cell migration by different intracellular signaling pathways.

Binding of the initiation factor sigma(70) to core RNA polymerase is a multistep process.

The interaction of RNA polymerase and its initiation factors is central to the process of transcription initiation. To dissect the role of this interface, we undertook the identification of the contact sites between RNA polymerase and sigma(70), the Escherichia coli initiation factor. We identified nine mutationally verified interaction sites between sigma(70) and specific domains of RNA polymerase and provide evidence that sigma(70) and RNA polymerase interact in at least a two-step process. We propose that a cycle of changes in the interface of sigma(70) with core RNA polymerase is associated with progression through the process of transcription initiation.

A coiled-coil from the RNA polymerase beta' subunit allosterically induces selective nontemplate strand binding by sigma(70).

For transcription to initiate, RNA polymerase must recognize and melt promoters. Selective binding to the nontemplate strand of the -10 region of the promoter is central to this process. We show that a 48 amino acid (aa) coiled-coil from the beta' subunit (aa 262--309) induces sigma(70) to perform this function almost as efficiently as core RNA polymerase itself. We provide evidence that interaction between the beta' coiled-coil and region 2.2 of sigma(70) promotes an allosteric transition that allows sigma(70) to selectively recognize the nontemplate strand. As the beta' 262--309 peptide can function with the previously crystallized portion of sigma(70), nontemplate recognition can be reconstituted with only 47 kDa, or 1/10 of holoenzyme.

Health-related quality of life among dialysis patients in Seattle and Aichi.

We used the 36-item Short-Form Health Survey to compare health-related quality of life (HRQOL) between 104 dialysis patients in Seattle, WA, and 2,178 patients in Aichi, JAPAN: Compared with Aichi patients, Seattle patients had lower scores on three scales related to physical HRQOL: Physical Functioning (PF; P = 0.03), Role-Physical (RP; P = 0.004), and Vitality (VT; P < 0.001). However, scores related to mental HRQOL were higher for Seattle patients compared with those of Aichi patients, which included scores for Role-Emotional (RE; P = 0.005) and Mental Health (MH; P < 0.001). Scores for Bodily Pain, General Health Perception, and Social Functioning did not differ significantly between the two groups. These differences persisted even after potential confounding factors were controlled for. However, after taking into account national norm data for the United States and Japan, differences in PF and VT disappeared, whereas differences in RP, RE, and MH persisted. These results suggest that the higher scores for PF and VT in Aichi patients were partly explained by the higher physical HRQOL of the Japanese general population. Although these data may not be representative of the total dialysis populations in the United States and Japan, they suggest potential differences in HRQOL between patients in the two countries. Additional research is needed to confirm these results and understand the factors associated with these differences. The findings suggest the need for further attention to the physical limitations of US dialysis patients and the mental health of Japanese dialysis patients.