Measurement of Lepton-Jet Correlation in Deep-Inelastic Scattering with the H1 Detector Using Machine Learning for Unfolding.

The first measurement of lepton-jet momentum imbalance and azimuthal correlation in lepton-proton scattering at high momentum transfer is presented. These data, taken with the H1 detector at HERA, are corrected for detector effects using an unbinned machine learning algorithm (multifold), which considers eight observables simultaneously in this first application. The unfolded cross sections are compared with calculations performed within the context of collinear or transverse-momentum-dependent factorization in quantum chromodynamics as well as Monte Carlo event generators.

Behavioural and psychological symptoms in general hospital patients with dementia, distress for nursing staff and complications in care: results of the General Hospital Study.

AIMS: Little is known about how behavioural and psychological symptoms of dementia (BPSD) manifest in the general hospital. The aim was to examine the frequency of BPSD in general hospitals and their associations with nursing staff distress and complications in care. METHODS: Cross-sectional representative study with 1469 patients aged ≥65, including 270 patients with dementia, of 33 randomly selected general hospitals in Germany. BPSD and complications were reported by nurses. RESULTS: Overall frequency of BPSD was higher in patients with dementia (76%) than without (38%). The most frequent symptoms in patients with dementia were nighttime disturbances (38%), depression (29%) and aberrant motor behaviour (28%) and the most distressing symptoms for nursing staff were delusions, aggression and nighttime disturbances. The overall frequency of BPSD increased from 67% in mild dementia, to 76% in moderate dementia and to 88% in severe dementia. The most frequent symptoms in patients without dementia were depression (19%), nighttime disturbances (13%) and irritability (13%). The most distressing symptoms were aggression and delusions, while the same symptoms were consistently rated as less distressing than in patients with dementia. Factor analysis revealed three independent groups of BPSD that explained 45% of the total variance. First, expansive symptoms (aggression, irritability, nighttime disturbances, aberrant motor behaviour and disinhibition) were frequent, distressing for nursing staff and associated with many complications. Second, psychotic symptoms (delusions and hallucinations) were infrequent, distressing and associated with some complications. Third, affective symptoms (apathy, anxiety and depression) were frequent, non-distressing and associated with few complications. The results did not change when cases with delirium were excluded from both groups. CONCLUSIONS: BPSD are common in older hospital patients with dementia and associated with considerable distress in nursing staff, as well as a wide range of special treatments needs and additional behavioural and medical complications. Management strategies are needed to improve the situation for both patients and hospital staff.

Dinaciclib is a novel cyclin-dependent kinase inhibitor with significant clinical activity in relapsed and refractory chronic lymphocytic leukemia.

Dinaciclib (SCH727965) is a selective CDKi chosen for clinical development based upon a favorable therapeutic index in cancer xenograft models. We performed a phase I dose escalation study of dinaciclib in relapsed and refractory chronic lymphocytic leukemia (CLL) patients with intact organ function and WBC<200 × 10(9) /l. Five separate dose levels (5 mg/m(2), 7 mg/m(2), 10 mg/m(2), 14 mg/m(2) and 17 mg/m(2)) were explored dosing on a weekly schedule × 3 with 1 week off (4-week cycles) using a standard 3+3 design with expansion cohorts to optimize safety. Fifty-two patients were enrolled with relapsed and refractory CLL. Escalation through cohorts occurred with two dose-limiting toxicity (DLTs) at the 17 mg/m(2) dose (tumor lysis syndrome (TLS) and pneumonia). The phase II expansion occurred at 14 mg/m(2) with 16 patients receiving this dose with one DLT (TLS). Additional stepped up dosing to the maximum tolerated dose was examined in 19 patients at this dose. Adverse events included cytopenias, transient laboratory abnormalities and TLS. Responses occurred in 28 (54%) of patients independent of del(17)(p13.1) with a median progression-free survival of 481 days. Dinaciclib is clinically active in relapsed CLL including those patients with high risk del(17)(p13.1) disease and warrants future study.

Capturing a photoexcited molecular structure through time-domain x-ray absorption fine structure.

The determination of the structure of transient molecules, such as photoexcited states, in disordered media (such as in solution) usually requires methods with high temporal resolution. The transient molecular structure of a reaction intermediate produced by photoexcitation of NiTPP-L2 (NiTPP, nickeltetraphenylporphyrin; L, piperidine) in solution was determined by x-ray absorption fine structure (XAFS) data obtained on a 14-nanosecond time scale from a third-generation synchrotron source. The XAFS measurements confirm that photoexcitation leads to the rapid removal of both axial ligands to produce a transient square-planar intermediate, NiTPP, with a lifetime of 28 nanoseconds. The transient structure of the photodissociated intermediate is nearly identical to that of the ground state NiTPP, suggesting that the intermediate adopts the same structure as the ground state in a noncoordinating solvent before it recombines with two ligands to form the more stable octahedrally coordinated NiTPP-L2.

Small-angle X-ray studies of soot inception and growth.

The high spectral intensity of X-rays produced by the undulator at the Basic Energy Sciences Synchrotron Radiation Center of Argonne's Advanced Photon Source has allowed us to perform small-angle X-ray scattering (SAXS) studies of the initial distribution of soot particles formed by various fuels. SAXS provides an in situ probe of the morphology of soot in the region between 1 and 100 nm and complements the ex situ technique of electron microscopy. The basic aspects of SAXS and its potential are illustrated with measurement on a laminar flame of acetylene in air. The more complex fuel toluene has been studied in a flat-flame burner that supports a CH4/H2/air or CO/H2/air diffusion flame stabilized by N2 co-flow. This burner produces a nearly constant temperature region above the flame where the pyrolysis and combustion of the heavier fuels occurs. Kinetic information is obtained by performing measurements of the scattered intensity profile as a function of the height above the burner. These profiles have been reduced to give the mean radius and dispersion of a distribution of spherical particles. Mean radii between 0.8 and 18 nm have been observed. The smallest of these is a factor of ten smaller than previously detected with Lorentz-Mie scattering. Near 1550 K, the soot distribution found in toluene shows a distinct step behavior that is consistent with model calculations.

An early step in Pseudomonas exotoxin action is removal of the terminal lysine residue, which allows binding to the KDEL receptor.

During the intoxication process, Pseudomonas exotoxin (PE) and immunotoxins containing PE internalize into the target cell and become processed into two fragments, and the carboxyl fragment translocates into the cytosol where it inactivates elongation factor 2. We have proposed that after internalization into cells the carboxyl-terminal fragment of PE (amino acids 280-613), which ends in REDLK, binds to the KDEL receptor (ERD2) which carries it to the endoplasmic reticulum, from which the PE fragment translocates to the cytosol. Earlier experiments showing that REDL but not REDLK binds to the KDEL receptor suggested that the terminal lysine is removed sometime during the intoxication process. To determine if and where this occurs, we exposed a peptide ending in REDLK to malignant cells in culture and found that binding to the KDEL receptor was restored. Restoration of receptor binding also occurred if a peptide or toxin ending in REDLK at its carboxyl terminus was incubated with plasma, indicating that the terminal lysine is removed prior to entry of the toxin into the cell. We conclude that plasma carboxypeptidase(s) cleave(s) the lysine residue from the carboxyl terminus of PE and PE-containing immunotoxins as an early and essential step in their cellular intoxication pathway.

Tunable laser flash absorption: a new technique for measuring rates and yields of chemical reactions at high temperatures.

The flash absorption technique, whereby light from an excimer laser is used to measure the kinetic behavior of absorbing species in the high temperature region behind a shock front with a linear array detector, has been extended by using tunable light from a high resolution, pulsed dye laser. The use of narrowband, tunable light allows us to access isolated rovibronic transitions and, thereby, obtain state-specific kinetic information. If the oscillator strength of the transition and the absorption line profile are known, the absolute concentration may be determined. We demonstrate the technique by measuring the temporal development of the hydroxyl radical as it is formed after propane has been thermally dissociated in the presence of oxygen. We conclude that accurate kinetic measurements can be made with hydroxyl concentrations of 10(15) cm(-3) This technique may also be applied to study any species which absorbs below 50,000 cm(-1).

An evaluation of distress following intraperitoneal immunization with Freund's adjuvant in mice.

Intraperitoneal immunization with Freund's adjuvant is frequently used to stimulate antibody production in mice. To evaluate the clinical and pathological effects of this technique, mice were immunized intraperitoneally with complete Freund's adjuvant and albumin, and the injection repeated 3-4 weeks later using incomplete Freund's adjuvant. This regimen induced a mean antibody titer against albumin of 1:280 within 7 days after booster immunization and increased the abdominal width, abdominal circumference and spleen weights of immunized animals. Food intake and body weight decreased after immunization, but returned to control levels within 1-2 weeks. Open-field activity was not affected. Neutrophilia, eosinophilia and monocytosis were present 7 days after immunization and persisted for the duration of the study. Gross and histopathological lesions included multiple granulomatous abdominal adhesions and lymphoid hyperplasia. Thus, intraperitoneal immunization with Freund's adjuvant and albumin produced some adverse effects in the animal (weight loss, neutrophilia and granulomatous peritonitis). However, the animals did not appear to be severely or chronically impaired, since food intake, body weight and locomotor activity were within normal limits for most of the post-immunization period.

Influence of videofilm-induced emotional stress on the flow properties of blood.

The hemorheologic effects of emotional stress induced by a videofilm were investigated in 10 healthy volunteers. Blood samples were obtained from the antecubital vein before, during, and after the end of the videofilm. Blood pressure and heart rate were simultaneously measured. There was a statistically significant increase in blood and plasma viscosity during and immediately after the end of the videofilm, which correlated with an increase in plasma catecholamine concentrations. This hemorheologic behavior can be explained as a result of an endogenous hemoconcentration that takes place if the Starling equilibrium of intravascular vs extravascular fluid is changed. These observations could lead to new aspects of the pathophysiology of acute myocardial infarction initiated by severe emotional stress.

Efficient monochromator to isolate VUV light generated by four-wave mixing techniques.

The lateral chromatic aberration from a LiF lens, which is positioned off-axis with respect to the incident light beams, is used to isolate the VUV light generated by the four-wave mixing technique from the intense pump light. The transmittance of the monochromator at the VUV wavelength is limited by the transmittance of a single lens. The ratio of transmitted-to-incident pump energy is 3.3 x 10(-6). A single monochromator with two interchangeable lenses can be used for either tightly focused or collimated pump beams.

Frequency shift and asymmetric line shape of the fourth anti-Stokes component from a hydrogen Raman shifter.

We have measured the spectral properties of the fourth anti-Stokes component of the output of a pressurized, molecular hydrogen, Raman shifter pumped by the intense output of a frequency-doubled narrowband pulsed dye laser. All the observed line shapes are asymmetric, with full widths at half-maximum ranging from 0.3 to 0.8 cm(-1). The spectral peak of the Raman-shifted light varies linearly with the intensity of the pump light and is given by sigma(rho,I) = sigma(rho) + AI. The previously measured density-dependent Stokes shift is sigma(rho), the intensity of the laser is I, and A is 1.5 +/- 0.2 cm(-1)/(TW/cm(2)). The electric field-induced shift and asymmetric line shape limit the accuracy and resolution of spectroscopic measurements made with light from a hydrogen Raman shifter. We propose that these observations may be explained by the ac Stark effect in the Raman shifting medium.

Effects of sodium chloride on pregnant sheep with reduced uteroplacental perfusion pressure.

This study investigated the effects of NaCl supplementation (5 mEq/kg/day) on the arterial pressure of pregnant and nonpregnant sheep with and without reduction of uteroplacental perfusion pressure. In pregnant sheep receiving NaCl supplementation during the third trimester, reduction of aortic pressure caudal to the kidneys to 65% of the upstream pressure (occlusion) caused a progressive increase in mean arterial pressure from 89 +/- 3 to 110 +/- 3 mm Hg over 2 weeks. Occlusion was accompanied by a decrease in urine flow. Six of seven sheep died or were killed because of severe respiratory distress. No abnormalities were detected in nonpregnant sheep or pregnant sheep receiving NaCl supplementation only. Pregnant sheep that were occluded but received no supplementary NaCl did not become hypertensive but aborted about 2 weeks after occlusion. These results indicate that reduction of uteroplacental perfusion pressure causes hypertension in NaCl-supplemented pregnant sheep but not in sheep receiving a normal, low sodium diet.

Effects of indomethacin upon cerebral hemodynamics of newborn pigs.

Treatment of unanesthetized newborn pigs with indomethacin trihydrate (5 +/- 1 mg/kg, intravenous) decreased cerebral blood flow uniformly throughout the brain by 18-28% without changing cardiac output, arterial pressure, or arterial blood gases and pH. Breathing 10% O2, 9% CO2 with the balance N2 (hypoxia/hypercapnia) caused cerebral blood flow to increase from 102 +/- 12 to 218 +/- 19 ml/100 g . min. Intravenous administration of indomethacin during hypoxia/hypercapnia caused a uniform decrease in cerebral flow throughout the brain to levels (94 +/- 5 ml/100 g . min) indistinguishable from those when the piglet was breathing ambient air. Further, 2.5 h later, the cerebral hyperemia caused by hypoxia/hypercapnia was attenuated markedly (129 +/- 19 ml/100 g . min). Vehicle treatment did not alter resting cerebral blood flow or cerebral hyperemia in response to hypoxia/hypercapnia. Measurements of 6-keto-prostaglandin F1 alpha, thromboxane B2, and prostaglandin E2 demonstrated that intravenously administered indomethacin crossed the blood-brain barrier of newborn pigs in sufficient quantity to inhibit prostanoid release into the cerebrospinal fluid passing over the surface of the brain. The mechanism by which indomethacin reduces cerebral blood flow and attenuates cerebral hyperemia cannot be determined from the present experiments. We conclude that intravenous administration of indomethacin decreases cerebral blood flow and attenuates cerebral hyperemia induced by severe, combined hypoxia/hypercapnia in newborn pigs.

Asphyxia and hyaline membrane disease in neonatal monkeys.

An animal model for studying the relationship between perinatal asphyxia and hyaline membrane disease (HMD) is described. The HMD developed in these Macaca mulatta (rhesus) and M. arctoides (stump tail) monkeys was clinically, physiologically, and histologically similar to that seen in human infants. The monkeys were delivered by cesarean section at a gestational age of 85-91% of term when surfactant, though present, was less than mature levels. Asphyxia at birth proved to be an important factor in disease development. Five minutes of asphyxia immediately before the first breath greatly increased the incidence and severity of HMD when compared to nonasphyxiated controls of a similar gestational age. Amniotic fluid L/S ratios did not differ significantly in the asphyxiated and control groups but data based on static pressure-volume studies of the excised lungs indicated that the surfactant activity of the asphyxiated group was significantly less. Lung maturity with regard to surfactant production appears to be a critical factor. The data from these experiments, together with data cited in the literature, strongly suggest that the lung and its surfactant system is most vulnerable to hypoxia and/or acidosis during the early stages of surfactant production. The asphyxiated non-human primate model used here should prove valuable for studying the pathogenesis of HMD and especially for further clarifying the relationship between perinatal asphyxia and HMD.

Changes in plasma arginine vasopressin during transition from fetus to newborn following minimal trauma delivery of lambs and goats.

Vasopressin in umbilical arterial and venous blood is high at delivery and may be important in the maintenance of arterial pressure and absorption of lung liquid. We used chronically instrumented near-term fetal lambs and goats to investigate the changes in plasma vasopressin that occur during perinatal cardiovascular transition following cesarean section without labor. Plasma arginine vasopressin was more than 5 times greater 15 min following birth than immediately prior to clamping the umbilicus, and it fell progressively over the ensuing 2-5 h to levels not significantly different from before birth. Fifteen min after delivery, neither arterial pressure, blood gases, nor pH appeared to account for the increase.

Mechanism of stimulation of pulmonary prostacyclin synthesis at birth.

In order to investigate the mechanism behind ventilation-induced pulmonary prostacyclin production at birth, chloralose anesthetized, exteriorized, fetal lambs were ventilated with a gas mixture that did not change blood gases (fetal gas) and unventilated fetal lungs were perfused with blood containing increased O2 and decreased CO2. Ventilation with fetal gas (3%O2, 5%CO2) increased net pulmonary prostacyclin (as 6-keto-PGF1 alpha) production from -5.1 +/- 4.4 to +12.6 +/- 7.6 ng/kg X min. When ventilation was stopped, net pulmonary prostacyclin production returned to nondetectable levels. Ventilation with gas mixtures which increased pulmonary venous PO2 and decreased PCO2 also stimulated pulmonary prostacyclin production, but did not have greater effects than did ventilation with fetal gas. In order to determine if increasing PO2 or decreasing PCO2 could stimulate pulmonary prostacyclin production independently from ventilation, unventilated fetal lamb lungs were perfused with blood that had PO2 and PCO2 similar to fetal blood, blood with elevated O2, and blood that had PO2 and PCO2 values similar to arterial blood of newborn animals. Neither increased O2 nor decreased CO2 in the blood perfusing the lungs stimulated pulmonary prostacyclin synthesis. We conclude that the mechanism responsible for the stimulation of pulmonary prostacyclin production with the onset of ventilation at birth is tissue stress during establishment of gaseous ventilation and rhythmic ventilation.

The onset of breathing at birth stimulates pulmonary vascular prostacyclin synthesis.

The purpose of the present study was to determine if pulmonary prostacyclin synthesis was stimulated by spontaneous onset of breathing by unanesthetized fetuses at birth. Cannulae were implanted and flow cuffs placed in fetal lambs and goats (0.93 term). Fetuses were delivered by cesarean section at 0.95 term and began breathing spontaneously. Prostacyclin in blood was determined by radioimmunoassay of its hydrolysis product, 6-ketoprostaglandin F1 alpha using methods that produced the same values in duplicate samples as did gas chromatography with electron capture detection. Fetal pulmonary prostacyclin production (left lung) [(left pulmonary venous concentration-pulmonary arterial concentration) X left pulmonary blood flow] was undetectable [-1.7 +/- 1.0 (SEM) ng PGI2 X kg-1 X min-1] and fetal pulmonary vascular resistance (left lung) high (5.1 +/- 0.9 mm Hg X kg X min X ml-1). Pulmonary prostacyclin production increased to 30.1 +/- 12.3 ngPGI2 X kg-1 X min-1 and pulmonary vascular resistance declined to 0.5 +/- 0.1 mm Hg X kg X min X ml-1 15 min after birth. Pulmonary vascular resistance remained low even though pulmonary prostacyclin production fell 2-5 h after birth. These results, coupled with earlier studies using indomethacin to inhibit prostaglandin synthesis, support the hypothesis that pulmonary prostacyclin synthesis participates in the decline of pulmonary vascular resistance that accompanies the onset of ventilation at birth, but may be less important in maintenance of low pulmonary vascular resistance once reduced pulmonary vascular tone has been established.