Origins of electronic band gap reduction in Cr/N codoped TiO2.

Recent studies indicated that noncompensated cation-anion codoping of wide-band-gap oxide semiconductors such as anatase TiO2 significantly reduces the optical band gap and thus strongly enhances the absorption of visible light [W. Zhu et al., Phys. Rev. Lett. 103, 226401 (2009)]. We used soft x-ray spectroscopy to fully determine the location and nature of the impurity levels responsible for the extraordinarily large (∼1 eV) band gap reduction of noncompensated codoped rutile TiO2. It is shown that Cr/N codoping strongly enhances the substitutional N content, compared to single element doping. The band gap reduction is due to the formation of Cr 3d3 levels in the lower half of the gap while the conduction band minimum is comprised of localized Cr 3d and delocalized N 2p states. Band gap reduction and carrier delocalization are critical elements for efficient light-to-current conversion in oxide semiconductors. These findings thus raise the prospect of using codoped oxide semiconductors with specifically engineered electronic properties in a variety of photovoltaic and photocatalytic applications.

The CD37-targeted antibody-drug conjugate IMGN529 is highly active against human CLL and in a novel CD37 transgenic murine leukemia model.

Therapeutic regimens for chronic lymphocytic leukemia (CLL) have increasingly utilized monoclonal antibodies since the chimeric anti-CD20 antibody rituximab was introduced. Despite improved clinical outcomes, current CLL therapies are not curative. Therefore, antibodies with greater efficacy and novel targets are desirable. One promising target is CD37, a tetraspanin protein highly expressed on malignant B-cells in CLL and non-Hodgkin lymphoma. Although several novel CD37-directed therapeutics are emerging, detailed preclinical evaluation of these agents is limited by lack of appropriate animal models with spontaneous leukemia expressing the human CD37 (hCD37) target. To address this, we generated a murine CLL model that develops transplantable hCD37+ leukemia. Subsequently, we engrafted healthy mice with this leukemia to evaluate IMGN529, a novel hCD37-targeting antibody-drug conjugate. IMGN529 rapidly eliminated peripheral blood leukemia and improved overall survival. In contrast, the antibody component of IMGN529 could not alter disease course despite exhibiting substantial in vitro cytotoxicity. Furthermore, IMGN529 is directly cytotoxic to human CLL in vitro, depletes B-cells in patient whole blood and promotes killing by macrophages and natural killer cells. Our results demonstrate the utility of a novel mouse model for evaluating anti-human CD37 therapeutics and highlight the potential of IMGN529 for treatment of CLL and other CD37-positive B-cell malignancies.

A phase I/II study of rituximab and etanercept in patients with chronic lymphocytic leukemia and small lymphocytic lymphoma.

Rituximab has modest activity in relapsed chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma but is associated with tumor necrosis factor-alpha (TNF-alpha) release that can cause CLL proliferation and inhibit apoptosis. We examined whether disruption of TNF-alpha by etanercept improves response to rituximab in CLL. Eligible patients had previously treated CLL with performance status 0-3. Patients received etanercept 25 mg subcutaneously twice weekly (weeks 1-5) and rituximab 375 mg/m(2) intravenously thrice weekly (weeks 2-5) using a phase I/II design. Primary end points were response and toxicity. The 36 enrolled patients had a median of two prior treatments; 50% were fludarabine refractory and 22% had del(17p13.1). Of the 34 response-evaluable patients, 10 (29%) responded, including 9 partial responses and 1 complete remission. Response was not affected by prior rituximab or fludarabine-refractory status, but no patients with del(17p13.1) responded. Median progression-free survival for responders was 9.0 months (range 1-43). Ten patients have had treatment-free intervals exceeding 12 months, including four who have remained untreated for 32, 43, 46 and 56 months. Adverse events were mild, including mild infusion reactions, transient cytopenias and grade 3 infections in 14% of the patients. The combination of etanercept and thrice weekly rituximab produces durable remissions in non-del(17p13.1) CLL patients and is well tolerated.

In vivo wireless ethanol vapor detection in the Wistar rat.

Traditional alcohol studies measure blood alcohol concentration to elucidate the biomedical factors that contribute to alcohol abuse and alcoholism. These measurements require large and expensive equipment, are labor intensive, and are disruptive to the subject. To alleviate these problems, we have developed an implantable, wireless biosensor that is capable of measuring alcohol levels for up to six weeks. Ethanol levels were measured in vivo in the interstitial fluid of a Wistar rat after administering 1 g/kg and 2 g/kg ethanol by intraperitoneal (IP) injection. The data were transmitted wirelessly using a biosensor selective for alcohol detection. A low-power piezoresistive microcantilever sensor array was used with a polymer coating suitable for measuring ethanol concentrations at 100% humidity over several hours. A hydrophobic, vapor permeable nanopore membrane was used to screen liquid and ions while allowing vapor to pass to the sensor from the subcutaneous interstitial fluid.

Effect of previous locoweed (Astragalus and Oxytropis species) intoxication on conditioned taste aversions in horses and sheep.

Locoweed species (Astragalus and Oxytropis spp.) are a serious toxic plant problem for grazing livestock. Horses and sheep have been conditioned to avoid eating locoweed using the aversive agent LiCl. The objective of this study was to determine if previous locoweed intoxication affects food aversion learning in horses and sheep. Horses and sheep were divided into 3 treatment groups: control (not fed locoweed and not averted to a novel feed); locoweed-novel feed averted (fed locoweed and averted to a novel feed); and averted (not fed locoweed and averted to a novel feed). Animals in the locoweed-novel feed averted groups were fed locoweed during 2 periods of 21 and 14 d, respectively, with each feeding period followed by a 14-d recovery period. Animals were averted to a novel test feed at the end of the first locoweed-feeding period, and periodically evaluated for the strength and persistence of the aversion. During the first recovery period, locoweed-novel feed averted horses ate less (9.5% of amount offered) of the test feed than did control horses (99.8%) and did not generally differ from averted horses (0%). During recovery period 2, locoweed-novel feed averted horses (4.3%) differed (P = 0.001) in consumption (% of offered) of the test feed from controls (100%) and the averted group (0%). Locoweed-novel feed averted sheep differed (P = 0.001) from controls (14.4 vs. 99.5%, respectively, during recovery period 1), whereas locoweed-novel feed averted sheep did not differ (P > 0.50) from averted sheep (0.6%). During the second recovery period, control sheep (100%) differed (P < 0.05) from averted (0%) and locoweed-novel feed averted (12.2%) groups. Two intoxicated sheep (locoweed-novel feed averted) partially extinguished the aversion during the first recovery period, but an additional dose of LiCl restored the aversion. Two of 3 intoxicated horses had strong aversions that persisted without extinction; 1 horse in the locoweed-novel feed averted group had a weaker aversion. These findings suggest that horses and sheep previously intoxicated by locoweeds can form strong and persistent aversions to a novel feed, but in some animals, those aversions may not be as strong as in animals that were never intoxicated.

Alemtuzumab induces caspase-independent cell death in human chronic lymphocytic leukemia cells through a lipid raft-dependent mechanism.

Alemtuzumab is a humanized IgG1 kappa antibody directed against CD52, a glycosyl-phosphatidylinositol linked cell-membrane protein of unknown function. Herein, we demonstrate that alemtuzumab promotes rapid death of chronic lymphocytic leukemia (CLL) cells in vitro, in a complement and accessory cell free system. Using minimal detergent solubilization of CLL membranes, we found that CD52 colocalizes with ganglioside GM-1, a marker of membrane rafts. Fluorescence microscopy revealed that upon crosslinking CD52 with alemtuzumab+anti-Fc IgG, large patches, and in many cases caps, enriched in CD52 and GM-1 formed upon the CLL cell plasma membrane. Depletion of membrane cholesterol or inhibition of actin polymerization significantly diminished the formation of alemtuzumab-induced caps and reduced alemtuzumab-mediated CLL cell death. We compared alemtuzumab-induced direct cytotoxicity, effector cell-mediated toxicity and complement-mediated cytotoxicity of CLL cells to normal T cells. The direct cytotoxicity and observed capping was significantly greater for CLL cells as compared to normal T cells. Cell-mediated and complement-mediated cytotoxicity did not significantly differ between the two cell types. In summary, our data support the hypothesis that alemtuzumab can initiate CLL cell death by crosslinking CD52-enriched lipid rafts. Furthermore, the differential direct cytotoxic effect suggests that CD52 directed antibodies could possibly be engineered to more specifically target CLL cells.

Conditioning taste aversions to locoweed (Oxytropis sericea) in horses.

Locoweed (Oxytropis sericea) is a serious poisoning problem for horses grazing on infested rangelands in the western United States. Our objectives were to determine 1) whether lithium chloride or apomorphine would condition aversions to palatable foods, and at what doses, and 2) whether horses could be averted to fresh locoweed in a pen and grazing situation. Apomorphine was not an acceptable aversive agent because at the dose required to condition an aversion (> or = 0.17 mg/kg BW), apomorphine induced unacceptable behavioral effects. Lithium chloride given via stomach tube at 190 mg/kg BW conditioned strong and persistent aversions to palatable feeds with minor signs of distress. Pen and grazing tests were conducted in Colorado to determine if horses could be averted to fresh locoweed. Pen tests indicated that most horses (5/6) were completely averted from locoweed. Treated horses ate 34 g of fresh locoweed compared to 135 g for controls (P < 0.01) during three pen tests when offered 150 g per test. One horse (T) in the treatment group ate locoweed each time it was offered in the pen, but ate no locoweed while grazing. In the grazing trial, control horses averaged 8.6% of bites of locoweed (P < 0.01) during the grazing portion of the study, whereas treated horses averaged <0.5%. One treated horse (S) accounted for all consumption; he consumed 15% of his bites as locoweed in a grazing bout on d 2 of the field study. Thereafter, he was dosed a second time with lithium chloride and ate no locoweed in the subsequent 5 d. Three of six horses required two pairings of lithium chloride with fresh locoweed to condition a complete aversion. The results of this study indicate that horses can be averted from locoweed using lithium chloride as an aversive agent, and this may provide a management tool to reduce the risk of intoxication for horses grazing locoweed-infested rangeland.

Drosophila rab GDI mutants disrupt development but have normal Rab membrane extraction.

Rab GTPases are essential for vesicular transport. Rab GDP dissociation inhibitor (GDI) binds to GDP-bound rabs, removes rabs from acceptor membranes and delivers rabs to donor membranes. We isolated lethal GDI mutations in Drosophila and analyzed their developmental phenotypes. To learn how these mutations affect GDI structure, the crystal structure of Drosophila GDI was determined by molecular replacement to a resolution of 3.0 A. Two hypomorphic, missense mutations are located in domain II of GDI at highly conserved positions, but not in previously identified sequence conserved regions. The mutant GDIs were tested for ability to extract rabs from membranes and showed wild-type levels of rab membrane extraction. The two missense alleles showed intragenic complementation, indicating that domain II of GDI may have two separable functions. This study indicates that GDI function is essential for development of a complex, multicellular organism and that puparium formation and pole cell formation are especially dependent on GDI function.

Biliary giardiasis in a patient with human immunodeficiency virus.

A 41-year-old man with human immunodeficiency virus (HIV) (CD4 count, 446/mm3) developed a protracted course of abdominal pain, weight loss, and increasing liver function tests after undergoing a metronidazole treatment regimen for Giardia enteritis. Three months later, endoscopic retrograde cholangiography (ERCP) showed dilated common and intrahepatic bile ducts and luminal irregularities of the common bile duct. Seven months after the onset of his acute diarrhea, a repeat ERCP with aspiration demonstrated many Giardia trophozoites and cysts in the bile and continued structural abnormalities consistent with cholangiopathy. A 10-day course of high-dose intravenous metronidazole did not resolve these signs or symptoms. A gallbladder ultrasound showed a thickened wall. Laparoscopic cholecystectomy led to resolution of abdominal pain and normalization of serum alkaline phosphatase over an 8-month period. Gallbladder histopathology revealed chronic cholecystitis, but no parasites were seen on hematoxylin and eosin staining or with Giardia antigen enzyme immunoassay testing of the gallbladder. The patient refused to undergo a follow-up ERCP, but a right upper quadrant ultrasound and computed tomography of the abdomen were normal.

Vibrational lifetime of bond-center hydrogen in crystalline silicon

The lifetime of the stretch mode of bond-center hydrogen in crystalline silicon is measured to be T1 = 7.8+/-0.2 ps with time-resolved, transient bleaching spectroscopy. The low-temperature spectral width of the absorption line due to the stretch mode converges towards its natural width for decreasing hydrogen concentration C(H), and nearly coincides with the natural width for C(H) approximately 1 ppm. The lifetimes of the Si-H stretch modes of selected hydrogen-related defects are estimated from their spectral widths and shown to range from 1.6 to more than 37 ps.

Hepatitis C.

In the latter half of the 20th century, HCV emerged as the most common cause of chronic liver disease, and will likely remain so. Since its initial discovery in 1989, rapid progress has been made in our understanding of the virology, epidemiology, natural history, diagnosis, and treatment of HCV. Over the next few decades, as further advancements are made, superior treatment options will become available.

Use of qualitative methods to study diet, acculturation, and health in Chinese-American women.

Improving the health status of minority populations in the United States is a major public health challenge. This report describes an anthropological approach to obtaining information needed for designing and evaluating a culturally appropriate dietary intervention for Chinese-Americans. Ninety-minute qualitative interviews were conducted with 30 less-acculturated Chinese-American women in their native language (Cantonese or Mandarin), soliciting information from participants regarding usual food consumption; knowledge, attitude, and beliefs about diet and disease; and factors that influence food choices. Interviews were recorded, translated, transcribed, and coded for themes. Two focus groups with 6 participants each were conducted to cross-validate the interview findings. Among our participants, breakfast was usually the first meal to be "Westernized," largely for reasons of convenience. Food quality, cost, and availability were some of the most important predictors of dietary change after immigration to the United States. Respondents said that there was a strong connection between diet and disease. However, they were not familiar with US dietary guidelines, food labels, or other sources of dietary information, but reported that friends and Chinese newspapers were their primary source of nutrition information. We used these findings to develop quantitative dietary survey instruments adapted for Chinese-Americans. This type of qualitative groundwork is an important precursor to the design, implementation, and evaluation of dietary interventions for minorities.

Congenital bronchoesophageal fistula in the adult: a case report.

Congenital bronchoesophageal fistula is a rare anomaly that may go undiagnosed for many years. There are <200 reported cases in the literature. Patients usually present with chronic cough, a history of multiple pneumonias, and, less often, hemoptysis. The most sensitive test to diagnose a bronchoesophageal fistula is barium esophagogram. Surgical resection is the treatment of choice and is definitive in almost all cases. We present the case of a 52-yr-old woman with a history of cough and multiple pneumonias who sought medical treatment for abdominal pain. We discuss the presentation and the radiographic, endoscopic, and surgical findings, along with a review of the literature.

Computer integration and time spent on direct patient nutritional care activities in an outpatient dialysis setting.

OBJECTIVE: To compare time spent in patient and administrative activities by nutrition professionals in a group of dialysis facilities, and relate differences to the degree of computer integration at the sites and between 2 time periods. DESIGN: Survey design, self-administered activity form, completed in 1992 and 1997. SETTING: Three of the largest outpatient dialysis centers in western Washington state. SUBJECTS: Ten nutrition professionals completed the activity forms. INTERVENTION: Activity form (recording time), questionnaire (results not reported here). MAIN OUTCOME MEASURES: Amount of time spent on administrative activities in 1997 and the number of patients and number of hours per nutrition professional per month spent with patients in 1997, compared with 1992. RESULTS: Time spent on administrative activities decreased in all facilities since 1992, with the largest decrease at the unit having the most computer integration. CONCLUSION: Extensive computer integration seems to allow for a decrease in the amount of time spent on administrative activities by nutrition professionals.

Prevalence of low albumin, suboptimal energy, and muscle stores in asian dialysis patients.

OBJECTIVE: Investigate the prevalence of low serum albumin levels (<3.2 g/L) and decreased arm muscle area percentiles and arm fat area percentiles in Asian patients compared with non-Asian patients treated with dialysis. DESIGN: Cross-sectional study in which serum albumin and anthropometric measurements were averaged over 6 months, and compared between patients of Asian ethnicity and patients of non-Asian ethnicity. SETTING: Eight outpatient dialysis facilities. SUBJECTS: Ninety-seven Asian and 513 non-Asian patients treated with hemodialysis or peritoneal dialysis. RESULTS: Height, weight, and body mass index were significantly lower in Asians compared with non-Asians (P <.001). Protein catabolic rate was significantly greater in Asian (1.17 +/- 0.29 g/kg) compared with non-Asian (0.97 +/- 0.28 g/kg) women (P <.001). Asian men (3.30 g/dL) and women (3. 26 g/dL) had lower serum albumin compared with non-Asian men (3.35 g/dL; P =.057) and women (3.34 g/dL; P =.040). The proportion of patients with serum albumin <3.2 g/dL was greater for both Asian women (35%) (P <.040) and men (30%) than non-Asian women (25%) and men (20%). After adjusting for important covariates, serum albumin remained significantly different between Asian and non-Asian patients (P <.05). The proportion below the fifth percentile for arm muscle area was significantly greater for both Asian men (54%) and women (19%) compared with non-Asian men (24%) and women (8%). Proportions of Asian and non-Asian women below the 10th and 5th percentile for arm fat area were similar. However, Asian men (54%) had a significantly greater fat depletion than non-Asian men (26%). CONCLUSION: Mean serum albumin was significantly lower in Asian patients on dialysis than in non-Asians. Muscle stores were depleted in Asian men and women compared with non-Asians, and fat stores were depleted in Asian men. Based on this study, Asian dialysis patients would seem to be at higher nutritional risk than non-Asians, particularly Asian men. Further research is needed to assess factors that affect serum albumin and mortality in Asian dialysis patients, and standards need to be developed to further assess anthropometric measurements in this population.

The prevalence and impact of 'atypical' days in 4-day food records.

OBJECTIVE: To understand how days with atypical food intake affect estimates of usual nutrient intake from 4-day food records. PARTICIPANTS/SETTING: Secondary analyses of 4-day food records (4DFRs) (n = 2,560) collected from 1,090 women, aged 50 to 79 years, who participated in the Women's Trial Feasibility Study in Minority Populations, a randomized dietary intervention trial. DESIGN: Food records were classified as atypical if participants marked one or more day's food intake as "more than usual" or "less than usual." Total amounts and nutrient densities (percent of energy or grams per 1,000 kcal) were examined for all macronutrients, fiber, vitamin C, beta carotene, and calcium. STATISTICAL ANALYSIS: Contingency tables were used to examine associations of demographic characteristics with the likelihood of completing a 4DFR with atypical intake days. Analysis of variance was used to test whether nutrient intake differed among records with and without atypical days. Student t tests were used to identify any differences in total energy and percent energy from fat among typical and atypical intake days. RESULTS: Approximately 16% of records included at least 1 atypical day. Reporting less-than-usual intake was associated with younger age, higher income, and higher body mass index. Black women were less likely to report more-than-usual intake than whites and Hispanics. Records with less-than-usual intake had lower intakes of all nutrients analyzed except alcohol; however, there were no differences in nutrient densities. Records with more-than-usual intake had higher intakes of alcohol and all nutrients except beta carotene and vitamin C, with higher nutrient density measures of alcohol and decreased nutrient density measures of protein, vitamin C, and fiber. CONCLUSIONS: Atypical intake days are common in 4DFRs and they have a large effect on mean total intakes of most nutrients. APPLICATIONS: It is important for researchers to collect information on atypical intake days included in a 4-day food record. Strategies are needed to incorporate information on atypical intake days when analyzing and interpreting research results.