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This study aimed to improve our understanding of the natural history of cystic fibrosis (CF) by comparing lung function and body mass index z-score (zBMI) between patients with different genotypes and identify a genotype with outcomes most comparable to homozygous ΔF508 patients. Data was obtained from the Canadian CF Registry between January 1st 2007-January 1st 2016. Patients were categorized into one of five groups based on their genotype. A mixed-effects model was conducted with adjustments for age, sex, age of diagnosis, and baseline clinical measures. Among 2612 patients, those with non-mild forms of CF, and particularly adult patients with the same functional allele classification were found to have a lung function trajectory comparable to individuals with the homozygous ∆F508 genotype (annual change in percent predicted forced expiratory volume in 1 s of −0.83, 95% CI: −0.93, −0.73). The rates of zBMI change over the study period were not significantly different between the genotype groups. This population-based study of Canadian CF patients provides adjusted rates of lung function decline and zBMI over ten years. The finding that there are different genotypes with comparable rates of lung function decline to patients of the homozygous ∆F508 group supports the use of multiple comparison groups to assess the long-term efficacy of emerging CF therapies. • This study of Canadian CF patients provides adjusted rates of lung function decline and zBMI over ten years. • We identified different genotypes with comparable rates of lung function decline to homozygous ΔF508 patients. • The long-term efficacy of new CF therapies can be assessed using this methodology and multiple genotype comparison groups. [ABSTRACT FROM AUTHOR]

We have monitored a newly erupted volcanic island in the Kingdom of Tonga, unofficially known as Hunga Tonga Hunga Ha'apai, by means of relatively frequent high spatial resolution (~50 cm) satellite observations. The new ~1.8 km2 island formed as a tuff cone over the course of a month‐long hydromagmatic eruption in early 2015 in the Tonga‐Kermadec volcanic arc. Such ash‐dominated eruptions usually produce fragile subaerial landscapes that wash away rapidly due to marine erosion, as occurred nearby in 2009. Our measured rates of erosion are ~0.00256 km3/year from derived digital topographic models. Preliminary measurements of the topographic expression of the primary tuff cone over ~30 months suggest a lifetime of ~19 years (and potentially up to 42 years). The ability to measure details of a young island's landscape evolution using satellite remote sensing has not previously been possible at these spatial and temporal resolutions. [ABSTRACT FROM AUTHOR]

Objective Osteoarthritis ( OA) of the hand can be a debilitating condition that hinders an individual's quality of life. With multiple joints within the hand that are commonly affected OA, an individual's ability to use their hand in everyday movements become more limited. The article aims to review literature on the aetiology and pathogenesis of OA, risk factors, characteristics of hand OA and the steps of diagnosis. Key findings The aetiology and pathogenesis of OA, in particular hand OA, is not fully understood. However, it is known that several factors play a role. Environmental factors, such as stress from mechanical loading, especially to vulnerable joints predispose individuals to developing OA. Extracellular matrix changes in protein levels have also been noted in individuals with OA. Linked to hand OA development are boney enlargements ( Herbeden's and Bouchard's nodes). Several risk factors for OA include: age, obesity, gender, smoking, genetics, diet and occupation. Various diagnostic methods include a combination of using radiographic methods, clinical presentation, a number of developed measurements and scales. Summary With OA having several risk factors and various causes and contributing elements, it is important to elucidate the pathogenesis of OA and determine exactly how risk factors play a role in its development. Because of the contributions from several elements, diagnosis is best when it uses multiple methods. In turn, understanding OA and making better diagnoses could lead to improved management of the condition through both pharmacological and non-pharmacological interventions. [ABSTRACT FROM AUTHOR]

Objective This article aims to review osteoarthritis of the hand and the role of the non-steroidal anti-inflammatory drug ( NSAID) naproxen on its management. We discuss the chemical and pharmacological properties of naproxen and the NSAID class, with an emphasis on its mechanism and adverse reactions. In the context of part I of this paper in characterizing hand osteoarthritis ( OA), we review clinical trials that have been conducted involving hand OA and naproxen. Key findings The therapeutic effect of NSAIDs stems from its role on inhibiting cyclo-oxygenase ( COX)-1 or COX-2 enzyme activity in the body. These enzymes play a major role in maintaining several functions in the body and due NSAIDs' inhibitory effects; many principle adverse reactions occur with the use of NSAIDs such as: gastrointestinal tract issues, cardiovascular risks, renal, hepatic, central nervous system and cutaneous. Review of clinical trials involving naproxen and hand OA show that it is significantly more efficacious when compared with placebo. Summary These studies, along with the finding that naproxen is of least cardiovascular risk in the NSAID class, may show that it can be part of one of the approaches in managing the condition. It is important to note that the optimal NSAID to use varies for each individual. The finding that the use of naproxen leads to the smallest increase in cardiovascular risk appeals to those at-risk individuals who suffer from OA and require pharmacological treatment for relief. [ABSTRACT FROM AUTHOR]

Fusarium wilt (caused by Fusarium oxysporum f. sp. loti) is a serious disease of birdsfoot trefoil, Lotus cornicu/atus L., reducing yield of forage and seed. In the early 1990s a breeding program was begun to breed a Fusarium wilt-resistant birdsfoot trefoil. Our objectives were to (i) determine progress from recurrent phenotypic selection for resistance to Fusarium wilt in six birdsfoot trefoil populations and (ii) compare forage yield and persistence of Fusarium wilt-resistant populations to unselected populations in field trials. Recurrent phenotypic selection was effective in improving resistance in the greenhouse, with mean improvement of 35% across all populations after three cycles of selection. In a field with high natural disease pressure, a population developed after two cycles of selection for resistance had lower levels of disease incidence and yielded 1.33 Mg ha-1 more than the mean of nine cultivars in the seeding year. The Fusarium wilt-resistant population had 52% higher plant stand than the mean of the other cultivars at the end of the first production year. In a trial inoculated with the Fusarium wilt organism, two cycle 3 populations averaged 28% more yield by June of the fourth production year and 22 more plants per m² than the mean of the unselected populations. Birdsfoot trefoil with resistance to Fusarium wilt yielded more and persisted longer than other cultivars under Fusarium wilt-infested field conditions. [ABSTRACT FROM AUTHOR]

In vitro experiments showed that the connecting tubule (CNT) sends a signal that dilates the afferent arteriole (Af-Art) when Na+ reabsorption in the CNT lumen increases. We call this process CNT glomerular feedback (CTGF) to differentiate it from tubuloglomerular feedback (TGF), which is a cross talk between the macula densa (MD) and the Af-Art. In TGF, the MD signals the Af-Art to constrict when NaCl transport by the MD is enhanced by increased luminal NaCl. CTGF is mediated by CNT Na+ transport via epithelial Na+ channels (ENaC). However, we do not know whether CTGF occurs in vivo or whether it opposes the increase in Af-Art resistance caused by TGF. We hypothesized that CTGF occurs in vivo and opposes TGF. To test our hypothesis, we conducted in vivo micropuncture of individual rat nephrons, measuring stop-flow pressure (PSF) as an index of glomerular filtration pressure. To test whether activation of CTGF opposes TGF, we used benzamil to block CNT Na+ transport and thus CTGF. CTGF inhibition with the ENaC blocker benzamil (1 μM) potentiated the decrease in PSF at 40 and 80 nl/min. Next, we tested whether we could augment CTGF by inhibiting NaCl reabsorption in the distal convoluted tubule with hydrochlorothiazide (HCTZ, 1 mM) to enhance NaCl delivery to the CNT. In the presence of HCTZ, benzamil potentiated the decrease in PSF at 20, 40, and 80 nl/min. We concluded that in vivo CTGF occurs and opposes the vasoconstrictor effect of TGF. [ABSTRACT FROM AUTHOR]

Background: In response to the requirements of the European Working Time Directive (EWTD), a national implementation group was formed to liaise with local implementation groups at nine different pilot sites. As part of this process, a pilot EWTD compliant rota was run for six weeks amongst general surgical SHOs in University Hospital Calway. Methods: A rota was devised for nine general surgical SHOs, the aim being to achieve EWTD compliance. SHOs were asked to complete questionnaires to assess the effectiveness of the pilot. Result: During the pilot SHOs were rostered for an average of 53.6 hours. Actual hours worked were 58.1 hours. Fifty-two point five per cent of working weeks were non-compliant with the provisions of the EWTD. Seventy per cent of the time SHOs felt that continuity of care was not achieved. Eighty-one per cent felt that patient care deteriorated during the pilot. SHOs spent an average of 2.5 days per week engaged in sessional commitments with their consultant. Fifty percent of SHOs missed elective operating sessions or outpatient clinics. SHOs attended an average of 1.3 emergency operations per week (range 0-8) and 5.5 elective procedures per week (range 0-12). All SHOs reported a deterioration in quantity or quality of training. However, 69% reported an improvement in their quality of life during the pilot. Conclusions: With this tightly defined shift system, hours worked were in breach of the provisions of the EWTD. Sixty-nine per cent of SHOs reported an improvement in quality of life, but all reported a deterioration in training and 81% felt that patient care suffered. [ABSTRACT FROM AUTHOR]

Deoxynivalenol (DON) levels are not easily predicted from visual disease assessment, and it is thought likely that environmental conditions such as temperature and moisture influence DON accumulation. This field study examined the influence of environmental moisture on DON accumulation in Fusarium-infected wheat (Triticum aestivum). The effect of extended mist irrigation applied from inoculation (at anthesis) until harvest was compared with mist irrigation applied from inoculation until disease assessment (at early dough), as is generally applied in screening nurseries used for germplasm selection and cultivar improvement. DON concentrations were quantified in kernels at early dough, hard dough, kernel hard, and maturity. Kernels from plots with extended mist irrigation generally had lower DON concentrations than those from plots where mist irrigation was not applied following disease assessment. DON concentrations tended to decrease from disease assessment until harvest, regardless of the irrigation treatment. DON concentrations in the cultivars moderately resistant to Fusarium head blight were lower than those in the susceptible cultivar. Environmental moisture is an important factor determining the DON content of Fusarium-infected wheat. [ABSTRACT FROM AUTHOR]

The renal afferent arterioles (Af-Arts) account for most of the renal vascular resistance, which is controlled similar to other arterioles and by tubuloglomerular feedback (TGF). The latter signal is generated by sensing sodium chloride concentrations in the macula densa; this in turn results in a signal which acts through the extraglomerular mesangium leading to constriction of the Af-Art. In the outer renal cortex, the connecting tubule (CNT) returns to the glomerular hilus and contacts the Af-Art suggesting that crosstalk may exist here as well. To investigate this, we simultaneously perfused a microdissected Af-Art and adherent CNT. Increasing the sodium chloride concentration perfusing the CNT significantly dilated preconstricted Af-Arts. We called this crosstalk ‘connecting tubule glomerular feedback’ (CTGF) to differentiate it from TGF. We tested whether entry of Na+ and/or CI− into the CNT is required to induce CTGF by replacing Na+ with choline+. Increasing choline chloride concentration did not dilate the Af-Art. To test whether epithelial Na channels (ENaCs) mediate CTGF, we blocked ENaC with amiloride and found that the dilatation induced by CTGF was completely blocked. Inhibiting sodium chloride cotransporters with hydrochlorothiazide failed to prevent Af-Art dilatation. Finally, we tested whether nitric oxide released by the CNT mediates CTGF by the addition of a non-selective nitric oxide synthase inhibitor to the CNT. This potentiated CTGF rather than blocking it. We suggest that crosstalk exists between CNTs and attached Af-Arts, which is initiated by sodium reabsorption through amiloride-sensitive channels and this can contribute to the regulation of renal blood flow and glomerular filtration.Kidney International (2007) 71, 1116–1121. doi:10.1038/sj.ki.5002190; published online 14 March 2007 [ABSTRACT FROM AUTHOR]

Adenosine triphosphate (ATP) is liberated from macula densa cells in response to increased tubular NaCl delivery. However, it is not known whether ATP from the macula densa is broken down to adenosine, or whether this adenosine mediates efferent arteriole (Ef-Art) tubuloglomerular feedback (TGF). We hypothesized that increased macula densa Ca2+, release of ATP and degradation of ATP to adenosine are necessary for Ef-Art TGF. Rabbit Ef-Arts and adherent tubular segments (with the macula densa) were simultaneously microperfused in vitro while changing the NaCl concentration at the macula densa. The Ef-Art was perfused orthograde through the end of the afferent arteriole (Af-Art). In Ef-Arts preconstricted with norepinephrine (NE), increasing NaCl concentration from 10 to 80 mM at the macula densa dilated Ef-Arts from 7.5±0.7 to 11.1±0.3 μm. Buffering increases in macula densa Ca2+ with the cell-permeant Ca2+ chelator BAPTA-AM diminished Ef-Art TGF from 3.1±0.3 to 0.1±0.2 μm. Blocking adenosine formation by adding α-β-methyleneadenosine 5′-diphosphate (MADP) blocked Ef-Art TGF from 2.9±0.5 to 0.1±0.2 μm. Increasing luminal NaCl at the macula densa from 10 to 45 mM caused a moderate Ef-Art TGF response, 1.3±0.1 μm. It was potentiated to 4.0±0.3 μm by adding hexokinase, which enhances conversion of ATP into adenosine. Our data show that in vitro changes in macula densa Ca2+ and ATP release are necessary for Ef-Art TGF. ATP is broken down to form adenosine, which mediates signal transmission of Ef-Art TGF.Kidney International (2007) 71, 861–866. doi:10.1038/sj.ki.5002161; published online 7 March 2007 [ABSTRACT FROM AUTHOR]

A simple procedure is used to formulate a Cu–Pb pair interaction function within the embedded atom (EAM) method framework. Embedding, density and pair functions for pure Cu and pure Pb are taken from previously published EAM studies. Optimization of the Cu–Pb potential was achieved by comparing with experiment the computed heats of mixing for Cu–Pb liquid alloys and the equilibrium phase diagram, the latter being determined via a thermodynamic integration technique. The topology of the temperature-composition phase diagram computed with this EAM potential is consistent with experiment and features a liquid–liquid miscibility gap, low solubility of Pb in solid Cu and a monotectic reaction at approximately 1012 K. [ABSTRACT FROM AUTHOR]

The prognosis in patients with primary brain tumors treated with surgery, radiotherapy and conventional chemotherapy remains poor. To improve outcome, combination high-dose chemotherapy (HDC) has been explored in children, but rarely in adults. This study was performed to determine the tolerability of three-drug combination high-dose thiotepa (T) and etoposide (E)-based regimens in pediatric and adult patients with high-risk or recurrent primary brain tumors. Thirty-one patients (13 children and 18 adults) with brain tumors were treated with high-dose chemotherapy: 19 with BCNU (B) and TE (BTE regimen), and 12 with carboplatin (C) and TE (CTE regimen). Patients received growth factors and hematopoietic support with marrow (n = 15), peripheral blood progenitor cells (PBPC) (n = 11) or both (n = 5). The 100 day toxic mortality rate was 3% (1/31). Grade III/IV toxicities included mucositis (58%), hepatitis (39%) and diarrhea (42%). Five patients had seizures and two had transient encephalopathy (23%). All patients had neutropenic fever and all pediatric patients required hyperalimentation. Median time to engraftment with absolute neutrophil count (ANC) >0.5 × 109/l was 11 days (range 8–37 days). Time to ANC engraftment was significantly longer (P = 0.0001) in patients receiving marrow (median 14 days, range 10–37) than for PBPC (median 9.5 days, range 8–10). Platelet engraftment >50 × 109/l was 24 days (range 14–53 days) in children. In adults, platelet engraftment >20 × 109/l was 12 days (range 9–65 days). In 11 patients supported with PBPC, there was a significant inverse correlation between CD34+ dose and days to ANC (rho = -0.87, P = 0.009) and platelet engraftment (rho = -0.85, P = 0.005), with CD34+ dose predicting time to engraftment following HDC. Overall, 30% of evaluable patients (7/24) had a complete response (CR) (n = 3) or partial response (PR) (n... [ABSTRACT FROM AUTHOR]

Introduction: Surgical intervention for giant inguino-scrotal herniae in the acute setting is high risk with significantly increased incidence of morbidity and mortality. While uncommon in modern practise, there are several surgical issues and approaches that need to be considered when this problem presents. Case Report and Discussion: We describe the unusual occurrence of acute duodenal rupture as a direct result of a giant inguino-scrotal hernia. The literature on the operative management of giant inguino-scrotal hernia is also reviewed. Conclusion: Giant inguino-scrotal herniae are best managed electively with full preoperative work up and assessment. Surgery in the acute patient is fraught with difficulty leading to increased morbidity. [ABSTRACT FROM AUTHOR]

The InSight lander carried an Instrument Deployment System (IDS) that included an Instrument Deployment Arm (IDA), scoop, five finger "claw" grapple, forearm-mounted Instrument Deployment Camera (IDC) requiring arm motion to image a target, and lander-mounted Instrument Context Camera (ICC), designed to image the workspace, and to place the instruments onto the surface. As originally proposed, the IDS included a previously built arm and flight spare black and white cameras and had no science objectives or requirements, or expectation to be used after instrument deployment (90 sols). During project development the detectors were upgraded to color, and it was recognized that the arm could be used to carry out a wide variety of activities that would enable both geology and physical properties investigations. During surface operations for two martian years, the IDA was used during major campaigns to image the surface around the lander, to deploy the instruments, to assist the mole in penetrating beneath the surface, to bury a portion of the seismometer tether, to clean dust from the solar arrays to increase power, and to conduct a surface geology investigation including soil mechanics and physical properties experiments. No other surface mission has engaged in such a sustained and varied campaign of arm and scoop activities directed at such a diverse suite of objectives. Images close to the surface and continuous meteorology measurements provided important constraints on the threshold friction wind speed needed to initiate aeolian saltation and surface creep. The IDA was used extensively for almost 22 months to assist the mole in penetrating into the subsurface. Soil was scraped into piles and dumped onto the seismometer tether six times in an attempt to bury the tether and ∼ 30 % was entrained in the wind and dispersed downwind 1-2 m, darkening the surface. Seven solar array cleaning experiments were conducted by dumping scoops of soil from 35 cm above the lander deck during periods of high wind that dispersed the sand onto the panels that kicked dust off of the panels into suspension in the atmosphere, thereby increasing the power by ∼15% during this period. Final IDA activities included an indentation experiment that used the IDA scoop to push on the ground to measure the plastic deformation of the soil that complemented soil mechanics measurements from scoop interactions with the surface, and two experiments in which SEIS measured the tilt from the arm pressing on the ground to derive near surface elastic properties. [ABSTRACT FROM AUTHOR]

Examines the role of tamoxifen and anastrazole on the inhibition of angiogenesis. Importance of angiogenesis for tumor growth and metastasis; Identification of angiogenesis as a prognostic factor for recurrence in breast cancer; Evaluation of the anti-angiogenic properties of endocrine therapies.

Examines the role of tamoxifen and anastrazole on the inhibition of angiogenesis. Importance of angiogenesis for tumor growth and metastasis; Identification of angiogenesis as a prognostic factor for recurrence in breast cancer; Evaluation of the anti-angiogenic properties of endocrine therapies.

Background: Central nervous system (CNS) germ cell tumors account for 3 % of all pediatric brain tumors in the USA. Presenting symptoms are typically location based with pineal tumors presenting with obstructive hydrocephalus and suprasellar tumors with hypothalamic/pituitary dysfunction and ophthalmologic abnormalities. Psychiatric manifestations such as psychosis and behavioral changes are atypical presentations of CNS germ cell tumors, with only 11 previously reported cases. Methods: This is a retrospective case series describing patients with CNS germ cell tumors with an atypical presentation including psychiatric manifestations. Information regarding clinical presentation, treatment course, and outcome were obtained. Results: We report seven patients who presented with psychiatric symptoms consisting of psychomotor delay as well as behavioral and mood changes. Six of the seven patients were diagnosed ≥6 months after onset of psychiatric symptoms. All of the seven are alive but five continue to have neurologic and psychiatric issues post treatment. Conclusions: Atypical presentations of CNS germ cell tumors can delay diagnosis and treatment and may be secondary to atypical locations as well as endocrine dysfunction manifesting as psychiatric symptoms. Delayed diagnosis did not appear to affect survival but earlier diagnosis may potentially be associated with better neurologic and psychiatric outcome. Patients who present with these symptoms and atypical neuroimaging should have a thorough evaluation for CNS germ cell tumors including serum and CSF markers. Clinicians should be aware of these less common presentations to aid in prompt diagnosis and treatment. [ABSTRACT FROM AUTHOR]

DIPG/DMG is a fatal brain tumor commonly found in the brainstem with a median overall survival of 1 year. The blood-brain barrier (BBB) poses a major challenge to the delivery of therapeutic agents. Over the past 4-years we opened two Phase I clinical trials using Delsona focused ultrasound (FUS) device developed at Columbia to treat pediatric and AYA patients with relapsed DMG. The first study, we delivered FUS with panobinostat and second study we gave concurrent etoposide. Here we present the experience of delivering neuronavigation based FUS for pediatric patients with progressive DMG from the two studies. Pediatric and AYA patients with biopsy proven DIPG/DMG at disease relapsed were enrolled onto clinicaltrial.org identified NCT04804709 (FUS with oral panobinostat) or clinicaltrial.org identified NCT05762419 (FUS with oral etoposide). Patients were allowed to have prior therapies, including radiation and reirradiation. FUS was delivered over the course of up to six or four cycles respectively. MRI was performed to validate BBB-opening and closure. For the FUS panobinostat study, we enrolled 5 patients and accrued 3. The study was closed prematurely when panobinostat was taken off the market. For the FUS etoposide study, we enrolled 3 patients and accrued 2. This study is currently open. For the two trials combined, we delivered over twenty-five FUS treatments. Four of five patients accrued had achieved BBB-opening. 3 of 5 patients had reirradiation prior to enrollment. All FUS delivery were performed as an outpatient procedure in the Department of Radiation Oncology. The average time for BBB-delivery defined as patient entering the treatment room to completion of treatment was approximately 47 minutes. Side effects from FUS was limited to one grade 1 dermatological toxicity. FUS-mediated BBB-opening delivered as an outpatient procedure is preliminarily feasible in children with relapsed DIPG/DMG. Further studies are needed to assess for efficacy. [ABSTRACT FROM AUTHOR]

During the Juno Mission's encounter with Ganymede on 7 June 2021, the Juno camera (JunoCam) acquired four images of Ganymede in color. These images covered one‐sixth of Ganymede at scales from 840 m to ∼4 km/pixel. Most of this area was only previously imaged by Voyager 1 in 1979, at lower spatial resolution and poorer image quality. No changes were observed over this area of Ganymede in the 42 years since Voyager. JunoCam provided overlapping coverage, from which we developed a digital elevation model of the best‐resolved area. A 3 km high dome at the subjovian point was confirmed, 450 km by 750 km. We used the JunoCam images to refine the geologic map of Ganymede in eastern Perrine Regio. Plain Language Summary: Juno flew by Jupiter's moon Ganymede on 7 June 2021, taking four color images. They covered about one‐sixth of Ganymede at a scale as small as 840 m/pixel, an improvement over the previous coverage from Voyager 1 in 1979. No changes were seen. Features were seen not previously recognized, including 10 possible cryovolcanoes. Topography of several features was derived from stereo coverage, including a 3 km high dome at the subjovian point, confirming observations made from Voyager. Key Points: In 2021, Juno camera (JunoCam) acquired close‐up images of Ganymede, providing improved spatial resolution relative to the 1979 Voyager 1 coverageWhile no changes were observed in the 42 years since Voyager, previously unrecognized paterae and craters were identifiedTopography derived from JunoCam confirmed a 3 km high dome at Ganymede's subjovian point and showed it to be elliptical in planform [ABSTRACT FROM AUTHOR]

The NASA InSight Lander on Mars includes the Heat Flow and Physical Properties Package HP3 to measure the surface heat flow of the planet. The package uses temperature sensors that would have been brought to the target depth of 3–5 m by a small penetrator, nicknamed the mole. The mole requiring friction on its hull to balance remaining recoil from its hammer mechanism did not penetrate to the targeted depth. Instead, by precessing about a point midway along its hull, it carved a 7 cm deep and 5–6 cm wide pit and reached a depth of initially 31 cm. The root cause of the failure – as was determined through an extensive, almost two years long campaign – was a lack of friction in an unexpectedly thick cohesive duricrust. During the campaign – described in detail in this paper – the mole penetrated further aided by friction applied using the scoop at the end of the robotic Instrument Deployment Arm and by direct support by the latter. The mole tip finally reached a depth of about 37 cm, bringing the mole back-end 1–2 cm below the surface. It reversed its downward motion twice during attempts to provide friction through pressure on the regolith instead of directly with the scoop to the mole hull. The penetration record of the mole was used to infer mechanical soil parameters such as the penetration resistance of the duricrust of 0.3–0.7 MPa and a penetration resistance of a deeper layer (> 30 cm depth) of 4.9 ± 0.4 MPa . Using the mole’s thermal sensors, thermal conductivity and diffusivity were measured. Applying cone penetration theory, the resistance of the duricrust was used to estimate a cohesion of the latter of 2–15 kPa depending on the internal friction angle of the duricrust. Pushing the scoop with its blade into the surface and chopping off a piece of duricrust provided another estimate of the cohesion of 5.8 kPa. The hammerings of the mole were recorded by the seismometer SEIS and the signals were used to derive P-wave and S-wave velocities representative of the topmost tens of cm of the regolith. Together with the density provided by a thermal conductivity and diffusivity measurement using the mole’s thermal sensors, the elastic moduli were calculated from the seismic velocities. Using empirical correlations from terrestrial soil studies between the shear modulus and cohesion, the previous cohesion estimates were found to be consistent with the elastic moduli. The combined data were used to derive a model of the regolith that has an about 20 cm thick duricrust underneath a 1 cm thick unconsolidated layer of sand mixed with dust and above another 10 cm of unconsolidated sand. Underneath the latter, a layer more resistant to penetration and possibly containing debris from a small impact crater is inferred. The thermal conductivity increases from 14 mW/m K to 34 mW/m K through the 1 cm sand/dust layer, keeps the latter value in the duricrust and the sand layer underneath and then increases to 64 mW/m K in the sand/gravel layer below. [ABSTRACT FROM AUTHOR]

Medullary thick ascending limbs ( mTAL) regulate Na balance and therefore blood pressure. We previously showed that cell swelling and luminal flow activates the mechanosensitive channel TRPV4 in mTAL. Aim We hypothesized that TRPV4 mediates flow-induced increases in intracellular Ca (Cai) in rat mTALs. Methods We performed ratiometric measurements of Cai in perfused mTALs. Results Increasing luminal flow from 0 to 20 nL min−1 caused Cai to peak 231 ± 29 nmol L−1 above basal concentrations ( n = 18). The general TRPV inhibitor ruthenium red at 15 and 50 μmol L−1 reduced peak Cai by 41 ± 9 ( P < 0.01; n = 5) and 77 ± 10% ( P < 0.02; n = 6). The selective TRPV4 inhibitor RN1734 at 10 and 50 μmol L−1 reduced peak Cai by 46 ± 11 ( P < 0.01; n = 7) and 76 ± 5% ( P < 0.02; n = 5) respectively. To specifically target TRPV4, mTALs were transduced with adenoviruses expressing TRPV4 small hairpin (sh) RNA. In non-transduced control mTALs, luminal flow generated a peak increase in Cai of 111 ± 21 nmol L−1 ( n = 8). In TRPV4sh RNA-transduced mTALs, the Cai peak was reduced to 56 ± 8 nmol L−1 ( P < 0.03, n = 9). Removing extracellular Ca completely abolished flow-induced increases in Cai. Increasing luminal flow in the presence of hexokinase 20 (U mL−1) to scavenge extracellular ATP did not modify significantly the increases in Cai induced by luminal flow. Finally, we studied the effect of the TRPV4 selective agonist GSK1016790A on Cai. In the absence of luminal flow, GSK1016790A (10 nmol L−1) increased Cai from 60 ± 11 nmol L−1 to 262 ± 71 nmol L−1 ( P < 0.05; n = 7). Conclusion We conclude that flow-induced increases in Cai are mediated primarily by TRPV4 in the rat mTAL. [ABSTRACT FROM AUTHOR]

Durable resistance to disease is a common component of plant defense systems in natural ecosystems and can be found in virtually all cultivated species. Agricultural production practices increase crop vulnerability to most diseases, so higher levels of resistance than occur in natural ecosystems may be needed. Monogenic resistance to highly specialized pathogens is often highly effective when first developed but is generally race-specific and nondurable, especially when characterized by hypersensitive host reactions. Partial resistance conditioned by several to many genes with additive effects is usually durable, particularly when it involves morphological or developmental changes in the plant. Exceptions to the general rule of nondurable monogenic resistance and durable polygenic resistance are presented. Recurrent selection is commonly used to develop cultivars with durable resistance, but durable resistance has also been achieved through pedigree breeding in small grains. Success in accumulating polygenic durable resistance to multiple diseases of maize and to leaf rust and stripe rust of wheat are described as the mixed record of success in breeding for late blight resistance in potato. The mlo gene for resistance to powdery mildew in barley offers an intriguing case of highly effective monogenic resistance that appears to be durable. Modern molecular genetic approaches offer promise not only for marker-assisted selection of partial resistance genes but also for creation of novel forms of resistance to plant diseases. Nevertheless, traditional breeding and field tests will still have an essential role in developing commercial cultivars. [ABSTRACT FROM AUTHOR]

Summary:Severe mucositis is a common cause of morbidity in hematopoietic stem cell transplant (HSCT) recipients. Glutamine has been shown to reduce mucositis in children receiving chemotherapy. Patients were randomized in a double-blind manner to receive glutamine or glycine at a dose of 2 g/m2/dose (maximum dose 4 g) twice daily until 28 days post transplant or discharge if sooner. Mucositis was graded by use of a modified Walsh scale. A total of 120 children were evaluable: 57 children received glutamine and 63 received glycine. The mean mucositis score was 3.0±0.3 vs 3.9±0.4 (P=0.07) in the glutamine and glycine groups, respectively. The glutamine group demonstrated a reduction in mean number of days of intravenous narcotics use (12.1±1.5 vs 19.3±2.8 in the glycine group, P=0.03) and total parenteral nutrition (17.3±1.7 vs 27.3±3.6 in glycine group, P=0.01). There was no statistically significant difference in toxicity between the two groups. Glutamine appears to be safe and beneficial in reducing the severity of mucositis. Strong consideration should be given to include oral glutamine supplementation as a routine part of supportive care of SCT patients.Bone Marrow Transplantation (2005) 36, 611–616. doi:10.1038/sj.bmt.1705084; published online 8 August 2005 [ABSTRACT FROM AUTHOR]

Summary:We report results of unrelated cord blood transplants (UCBT) in 29 pediatric recipients in one center and the risk factors associated with survival. Median age: 9 years (0.5-20); diagnosis: ALL (9), AML (4), CML (1), HD (3), HLH (1), NHL (3), NBL (2); B-thal (1), FA (1), FEL (1), Krabbe (1), WAS (1), SAA (1); median follow-up: 11 months; conditioning: total body irradiation (TBI)-ablative (14), chemotherapy-ablative (6) and reduced intensity chemotherapy (9); GVHD prophylaxis: MMF/FK506 (18), cyclosporin A (CsA)+steroids±MMF (7) or CsA+methotrexate (MTX) (4); median total nucleated cells (TNC): 3.8 × 107/kg (1.1-11); median CD34+: 2.3 × 105/kg (0.2-9.9); and HLA match: 2 (6/6), 5 (5/6), 22 (4/6). Neutrophil engraftment by cumulative incidence curves 63% (median 28 (95% confidence interval (CI) 18-32)). Probability of ?grade II acute graft-versus-host disease (aGVHD) by day +60 27%, ?grade III aGVHD 20% and chronic graft-versus-host disease 3%. Estimated 1-year overall survival (OS) 46% (95% CI 30-71) and standard risk 60% (95% CI 29-100%). Variables associated with improved survival by multivariate analysis include non-TBI-ablative conditioning (P=0.024), CD34+/kg (P=0.038) and gender (P=0.048). These results suggest that CD34/kg cell dose and non-TBI-ablative conditioning may be important variables influencing OS following UCBT in pediatric recipients. Given the small number of patients, these results should be viewed cautiously.Bone Marrow Transplantation (2004) 34, 129-136. doi:10.1038/sj.bmt.1704537 Published online 26 April 2004 [ABSTRACT FROM AUTHOR]

Diffuse Midline Glioma with H3K27M mutation (DMG) is a universally fatal tumor primarily treated with radiotherapy (RT) and typically unresponsive to immune-based therapies. FLASH is a novel RT technique associated with decreased toxicity and effective tumor control in glioma models as well as immune-sparing properties in other cancer models. However, the effect of FLASH on the DMG tumor immune microenvironment (TIME) has not yet been explored. Using a syngeneic murine brainstem DMG, we performed single-cell RNA sequencing on CD45+ cells isolated from tumors 4 days after posterior fossa irradiation (15Gy x 1, 9MeV), utilizing either ultra-high dose rate (90Gy/sec, FLASH) or conventional (2Gy/min, CONV) RT, and compared to unirradiated tumor (SHAM). For differential gene expression analysis, we compared CONV to SHAM (CvS) and FLASH to SHAM (FvS). We also performed single cell gene set enrichment scores (ssGSEA) for evaluation of immune signatures from gene ontology (GO); ssGSEA scores were deemed significant by a p<0.05 using Mann-Whitney U test. We validated our most robust immune markers with dual immunofluorescence. Unsupervised clustering of 23,165 CD45+ cells revealed 16 immune clusters, including subtypes of resident microglia (MG, 78.2% of total cells), lymphocytes (6.4%), macrophages (MPs, 5.2%), monocytes (1.8%), and dendritic cells (DCs, 1.7%). MG consisted of four distinct subtypes representing a spectrum of homeostatic to activated cellular states. In the most activated MG subtype, both CONV and FLASH showed an upregulation of interferon (IFN) genes such as Isg15 (Fold Change (FC) 1.03 CvS, 0.94 FvS) and Ifit3 (FC 0.77 CvS, 0.66 FvS) when compared to SHAM. Furthermore, ssGSEA of MG found IFN scores increased in both FvS (p < 0.0001) and CvS (p < 0.0001) while TGFbR signaling score was increased in FvS (p < 0.0001) and decreased in CvS (p < 0.0001). In non-resident myeloid clusters, the most differential response was found in MPs and DCs with robust upregulation of IFN genes for CvS (Isg15 FC 2.30 MPs, 2.67 DCs; Ifit3 FC 2.02 MPs, 2.06 DCs), while this response was not seen with FvS. This was confirmed with ssGSEA with increased IFN scores in both MPs (CvS p<0.0001, p=0.04) and DCs (CvS p<0.0001, FvS p=0.69). FLASH showed an increase in anti-inflammatory MP markers such as Mrc1, Cd163, and Maf (FC 1.40, 1.11, 1.19) and an upregulated myeloid-derived suppressor cell signature in monocytes (FvS, p < 0.0001), not seen in CvS (p = 0.09). Our work is the first to map CONV and FLASH immune alterations with single-cell resolution in the DMG TIME. FLASH induces IFN differentially across microglia and non-resident myeloid subsets. Further exploration is warranted to understand how FLASH impacts tumor growth through differential cytokine signaling, inflammatory responses and immune checkpoint expression within the DMG TIME. [ABSTRACT FROM AUTHOR]

The outcome of children, adolescents and young adults (CAYA) with poor-risk recurrent/refractory lymphoma is dismal (⩽30%). To overcome this poor prognosis, we designed an approach to maximize an allogeneic graft vs lymphoma effect in the setting of low disease burden. We conducted a multi-center prospective study of myeloablative conditioning (MAC) and autologous stem cell transplantation (AutoSCT), followed by a reduced intensity conditioning (RIC) and allogeneic hematopoietic cell transplantation (AlloHCT) in CAYA, with poor-risk refractory or recurrent lymphoma. Conditioning for MAC AutoSCT consisted of carmustine/etoposide/cyclophosphamide, RIC consisted of busulfan/fludarabine. Thirty patients, 16 Hodgkin lymphoma (HL) and 14 non-Hodgkin lymphoma (NHL), with a median age of 16 years and median follow-up of 5years, were enrolled. Twenty-three patients completed both MAC AutoSCT and RIC AlloHCT. Allogeneic donor sources included unrelated cord blood (n=9), unrelated donor (n=8) and matched siblings (n=6). The incidence of transplant-related mortality following RIC AlloHCT was only 12%. In patients with HL and NHL, 10 year EFS was 59.8% and 70% (P=0.613), respectively. In summary, this approach is safe, and long-term EFS with this approach is encouraging considering the poor-risk patient characteristics and the use of unrelated donors for RIC AlloHCT in the majority of cases. [ABSTRACT FROM AUTHOR]

BU and CY (BU/CY; 200 mg/kg) before HLA-matched sibling allo-SCT in children with sickle cell disease (SCD) is associated with ~85% EFS but is limited by the acute and late effects of BU/CY myeloablative conditioning. Alternatives include reduced toxicity but more immunosuppressive conditioning. We investigated in a prospective single institutional study, the safety and efficacy of a reduced-toxicity conditioning (RTC) regimen of BU 12.8-16 mg/kg, fludarabine 180 mg/m2, alemtuzumab 54 mg/m2 (BFA) before HLA-matched sibling donor transplantation in pediatric recipients with symptomatic SCD. Eighteen patients, median age 8.9 years (2.3-20.2), M/F 15/3, 15 sibling BM and 3 sibling cord blood (CB) were transplanted. Mean whole blood and erythroid donor chimerism was 91% and 88%, at days +100 and +365, respectively. Probability of grade II-IV acute GVHD was 17%. Two-year EFS and OS were both 100%. Neurological, pulmonary and cardiovascular function were stable or improved at 2 years. BFA RTC and HLA-matched sibling BM and CB allo-SCT in pediatric recipients result in excellent EFS, long-term donor chimerism, low incidence of GVHD and stable/improved organ function. [ABSTRACT FROM AUTHOR]

The objective of this study was prospectively to investigate the health-related quality of life (HRQOL) of 80 pediatric recipients of allo-SCT for malignant and non-malignant diseases. The PedsQL 4.0 was used to assess self-reported physical, emotional and social functioning of children 5 years old once, pre-allo-SCT and on days +100, +180, +365 and +730. Emotional and social functioning was stable pre-to-post-allo-SCT and comparable to the normative sample (P>0.05), and physical functioning was 17 points lower pre-allo-SCT (P0.01) with improved scores equivalent to the norms by day +730. Lower physical scores were reflected by 50-54% of children reporting difficulties with movement, strength, pain and fatigue. At baseline, children ages 5-7 reported lower social functioning (P<0.05) and patients with non-malignant disease reported better physical functioning (P<0.05). Emotional functioning in ages 8-12 improved over time (P<0.05). More than 50% of the participants were minority and their HRQOL was similar to non-minority participants. Physical functioning significantly improved for recipients of reduced-toxicity conditioning (P0.01), significantly worsened for patients with chronic GVHD (cGVHD; P<0.05), and significantly decreased in recipients of matched-unrelated donor transplant who developed cGVHD (P<0.05). Multidisciplinary efforts are necessary to identify and support pediatric patients' physical needs to improve functional outcomes. [ABSTRACT FROM AUTHOR]

Intravenous BU divided four times daily (q6 h) has been shown to be safe and effective in pediatric allo-SCT recipients. Though less frequent dosing is desirable, pharmacokinetic (PK) data on twice daily (q12 h) i.v. BU administration in pediatric allo-SCT recipients is limited. We prospectively examined the PK results in a cohort of pediatric allo-SCT recipients receiving i.v. BU q12 h as part of conditioning before allo-SCT. BU levels were obtained after the first dose of conditioning. PK parameter analysis (n=49) yielded the following 95% confidence intervals (CI95): weight-normalized volume of distribution: 0.65-0.73 L/kg; t1/2: 122-147 min; weight-normalized clearance (CLn): 3.4-4.3 mL/min/kg; and area under the curve: 1835-2180 mmol × min/L. From these results, a steady state concentration was calculated with CI95 between 628-746 ng/mL. Comparison between recipients 4 vs >4 years old revealed significant differences in t1/2 (mean: 115 vs 146 min, P=0.008) and CLn (mean: 4.4 vs 3.5 mL/min/kg, P=0.038). Intravenous BU q12 h had a comparable PK to i.v. BU q6 h PK seen in the literature, and in pediatric allo-SCT recipients, is a feasible, attractive alternative to i.v. q6h dosing. [ABSTRACT FROM AUTHOR]

We report the results of a pilot study of a BU-fludarabine-alemtuzumab (BFA)-reduced toxicity conditioning (RTC) followed by allogeneic hematopoietic SCT (AlloHSCT) in 12 children and adolescents (<21 years) with malignant and non-malignant diseases. Stem cell sources were: two unrelated cord blood, one unrelated BM, two related and seven unrelated PBSC. Positive CD34 selection was performed in five unrelated PBSC grafts. RCT was carried out with BFA, and GVHD prophylaxis was FK506 and mycophenolate mofetil. The median time for neutrophil and platelet engraftment was 16 and 31 days, respectively. The P of developing grade II, grade III aGVHD and cGVHD was 41.6, 25 and 9%, respectively. Only 1 out of 12 developed grade III toxicity. There was one primary and no secondary graft failure. Mixed donor chimerism on day 100 and 1 year was median 99 and 96%, respectively; 90% of recipients achieved 80% donor chimerism. The 3-year overall survival (OS) in all patients was 91.7±8% (100% for malignant vs 80% for non-malignant diseases, ns). In all, 11 (91%) patients remain alive at median 2.8 (0.3-6.8) years. RTC followed by AlloHSCT, based on BFA conditioning, is feasible and tolerable in children and adolescents, and results in prompt achievement of durable mixed donor chimerism and excellent OS. [ABSTRACT FROM AUTHOR]

The objective of this study was to assess the incidence, risk factors, outcome and impact on OS of pericardial effusion (PEF) in a cohort of 156 pediatric SCT recipients. The mean age was 8.15±6.25 years. In all, 74% of the patients had malignant disease and 35% of the patients received autologous stem cell grafts. Twenty-three subjects developed effusion at 2.75±3.54 months after SCT. The overall probability of developing a PEF after SCT was 16.9%. In the multivariate analysis of risk factors associated with time to PEF, increased age, allogeneic risk status and conditioning type, were all significant factors. In a multivariate analysis of time to death, PEF, CMV status and risk status were all independent risk factors. PEF, however, had the highest HR of 3.334. Of the 23 patients with PEF, 19 died (82.6%); however, none died as a direct result of pericardial tamponade. In summary, our results suggest that PEF is a significant risk factor for post transplant mortality. These results suggest a need for more frequent evaluation and monitoring for development of PEF. Studies are needed to determine the etiology of, and new therapeutic strategies for, PEF in the post-SCT population. [ABSTRACT FROM AUTHOR]

Hydrogen has been inferred to occur in enhanced concentrations within permanently shadowed regions and, hence, the coldest areas of the lunar poles. The Lunar Crater Observation and Sensing Sate[rite (LCROSS) mission was designed to detect hydrogen-bearing volatiles directly. Neutron flux measurements of the Moon's south polar region from the Lunar Exploration Neutron Detector (LEND) on the Lunar Reconnaissance Orbiter (LRO) spacecraft were used to select the optimal impact site for LCROSS. LEND data show several regions where the epithermal neutron flux from the surface is suppressed, which is indicative of enhanced hydrogen content. These regions are not spatially coincident with permanently shadowed regions of the Moon. The LCROSS impact site inside the Cabeus crater demonstrates the highest hydrogen concentration in the lunar south polar region, corresponding to an estimated content of 0.5 to 4.0% water ice by weight, depending on the thickness of any overlying dry regolith layer. The distribution of hydrogen across the region is consistent with buried water ice from cometary impacts, hydrogen implantation from the solar wind, and/or other as yet unknown sources. [ABSTRACT FROM AUTHOR]

The design of the Lunar Exploration Neutron Detector (LEND) experiment is presented, which was optimized to address several of the primary measurement requirements of NASA’s Lunar Reconnaissance Orbiter (LRO): high spatial resolution hydrogen mapping of the Moon’s upper-most surface, identification of putative deposits of appreciable near-surface water ice in the Moon’s polar cold traps, and characterization of the human-relevant space radiation environment in lunar orbit. A comprehensive program of LEND instrument physical calibrations is discussed and the baseline scenario of LEND observations from the primary LRO lunar orbit is presented. LEND data products will be useful for determining the next stages of the emerging global lunar exploration program, and they will facilitate the study of the physics of hydrogen implantation and diffusion in the regolith, test the presence of water ice deposits in lunar cold polar traps, and investigate the role of neutrons within the radiation environment of the shallow lunar surface. [ABSTRACT FROM AUTHOR]

Background: In response to the requirements of the European Working Time Directive (EWTD), a national implementation group was formed to liaise with local implementation groups at nine different pilot sites. As part of this process, a pilot EWTD compliant rota was run for six weeks amongst general surgical SHOs in University Hospital Galway.Methods: A rota was devised for nine general surgical SHOs, the aim being to achieve EWTD compliance. SHOs were asked to complete questionnaires to assess the effectiveness of the pilot.Result: During the pilot SHOs were rostered for an average of 53.6 hours. Actual hours worked were 58.1 hours. Fifty-two point five per cent of working weeks were non-compliant with the provisions of the EWTD. Seventy per cent of the time SHOs felt that continuity of care was not achieved. Eighty-one per cent felt that patient care deteriorated during the pilot. SHOs spent an average of 2.5 days per week engaged in sessional commitments with their consultant. Fifty percent of SHOs missed elective operating sessions or outpatient clinics. SHOs attended an average of 1.3 emergency operations per week (range 0-8) and 5.5 elective procedures per week (range 0-12). All SHOs reported a deterioration in quantity or quality of training. However, 69% reported an improvement in their quality of life during the pilot.Conclusions: With this tightly defined shift system, hours worked were in breach of the provisions of the EWTD. Sixty-nine per cent of SHOs reported an improvement in quality of life, but all reported a deterioration in training and 81% felt that patient care suffered. [ABSTRACT FROM AUTHOR]

There is a significant amount of morbidity and mortality following myeloablative umbilical cord blood transplantation (UCBT). Reduced intensity (RI) conditioning offers an alternative to myeloablative conditioning before UCBT. We investigated RI-UCBT in 21 children and adolescents with malignant (n=14), and non-malignant diseases (n=7). RI conditioning consisted of fludarabine (150–180 mg/m2) with either busulfan (8 mg/kg)+rabbit antithymocyte globulin (R-ATG; n=16) or cyclophosphamide+R-ATG±etoposide (n=5). Human leukocyte antigen match: 4/6 (n=13), 5/6 (n=5) and 6/6 (n=3). The median total nucleated cell and CD34+ cell dose per kilogram were 3.58 × 107 and 2.54 × 105, respectively. The median time for neutrophil and platelet engraftment was 17.5 and 52 days, respectively. There were six primary graft failures (chronic myelogenous leukemia (CML), β-thalassemia, hemophagocytic lymphohistiocytosis (HLH) and myelodysplastic syndrome (MDS)). The probability of developing grade II to grade IV acute graft-versus-host disease (GVHD) and chronic GVHD was 28.6 and 16.7%, respectively. Incidence of transplant-related mortality (TRM) was 14%. The 5 years overall survival (OS) in all patients was 59.8%. The 5 years OS for patients with average versus poor-risk malignancy was 77.8 versus 22.2% (P=0.03). RI-UCBT may result in graft failure in specific high-risk chemo-naïve patients (CML, β-thalassemia, HLH and MDS), but in more heavily pretreated pediatric and adolescent recipients results in rapid engraftment and may be associated with decreased severe GVHD and TRM.Bone Marrow Transplantation (2007) 40, 621–631; doi:10.1038/sj.bmt.1705785; published online 30 July 2007 [ABSTRACT FROM AUTHOR]

Summary:In an effort to improve the outcome of poor-risk lymphoma patients, we evaluated a novel regimen of tandem high-dose chemotherapy (THDC) with autologous stem cell transplantation. A total of 41 patients (median age 40 years, range 15–68 years) with poor-risk non-Hodgkin's lymphoma and Hodgkin's disease were enrolled. THDC consisted of melphalan (180 mg/m2) and escalating dose mitoxantrone (30–50 mg/m2) (MMt) for the first conditioning regimen, and thiotepa (500 mg/m2), carboplatin (800 mg/m2), and escalating dose etoposide phosphate (400–850 mg/m2), (ETCb) as the second regimen. In all, 31 patients (76%) completed both transplants, with a median time between transplants of 55 days (range 26–120). The maximum tolerated dose was determined as 40 mg/m2 for mitoxantrone and 550 mg/m2 for etoposide phosphate. The overall toxic death rate was 12%. Following high-dose chemotherapy, 10 of 24 evaluable patients (42%) were in CR. The two-year overall survival and event-free survival is 67% (95% CI, 52–81%) and 45%, (95% CI, 29–61%) for the 41 patients enrolled; and 69% (95% CI, 525–586%) and 48% (95% CI, 30–67%) for the 31 patients completing both transplants. This THDC regimen is feasible but with notable toxicity in heavily pretreated patients; its role in the current treatment of high-risk lymphoma remains to be determined.Bone Marrow Transplantation (2005) 36, 491–497. doi:10.1038/sj.bmt.1705103; published online 25 July 2005 [ABSTRACT FROM AUTHOR]

Summary:Reduced intensity (RI) allogeneic stem cell transplantation (AlloSCT) was initially demonstrated in adults following HLA-matched family and unrelated adult donor AlloSCT. There is little information about RI AlloSCT in children. We report results of a pilot study of RI AlloSCT in 21 recipients (?21 years). Age: median 13 (0.5-21) years, 8F:13M, 14 unrelated cord blood units (UCB) (10 4/6, 4 5/6), two related BM (6/6, 5/6), four related PBSC (2 6/6, 2 5/6), and one related BM+PBSC (6/6). RI: fludarabine, busulfan (n=14); fludarabine, cyclophosphamide (n=4); fludarabine, melphalan (n=1); total body irradiation, fludarabine, cyclophosphamide (n=1); or fludarabine, cyclophosphamide, and etoposide (n=1). Graft-versus-host disease prophylaxis: FK506 0.03?mg/kg/day and mycophenolate mofetil 15?mg/kg/q 12?h. UCB median nuc/kg and CD34/kg was 4.3 × 107/kg (0.9-10.8) and 1.9 × 105/kg (0.3-6.9), and related BM/PBSC median nuc/kg and CD34/kg was 8.3 × 108 (4.7-18.9) and 5.0 × 106/kg (4.6-6.4). Maximal chimerism following unrelated cord blood transplantation, 100% × 7, 98% × 1, 95% × 2, 55% × 1, and 0% × 3; related PBSC/BM, 100% × 5, 65% × 1, and 55% × 1. Graft failure occurred in 5/21 (24%). In summary, RI AlloSCT in children is feasible and tolerable (?25% GF) and results in ?85% of recipients initially achieving ?50% donor chimerism.Bone Marrow Transplantation (2004) 33, 613-622. doi:10.1038/sj.bmt.1704399 Published online 19 January 2004 [ABSTRACT FROM AUTHOR]

The NEAR laser rangefinder (NLR) obtained more than 16 million range returns from asteroid 433 Eros. We present the first results from analyses of topographic profiles interpreted with the aid of simultaneous, boresighted images obtained by the NEAR multispectral imager (MSI). The location of the NLR boresight relative to that of MSI is determined by detailed correlations of ranging data and simultaneous images, including cases where the laser boresight slewed off and on the limb of the asteroid and cases where the laser illuminated a boulder close to the time of an image. In the data presented, the precision of the range measurements is about 1 m, with the minimum spot diameter under 5 m, and successive spots are contiguous or overlapping. Elevation on the irregular object Eros is given with respect to the gravitational and centrifugal potential. Landslides in craters are characterized. Possible crater benches are identified. Examples of infilled craters are presented. These observations suggest a depth of unconsolidated regolith, which is subject to sliding, of typically a few tens of meters. An example of structurally controlled cratering is presented. Examples of tectonic features are described. Surface roughness on Eros is approximately self-affine from scales of a few meters to hundreds of meters. A comparison of fractal statistics shows that Eros is extremely rough on observed scales, when compared to terrestrial a''a lava on submeter scales and undisturbed lunar regolith on subcentimeter scales. [Copyright &y& Elsevier]

Background: There is evidence that macula densa nitric oxide (NO) inhibits tubuloglomerular feedback (TGF). However, TGF response is not altered in mice deficient in neuronal nitric oxide synthase (nNOS) (-/-). Furthermore, nNOS expression in the macula densa is inversely related to salt intake, yet micropuncture studies have shown that NOS inhibition potentiates TGF in rats on high sodium intake but not in rats on a low-salt diet. These inconsistencies may be due to confounding systemic factors, such as changes in circulating renin. To further clarify the role of macula densa nNOS in TGF response, independent of systemic factors, we tested the hypothesis that (1) TGF response is inversely related to sodium intake, and (2) during low sodium intake, NO produced by macula densa nNOS tonically controls the basal diameter of the afferent arteriole (Af-Art).Methods: Af-Arts and attached macula densas were simultaneously microperfused in vitro. TGF response was determined by measuring Af-Art diameter before and after increasing NaCl in the macula densa perfusate. TGF response was studied in wild-type (+/+) and nNOS knockout mice (-/-), as well as in juxtaglomerular apparatuses (JGAs) from rabbits fed a low-, normal-, or high-NaCl diet.Results: TGF responses were similar in nNOS +/+ and -/- mice. However, in nNOS +/+ mice, 7-nitroindazole (7-NI) perfused into the macula densa significantly potentiated the TGF response (P = 0.001), while in nNOS -/- mice, this potentiation was absent. In rabbits on three different sodium diets, TGF responses were similar and were potentiated equally by 7-NI. However, in JGAs from rabbits on a low-NaCl diet, adding 7-NI to the macula densa while perfusing it with low-NaCl fluid caused Af-Art vasoconstriction, decreasing the diameter by 14% (from 21.7 +/- 1.3 to 18.6 +/- 1.5 microm; P < 0.001). This effect was not observed in JGAs from rabbits fed a normal- (19.0 +/- 0.5 vs. 19.3 +/- 0.8 microm after 7-NI) or high-NaCl diet (18.6 +/- 0.7 vs. 18.4 +/- 0.7 microm).Conclusions: First, in this in vitro preparation, chronic changes in macula densa nNOS do not play a major role in the regulation of TGF. Compensatory mechanisms may develop during chronic alteration of nNOS that keep TGF relatively constant. Second, nNOS regulates TGF response acutely. Third, the results obtained in the +/+ and -/- mice also confirm that the effect of 7-NI is due to inhibition of macula densa nNOS. Finally, during low sodium intake (without induction of TGF), the regulation of basal Af-Art resistance by macula densa nNOS suggests that NO in the macula densa helps maintain renal blood flow during the high renin secretion caused by low sodium intake. [ABSTRACT FROM AUTHOR]

Forty-two patients (29 newly diagnosed) with high grade gliomas (n = 37), medulloblastoma (n = 2) or non-biopsied tumors (n = 3) with supratentorial (n = 24), brain stem (n = 11), posterior fossa (n = 5) or spinal (n = 2) location were eligible for this study with adequate organ function and no bone marrow tumor infiltration. Median patient age was 12.2 years (range, 0.7–46.8). A total of 600 mg/m2 BCNU, 900 mg/m2 thiotepa and 1500 or 750 mg/m2 etoposide (VP-16) was administered followed by autologous bone marrow reinfusion (ABMR). Twenty-one newly diagnosed patients received local irradiation (RT) post ABMR. Nine early deaths were observed (21%), as well as one secondary graft failure. Half of the patients aged 18 years or older experienced toxic deaths, whereas only 15% of patients younger than 18 years experienced toxic death (P = 0.05). Of 25 evaluable newly diagnosed patients, 20% achieved complete remission (CR) and 4% partial remission (PR), while 28% remained in continuing complete remission (CCR) and 44% remained with stable disease prior to RT. Of eight evaluable patients with recurrent disease, one achieved CR and two PR, while one remained in CCR and four with stable disease for 1 to 110.2 months. Overall survival was 36%, 24% and 17% at 1, 2 and 3 years following ABMR, with three newly diagnosed patients and one patient treated for recurrent disease being alive, without disease progression 64.4, 67.0, 86.3 and 110.2 months after ABMR, respectively. The combination of high-dose BCNU/ thiotepa/VP-16 has substantial toxicity but definite activity for high risk CNS tumors. Similar protocols with lower toxicity merit further evaluation in both newly diagnosed and recurrent CNS tumors. Bone Marrow Transplantation (2000) 26, 153–160. [ABSTRACT FROM AUTHOR]

Background: Sulfonylurea receptors are classified as either high-affinity type 1 (SUR1) or low-affinity type 2 receptors (SUR2), and the gene expression of SURs has recently been demonstrated in kidney. However, functional data regarding a renal SUR are lacking. We previously demonstrated that mesangial cell (MC) gene and protein expression of extracellular matrix components were up-regulated by the sulfonylurea, tolazamide. After noting this biological response, we next sought to investigate the presence of a sulfonylurea receptor in rat MCs.Methods: Equilibrium binding studies employing [3H]glibenclamide as a ligand were performed on crude MC membrane preparations. Gene expression for SUR was explored by Northern analysis of cultured MCs and whole kidney tissue. The effect of sulfonylurea on intracellular Ca2+ in MCs was assayed by spectrofluorometry, and glibenclamide-induced changes in the contractility of MCs were assessed.Results: MCs bound [3H]glibenclamide with a KD of 2.6 microM and a Bmax of 30.4 pmol/mg protein as determined by Scatchard analysis. Three SUR2 transcripts were detected in MCs. A major transcript was detected at 5.5 kb and minor transcripts at 7.5 and 8.6 kb. Following sulfonylurea treatment of MCs, real-time videomicroscopy revealed intense MC contraction, coinciding with oscillatory increments of intracellular Ca2+ concentration. Further evidence of sulfonylurea-induced MC contraction was demonstrated by glibenclamide-induced deformation of a silicone rubber substrate.Conclusions: These results demonstrate that SUR2 resides on MCs. Functional activation of this receptor by sulfonylurea induces Ca2+ transients that result in MC contraction. [ABSTRACT FROM AUTHOR]