The place of modeling in cognitive science.
I consider the role of cognitive modeling in cognitive science. Modeling, and the computers that enable it, are central to the field, but the role of modeling is often misunderstood. Models are not intended to capture fully the processes they attempt to elucidate. Rather, they are explorations of ideas about the nature of cognitive processes. In these explorations, simplification is essential-through simplification, the implications of the central ideas become more transparent. This is not to say that simplification has no downsides; it does, and these are discussed. I then consider several contemporary frameworks for cognitive modeling, stressing the idea that each framework is useful in its own particular ways. Increases in computer power (by a factor of about 4 million) since 1958 have enabled new modeling paradigms to emerge, but these also depend on new ways of thinking. Will new paradigms emerge again with the next 1,000-fold increase?


Association of irritable bowel syndrome and sleep apnea in patients referred to sleep laboratory.
Irritable bowel syndrome (IBS) is assumed as one of the most frequent gastrointestinal disorders, which decreases the patient's quality of life. IBS pathogenesis, however, is not clearly defined. It seems that sleep apnea induces or escalates IBS clinical symptoms. This study aims at evaluating of IBS prevalence in patients, who are afflicted or are not afflicted with sleep apnea. This was a case-control study, which was implemented in a sleep laboratory located in Isfahan, Iran. We recruited 200 patients being more than 15 years from 2014 to 2015. Based on the apnea-hypopnea index (AHI), we recruited 100 patients in each of two groups: negative sleep apnea (NSA) (AHI ≤4) and positive sleep apnea (PSA) (AHI >4). IBS was diagnosed through a Rome III diagnostic questionnaire. Overall, the prevalence of IBS among patients referred to sleep laboratory was 17.6%. Indeed, IBS prevalence in NSA and PSA groups were 8.2% and 27.1%, respectively. Furthermore, odds ratio of IBS in PSA group versus NSA was 3.92 (95% confidence interval = 1.58-9.77, P = 0.003). Our results showed that the prevalence of IBS did not differ significantly between various severity of sleep apnea (P = 0.452). This study showed that there was a positive association between sleep apnea and IBS.


Impact of modified radical mastectomy on health-related quality of life in women with early stage breast cancer.
Systematic reviews favor a better body image and sexual activity in patients who have undergone conservative breast surgery (BCS) compared to modified radical mastectomy (MRM). In those patients with the same survival, MRM remains the surgical choice among both surgeons and patients in Iran as well as in many other countries. This cross-sectional study focuses on health-related quality of life in early stage breast cancer patients following BCS and MRM. From all post-op patients who referred to the Motahari Clinic, Shiraz, Iran, we used a convenient sampling method to select 160 MRM patients and 127 who underwent BCS. Translated copies of the EORTC QLQ-C30 (version 3) and the EORTC QLQ-BR23 questionnaires, in addition to a third questionnaire which was customized and prepared for this study, were completed by the patients under our supervision The two groups were compared by a multivariate method (Hotelling's trace test) after controlling for variables with unequal values such as disease stage, hormonal and radiotherapy treatments, and patients' role in the choice of surgery. We noted a significant difference (P < 0.001) attributed to a significantly better BI in the BCS group (average: 78.49 ± 23.14) compared to the MRM group (average: 60.71 ± 23.14). We concluded that in terms of body image, BCS has a better impact on health-related quality of life.


pistillata-5, an Arabidopsis B class mutant with strong defects in petal but not in stamen development.
The Arabidopsis floral organ identity genes APETALA3 (AP3) and PISTILLATA (PI) encode related DNA-binding proteins of the MADS family. Considerable evidence supports the hypothesis that a heterodimer of AP3 and PI is an essential component of B class activity. All ap3 and pi alleles characterized to date exhibit equivalent phenotypic defects in both whorls 2 and 3. In strong ap3 and pi mutants, petals and stamens are missing and sepals and carpels develop in their place. Weak ap3 and pi mutants exhibit partial conversions of petals to sepals and stamens to carpels. In this report, we describe the isolation and characterization of pi-5, an unusual B class mutant that exhibits defects in whorl 2 where sepals develop in place of petals, but third whorl stamens are most often normal. pi-5 flowers resemble those from 35S::SEP3 antisense plants. pi-5 contains missense mutation in the K domain (PIE125K). PIE125K exhibits defects in heterodimerization with its partner protein AP3. Via a reverse yeast two-hybrid screen, AP3K139E was isolated as a compensatory mutant of PIE125K. The compensatory interaction between PIE125K and AP3K139E is observed both in yeast two-hybrid assays and in planta. On its own, AP3K139E exhibits defects in specifying both petal and stamen identity. In addition, PIE125K is defective in interaction with SEPALLATA proteins in both two- and three-hybrid assays suggesting that PIE125K is defective in forming higher order complexes of MADS proteins. The decreased concentration of PI/AP3/SEP complexes offers an explanation for the petal defects observed in both pi-5 and 35S::SEP3 antisense plants.


Two siblings with PRKDC defect who presented with cutaneous granulomas and review of the literature.
V(D)J recombination, during which recognition and repair of broken DNA chains are accomplished by non-homologous end joining pathway, is a critical process in B and T cell development.Null mutations of each enzyme or protein of this pathway result in T- B- NK+ severe combined immunodeficiency whereas hypomorphic mutations result in atypical(leaky)severe combined immunodeficiency forms. We present two siblings with PRKDC (Protein Kinase, DNA-Activated, Catalytic Polypeptide) mutation who presented with granulomatous skin lesions and recurrent lung infections. Primary immune deficiencies may initially present with skin findings. Disruption in central and peripheral B-cell tolerance and impaired intrathymic T-cell maturation,a central player in T-cell tolerance, have been identified as the mechanism of autoimmunity and granuloma seen in patients. The variation in clinical phenotypes of patients with PRKDC mutation suggests that additional factors such as modifying genes, epigenetic and environmental factors may affect the severity and clinical phenotype of the disease. Functional studies during the follow-up and evaluation before and after hematopoeitic stem cell transplantation will hopefully increase our knowledge about the autoimmune and inflammatory process of the disease spectrum.


Associations between subclinical thyroid disease and metabolic syndrome.
Thyrotropin levels are outside normal reference range in subclinical thyroid disease. Metabolic syndrome (MetS) involves clustered cardiovascular risk factors, including abnormal lipids, insulin resistance, and hypertension. This study aimed to investigate associations between subclinical thyroid disease, thyrotropin levels, and metabolic syndrome in healthy subjects and identify associated biochemical markers. This cross-sectional study evaluated 9,055 healthy subjects examined at the Health Management Center, National Taiwan University Hospital from January 1, 2009 to December 31, 2009. Data collected included age, sex, height, weight, body mass index, waist circumference, pulse rate, and systolic/diastolic blood pressure. History of pregnancy, smoking/drinking status, family/personal thyroid disease, diabetes, dyslipidemia, and hypertension was obtained. Laboratory data included thyroid function tests, fasting glucose level, lipid profile, and C-reactive protein level. Participants were classified into subclinical hypothyroidism, subclinical hyperthyroidism, and euthyroid groups according to thyrotropin levels. In euglycemic subjects, thyroid-stimulating hormone (TSH) levels correlated positively with waist circumference, triglycerides (TG), non-high density lipoprotein (HDL) cholesterol, diastolic blood pressure. In subclinical hyperthyroid subjects, TSH levels correlated positively with low density lipoprotein cholesterol (LDL-C), non-HDL cholesterol. No significant correlations were found between TSH levels and variables in the subclinical hypothyroid group. In the entire study population, TSH levels correlated positively with TG, non-HDL cholesterol, and systolic blood pressure (SBP)/diastolic blood pressure (DBP), but no correlation was shown with HDL-C. No significant associations were seen between MetS prevalence and thyrotropin levels. No clinically relevant biochemical markers, differences in thyrotropin levels, or statistical correlations are shown between subclinical thyroid disease and metabolic syndrome in healthy individuals.


[The relationship between the production of nitric oxide and the injury of cardiomyocytes caused by in vivo rat regional myocardial ischemia and reperfusion].
Changes in nitric oxide concentration in rat myocardium in vivo during temporary occlusion of the anterior descending coronary artery, followed by reperfusion were studied by microdialysis assay in risk and intact areas by using an NO spin trap (complex of ferrous ions with N-methyl-D, L-glucamine dihiocarbamate, Fe3+-MGD2). The amplitude of the EPR signal of the NO spin adduct NO-Fe2+-MGD2 in the risk area increased during the 40-min occlusion and remained higher than the initial level during 60-min postischemic reperfusion, indicating a substantial nitric oxide production. The size of the infarction in the risk area by the end of reperfusion was 47 +/- 3 %, the contents of ATP, phosphocreatine, and total creatine decreased to 44 +/- 4, 51 +/- 5, and 60 +/- 3 %, correspondingly, as compared with initial values, and the level of lactate was six times higher than the initial one. In the intact area of the left ventricle, the level of nitric oxide and high-energy metabolites did not change throughout the experiment. It was shown that the intensive nitric oxide production, in acute regional ischemia and reperfusion are related to the disturbance of energy metabolism, the damage to cytoplasmic membranes, and the death of cardiomyocytes.


N-acetylcysteine prevents lung inflammation after short-term inhalation exposure to concentrated ambient particles.
Lung inflammation is a key response to increased levels of particulate air pollution (PM); however, the cellular mechanisms leading to this response are poorly understood. To determine whether oxidants are implicated in PM-dependent lung inflammation, we tested the ability of N-acetylcysteine (NAC) to prevent lung inflammation in a rat model of short-term exposure to concentrated ambient particles (CAPs). Adult Sprague-Dawley rats were exposed to either CAPs aerosols (CAPs mass concentration 1060 +/- 300 microg/m(3)) or filtered air (Sham controls) for 5 h. NAC-treated rats received 50 mg/kg (ip) NAC 1 h prior to exposure to CAPs. Oxidative stress and recruitment of inflammatory cells into bronchoalveolar lavage were evaluated 24 h after removal of the animals from the exposure chamber. Rats breathing CAPs aerosols showed significant oxidative stress, determined by the accumulation of thiobarbituric reactive substances (TBARS, 90 +/- 15 pmol/mg protein; sham control: 50 +/- 5 pmol/mg protein, p < 0.02) and oxidized proteins (1.6 +/- 0.4 nmol/mg protein, sham: 0.70 +/- 0.02 nmol/mg protein, p < 0.01) in their lungs. CAPs-induced oxidative stress was associated with increased numbers of polymorphonuclear leukocytes in bronchoalveolar lavage (BAL) (9 +/- 2%; sham: 1.6 +/- 0.5%, p < 0.001) and slight lung edema (wet/dry ratio: 4.77 +/- 0.03, sham: 4.69 +/- 0.02). No significant change was found in BAL protein concentration, total cell count, or lactate dehydrogenase (LDH) activity. NAC pretreatment effectively prevented CAPs-induced TBARS accumulation (30 +/- 10 pmol/mg protein, p < 0.006), lung edema (4.64 +/- 0.08, p < 0.05), and polymorphonuclear neutrophil (PMN) influx into the lungs (2.1 +/- 0.5%, p < 0.001), but did not alter the protein carbonyl content. Histological evaluation of tissue samples confirmed the BAL findings. CAPs-exposed animals showed slight bronchiolar inflammation and thickened vessels at the bronchiole, whereas NAC treated animals showed no histological alterations. Regression analyses showed strong associations between increased TBARS accumulation and the CAPs content of Al, Si, and Fe, and trends of association between carbonyl content and Cr and Na concentrations, and between BAL PMN count and Cr, Zn, and Na. These data demonstrate that oxidants are critical mediators of the inflammatory response elicited by PM inhalation.


E2F1-directed activation of Bcl-2 is correlated with lactoferrin-induced apoptosis in Jurkat leukemia T lymphocytes.
Lactoferrin (Lf) has been shown to control the proliferation of a variety of mammalian cells. Recently, we reported that human Lf induces apoptosis via a c-Jun N-terminal kinases (JNK)-associated Bcl-2 pathway that stimulates programmed cell death. In order to gain insight into the mechanism underlying Lf-triggered apoptotic features, we attempted to determine the mechanisms whereby the Lf-induced Bcl-2 family proteins exert their pro- or anti-apoptotic effects in Jurkat leukemia T lymphocytes. Treatment of the cells with high concentrations of Lf resulted in a significant reduction in in vitro growth and cell viability. As the levels of Lf increased, greater quantities of CDK6 and hyper-phosphorylated retinoblastoma protein were produced, resulting in the induction of E2F1-dependent apoptosis. Simultaneously, PARP and caspases were efficiently cleaved during Lf-induced apoptosis. The E2F1-induced apoptotic process occurred preferentially in p53-deficient Jurkat leukemia cells. Therefore, we attempted to determine whether E2F1-regulated Bcl-2 family proteins involved in the apoptotic process were relevant to Lf-induced apoptosis. We found that Lf increased the interaction of Bcl-2 with the pro-apoptotic protein Bad, whereas the total protein levels did not change significantly. Our results, collectively, suggest that Lf exploits the control mechanism of E2F1-regulated target genes or Bcl-2 family gene networks involved in the apoptotic process in Jurkat human leukemia T lymphocytes.


Volatile substance misuse in the United States.
Volatile substance misuse (VSM) is prevalent in the United States and associated with manifold deleterious outcomes. This review summarizes research on: (1) the prevalence of VSM in the United States and its trends since 1975, (2) population subgroups at an elevated risk for VSM, (3) key correlates of VSM, (4) psychosocial consequences of VSM, including emerging public health threats, and (5) etiological and contextual considerations of VSM use. Implications for future research and practice with volatile substance misusers in the United States are identified.


Association of Changes in Mood Status and Psychosocial Well-Being with Depression During Interferon-Based Treatment for Hepatitis C.
The aims of this prospective study were to investigate temporal changes in mood status and distress level, as well as the development of depression, during pegylated interferon (PEG-IFN)-based treatment of patients with chronic hepatitis C (CHC). We also explored whether baseline demographic, psychiatric, and personality traits predicted the evolution of depression. CHC patients without depression were screened with laboratory tests; psychiatric interviews; and evaluations of mood symptoms, level of distress, and personality traits. A total of 67 treatment-naïve patients with CHC were consecutively treated with PEG-IFN-α-2a plus ribavirin for 48 (genotype 1, n=29) or 24 (genotype 2, n=38) weeks. Patients were followed prospectively every 4 weeks during the treatment period. Seven patients (10.4%) were diagnosed with major depressive disorder (MDD), and eight (11.9%) developed subsyndromal depression. Times to onset of MDD and subsyndromal depression were 6.67±5.01 and 11.11±5.58 weeks, respectively, after initiation of treatment. Patients who developed MDD had significantly increased fatigue and anxiety and poor psychological well-being during the course of treatment. Pretreatment subthreshold mood symptoms were a significant predictor of depression. An early psychiatric assessment may be helpful in improving psychological well-being in those with CHC, leading to adherence to PEG-IFN-based treatment.


Timing of procedural stroke and death in asymptomatic patients undergoing carotid endarterectomy: individual patient analysis from four RCTs.
The effectiveness of carotid endarterectomy (CEA) for stroke prevention depends on low procedural risks. The aim of this study was to assess the frequency and timing of procedural complications after CEA, which may clarify underlying mechanisms and help inform safe discharge policies. Individual-patient data were obtained from four large carotid intervention trials (VACS, ACAS, ACST-1 and GALA; 1983-2007). Patients undergoing CEA for asymptomatic carotid artery stenosis directly after randomization were used for the present analysis. Timing of procedural death and stroke was divided into intraoperative day 0, postoperative day 0, days 1-3 and days 4-30. Some 3694 patients were included in the analysis. A total of 103 patients (2·8 per cent) had serious procedural complications (18 fatal strokes, 68 non-fatal strokes, 11 fatal myocardial infarctions and 6 deaths from other causes) [Correction added on 20 April, after first online publication: the percentage value has been corrected to 2·8]. Of the 86 strokes, 67 (78 per cent) were ipsilateral, 17 (20 per cent) were contralateral and two (2 per cent) were vertebrobasilar. Forty-five strokes (52 per cent) were ischaemic, nine (10 per cent) haemorrhagic, and stroke subtype was not determined in 32 patients (37 per cent). Half of the strokes happened on the day of CEA. Of all serious complications recorded, 44 (42·7 per cent) occurred on day 0 (20 intraoperative, 17 postoperative, 7 with unclear timing), 23 (22·3 per cent) on days 1-3 and 36 (35·0 per cent) on days 4-30. At least half of the procedural strokes in this study were ischaemic and ipsilateral to the treated artery. Half of all procedural complications occurred on the day of surgery, but one-third after day 3 when many patients had been discharged.


Monitoring Antibiotic Usage in German Dairy and Beef Cattle Farms-A Longitudinal Analysis.
It is well-established that antimicrobial use is a major factor for the development of antimicrobial resistance. To analyze the associations between antimicrobial resistance and usage of antimicrobial agents, data from monitoring and surveillance systems are crucial. Within the project VetCAb (Veterinary Consumption of Antibiotics), antibiotic usage data in German livestock is regularly collected and evaluated. Based on a cross-sectional study in 2011, the project was continued as the longitudinal study VetCAb-Sentinel with ongoing participant recruitment and data collection from 2013. The data collection is based on official German application and delivery forms (ADF), voluntarily provided by veterinarians and farmers. In this study the results of antibiotic usage data of dairy cows, dairy calves and beef cattle were described, using a semi-annual treatment frequency, and 95,944 ADF issued between 2011 and 2015 were analyzed. Results show that the median of the treatment frequency in dairy calf and beef cattle holdings slightly decreased from 0.4 to 0.3 and from 0.2 to 0 days, respectively, whereas the median in dairy cow holdings ranged between 1.9 and 2.3 during the observed period. Temporal changes and the effect of the factors "farm size" and "region" on the treatment frequency were investigated, using multiple linear mixed and logistic regression models. Generally, the factor "time" has a statistically significant impact on the treatment frequency in all production types. In addition, a temporal trend test over the first six half-years shows that an increasing linear trend can be stated in dairy cows and dairy calves (p = 0.017; p = 0.004, respectively). If the time-period is extended to all eight half-years under study, this turns into a quadratic effect (dairy cows: p = 0.006; dairy calves: p < 0.001). In dairy calves and beef cattle the factor "farm size" also has a statistically significant impact. The factor "region," in contrast, shows no statistically significant impact at all. Compared to other livestock populations in Germany, the use of antimicrobials in dairy cows, dairy calves, and beef cattle appears to be low, but varies across several associated factors. Considering these effects, it is recommended that the size of dairy calf and beef cattle holdings is regularly considered in the evaluation of antimicrobial usage data over time.


Oral fenretinide in biochemically recurrent prostate cancer: a California cancer consortium phase II trial.
Fenretinide is a synthetic retinoid that is cytotoxic to a variety of cancers. We conducted a phase II trial of oral fenretinide in patients with biochemically recurrent prostate cancer. Eligible patients had histologically confirmed prostate cancer and a confirmed rising prostate-specific antigen (PSA) >or= 2 ng/mL following either radical prostatectomy and/or pelvic radiation therapy, without clinical or radiographic evidence of metastasis. The primary endpoint was PSA response, which was defined as a confirmed decrease by >or=50%, and >or=5 ng/mL, from the pretreatment value. Treatment comprised oral fenretinide 900 mg/m2 twice daily for 1 week, every 3 weeks, for 1 year. After a median follow-up of 17.7 months, out of 23 patients, 7 (30%) patients had PSA stable disease (SD), 11 (48%) patients had PSA progression within 3 months, 4 patients had minimal increases over 3 months that did not qualify as SD or progression (17%), and one patient (4%) was not evaluable. Median time to PSA progression was 4.6 months (95% CI, 3.2-8.2 months). Observed grade 3 toxicities included fatigue, pain, hypermagnesemia, a rise in lipase, and nyctalopia. Although well-tolerated, oral fenretinide did not meet prespecified PSA criteria for response in biochemically recurrent prostate cancer; however, 30% of patients had SD, which suggests modest single-agent clinical activity. The role of different formulations of fenretinide, which might allow for higher serum concentrations of the drug, is currently under investigation.


Connexin 35/36 is phosphorylated at regulatory sites in the retina.
Connexin 35/36 is the most widespread neuronal gap junction protein in the retina and central nervous system. Electrical and/or tracer coupling in a number of neuronal circuits that express this connexin are regulated by light adaptation. In many cases, the regulation of coupling depends on signaling pathways that activate protein kinases such as PKA, and Cx35 has been shown to be regulated by PKA phosphorylation in cell culture systems. To examine whether phosphorylation might regulate Cx35/36 in the retina we developed phospho-specific polyclonal antibodies against the two regulatory phosphorylation sites of Cx35 and examined the phosphorylation state of this connexin in the retina. Western blot analysis with hybrid bass retinal membrane preparations showed Cx35 to be phosphorylated at both the Ser110 and Ser276 sites, and this labeling was eliminated by alkaline phosphatase digestion. The homologous sites of mouse and rabbit Cx36 were also phosphorylated in retinal membrane preparations. Quantitative confocal immunofluorescence analysis showed gap junctions identified with a monoclonal anti-Cx35 antibody to have variable levels of phosphorylation at both the Ser110 and Ser276 sites. Unusual gap junctions that could be identified by their large size (up to 32 microm2) and location in the IPL showed a prominent shift in phosphorylation state from heavily phosphorylated in nighttime, dark-adapted retina to weakly phosphorylated in daytime, light-adapted retina. Both Ser110 and Ser276 sites showed significant changes in this manner. Under both lighting conditions, other gap junctions varied from non-phosphorylated to heavily phosphorylated. We predict that changes in the phosphorylation states of these sites correlate with changes in the degree of coupling through Cx35/36 gap junctions. This leads to the conclusion that connexin phosphorylation mediates changes in coupling in some retinal networks. However, these changes are not global and likely occur in a cell type-specific or possibly a gap junction-specific manner.


A Loading Micafungin Dose in Critically Ill Patients Undergoing Continuous Venovenous Hemofiltration or Continuous Venovenous Hemodiafiltration: A Population Pharmacokinetic Analysis.
In this study, the authors aimed to compare the pharmacokinetics (PK) of micafungin in critically ill patients receiving continuous venovenous hemofiltration (CVVH, 30 mL·kg-1·h-1) with those of patients receiving equidoses of hemodiafiltration (CVVHDF, 15 mL·kg-1·h-1 + 15 mL·kg-1·h-1) and determine the optimal dosing regimen using the developed model. Patients with septic shock undergoing continuous renal replacement therapy and receiving a conventional dose of 100 mg micafungin once daily were eligible for inclusion. Total micafungin plasma concentrations from 8 CVVH sessions and 8 CVVHDF sessions were subjected to a population PK analysis using Pmetrics. Validation of the model performance was reinforced by external validation. Monte Carlo simulations were performed considering the total ratio of free drug area under the curve (AUC) over 24 hours to the minimum inhibitory concentration (MIC) (AUC0-24/MIC) in plasma. The median total body weight (min-max) was 94.8 (66-138) kg. Micafungin concentrations were best described by a 2-compartmental PK model. No covariates, including continuous renal replacement therapy modality (CVVH or CVVHDF), were retained in the final model. The mean parameter estimates (SD) were 0.96 (0.32) L/h for clearance and 14.8 (5.3) L for the central compartment volume. External validation confirmed the performance of the developed PK model. Dosing simulations did not support the use of standard 100 mg daily dosing, except for Candida albicans on the second day of therapy. A loading dose of 150 mg followed by 100 mg daily reached the probability of target attainment for all C. albicans and C. glabrata, but not for C. krusei and C. parapsilosis. No difference was observed in micafungin PK between equidoses of CVVH and CVVHDF. A loading dose of 150 mg is required to achieve the PK/PD target for less susceptible Candida species from the first day of therapy.


High frequency of Parkin exon rearrangements in Mexican-mestizo patients with early-onset Parkinson's disease.
Parkin mutations in patients with early-onset Parkinson's disease (EOPD) are estimated to occur in 49% of familial cases and 18% of sporadic cases. We analyzed the entire sequence-coding region and dosage mutations of parkin in 63 Mexican-mestizo EOPD patients and 120 controls. Parkin mutations were present in 34 patients (54.0%). Exon rearrangements, predominantly spanning exons 9 and 12 (31.7% and 19.0%, respectively) were present in 32 patients, with 17.5% carrying simple heterozygous and 25.4% carrying compound heterozygous parkin mutations. A higher frequency of parkin exon rearrangements than of sequence mutations was observed. Patients with parkin exons 9 and 12 rearrangements showed a later age at onset than did cases with other regions affected (40.3 ± 4.5 vs 30.1 ± 8.8; P = .005), suggesting a mutational hot spot in the etiology of Mexican-mestizo patients with EOPD. To our knowledge, this study represents the largest sampling of Mexican-mestizo patients with EOPD cases for which parkin sequence and dosage alterations were analyzed. .


Effects of trace mineral injections on measures of performance and trace mineral status of pre- and postweaned beef calves.
Three experiments were conducted to examine the effects of injectable trace minerals (ITM) on measures of trace mineral status and performance in pre- and postweaned Brangus-crossbred beef calves. In Exp. 1, calves were assigned to treatments in alternating birth order (n = 150; 75/treatment), consisting of a 1-mL subcutaneous injection of ITM (MultiMin 90; MultiMin USA, Inc., Fort Collins, CO) or sterile saline. The ITM formulation consisted of 60, 10, 15, and 5 mg/mL of Zn, Mn, Cu, and Se. Treatments were readministered at 100 and 200 d of age. Calf BW was recorded at birth and on d 100, 150, 200, and 250 (weaning). Trace mineral status was assessed in liver biopsy samples (n = 12/treatment) collected on d 150, 200, and 250. Administration of ITM had no impact on BW gain (P ≥ 0.55) but did result in greater (P ≤ 0.02) concentrations of liver Cu and Se and lesser (P = 0.05) liver Fe concentrations compared to saline-injected calves. In Exp. 2, 24 heifers were selected from the weaned calves of Exp. 1 (n = 12/treatment) and transported 1,600 km. Remaining on their original treatments, heifers were administered 5 mL of ITM or saline following transport (d 0). Blood samples, for acute phase protein (APP) analysis, were collected on d 0, 1, 3, 6, 9, and 13 and liver biopsy samples for assessment of trace mineral status on d 13. Plasma APP concentrations increased in all calves following weaning and transport but concentrations were greatest (P < 0.05) in ITM- vs. saline-injected heifers on d 6 and 9. Liver concentrations of Cu, Se, and Zn were greater (P ≤ 0.04) but ADG lesser (P = 0.05) for heifers receiving ITM vs. saline. In Exp. 3, 34 heifers, without previous exposure to ITM, were enrolled in a 177-d development study (n = 17/treatment). Treatments consisted of 2.5-mL injections of ITM or sterile saline on d 0, 51, and 127. Humoral immune response to an injection of porcine red blood cells (PRBC) was evaluated on d 51. Trace mineral status was evaluated in liver biopsy samples collected on d 177. Overall heifer ADG, PRBC antibody titers, and liver Se concentrations were greatest (P ≤ 0.06) for ITM vs. control heifers. Collectively, these studies demonstrate an increased trace mineral status, a greater humoral response to novel antigen, and a heightened APP response to weaning and transport stress in pre- and postweaned beef calves administered ITM.


Cloning and sequencing of the genes encoding cyclic tetrasaccharide-synthesizing enzymes from Bacillus globisporus C11.
The genes for isomaltosyltransferase (CtsY) and 6-glucosyltransferase (CtsZ), involved in synthesis of a cyclic tetrasaccharide from alpha-glucan, have been cloned from the genome of Bacillus globisporus C11. The amino-acid sequence deduced from the ctsY gene is composed of 1093 residues having a signal sequence of 29 residues in its N-terminus. The ctsZ gene encodes a protein consisting of 1284 residues with a signal sequence of 35 residues. Both of the gene products show similarities to alpha-glucosidases belonging to glycoside hydrolase family 31 and conserve two aspartic acids corresponding to the putative catalytic residues of these enzymes. The two genes are linked together, forming ctsYZ. The DNA sequence of 16,515 bp analyzed in this study contains four open reading frames (ORFs) upstream of ctsYZ and one ORF downstream. The first six ORFs, including ctsYZ, form a gene cluster, ctsUVWXYZ. The amino-acid sequences deduced from ctsUV are similar in to a sequence permease and a sugar-binding protein for the sugar transport system from Thermococcus sp. B1001. The third ctsW encodes a protein similar to CtsY, suggested to be another isomaltosyltransferase preferring panose to high-molecular-mass substrates.


Veterinarian satisfaction with companion animal visits.
To measure veterinarian satisfaction with companion animal visits through an adaptation of a previously validated physician visit satisfaction scale and to identify demographic, personality, appointment, and communication factors that contribute to veterinarian visit satisfaction. Cross-sectional descriptive study. Random sample of 50 companion animal practitioners in southern Ontario, Canada, and convenience sample of 300 clients and their pets. For each practitioner, 6 clinical appointments were videotaped, and the resulting 300 videotapes were analyzed by use of the Roter interaction analysis system. The physician satisfaction scale, Rosenberg self-esteem scale, and interpersonal reactivity index were used to measure veterinarian visit satisfaction, self-esteem, and empathy, respectively. Linear regression analysis was conducted to study the relationship between factors and veterinarian visit satisfaction. Veterinarian visit satisfaction ranged from 1 to 5 (mean ± SD, 3.97 ± 0.99) and differed significantly between wellness appointments (mean scale score, 4.13) and problem appointments (mean scale score, 3.81). Various elements of client and veterinarian communication as well as personality measures of veterinarian self-esteem and empathy were associated with veterinarian satisfaction. The specific factors differed depending on the nature of the appointment. Results suggested that veterinarian visit-specific satisfaction is enhanced through the use of communication that builds relationships with clients and is associated with degrees of veterinarian empathetic concern and veterinarian self-esteem. The implications extend to overall job satisfaction and its potential link to the health and well-being of individual veterinarians.


Cytokine-regulated expression of activated leukocyte cell adhesion molecule (CD166) on monocyte-lineage cells and in rheumatoid arthritis synovium.
To determine whether monocyte/macrophage expression of the CD6 ligand, activated leukocyte cell adhesion molecule (ALCAM) (CD166), is regulated by cytokines during inflammation in rheumatoid arthritis (RA). We used flow cytometry to test whether cytokines present in rheumatoid synovium could regulate ALCAM cell surface expression on peripheral blood (PB) monocytes and RA synovial fluid (SF) macrophages, and we examined ALCAM expression in situ in RA synovium by immunofluorescence. The monocyte differentiation factors interleukin-3, macrophage colony-stimulating factor (M-CSF), and granulocyte-macrophage colony-stimulating factor augmented ALCAM expression on PB monocytes. ALCAM was expressed on monocyte-lineage cells in situ in inflamed synovium from patients with RA (9 of 9), but not in uninflamed synovium from patients with joint trauma (0 of 3). Furthermore, in vitro culture-induced ALCAM expression on PB monocytes and CD14+ RA SF cells was inhibited by an M-CSF neutralizing antibody. ALCAM expression on PB and SF monocytes/macrophages is enhanced by M-CSF.


The impacts of reduced connectivity on multiple facets of aquatic insect diversity in floodplain wetlands, Northeast China.
River-floodplain ecosystems are highly complex and dynamic systems that are subjected to human disturbance, such as the construction of levees. Aquatic insects are among the most widely used indicators to assess human impacts on floodplain wetlands. Most studies are still based on taxonomic biodiversity. However, trait-based approaches remain limited, which could impede the development of effective management strategies. Here, we investigated aquatic insect assemblages in eleven pairs of wetlands along the Wusuli River in two seasons (Spring and Autumn) and assessed their responses to the impact of levee construction, considering taxonomic and functional diversity. We found that pooled species richness (73 taxa) in river-connected wetlands was almost twice of that in levee-blocked wetlands (37 taxa). Six and one indicator taxa for river-connected wetlands were identified in May and October, respectively, while no indicator taxon for the levee-blocked wetlands was identified. Moreover, taxonomic and functional alpha diversity in river-connected wetlands was much higher than in levee-blocked wetlands, but beta diversity showed a contrasting pattern. Additionally, multivariate dispersion analysis indicated a more evident difference in beta diversity between river-connected and levee-blocked wetlands in May than in October, likely due to the temporary lateral connection in summer (i.e., water flowed over levees during flood events). Our results revealed that anthropogenic impacts (e.g., levee construction and agricultural activity) weakened the connectivity of floodplain wetland ecosystems, leading to decreased taxonomic and functional diversity of aquatic insects in isolated wetlands. Our study highlights the importance of combining taxonomic and trait-based approaches in biomonitoring programs of floodplain wetland ecosystems. It also underscores the necessity of restoring habitat connectivity of wetland ecosystems (e.g., river-floodplain connectivity and connections between different wetlands) to facilitate biodiversity recovery and enhance ecological functions and services supported by these valuable ecosystems.


Ion-chelation based digital barcodes for multiplexing of a suspension array.
Ion-chelated microbeads (ICMs) for suspension arrays can be prepared by chelating metal ions (MIs), which are used as encoding materials. Stimulating the ICMs, laser induced breakdown spectra (LIBs) can be obtained and the atomic spectra of the chelated ions are chosen as the decoding signals. Our ICMs show digital characteristics with high stability due to the properties of LIBs. And, since there are many available coding materials and different kinds of coding materials can be easily combined, the coding capacity can be considerably enlarged. Further, the background interference in fluoroimmunoassay detection could be avoided, because the ICMs contain no fluorescence emission. In our studies, we achieved a total of 15 types of barcodes by taking full advantage of 4 kinds of ions, then a fluoroimmunoassay was performed to demonstrate the specificity and detection performance of our ICMs in multiplexing and the detection limit could reach 1.49 × 10-10 M, showing promising potential in applications.


The interface of functional biotribology and regenerative medicine in synovial joints.
Biotribology is the science of biological surfaces in sliding contact encompassing the concepts of friction, wear, and lubrication of interacting surfaces. This bioscience field has emerged from the classical field of tribology and is of paramount importance to the normal function of numerous tissues, including articular cartilage, blood vessels, heart, tendons, ligaments, and skin. Surprisingly, relatively little attention has been given to the restoration of surface characteristics in the fields of tissue engineering and regenerative medicine-the science of design and manufacture of new tissues for the functional restoration of impaired or diseased organs that depend on inductive signals, responding stem cells, and extracellular matrix scaffolding. Analogous to ancient civilizations (c. 3000 B.C.) that introduced wheeled vehicles, sledges for transporting heavy blocks, and lubricants, modern biotribologists must aim to restore surface characteristics to regenerated tissues and develop novel biomaterials with optimal tribological properties. The objective of this article is to highlight the significance of functional biotribology in the physiology of body surfaces and provide a comprehensive overview of unresolved issues and controversies as it relates to regenerative medicine. Specific attention is placed on the molecular basis of lubrication, mechanical and biochemical regulation of lubricating molecules, and the need to study wear processes in articular cartilage, especially in light of degenerative diseases, such as osteoarthritis. Surface engineering of replacement tissues exhibiting low friction and high wear resistance is examined using articular cartilage as an illustrative model system.


INTRODUCTION: Securing Reproductive Justice After Dobbs.
When we conceptualized this symposium, Roe v. Wade1 was still the law of the land, albeit precariously. We aimed to commemorate its fiftieth anniversary by exploring historical, legal, medical, and related dimensions of access to abortion as well as the challenges ahead to secure reproductive justice. With the leak of the U.S. Supreme Court's decision in Dobbs v. Jackson Women's Health Organization on May 2, 2022, we shifted to mark the dawn of a new era. In the nearly identical official opinion announced on June 24, 2022,2 Justice Samuel Alito, writing for the majority (6-3), overturned Roe and Planned Parenthood of Southeastern Pennsylvania v. Casey.3.


Characterizing the effects of the juxtamembrane domain on vascular endothelial growth factor receptor-2 enzymatic activity, autophosphorylation, and inhibition by axitinib.
The catalytic domains of protein kinases are commonly treated as independent modular units with distinct biological functions. Here, the interactions between the catalytic and juxtamembrane domains of VEGFR2 are studied. Highly purified preparations of the receptor tyrosine kinase VEGFR2 catalytic domain without (VEGFR2-CD) and with (VEGFR2-CD/JM) the juxtamembrane (JM) domain were characterized by kinetic, biophysical, and structural methods. Although the catalytic parameters for both constructs were similar, the autophosphorylation rate of VEGFR2-CD/JM was substantially faster than VEGFR2-CD. The first event in the autophosphorylation reaction was phosphorylation of JM residue Y801 followed by phosphorylation of activation loop residues in the CD. The rates of activation loop autophosphorylation for the two constructs were determined to be similar. The autophosphorylation rate of Y801 was invariant on enzyme concentration, which is consistent with an intramolecular reaction. In addition, the first biochemical characterization of the advanced clinical compound axitinib is reported. Axitinib was found to have 40-fold enhanced biochemical potency toward VEGFR2-CD/JM (K(i) = 28 pM) compared to VEGFR2-CD, which correlates better with cellular potency. Calorimetric studies, including a novel ITC compound displacement method, confirmed the potency and provided insight into the thermodynamic origin of the potency differences. A structural model for the VEGFR2-CD/JM is proposed based on the experimental findings reported here and on the JM position in c-Kit, FLT3, and CSF1/cFMS. The described studies identify potential functions of the VEGFR2 JM domain with implications to both receptor biology and inhibitor design.


1H-NMR Metabolite Fingerprinting Analysis Reveals a Disease Biomarker and a Field Treatment Response in Xylella fastidiosa subsp. pauca-Infected Olive Trees.
Xylella fastidiosa subsp. pauca is a xylem-limited bacterial phytopathogen currently found associated on many hectares with the "olive quick decline syndrome" in the Apulia region (Southern Italy), and the cultivars Ogliarola salentina and Cellina di Nardò result in being particularly sensitive to the disease. In order to find compounds showing the capability of reducing the population cell density of the pathogen within the leaves, we tested, in some olive orchards naturally-infected by the bacterium, a zinc-copper-citric acid biocomplex, namely Dentamet®, by spraying it to the crown, once per month, during spring and summer. The occurrence of the pathogen in the four olive orchards chosen for the trial was molecularly assessed. A 1H NMR metabolomic approach, in conjunction with a multivariate statistical analysis, was applied to investigate the metabolic pattern of both infected and treated adult olive cultivars, Ogliarola salentina and Cellina di Nardò trees, in two sampling periods, performed during the first year of the trial. For both cultivars and sampling periods, the orthogonal partial least squares discriminant analysis (OPLS-DA) gave good models of separation according to the treatment application. In both cultivars, some metabolites such as quinic acid, the aldehydic form of oleoeuropein, ligstroside and phenolic compounds, were consistently found as discriminative for the untreated olive trees in comparison with the Dentamet®-treated trees. Quinic acid, a precursor of lignin, was confirmed as a disease biomarker for the olive trees infected by X. fastidiosa subsp. pauca. When treated with Dentamet®, the two cultivars showed a distinct response. A consistent increase in malic acid was observed for the Ogliarola salentina trees, whereas in the Cellina di Nardò trees the treatments attenuate the metabolic response to the infection. To note that in Cellina di Nardò trees at the first sampling, an increase in γ-aminobutyric acid (GABA) was observed. This study highlights how the infection incited by X. fastidiosa subsp. pauca strongly modifies the overall metabolism of olive trees, and how a zinc-copper-citric acid biocomplex can induce an early re-programming of the metabolic pathways in the infected trees.


Recent clinical trials in valvular heart disease.
With widespread adoption of transcatheter aortic valve replacement, there has been a change in the approach to management of valvular heart disease. New interest has taken hold in transcatheter therapies for valvular heart disease, as well as research into pathophysiology and progression of disease. Additionally, several key trials have further refined our understanding of surgical management of valvular heart disease. This review will elucidate recent clinical trial data leading to changes in practice. There have been several landmark trials expanding the indications for transcatheter aortic valve replacement. Additionally, although still early, trials are beginning to demonstrate the feasibility and safety of transcatheter mitral valves. Options for transcatheter management of right-sided valvular disease continue to evolve, and these are areas of active investigation. The emergence of novel therapies for valvular heart disease has expanded the management options available, allowing physicians to better individualize treatment of patients with valvular heart disease. This review will focus on the recent (within 2 years) trials in this field of interest.


Cow's urine concoction: its chemical composition, pharmacological actions and mode of lethality.
A review of current information on the composition, pharmacological actions and mode of death from cow's urine concoction (CUC) toxicity is presented. The concoction is prepared from leaves of tobacco, garlic and basil; lemon juice, rock salt and bulbs of onion. The latter items are soaked in the urine from cows which acts as the vehicle in which the active principles in these constituents dissolve. Over fifty chemical compounds have been identified in CUC. The major compounds it contains are benzoic acid, phenylacetic acid, p-cresol, thymol and nicotine. The chemical composition and pharmacological cations of the individual components of CUC are also reviewed. Observations of CUC poisoning in man and experimental animals showed that the main effects of CUC are severe depression of respiration, cardiovascular system, the central nervous system and hypoglycaemia. These toxic effects acting singly or in combination are believed to be the cause(s) of death from CUC. Management is geared towards correcting these adverse effects.


Inhibition of mouse hepatocyte apoptosis via anti-Fas ribozyme.
To investigate the effects of anti-Fas ribozyme on Fas expression and apoptosis in primary cultured mouse hepatocytes. Mouse hepatocytes were isolated by using collagenase irrigation. A hammerhead ribozyme targeting the Fas mRNA was constructed, and transfected into mouse hepatocytes via Effectene. Then Fas expression in mouse hepatocytes was detected by RT-PCR and western blotting. After being treated with anti-Fas antibody (JO2), hepatocytes viability was measured with MTT assay. Caspase-3 proteolytic activity was detected, and cell apoptosis was measured according to Annexin V-FITC apoptosis detection kit. Fas expressed in primary mouse hepatocytes. Fas expression in hepatocytes transfected with anti-Fas ribozyme was decreased remarkably and correlated with the resistance to Fas-mediated apoptosis as determined by flow cytometry and caspase-3 proteolytic activity. Anti-Fas ribozyme can remarkably decrease the Fas expression in mouse hepatocytes, thus inhibit Fas-mediated apoptosis in hepatocytes. It is suggested that anti-Fas ribozyme could significantly increase the resistance of transplanted hepatocytes to apoptosis and improve the survival of transplanted hepatocytes.


Quality of life for patients in an end-stage renal disease programme.
A group of 128 patients in an end-stage renal disease programme in Natal was studied in order to assess the relative success of the different treatment modalities in achieving optimal patient rehabilitation in regard to employability and social, psychological and medical status. Confirmation that successful transplantation achieves the best quality of life was obtained.


3D printed porous titanium cages filled with simvastatin hydrogel promotes bone ingrowth and spinal fusion in rhesus macaques.
Three-dimensional (3D) printing technology can be used to manufacture implants with individualized external shapes, internal porous structures and elastic moduli similar to those of natural bone, although such implants lack biological activity. Here, we developed a porous titanium cage by electron beam melting that was filled with simvastatin/poloxamer 407 hydrogel and evaluated bone ingrowth and spinal fusion. Six adult male rhesus macaques underwent interbody fusion of the L3/4 (cage without simvastatin or hydrogel), L4/5 (cage with 0.5 mg simvastatin in hydrogel) and L5/6 (cage with 0 mg simvastatin in hydrogel) segments. 18F-NaF PET/CT imaging confirmed that simvastatin/poloxamer 407 hydrogel increased bone blood flow, osteoblastic activity and bone ingrowth; histological analysis demonstrated that simvastatin/poloxamer 407 hydrogel promoted bone ingrowth in and osseointegration around the L4/5 cages; and biomechanical analysis verified that simvastatin/poloxamer 407 hydrogel enhanced spinal fusion. We conclude that 3D-printed porous cages containing simvastatin hydrogel promote bone ingrowth and spinal fusion, which could be a convenient and promising method for clinical translation. Using PET/CT to monitor the osteoblast activity may provide a new method for assessing the intervertebral fusion effect in preclinical study or clinical postoperative evaluation.


High Readmission Rates and Mental Distress 1 yr After Ablation for Atrial Fibrillation or Atrial Flutter: A NATIONWIDE SURVEY.
Today, catheter ablation is a widely used treatment for atrial fibrillation (AF) and atrial flutter (AFL). Knowledge on long-term patient-reported outcomes and readmissions is lacking and is warranted to plan optimal follow-up care. Objectives were to describe patient-reported outcomes including perceived health, quality of life, anxiety, depression, and physical activity compared with an age- and sex-matched reference population without longstanding disease; readmissions and mortality; and factors associated with suboptimal patient-reported outcomes. A nationwide cross-sectional survey mailed to 627 adults 6 to 12 mo after ablation for AF or AFL including; Short Form-36 (SF-36), HeartQoL, Hospital Anxiety Depression Scale, and questions about physical activity. Readmission rates and mortality were obtained and regression analyses were performed. Comparing the patient group (response rate: 74%, n = 462) with an age- and sex-matched reference population with no long-lasting disease, differences were found in all subscales of SF-36 and leisure-time physical activity in favor of the reference group (P < .001). Within 1 yr, 411 patients (59%) were readmitted and the total number of readmissions was 1167. Altogether, 227 (33%) patients were electively readmitted and 330 (48%) were acutely readmitted. Ten patients (1.4%) died. Age > 59 yr, female sex, high comorbidity, and readmission were associated with low physical health, low perceived health, and low quality of life. Patients treated for AF or AFL experienced decreased mental and physical health and high readmission rates 6 to 12 mo following catheter ablation. Closer multidisciplinary follow-up or cardiac rehabilitation after ablation for AF or AFL may be needed.


The cis-isomer performs better than the trans-isomer in porphyrin-sensitized solar cells: interfacial electron transport and charge recombination investigations.
We report characterizations and device performance for dye-sensitized solar cells using cis- and trans-isomers of 2D-π-2A zinc porphyrins with carboxyphenyl and thienyl groups in their meso-positions. Under identical experimental conditions with similar dye loadings, we observed overall power conversion efficiencies of 2.44% and 0.88% for devices made of cis-2S2A and trans-2S2A, respectively. This uneven performance among cis and trans isomers under the same experimental conditions can be rationalized with detailed investigations via spectroscopic, quantum chemical, and femtosecond fluorescence up-conversion investigations. Density functional theory (DFT) calculations show that a small amount of electron density is localized over carboxyphenyl groups in the LUMO of cis-2S2A, but there is no electron density populated on the carboxyphenyl groups in the LUMO of trans-2S2A. The femtosecond fluorescence decay measurements revealed that the excited-state lifetime of trans-2S2A on Al2O3 is half of that of cis-2S2A on Al2O3. Moreover, the dye-to-TiO2 electron injection time of trans-2S2A is 2.54 ps, which is shorter than that of cis-2S2A/TiO2 (2.95 ps). Electrochemical impedance spectra measured under one sun illumination also revealed that the charge recombination time of cis-2S2A is longer than that of trans-2S2A. This thorough understanding of isomeric effects on the performance of porphyrins will serve as a guideline for the design of future sensitizing dyes for solar cells.


High cristobalite and high tridymite in a middle eocene deep-sea chert.
The high-temperature forms of cristobalite and tridymite have been found occurring in a Middle Eocene, radiolarian-rich claystone. Evidence indicates that these crystals formed at low temperature and were chemical precipitates. Scanning electron microscopy, energy-dispersive x-ray analysis (microprobe), and x-ray diffraction provided the data upon which the determinative mineralogy was based.


Low hospital referral rates of school scoliosis screening positives in an urban district of mainland China.
Significant prevalence rates of adolescent scoliosis in China were suggested in previous studies. However, school screenings for adolescent scoliosis have been suspended due to low rates of positive detection under the past screening system in China. The present study was undertaken to screen for adolescent scoliosis in middle school students under a modern assessment system in a district of Shanghai. We performed a population-based, cross-sectional study of a middle school scoliosis screening program in the Jingan district. In 2015, schoolchildren were initially screened by visual inspection of clinical signs and the forward-bending test. Suspected cases were referred for radiography in hospital for scoliosis diagnosis. A total of 5327 middle school students (grades 6-8) were screened with 520 (9.76%) positives (the positive rates of girls and boys at 15.28% and 4.59%, respectively) and no statistically significant difference among grades. Only 301 positives (57.9%) followed the referral for hospital radiography. There were 102 cases (33.9%) that were diagnosed with scoliosis by radiography criteria (Cobb angle ≥10°) including mild scoliosis (Cobb 10-25) for 94 cases and moderate scoliosis (Cobb 25-40) for 8 cases, and false-positives (Cobb 0) for 39 cases. The putative prevalence rate was estimated as 1.9% from the referred students. Under an accurate and modern assessment system, school screenings can detect scoliosis at a significant rate, but awareness of scoliosis risks is needed for residents in China to take up referrals for hospital diagnosis after school screenings.


Nucleoside diphosphokinase and cell cycle control in the fission yeast Schizosaccharomyces pombe.
Centrifugal elutriation was used to prepare synchronous cultures of Schizosaccharomyces pombe. Nucleoside diphosphokinase activity was measured throughout the cell cycle. In the wild-type strain (972) nucleoside diphosphokinase activity doubled in a stepwise fashion. The midpoint of the rise in enzyme activity was at 0.65 of a cycle, 0.29 of a cycle before the next S phase. Synchronous cultures of the mutant wee 1-6 were also prepared. In this strain S phase is delayed, occurring about 0.3 cycle later than in the wild-type. In wee 1-6 the midpoint of the stepwise doubling in nucleoside diphosphokinase activity occurred at 0.084; showing that the rise in enzyme activity is also delayed. Addition of cycloheximide to an exponentially growing culture caused an immediate inhibition of protein synthesis, yet nucleoside diphosphokinase activity continued to increase exponentially for a further 300 min. This indicates that the stepwise doubling of nucleoside diphosphokinase activity during the cell cycle is not achieved by a simple control on protein synthesis. Two temperature-sensitive cdc- mutants were also used: cdc2-33, a mutant whose single genetic lesion results in the twin defects of a loss of mitotic control and a loss of commitment to the cell cycle; and cdc 10-129, which has a defect in DNA replication. In both mutants a temperature shift-up of an asynchronously growing culture from the permissive (25 degrees C) to the restrictive temperature (36.5 degrees C) results in a rapid inhibition of DNA replication. In both mutants nucleoside diphosphokinase continues to increase exponentially. Therefore, although nucleoside diphosphokinase is required for DNA replication, apparently DNA replication is not required for an increase in nucleoside diphosphokinase activity.


Interventions for motor apraxia following stroke.
Apraxia is a cognitive disorder that can occur after stroke. It prevents a person from carrying out a learned movement. Various interventions are used to treat apraxia but evidence of their benefit has been lacking. To determine which therapeutic interventions targeted at motor apraxia reduce disability. We searched the Cochrane Stroke Group Trials Register (last searched November 2006). In addition, we searched the following databases: the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 3, 2006), MEDLINE (1966 to November 2007), EMBASE (1980 to November 2006), CINAHL (1982 to November 2006), PsycINFO (1974 to November 2006), the Research Index of the Occupational Therapy Journal (searched November 2006), REHABDATA (1956 to November 2006), the National Research Register (searched November 2006) and Current Controlled Trials Register (searched November 2006). We reviewed the reference lists of all articles that we identified as relevant. We made efforts to find both published and unpublished trials by writing to key authors and journals. Randomised controlled trials of therapeutic intervention for motor apraxia in stroke. One review author searched the titles, abstracts and keywords. Four review authors extracted data and analysed trial quality. We contacted investigators for further details of trials if necessary. Three trials including a total of 132 participants were included in the review. There was evidence of a small and short-lived therapeutic effect in the two studies that reported change in activities of daily living (102 participants) but this was not considered clinically significant and did not persist at the longer-term follow up. There is insufficient evidence to support or refute the effectiveness of specific therapeutic interventions for motor apraxia after stroke. Further research of higher quality is required. As we did not review whether patients with apraxia benefit from rehabilitation input in general, they should continue to receive general stroke rehabilitation services.


The health belief model and cardiac rehabilitation.
The Health Belief Model and the questionnaire presented can be a useful tool in providing professional nursing care of the cardiac patient. The HBM has evolved through different purposes and uses, but always has as its underlying goal that of predicting behavior. Utilizing this specific tool, the HBM framework not only aids in predicting behavior but also indicates areas in a patient's health beliefs where nurses may intervene and provide quality care.


Distinct chemokine receptor axes regulate Th9 cell trafficking to allergic and autoimmune inflammatory sites.
Migration of Th cells to peripheral sites of inflammation is essential for execution of their effector function. The recently described Th9 subset characteristically produces IL-9 and has been implicated in both allergy and autoimmunity. Despite this, the migratory properties of Th9 cells remain enigmatic. In this study, we examined chemokine receptor usage by Th9 cells and demonstrate, in models of allergy and autoimmunity, that these cells express functional CCR3, CCR6, and CXCR3, chemokine receptors commonly associated with other, functionally opposed effector Th subsets. Most Th9 cells that express CCR3 also express CXCR3 and CCR6, and expression of these receptors appears to account for the recruitment of Th9 cells to disparate inflammatory sites. During allergic inflammation, Th9 cells use CCR3 and CCR6, but not CXCR3, to home to the peritoneal cavity, whereas Th9 homing to the CNS during experimental autoimmune encephalomyelitis involves CXCR3 and CCR6 but not CCR3. To our knowledge, these data provide the first insights into regulation of Th9 cell trafficking in allergy and autoimmunity.


[New aspects of hexobarbital metabolism: stereoselective metabolism, new metabolic pathway via GSH conjugation, and 3-hydroxyhexobarbital dehydrogenases].
Hexobarbital, a short-acting hypnotic, is metabolized to 3'-hydroxyhexobarbital by cytochrome P450, and then to 3'-oxohexobarbital by liver cytosolic dehydrogenase. New methods of separation for hexobarbital and its metabolites by TLC have been developed and applied to study the metabolism of hexobarbital enantiomers and stereoselective metabolism of hexobarbital. (+)-Hexobarbital preferentially was transformed into beta-3'-hydroxyhexobarbital and the (-)-enantiomer preferentially transformed into alpha-3'-hydroxyhexobarbital by rat liver microsomes. Glucuronidation and dehydrogenation of 3'-hydroxyhexobarbital were also stereoselective and the S-configuration at the 3'-position was preferred. Alpha-3'-hydroxyhexobarbital from (-)-hexobarbital and the beta-isomer from (+)-hexobarbital were shown to be preferentially conjugated with glucuronic acid in rabbit urine, and to be preferentially dehydrogenated to form 3'-oxohexobarbital by rabbit and guinea pig 3-hydroxyhexobarbital dehydrogenases. A new metabolic pathway of hexobarbital was found in which 3'-oxohexobarbital reacts with glutathione to form 1,5-dimethylbarbituric acid and a cyclohexenone-glutathione adduct, a novel metabolite. 1,5-dimethylbarbituric acid was excreted into the urine and the cyclohexenone-glutathione adduct into the bile of rats dosed with hexobarbital. 3-hydroxyhexobarbital dehydrogenases that dehydrogenate 3-hydroxyhexobarbital into 3'-oxohexobarbital were purified from the liver cytosol of rabbits, guinea pigs, goats, rats, mice, hamsters, and humans and characterized. These enzymes were monomeric proteins and had molecular weights of about 34500-42000, and used NAD(+) and NADP(+) as cofactors, except for the human enzyme that had a molecular weight of about 58000 and used NAD(+) alone. Each enzyme exhibited its own characteristics. Substrate specificity demonstrated that 3-hydroxyhexobarbital dehydrogenases dehydrogenate not only alpha,beta-unsaturated cyclic and acyclic secondary alcohols but also some 17 beta-, 3 alpha-hydroxysteroids or both, except for the human enzyme. The amino acid sequence of the hamster enzyme indicated that it belongs to the aldo-keto reductase superfamily and hydroxysteroid dehydrogenase subfamily.


Homozygous diploid deletion strains of Saccharomyces cerevisiae that determine lag phase and dehydration tolerance.
This study identifies genes that determine length of lag phase, using the model eukaryotic organism, Saccharomyces cerevisiae. We report growth of a yeast deletion series following variations in the lag phase induced by variable storage times after drying-down yeast on filters. Using a homozygous diploid deletion pool, lag times ranging from 0 h to 90 h were associated with increased drop-out of mitochondrial genes and increased survival of nuclear genes. Simple linear regression (R2 analysis) shows that there are over 500 genes for which > 70% of the variation can be explained by lag alone. In the genes with a positive correlation, such that the gene abundance increases with lag and hence the deletion strain is suitable for survival during prolonged storage, there is a strong predominance of nucleonic genes. In the genes with a negative correlation, such that the gene abundance decreases with lag and hence the strain may be critical for getting yeast out of the lag phase, there is a strong predominance of glycoproteins and transmembrane proteins. This study identifies yeast deletion strains with survival advantage on prolonged storage and amplifies our understanding of the genes critical for getting out of the lag phase.


The evaluation of importance of safety behaviors in a steel manufacturer by entropy.
This study aimed to evaluate the workers safety behavior and to determine the importance of each unsafe behavior in an Iranian steel manufacturing company. This study was conducted in Mobareke steel manufacturing company, which is located in the middle of Iran, in 2007. The methodology was based on the safety behavior sampling (SBS) technique and entropy. After specifying the unsafe behaviors and with reference to the results of a pilot study a sample of 3248 was determined, with a sampling accuracy of 5% and confidence level of 95%. The results indicated that 41.8% of workers behaviors were unsafe. The most frequent unsafe behaviors were inappropriate use of personal protective equipments (PPEs) with 32% of total unsafe behaviors. The results also notified a significant relationship between age, job experience and educational level on unsafe behaviors (P< 0.05). The highest weight, which is obtained by entropy, belongs to using inappropriate tools with weight of 0.1425. The ultimate findings of the study showed that a considerable number of workers' behaviors were unsafe, which is one of the main antecedents of industrial accidents. Considering catastrophic consequences of accidents in steel manufacturing industry, the results emphasize on diminishing unsafe behaviors and recommends applying behavior based safety principles.


Let's Get to the Point: Comparing Insertion Characteristics and Scope Damage of Flat-Tip and Ball-Tip Holmium Laser Fibers.
A ball-tip holmium laser fiber (TracTip; Boston Scientific) has been developed to theoretically reduce damaging friction forces generated within a ureteroscope working channel. We compared the insertional forces and damage with a ureteroscope inner lining when inserting standard flat-tip and ball-tip laser fibers. A standard ureteroscope channel liner was placed in a 3D-printed plastic mold. Molds were created at four angles of deflection (30°, 45°, 90°, and 180°) with a 1 cm radius of curvature. New 200 μm ball-tip (TracTip; Boston Scientific) and 200 μm flat-tip (Flexiva; Boston Scientific) laser fibers were advanced through the liner using a stage controller. A strain gauge was used to measure force required for insertion. Each fiber was passed 600 times at each angle of deflection. The ureteroscope liner was changed every 150 passes. Leak testing was performed every 50 passes or when the insertional force increased significantly to assess damage to the liner. At all deflection angles, the average insertional force was significantly lower with the ball-tip laser fibers compared with flat-tip laser fibers (p < 0.001). All trials with the ball-tip lasers were completed at each angle without any leaks. Two of four trials using flat-tip fibers at 45° deflection caused liner leaks (at 91 and 114 passes). At 90° deflection, all flat-tip trials caused liner leaks on first pass. The 180° trials could not physically be completed with the flat-tip laser fiber. Within the flat- and ball-tip groups, an increasing amount of force was needed to pass the fiber as the degree of deflection increased (p < 0.001). The ball-tip holmium laser fiber can be safely passed through a deflected ureteroscope without causing liner perforation. The standard flat-tip fiber requires greater insertion force at all angles and can cause the ureteroscope liner to leak if it is deflected 45° or more.


Enzymatic Changes in Red Blood Cells of Diamond-Blackfan Anemia.
Diamond-Blackfan anemia is a congenital bone marrow failure syndrome characterized by red blood cell (RBC) aplasia with varied malformations in infants. Elevated activity of adenosine deaminase (ADA) has been considered as a useful biomarker of Diamond-Blackfan anemia, and ADA assay has been shown to be more sensitive than genetic diagnosis. Approximately, 80% of the examined patients showed elevated ADA activity, whereas genetic tests of ribosome subunit genes identified mutations in approximately 60% of the patients. We previously reported that reduced glutathione (GSH) levels in RBCs may serve as a biomarker of Diamond-Blackfan anemia. In this study, to confirm the universality of our data, we extended the analysis to seven RBC enzymes and GSH of 14 patients with Diamond-Blackfan anemia and performed a cross-analysis study using enzyme activity assay and recently reported proteome data. Statistical analysis revealed that both data exhibited high similarity, upregulation in the hexokinase and pentose-phosphate pathway, and downregulation in glycolytic enzymes such as phosphofructokinase and pyruvate kinase, in the RBCs obtained from the subjects with Diamond-Blackfan anemia. The only discrepancy between enzyme activity and proteome data was observed in glucose-6-phosphate dehydrogenase (G6PD), as increased G6PD activity showed no relation with the significant elevation in protein levels. These results suggest that our enzymatic activity data of Diamond-Blackfan anemia are universal and that the enzymatic activation of G6PD via a hitherto-unveiled mechanism is another metabolic feature of RBCs of Diamond-Blackfan anemia.


[Management and clinical thinking of Coronavirus Disease 2019].
In December 2019, the 2019 novel coronavirus pneumonia (NCP, officially named Coronavirus Disease 2019(COVID-19) by the World Health Organization) broke out in Wuhan, Hubei, and it quickly spread to the whole country and abroad. The situation was at stake. The sudden and serious COVID-19 epidemic has brought us a lot of urgent problems. How to effectively control the spread of COVID-19? When does the population infection rate rise to its peak? What will eventually be the number of infected patients? How to make early diagnosis? What effective antiviral drugs are available? How to effectively treat with existing drugs? Can it successfully improve the survival rate of critically patients? In response to the above questions, we put forward corresponding suggestions and reflections from the perspective of the infectious clinician.


Hyperglycemia, Classified with Multiple Biomarkers Simultaneously in Men without Diabetes, and Risk of Fatal Prostate Cancer.
The association between hyperglycemia and prostate cancer risk is inconsistent, and its association with prostate cancer mortality is understudied. Thus, we investigated the association between hyperglycemia and prostate cancer risk and mortality using multiple biomarkers simultaneously to classify hyper- and normoglycemia. We conducted a prospective analysis of 5,162 cancer-free men attending visit 2 (1990-1992) of the Atherosclerosis Risk in Communities (ARIC) study followed for total (N = 671) and lethal (N = 69) prostate cancer incidence and prostate cancer mortality (N = 64) through 2012. Men without diagnosed diabetes were classified as normo- or hyperglycemic using joint categories of fasting glucose, glycated hemoglobin, and glycated albumin (or fructosamine) defined by clinical or research cutpoints. We evaluated the multivariable-adjusted association of hyperglycemia with prostate cancer incidence and mortality using Cox proportional hazards regression; men with diagnosed diabetes were included as a separate exposure category. Among 4,753 men without diagnosed diabetes, 61.5% were classified as having hyperglycemia (high on ≥1 biomarker). HbA1c and glycated albumin together classified 61.9% of 1,736 men with normal fasting glucose as normoglycemic. Compared with men who were normal on all three biomarkers, men who were high on ≥1 biomarker had an increased risk of lethal [HR, 2.50; 95% confidence interval (CI), 1.12-5.58] and fatal (HR, 3.20; 95% CI, 1.26-8.48) disease, but not total prostate cancer incidence (HR, 0.98; 95% CI, 0.81-1.20); associations were similar including fructosamine instead of glycated albumin. Our findings indicate hyperglycemia is associated with an increased risk of lethal and fatal prostate cancer, but not total prostate cancer incidence.


Is there a functional way of responding to paranoid intrusions? Development of the Reactions to Paranoid Thoughts Scale.
Although many people experience paranoid thoughts occasionally, most do not develop clinically relevant paranoia, possibly due to a more functional way of responding. The aim of this study was to create a scale to investigate how healthy individuals react to paranoid thoughts. Paranoid thoughts were assessed with the Paranoia Checklist (Freeman et al., 2005). The 69-item Reactions to Paranoid Thoughts Scale (RePT) was created in a series of steps. Interviews were conducted to create a preliminary set of items. Principal components analysis of the data from a healthy sample (N=408) revealed a stable 10-factor solution explaining 69% of the total variance. These factors included depressive, composed, communicative, rational, believing, devaluating, physical, positive distracting, normalising, and concealing reactions to paranoid thoughts. Cronbach's alphas for these factors ranged from .77 to .97. Overall, the strength and pattern of correlations with scales that assess reactions to unwanted thoughts or stressors indicated good convergent and divergent validity of the factors. The most frequently applied reactions to paranoid thoughts were normalising, rational, and composed responses. Persons with more frequent paranoid thoughts were characterised by increased levels of dysfunctional reactions, such as depressive, believing, and concealing reactions in comparison to persons with less frequent paranoid thoughts. It may prove beneficial to teach persons at risk of psychosis or those with attenuated symptoms new ways of responding to paranoid thoughts.


Sexual and psychological functioning in women after pelvic surgery for gynaecological cancer.
Pelvic surgery for gynecological cancer can affect sexuality through a number of anatomical, physiological and psychological mechanisms. We aimed to examine the prevalence of sexual dysfunction and psychological functioning in women who underwent pelvic surgery for gynecological cancer. Fifty women who underwent pelvic surgery for vulvar, cervical or endometrial cancer in a gynecological oncology unit completed questionnaires evaluating marital satisfaction (DAS), depression (BDI-II) and sexual functioning (SSFS and an in-house Specific Sexual Problems Questionnaire). Medical records were used to obtain disease-specific data. The control group consisted of 39 healthy age-matched control women attending an outpatient screening clinic. Significantly more women with gynaecological cancer than controls reported sexual problems (83 vs 20%), including decreased desire (76 vs 14%) and impaired vaginal lubrication (42 vs 9%). Pelvic surgery was specifically related to changed intensity of orgasm (43%), reduced vaginal sensitivity (38%), vaginal elasticity (30%), superficial dyspareunia (27%), vaginal narrowing (26%) and shortening (22%). Although no significant differences were found between either group for depression (17% vs 13%) or total quality of the partner relationship, women with a history of gynecological cancer reported significant lower marital cohesion. These results indicate that although the psychological adjustment of women who underwent pelvic surgery seems to be satisfactory, they seem to be at risk for sexual dysfunctions.


Outcomes of UCB transplantation are comparable in FLT3+ AML: results of CIBMTR, EUROCORD and EBMT collaborative analysis.
Allogeneic hematopoietic cell transplantation (HCT) from siblings or unrelated donors (URD) during complete remission (CR) may improve leukemia-free survival (LFS) in FMS-like tyrosine kinase 3+ (FLT3+) acute myeloid leukemia (AML), which has poor prognosis because of high relapse rates. Umbilical cord blood (UCB) HCT outcomes are largely unknown in this population. We found that compared with sibling HCT, relapse risks were similar after UCB (n=126) (hazard ratio (HR) 0.86, P=0.54) and URD (n=91) (HR 0.81, P=0.43). UCB HCT was associated with statistically higher non-relapse mortality compared with sibling HCT (HR 2.32, P=0.02), but not vs URD (HR 1.72, P=0.07). All three cohorts had statistically nonsignificant 3-year LFS: 39% (95% confidence interval (CI): 30-47) after UCB, 43% (95% CI: 30-54) after sibling and 50% (95% CI: 40-60) after URD. Chronic graft-versus-host disease rates were significantly lower after UCB compared with either sibling (HR 0.59, P=0.03) or URD (HR 0.49, P=0.001). Adverse factors for LFS included high leukocyte count at diagnosis and HCT during CR2 (second CR). UCB is a suitable option for adults with FLT3+ AML in the absence of an human leukocyte antigen-matched sibling and its immediate availability may be particularly important for FLT3+ AML where early relapse is common, thus allowing HCT in CR1 (first CR) when outcomes are best.


Claudin-16 and claudin-19 function in the thick ascending limb.
Claudin-16 and claudin-19 play a major role in the regulation of magnesium reabsorption in the thick ascending limb (TAL). This review describes recent findings of the physiological function of claudin-16 and claudin-19 underlying normal transport function for magnesium reabsorption in the TAL. Mutations in the genes encoding the tight junction proteins claudin-16 and claudin-19 cause the inherited human renal disorder familial hypomagnesemia with hypercalciuria and nephrocalcinosis. The cation selectivity of the tight junction is vital for generating the lumen positive transepithelial potential in the TAL, which drives paracellular absorption of magnesium. Claudin-16 and claudin-19 require each other for assembly into tight junctions in the TAL. Heteromeric claudin-16 and claudin-19 interaction forms a cation selective tight junction paracellular channel. Loss of either claudin-16 or claudin-19 in the mouse kidney abolishes the cation selectivity for the TAL paracellular pathway, leading to excessive renal wasting of magnesium. Epithelial paracellular channels are increasingly understood to be formed from claudin oligomeric complexes. In the mouse TAL, claudin-16 and claudin-19 cooperate to form cation-selective paracellular channels required for normal levels of magnesium reabsorption. Different subsets of the claudin family of tight junction proteins are found distributed throughout the nephron, and understanding their roles in paracellular ion transport will be fundamental to understanding renal ion homeostasis.


Introduction to the special issue on the behavior analysis and treatment of drug addiction.
Extensive evidence from the laboratory and the clinic suggests that drug addiction can be viewed as operant behavior and effectively treated through the application of principles of operant conditioning. Contingency management interventions that arrange for the direct reinforcement of drug abstinence or of other therapeutically important target behaviors (e.g., regular use of drug abuse treatment medications) are among the most studied type of operant treatments. Behavior analysts have contributed to the substantial and rapidly growing literature on operant treatments for drug addiction, but the publications of this work usually appear in medical, clinical psychology, or drug abuse journals. This special issue of the Journal of Applied Behavior Analysis represents an effort to bring this important work to the attention of the behavior-analytic community. The articles in this special issue illustrate both the enormous potential of contingency management interventions to address the serious and seemingly intractable problem of drug addiction as well as the real challenges involved in attempting to develop and disseminate treatments that will produce substantial and lasting changes in the lives of individuals plagued by the chronic problem of drug addiction.


De novo adipogenesis in mice at the site of injection of basement membrane and basic fibroblast growth factor.
Autografting of fat pads has a long history in plastic and reconstructive surgery for augmentation of lost soft tissue. However, the results are disappointing because of absorption of the grafts with time. The fate of transplanted fat is linked to adipose precursor cells distributed widely in connective tissues. Adipocyte precursor cells can proliferate and mature into adipocytes even in the adult body depending on microenvironment. When reconstituted basement membrane, Matrigel, supplemented with more than 1 ng/ml bFGF was injected s.c. into 6-week-old mice, the neovascularization induced within 1 week was followed by migration of endogenous adipose precursor cells, and a clearly visible fat pad was formed. The pad grew until 3 weeks after the injection and persisted for at least 10 weeks. Such de novo adipogenesis was induced reproducibly by s.c. injection of Matrigel and bFGF over the chest, lateral abdomen, or head. Adipogenesis could be induced even in ear cartilage or in muscle. Thus, our results demonstrated that an abundant population of adipose precursor cells is distributed widely in connective tissues of the adult body and that they migrate into the neovascularized plug of Matrigel for proliferation and maturation. These results suggest a technique of augmenting lost soft tissue in plastic and reconstructive surgery.


Sertindole improves both the positive and negative symptoms of schizophrenia: Results of a phase III trial.
This large multicentre, double-blind, randomized study was designed to evaluate four doses of sertindole and haloperidol 10 mg in the treatment of patients with DSM-III-R schizophrenia. 617 patients were randomized, of whom 595 were included in an intention-to-treat analysis. 375 patients completed the study. Patients were randomized to receive sertindole 8 mg/day, sertindole 16 mg/day, sertindole 20 mg/day, sertindole 24 mg/day or haloperidol 10 mg/day for 56days. Efficacy was assessed through the changes in score on the Positive and Negative Syndrome Scale (PANSS), and the Clinical Global Impressions (CGI) scale. Improvement in all end-points was observed for all treatment groups. Sertindole 16 mg showed significantly greater efficacy against negative symptoms than haloperidol 10 mg. The optimal dose of sertindole was 16 mg/day. Sertindole 8 mg appeared to be suboptimal with respect to efficacy, and increasing the dose of sertindole above 20 mg did not appear to offer any additional benefit. Sertindole at all doses caused significantly fewer extrapyramidal symptoms than haloperidol. Sertindole is effective against positive and negative symptoms of schizophrenia within the dose range 12-24 mg daily, with an optimal starting dose of 16 mg daily. Efficacy is comparable to 10 mg of haloperidol with no difference in the time course of treatment response. The dose response relationship for efficacy with sertindole seems to plateau at about 16 mg daily with no demonstrable difference in increasing doses above this point. (Int J Psych Clin Pract 2000; 4:55-62).


Evaluation of matrix-assisted laser desorption ionization-time of flight mass spectrometry for identification of human oral Capnocytophaga species.
Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) was evaluated for rapid identification of cfxA PCR positive and negative Capnocytophaga strains. Colonies were grown on blood agar, incubated anaerobically at 37 °C for 48 h, and were then evaluated by MALDI-TOF MS and 16S rRNA gene sequencing. Both methods identified all colonies to the genus level. The MALDI-TOF MS method gave the same result, at the species level, as 16S rRNA gene sequencing for 41/53 Capnocytophaga sp. strains (77.4%), but the limit of this technique was the absence of some species (C. leadbetteri, C. AHN) in the Biotyper-Bruker® database used in this study. Distinction between the cefotaxime resistant and susceptible strains was unsuccessful using the MALDI-TOF MS method. This technique had low discriminatory power to rapidly detect beta-lactamase-producing Capnocytophaga strains in clinical samples. However, the results from a score-oriented dendrogram confirmed MALDI-TOF MS is a rapid, inexpensive, and reliable method for Capnocytophaga species identification. Enrichment of the reference database used (Biotyper®) will improve future results.


Intensity of immunosuppressive therapy and the incidence of Pneumocystis carinii pneumonitis.
One hundred and forty-nine children with acute lymphocytic leukemia treated according to a prospective protocol were randomized after induction of remission and central nervous system (CNS) irradiation to receive maintenance chemotherapy with 1, 2, 3, or 4 chemotherapy agents. The incidence of P. carinii pneumonitis (PCP) was 5.0, 2.3, 2.2, and 22.4%, respectively, during the period of maintenance therapy. An additional 31 patients enrolled in the same study were placed in special categories to receive three drugs for maintenance plus supplemental chemotherapy or irradiation because of CNS leukemia on admission, remission failure, ediastinal mass, or generalized lymphosarcoma without bone marrow involvement. The incidences of PCP in these groups were 16.7, 30.0, 35.7, and 0%, respectively, during the period of maintenance therapy.


Statistical tools and status symbols.
This paper sets the stage for a series of edited papers which follow. It is argued that obvious statistical blunders (mortal sins) have not disappeared entirely from the aging literature, but that the most frequent error now is that of choosing a less powerful analytic solution when a more powerful (and equally applicable) one is at hand (a venial sin). Clearly, it is argued, power must be considered in relationship to the theoretical model, the condition of the data set, and the research question. Editors and reviewers, it is argued, must cut through the "glitter" of new fads and the security of tradition in order to objectively consider the merits of new statistical applications. More importantly, without knowledge of the issues, limitations, and advantages of contemporary and emerging analytic techniques, authors cannot make good analytic choices and defend them effectively. The time between presentation of innovative approaches in the quantitative journals and application in the aging literature contributes to traditionalism in data analysis. Overzealousness by advocates of new approaches often contributes to premature embracing of them. Thus the papers that follow were designed to bring new methods to the "working-researcher" with a frank appraisal of assumptions, proper and improper applications, and limitations. Authors of these papers were challenged to communicate in plain and understandable terms and to provide practical examples.


Splanchnic hyperemia and hypervolemia during Valsalva maneuver in postural tachycardia syndrome.
Prior work demonstrated dependence of the change in blood pressure during the Valsalva maneuver (VM) on the extent of thoracic hypovolemia and splanchnic hypervolemia. Thoracic hypovolemia and splanchnic hypervolemia characterize certain patients with postural tachycardia syndrome (POTS) during orthostatic stress. These patients also experience abnormal phase II hypotension and phase IV hypertension during VM. We hypothesize that reduced splanchnic arterial resistance explains aberrant VM results in these patients. We studied 17 POTS patients aged 15-23 yr with normal resting peripheral blood flow by strain gauge plethysmography and 10 comparably aged healthy volunteers. All had normal blood volumes by dye dilution. We assessed changes in estimated thoracic, splanchnic, pelvic-thigh, and lower leg blood volume and blood flow by impedance plethysmography throughout VM performed in the supine position. Baseline splanchnic blood flow was increased and calculated arterial resistance was decreased in POTS compared with control subjects. Splanchnic resistance decreased and flow increased in POTS subjects, whereas splanchnic resistance increased and flow decreased in control subjects during stage II of VM. This was associated with increased splanchnic blood volume, decreased thoracic blood volume, increased heart rate, and decreased blood pressure in POTS. Pelvic and leg resistances were increased above control and remained so during stage IV of VM, accounting for the increased blood pressure overshoot in POTS. Thus splanchnic hyperemia and hypervolemia are related to excessive phase II blood pressure reduction in POTS despite intense peripheral vasoconstriction. Factors other than autonomic dysfunction may play a role in POTS.


Glycosylated Triterpenoids as Endosomal Escape Enhancers in Targeted Tumor Therapies.
Protein-based targeted toxins play an increasingly important role in targeted tumor therapies. In spite of their high intrinsic toxicity, their efficacy in animal models is low. A major reason for this is the limited entry of the toxin into the cytosol of the target cell, which is required to mediate the fatal effect. Target receptor bound and internalized toxins are mostly either recycled back to the cell surface or lysosomally degraded. This might explain why no antibody-targeted protein toxin has been approved for tumor therapeutic applications by the authorities to date although more than 500 targeted toxins have been developed within the last decades. To overcome the problem of insufficient endosomal escape, a number of strategies that make use of diverse chemicals, cell-penetrating or fusogenic peptides, and light-induced techniques were designed to weaken the membrane integrity of endosomes. This review focuses on glycosylated triterpenoids as endosomal escape enhancers and throws light on their structure, the mechanism of action, and on their efficacy in cell culture and animal models. Obstacles, challenges, opportunities, and future prospects are discussed.


Regulation of L-type calcium channel sparklet activity by c-Src and PKC-α.
The activity of persistent Ca²⁺ sparklets, which are characterized by longer and more frequent channel open events than low-activity sparklets, contributes substantially to steady-state Ca²⁺ entry under physiological conditions. Here, we addressed two questions related to the regulation of Ca²⁺ sparklets by PKC-α and c-Src, both of which increase whole cell Cav1.2 current: 1) Does c-Src activation enhance persistent Ca²⁺ sparklet activity? 2) Does PKC-α activate c-Src to produce persistent Ca²⁺ sparklets? With the use of total internal reflection fluorescence microscopy, Ca²⁺ sparklets were recorded from voltage-clamped tsA-201 cells coexpressing wild-type (WT) or mutant Cav1.2c (the neuronal isoform of Cav1.2) constructs ± active or inactive PKC-α/c-Src. Cells expressing Cav1.2c exhibited both low-activity and persistent Ca²⁺ sparklets. Persistent Ca²⁺ sparklet activity was significantly reduced by acute application of the c-Src inhibitor PP2 or coexpression of kinase-dead c-Src. Cav1.2c constructs mutated at one of two COOH-terminal residues (Y²¹²²F and Y²¹³⁹F) were used to test the effect of blocking putative phosphorylation sites for c-Src. Expression of Y²¹²²F but not Y²¹³⁹F Cav1.2c abrogated the potentiating effect of c-Src on Ca²⁺ sparklet activity. We could not detect a significant change in persistent Ca²⁺ sparklet activity or density in cells coexpressing Cav1.2c + PKC-α, regardless of whether WT or Y²¹²²F Cav1.2c was used, or after PP2 application, suggesting that PKC-α does not act upstream of c-Src to produce persistent Ca²⁺ sparklets. However, our results indicate that persistent Ca²⁺ sparklet activity is promoted by the action of c-Src on residue Y²¹²² of the Cav1.2c COOH terminus.


Cannabis use and bariatric surgery psychology practice: survey and insights.
Cannabis is second only to alcohol as a substance of abuse and dependence in the United States. While there is extensive research examining alcohol use and bariatric surgery, there is currently little research and there are no published guidelines specific to cannabis use and bariatric surgery. To identify major themes and general guidelines applied by bariatric surgery psychology clinicians. This practice survey was disseminated to bariatric surgery psychologists at various U.S. academic medical centers, hospitals, and private practices. An electronic, 35-question survey was sent to 47 bariatric surgery psychologists to collect information on current clinical practice guidelines regarding cannabis use before and after bariatric surgery. The survey questionnaire was completed by 34 (72.34%) bariatric surgery psychologists. The major identified themes included: (1) the lack of a standardized assessment of cannabis use; (2) a requirement for 3 months of abstinence from cannabis before bariatric surgery; (3) recommended lifetime abstinence from cannabis after bariatric surgery; and (4) discussion of cannabis use risks following bariatric surgery, including appetite stimulation, addiction potential, and possible negative impacts on judgment. Cannabis use will likely further increase in the United States. This survey highlighted common bariatric surgery psychology practices in the absence of extensive research and published guidelines. These findings suggest a preliminary framework with which to address cannabis use in patients seeking bariatric surgery. It is recommended that professional organizations and societies build on these initial survey findings to develop guidelines for more consistent, evidence-based practice regarding cannabis use and bariatric surgery.


Clinical characteristics associated with poor outcome in patients acutely infected with Influenza A.
We sought to identify certain clinical characteristics associated with a poor clinical outcome in patients acutely infected with Influenza A. We performed a retrospective chart review of inpatients with acute Influenza A infection comparing a poor outcome group (POG; n=27), defined as patients who died and/or developed respiratory failure or shock, with a usual outcome group (UOG; n=105). Compared with the UOG, the POG had a significantly greater percentage of patients with: a history of chronic obstructive pulmonary disease (41% vs 20%), coronary artery disease (63% vs 38%), congestive heart failure (44% vs 23%), transient ischemic attack (TIA) or stroke (44% vs 21%), chronic renal insufficiency (22% vs 8%) and dialysis (11% vs 1%). Shortness of breath as a chief complaint (74% vs 44%), lower initial oxygen saturations (0.86 vs 0.92), as well as higher mean respiratory rates (28/minute vs 22/minute) occurred more frequently in the POG. The POG also had a greater frequency of CHF/ vascular congestion (26% vs 8%), and interstitial involvement (22% vs 6%) on admission chest roentgenogram. Independent predictors of poor outcome identified by multivariate analysis included low oxygen saturation on admission, history of TIA or stroke, and history of dialysis. The presence of certain comorbidities as well as clinical and radiographic evidence of respiratory compromise on admission may be helpful in identifying high-risk patients acutely infected with Influenza A.


Decrease in immune activation in HIV-infected patients treated with highly active antiretroviral therapy correlates with the function of hematopoietic progenitor cells and the number of naive CD4+ cells.
This study was conducted to determine the impact of immune activation, cytokine production and apoptosis on the naive CD4+ cell count and the function of hematopoietic progenitor cells during the initial phase of highly active antiretroviral therapy (HAART). Blood samples from 11 HIV-infected patients were collected prior to HAART and after 4 and 12 weeks of therapy. Flow cytometry was used to determine the naive CD4+ count and activated T cells. The cloning efficiency of progenitor cells was determined using a colony-forming cells assay. Finally, apoptosis and cytokine production were determined. During the study period, the naive CD4+ count and the cloning efficiency increased significantly. Immune activation was found in HIV-infected patients and decreased during HAART. The level of immune activation correlated negatively with both the naive CD4+ count and the function of progenitor cells. A negative correlation was found between apoptosis and the naive CD4+ count. Alterations in cytokine production during HAART or correlation between cytokine production and the naive CD4+ count or the cloning efficiency of progenitor cells were not detected. In conclusion, immune activation in HIV-infected patients treated with HAART is inversely correlated with the function of progenitor cells and the naive CD4+ count.


Demonstration of rotavirus antigen in trypsin-digested paraffin tissue sections by immunofluorescence.
Trypsin-digested paraffin tissue sections were used to demonstrate rotavirus particles in small intestinal epithelial cells of dirrheic neonatal calves, using direct fluorescent-antibody assay. The results were compared with other techniques to demonstrate rotavirus particles in tissue sections by immunofluorescence. Enzyme treatment of deparaffinized tissue sections gave excellent results with distinct specific fluorescence and minimal background. Prior staining of the tissue section with Mayer's hematoxylin made simultaneous observation of the same tissue section by light and ultraviolet microscopies possible.