Are judgments a form of data clustering? Reexamining contrast effects with the k-means algorithm.
A number of theories have been proposed to explain in precise mathematical terms how statistical parameters and sequential properties of stimulus distributions affect category ratings. Various contextual factors such as the mean, the midrange, and the median of the stimuli; the stimulus range; the percentile rank of each stimulus; and the order of appearance have been assumed to influence judgmental contrast. A data clustering reinterpretation of judgmental relativity is offered wherein the influence of the initial choice of centroids on judgmental contrast involves 2 combined frequency and consistency tendencies. Accounts of the k-means algorithm are provided, showing good agreement with effects observed on multiple distribution shapes and with a variety of interaction effects relating to the number of stimuli, the number of response categories, and the method of skewing. Experiment 1 demonstrates that centroid initialization accounts for contrast effects obtained with stretched distributions. Experiment 2 demonstrates that the iterative convergence inherent to the k-means algorithm accounts for the contrast reduction observed across repeated blocks of trials. The concept of within-cluster variance minimization is discussed, as is the applicability of a backward k-means calculation method for inferring, from empirical data, the values of the centroids that would serve as a representation of the judgmental context.


FOLFOXIRI Plus Bevacizumab as Conversion Therapy for Patients With Initially Unresectable Metastatic Colorectal Cancer: A Systematic Review and Pooled Analysis.
The combination of fluorouracil, oxaliplatin, and irinotecan plus bevacizumab (FOLFOXIRI-Bev) is an established and effective first-line chemotherapy regimen for metastatic colorectal cancer. However, resection rates of metastases and overall survival with this schedule have never been systematically evaluated in published studies including, but not limited to, the TRIBE (TRIplet plus BEvacizumab) trial. To assess the clinical efficacy of FOLFOXIRI-Bev, including outcomes and rates of surgical conversions. A systematic review was conducted in October 2016 in concordance with the PRISMA guidelines of PubMed, the Cochrane Central Register of Controlled Trials, SCOPUS, Web of Science, Google Scholar, CINAHL, Ovid, and EMBASE using the terms FOLFOXIRI and bevacizumab and (colorectal cancer). Clinical trials, retrospective case series, and prospective case series that used FOLFOXIRI-Bev for the treatment of initially unresectable metastatic colorectal cancer in humans were included. Individual case reports and retrospective case series with fewer than 10 patients were excluded. Data were extracted independently by 2 reviewers on a predesigned, standardized form. Ultimately, data were aggregated to obtain the pooled effect size of efficacy, according to the random-effects model and weighted for the number of patients included in each trial. Median overall survival and progression-free survival, overall response rates, and rates of R0 surgical conversions and overall surgical conversions. Eleven FOLFOXIRI-Bev studies published between 2010 and 2016 met the inclusion criteria and were pooled for analysis. The studies included 889 patients, with 877 patients clinically evaluable for overall response rates. The objective response rate to FOLFOXIRI-Bev was 69% (95% CI, 65%-72%; I2 = 25%). The rate of overall surgical conversions was 39.1% (95% CI, 26.9%-52.8%), and the rate of R0 surgical conversions was 28.1% (95% CI, 18.1%-40.8%). Median pooled overall survival was 30.2 months (95% CI, 26.5-33.7 months) in 6 trials with data available, and progression-free survival was 12.4 months (95% CI, 10.0-14.3 months) in 9 trials with data available. In meta-regression analysis, variables significantly associated with conversion surgery were disease limited to the liver and a higher median number of cycles (close to 12). For patients with surgically unresectable metastatic colorectal cancer, FOLFOXIRI-Bev is associated with a significant overall response rate. Such an effective regimen leads to a probability of surgical conversion of distant metastases approaching 40%, with more than one-fourth of patients having an R0 resection.


Sleep quality and nocturnal pain in patients with hip osteoarthritis.
Osteoarthritis (OA) is a common condition of the hip. Patients with hip OA often report nocturnal pain, yet little is known how it affects sleep quality. The purpose of this paper was to assess how hip arthritis affects sleep quality. We hypothesized that hip pain caused by hip OA affects sleep quality in adult patients.This is a prospective, cross-sectional study of patients who were diagnosed with hip OA. Patients were evaluated using Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), hip outcome score (HOS), and modified Harris hip score (mHHS). Sleep quality was assessed using Pittsburgh Sleep Quality Index (PSQI). A multiple regression model was used to assess factors associated with poor sleep quality.A total of 106 patients were analyzed. All patients had a Tonnis grade of 2 or 3 and American Society of Anesthesiologists (ASA) classification of 2. WOMAC, HOS, and mHHS were significantly and negatively correlated with PSQI. The multiple regression model, WOMAC, short form health survey vitality, ASA classification, and history of obstructive sleep apnea were associated with poor sleep quality (R = 0.60, P < .001).Patients with hip OA, who report a symptomatic hip, are susceptible to reduced sleep quality. There is a correlation between worsening HOSs and sleep quality. The WOMAC score is a significant predictor of poor sleep quality. Patients with poor hip metrics should be screened for sleep disturbance.


Clinicopathological features and microsatellite instability (MSI) in colorectal cancers from African Americans.
African Americans (AAs) have a 1.5 times higher risk of colorectal carcinoma (CRC) than Caucasians. Gene silencing through CpG island hypermethylation has been associated with the genesis or progression of microsatellite instability (MSI) largely due to 1 target for hypermethylation being the DNA mismatch repair gene hMLH1; there is anecdotal evidence of an increased incidence of MSI among AAs. P16 and hMLH1 can be inactivated by hypermethylation of their respective promoter regions, abrogating the ability to regulate cell proliferation and repair processes. We studied such methylation, as well as hMHS2 expression in colorectal cancers from AA patients to determine if MSI is associated with epigenetic silencing. Experiments were conducted on matched normal and colon cancer tissues from AA patients (n = 51). A total of 5 microsatellite markers (D2S123, D5S346, D17S250, BAT25 and BAT26) were used to evaluate MSI status. P16 and hMLH1 promoter methylation status was determined following bisulfite modification of DNA and using methylation specific PCR, while immunohistochemistry (IHC) was used to examine expression of hMLH1 and hMSH2. A total of 22 (43%) cancers demonstrated microsatellite instability-high (MSI-H), while 27 were microsatellite stable (MSS) and 2 were microsatellite instability-low (MSH-L). Most of the MSI-H tumors were proximal, well differentiated and highly mucinous. Most patients in the MSI-H group were females (68%). The p16 promoter was methylated in 19 of 47 (40%) tumors. A total of 7 of these CRCs demonstrated MSI-H (33%). The hMLH1 promoter was methylated in 29 of 34 (85%) tumors, of which 13 CRCs demonstrated MSI-H (87%). hMLH1 and hMSH2 staining was observed in 66% and 38% of MSI-H tumors, respectively. Overall, the prevalence of MSI-H colorectal tumor was 2-3-fold higher, while the defect in the percentage expression of mismatch repair (MMR) genes (hMLH1 and hMSH2) was similar in AA patients compared to the U.S. Caucasian population. Similar numbers of AA MSS tumors with p16 and hMLH1 methylation likely indicate hemimethylation of genes that might reflect environmental or genetic influences that might be more common in the AA population.


An evaluation of nurse rostering practices in the National Health Service.
An evaluation of nurse rostering practices in the National Health Service The scheduling of nursing time on hospital wards is critical to the delivery of patient care, resource utilization and employee satisfaction. Over the past decade many hospital wards in the United Kingdom (UK) have moved away from the traditional planning of rosters by a single manager, towards more participative processes known as self-rostering and team rostering. This paper tests the hypothesis, developed from the literature, that the three types of rostering approach may be positioned along a continuum. Self-rostering at one extreme, is conducive to staff empowerment, motivation and roster effectiveness, whilst departmental rostering, at the other, leads to perceived autocracy, reduced empowerment, lower levels of staff motivation and roster effectiveness. Team rostering is positioned mid-way on this continuum. This paper reports the findings of an empirical study of nurse rostering practices in the UK National Health Service (NHS), with a view to developing an understanding of the implications of implementing these three rostering approaches and testing the above hypothesis. The survey of rostering practices in 50 NHS wards, and in-depth case studies of seven wards, revealed that each of the three rostering approaches has benefits and limitations and a picture emerges quite different from that implied by the research hypothesis. Whilst the literature suggests that the choice of rostering approach determines the level of perceived autocracy, staff motivation and roster effectiveness, it is proposed in this paper that selection of rostering approach should be contingent upon operational context. The paper concludes with a framework which stipulates that the choice of rostering approach for a ward should be determined on the basis of four contingent variables, namely, ward size, demand variability, demand predictability, and complexity of skill mix. It is recommended that departmental rostering be applied in large wards with complex rostering problems, whilst team rostering is more appropriate for medium sized wards, and self-rostering appropriate for small wards.


Profiling families in conflict: Multigenerational continuity in conflict predicts deleterious adolescent and adult outcomes.
The present study investigated the associations between multigenerational continuity in family conflict and current psychopathology symptoms and social impairment experienced by parents and adolescents. We sampled 246 families from a multigenerational, high-risk, longitudinal study of parents (G1s) and their children (G2s), followed from adolescence (Mage = 14.3 years, 57% female, 71% Caucasian, 26% Hispanic or Latino) to adulthood as well as the children of G2 targets (G3s; Mage = 12.1 years, 47% female, 51% Caucasian, 33% Hispanic or Latino). Family conflict was measured by composite latent variables incorporating mother, father, and adolescent reports in G1-G2 families and incorporating G2 target, G2 target's spouse, and G3 adolescent report in G2-G3 families. Indicators of G2 and G3 impairment including psychopathology symptoms (e.g., internalizing, externalizing, and substance use symptoms) and social role impairment (e.g., marital satisfaction, parenting behavior) were predicted from G1-G2 family conflict, G2-G3 family conflict, and the interaction between G1-G2 and G2-G3 family conflict. Results indicate that G1-G2 family conflict uniquely predicted indicators of G2 and G3 psychopathology, as well as G2 social impairment, even after controlling for more temporally proximal G2-G3 family conflict. Results further indicate that for G2 externalizing, internalizing, and marital functioning outcomes, high G2-G3 family conflict was associated with highest G2 impairment when G1-G2 family conflict was also high. It appears that for many G2 outcomes the interactive effects of multigenerational conflict are associated with greater risk for impairment. (PsycINFO Database Record


Infectious disease transmission and behavioural allometry in wild mammals.
Animals' social and movement behaviours can impact the transmission dynamics of infectious diseases, especially for pathogens transmitted through close contact between hosts or through contact with infectious stages in the environment. Estimating pathogen transmission rates and R0 from natural systems can be challenging. Because host behavioural traits that underlie the transmission process vary predictably with body size, one of the best-studied traits among animals, body size might therefore also predict variation in parasite transmission dynamics. Here, we examine how two host behaviours, social group living and the intensity of habitat use, scale allometrically using comparative data from wild primate, carnivore and ungulate species. We use these empirical relationships to parameterize classical compartment models for infectious micro- and macroparasitic diseases, and examine how the risk of pathogen invasion changes as a function of host behaviour and body size. We then test model predictions using comparative data on parasite prevalence and richness from wild mammals. We report a general pattern suggesting that smaller-bodied mammal species utilizing home ranges more intensively experience greater risk for invasion by environmentally transmitted macroparasites. Conversely, larger-bodied hosts exhibiting a high degree of social group living could be more readily invaded by directly transmitted microparasites. These trends were supported through comparison of micro- and macroparasite species richness across a large number of carnivore, primate and ungulate species, but empirical data on carnivore macroparasite prevalence showed mixed results. Collectively, our study demonstrates that combining host behavioural traits with dynamical models of infectious disease scaled against host body size can generate testable predictions for variation in parasite risk across species; a similar approach might be useful in future work focused on predicting parasite distributions in local host communities.


Complete resection of a rare intrahepatic variant of a choledochal cyst.
The vast majority of choledochal cysts occur as either saccular or diffuse fusiform dilatation of the extrahepatic bile duct. We describe the complete resection of a rare single intrahepatic choledochal cyst communicating with the extrahepatic biliary tree. While previous reports describe partial resection with enteral drainage, we performed a complete resection of this rare choledochal cyst.


High-accuracy standard specimens for the line-focus-beam ultrasonic material characterization system.
We prepared standard specimens for the line-focus-beam ultrasonic material characterization system to obtain absolute values of the propagation characteristics (phase velocity and attenuation) of leaky surface acoustic waves (LSAWs). The characterization system is very useful for evaluating and analyzing specimen surfaces. The calibration accuracy of these acoustic parameters depends on the accuracy of acoustical physical constants (elastic constants, piezoelectric constants, dielectric constants, and density) determined for standard specimens. In this paper, we developed substrates of nonpiezoelectric single crystals (viz., gadolinium gallium garnet [GGG], Si, and Ge) and an isotropic solid (synthetic silica [SiO2] glass) as standard specimens. These specimens can cover the phase velocity range of 2600 to 5100 m/s for Rayleigh-type LSAWs. To determine the elastic constants with high accuracy, we measured velocities by the complex-mode measurement method and corrected diffraction effects. Measurements of bulk acoustic properties (bulk wave velocity and density) were conducted around 23 degrees C, and bulk wave velocities were obtained with an accuracy of within +/-0.004%. We clearly detected differences in acoustic properties by comparing the obtained results with the previously published values; the differences were considered to be due to differences of the specimens used. We also detected differences in acoustic properties among four SiO2 substrates produced by different manufacturers.


Public health hazards of meat from small ruminants: the perspective of Australia.
The production of meat from sheep and goats in Australia occurs almost entirely at pasture in zones known as the semi-arid pastoral zone, the wheat-sheep zone (where sheep and crops form an agricultural rotation system) and the high rainfall zone. Each zone has particular factors which affect the human health hazards associated with sheep and goat meat and the opportunities for prevention. The authors provide an overview of small ruminant production in Australia and a synopsis of the diseases encountered, including the factors which influence epidemiology. Animal health arrangements for underwriting food safety at the pre-harvest and post-harvest stages of production in Australia are also outlined. Specific public health hazards related to sheep and goat meat, together with measures for prevention, are considered under the headings of zoonoses, enteropathogens and chemical residues.


Instrumental motor predictors of neuroleptic-induced parkinsonism in newly medicated schizophrenia patients.
Previous studies suggest that many untreated schizophrenia patients exhibit motor disturbances. On the basis of these findings, the authors hypothesized that preexisting extrapyramidal movement disorders may increase the risk of developing neuroleptic-induced parkinsonism (NIP). Thirty-five newly medicated psychotic patients underwent pretreatment clinical and instrumental motor and psychiatric assessments. Posttreatment ratings of parkinsonism were conducted at monthly intervals for the first 3 months and every 3 months thereafter. Thirteen patients (37%) developed NIP. Advanced age and pretreatment extrapyramidal disturbances predicted NIP. Life-table survival curves indicated that patients with pretreatment instrumental rigidity developed clinically significant NIP earlier than those without rigidity. These findings suggest that pretreatment motor dysfunction may be a risk factor for drug-induced parkinsonism, especially among older patients.


Calcium antagonists--terminology, classification and comparison.
A survey is given of the terminology and classification of calcium antagonistic drugs. Calcium entry blockers are defined as drugs of which the major effect is the selective blockade of the slow inward current across the membrane, also under physiological conditions. Calcium overload blockers are defined as compounds which prevent the overloading of the cell with calcium under pathological, ischemic conditions. Both types of drugs should be considered as examples of different principles, although compounds which possess both properties simultaneously are known to exist. Furthermore, a comparison is made between the various groups of calcium entry blockers and calcium overload blockers, with respect to their chemical, pharmacological and therapeutic properties, including their organ specificity.


Tunable, nondispersive optical filter using photonic Hilbert transformation.
We propose and numerically demonstrate a new design concept for implementing nondispersive complementary (band-pass/band-reject) optical filters with a wide range of bandwidth tunability. The device consists of two photonic Hilbert transformers (PHTs) incorporated into a Michelson interferometer (MI). By controlling the central frequency of PHTs with respect to each other, both the central frequency and the spectral width of the rejection/pass bands of the filter are proved to be tunable. Bandwidth tuning from 260 MHz to 60 GHz is numerically demonstrated using two readily feasible fiber Bragg grating-based PHTs. The designed filter offers a high extinction ratio between the pass band and rejection band (>20 dB in the narrow-band filtering case) with a very sharp transition with a slope of 170 dB/GHz from rejection to pass band.


DC-SCRIPT is a novel regulator of the tumor suppressor gene CDKN2B and induces cell cycle arrest in ERα-positive breast cancer cells.
Breast cancer is one of the most common causes of cancer-related deaths in women. The estrogen receptor (ERα) is well known for having growth promoting effects in breast cancer. Recently, we have identified DC-SCRIPT (ZNF366) as a co-suppressor of ERα and as a strong and independent prognostic marker in ESR1 (ERα gene)-positive breast cancer patients. In this study, we further investigated the molecular mechanism on how DC-SCRIPT inhibits breast cancer cell growth. DC-SCRIPT mRNA levels from 190 primary ESR1-positive breast tumors were related to global gene expression, followed by gene ontology and pathway analysis. The effect of DC-SCRIPT on breast cancer cell growth and cell cycle arrest was investigated using novel DC-SCRIPT-inducible MCF7 breast cancer cell lines. Genome-wide expression profiling of DC-SCRIPT-expressing MCF7 cells was performed to investigate the effect of DC-SCRIPT on cell cycle-related gene expression. Findings were validated by real-time PCR in a cohort of 1,132 ESR1-positive breast cancer patients. In the primary ESR1-positive breast tumors, DC-SCRIPT expression negatively correlated with several cell cycle gene ontologies and pathways. DC-SCRIPT expression strongly reduced breast cancer cell growth in vitro, breast tumor growth in vivo, and induced cell cycle arrest. In addition, in the presence of DC-SCRIPT, multiple cell cycles related genes were differentially expressed including the tumor suppressor gene CDKN2B. Moreover, in 1,132 primary ESR1-positive breast tumors, DC-SCRIPT expression also correlated with CDKN2B expression. Collectively, these data show that DC-SCRIPT acts as a novel regulator of CDKN2B and induces cell cycle arrest in ESR1-positive breast cancer cells.


Autotransplants in men with breast cancer. ABMTR Breast Cancer Working Committee. Autologous Blood and Marrow Transplant Registry.
The purpose of this study was to determine the outcome of high-dose therapy with autologous hematopoietic stem cell support (autotransplants) in men with breast cancer. We studied 13 men receiving autotransplants for breast cancer and reported to the Autologous Blood and Marrow Transplant Registry (ABMTR) by 10 centers. Six men had stage 2 breast cancer, four had stage 3, and three had metastatic breast cancer. Of twelve tumors tested, all were estrogen receptor positive. Median age at transplant was 50 years. The most common conditioning regimen was cyclophosphamide, thiotepa and carboplatin (n = 5); the remaining eight men received other alkylator-based regimens. Three men received bone marrow, eight received blood stem cells, and two received both for hematopoietic support. All patients had hematopoietic recovery. There were no unexpected regimen-related toxicities. Of 10 men receiving autotransplants as adjuvant therapy, three relapsed 3, 5 and 50 months post-transplant and died 16, 19 and 67 months post-transplant. Seven of 10 are disease-free with median follow-up of 23 months (range 6-50 months). Of three men treated for metastatic breast cancer, one had progressive disease and two recurrent disease at 6, 7 and 16 months post-transplant. In conclusion, results of autotransplants for male breast cancer appear similar to those reported for women receiving autotransplants for breast cancer.


Is calcium a mediator of infarct size reduction with preconditioning in canine myocardium?
The cellular mechanisms by which brief episodes of ischemia protect or "precondition" the heart and limit infarct size caused by a later period of sustained coronary artery occlusion remain unresolved. We propose that calcium may be an important mediator in eliciting this cardioprotection. To test this hypothesis, anesthetized dogs received a 15-minute intracoronary infusion of 20 mmol/L CaCl2 or saline before undergoing 1 hour of coronary occlusion and 4 hours of reperfusion (protocol 1). Collateral blood flow during occlusion was measured with radiolabeled microspheres, area at risk of infarction (AR) was delineated by injection of blue dye, and area of necrosis (AN) was determined by tetrazolium staining. AN/AR was reduced from 20+/-5% in the saline-treated controls to 9+/-3% in CaCl2-treated dogs (P<.05). Additional animals underwent 10 minutes of preconditioning ischemia or a comparable waiting period before the 1-hour test occlusion (protocol 2). Administration of 5-(N,N-dimethyl)-amiloride (an inhibitor of calcium influx via Na+-H+ and Na+-Ca2+ exchange) before the preconditioning stimulus attenuated the protective effect of ischemic preconditioning: AN/AR was 12+/-1%, larger than the value of 4+/-1% observed in preconditioned dogs that received saline (P<.05) and comparable to the values of 12+/-3% and 14+/-3% seen in saline- and dimethylamiloride-treated controls. Brief intracoronary infusion of CaCl2 mimicked, whereas treatment with dimethylamiloride blocked, infarct size reduction with preconditioning, thereby implicating calcium as a mediator of preconditioning in this canine model.


Evaluation of calcium sulphate barrier to collagen membrane in intrabony defects.
The aim of this study was to clinically and radiographically evaluate and compare treatment of intrabony defects with the use of decalcified freeze-dried bone allograft in combination with a calcium sulphate barrier to collagen membrane. Twelve patients having chronic periodontal disease aged 20 to 50 years and with a probing depth >6 mm were selected. Classification of patient defects into experimental and control groups was made randomly. In the test group, a calcium sulphate barrier membrane, and in control group, a collagen membrane, was used in conjunction with decalcified freeze-dried bone graft in both sides. Ancillary parameters as well as soft tissue parameters along with radiographs were taken at baseline and after 6 months of surgery. Parameters assessed were plaque index, modified gingival index, probing depth, relative attachment level, and location of the gingival margin. A Student's t-test was done for intragroup and a paired t-test for intergroup analysis. Intragroup analysis revealed statistically significant improvement in all the ancillary parameters and soft tissue parameters with no statistically significant difference in intergroup analysis. The study concluded that a calcium sulphate barrier was comparable to collagen membrane in achieving clinical benefits and hence it can be used as an economical alternative to collagen membrane.


Modifiable risk factors for scald injury in children under 5 years of age: A Multi-centre Case-Control Study.
To determine the relationship between a range of modifiable risk factors and medically attended scalds in children under the age of 5 years. Multicentre matched case-control study in acute hospitals, minor injury units and GP practices in four study centres in England. Cases comprised 338 children under 5 presenting with a scald, and 1438 control participants matched on age, gender, date of event and study centre. Parents/caregivers completed questionnaires on safety practices, safety equipment use, home hazards and potential confounders. Odds ratios were estimated using conditional logistic regression. Parents of cases were significantly more likely than parents of controls to have left hot drinks within reach of their child (adjusted odds ratio (AOR) 2.33, 95%CI 1.63 to 3.31; population attributable fraction (PAF) 31%). They were more likely not to have taught children rules about climbing on kitchen objects (AOR 1.66, 95%CI 1.12 to 2.47; PAF 20%); what to do or not do when parents are cooking (AOR 1.95, 95%CI 1.33 to 2.85; PAF 26%); and about hot things in the kitchen (AOR 1.89, 95%CI 1.30 to 2.75; PAF 26%). Some scald injuries may be prevented by parents keeping hot drinks out of reach of children and by teaching children rules about not climbing on objects in the kitchen, what to do or not do whilst parents are cooking using the top of the cooker and about hot objects in the kitchen. Further studies, providing a more sophisticated exploration of the immediate antecedents of scalds are required to quantify associations between other hazards and behaviours and scalds in young children.


Defining elimination as a public health problem for schistosomiasis control programmes: beyond prevalence of heavy-intensity infections.
WHO's 2021-30 road map for neglected tropical diseases (NTDs) outlines disease-specific and cross-cutting targets for the control, elimination, and eradication of NTDs in affected countries. For schistosomiasis, the criterion for elimination as a public health problem (EPHP) is defined as less than 1% prevalence of heavy-intensity infections (ie, ≥50 Schistosoma haematobium eggs per 10 mL of urine or ≥400 Schistosoma mansoni eggs per g of stool). However, we believe the evidence supporting this definition of EPHP is inadequate and the shifting distribution of schistosomiasis morbidity towards more subtle, rather than severe, morbidity in the face of large-scale control programmes requires guidelines to be adapted. In this Viewpoint, we outline the need for more accurate measures to develop a robust evidence-based monitoring and evaluation framework for schistosomiasis. Such a framework is crucial for achieving the goal of widespread EPHP of schistosomiasis and to meet the WHO road map targets. We encourage use of overall prevalence of schistosome infection (instead of the prevalence of heavy-intensity infections), development of species-dependent and age-dependent morbidity markers, and construction of a standardised monitoring and evaluation protocol.


Effect of temperature, nutrients, calcium, and cAMP on motility of human spermatozoa.
The motility of human spermatozoa and its regulation were examined on cells isolated from other seminal components and purified into fractions of uniform progressive motility. The percent motile cells and estimates of their translational speed were determined by visual inspection, by stroboscopy, and by photon correlation spectroscopy; microcinematography and gradient centrifugation were occasionally used to clarify discrepancies. The motility of isolated spermatozoa could be maintained for periods up to 24 h at 4 or 37 degrees C; the presence of seminal fluid was not required and even provoked a reversible inhibition at 4 degrees C. Albumin facilitated cell movement between microscopic glass plates but had no effect on progressive motility per se, as evidenced by other techniques. During incubations of up to 2 h, progressive cell motility occurred independently of extracellular glucose and calcium but responded to variations in adenosine 3',5'-cyclic monophosphate and calcium. Dibutyryl cAMP increased forward motility, whereas ethyleneglycol-bis(beta-aminoethylether)-N,N'-tetraacetic acid reversibly immobilized the spermatozoa in a calcium-dependent manner; phosphodiesterase inhibition resulted in increased vibration of sperm heads without any effect on progressive motility. Longer incubation periods required the presence of extracellular nutrients. These experiments further demonstrate that several motility measuring techniques should be used in parallel to distinguish the various components of cell movement, to exclude aspecific effects, and to supplement the shortcomings of each individual technique. Such procedure could clarify the various discrepancies that have been reported so far and should lead to a better understanding of the regulation of human sperm motility.


Quantitative analysis of global ubiquitination in HeLa cells by mass spectrometry.
Ubiquitination regulates a host of cellular processes by labeling proteins for degradation, but also by functioning as a regulatory, nonproteolytic posttranslational modification. Proteome-wide strategies to monitor changes in ubiquitination profiles are important to obtain insight into the various cellular functions of ubiquitination. Here we describe generation of stable cell lines expressing a tandem hexahistidine-biotin tag (HB-tag) fused to ubiquitin for two-step purification of the ubiquitinated proteome under fully denaturing conditions. Using this approach we identified 669 ubiquitinated proteins from HeLa cells, including 44 precise ubiquitin attachment sites on substrates and all seven possible ubiquitin chain-linkage types. To probe the dynamics of ubiquitination in response to perturbation of the ubiquitin/proteasome pathway, we combined ubiquitin profiling with quantitative mass spectrometry using the stable isotope labeling with amino acids in cell culture (SILAC) strategy. We compared untreated cells and cells treated with the proteasome inhibitor MG132 to identify ubiquitinated proteins that are targeted to the proteasome for degradation. A number of proteasome substrates were identified. In addition, the quantitative approach allowed us to compare proteasome targeting by different ubiquitin chain topologies in vivo. The tools and strategies described here can be applied to detect changes in ubiquitination dynamics in response to various changes in growth conditions and cellular stress and will contribute to our understanding of the ubiquitin/proteasome system.


Minimal preparation designs for single posterior indirect prostheses with the use of the Cerec system.
The advantages of minimally invasive dentistry are well established, especially for direct restorations. However, when it comes to indirect restorations traditional tooth preparation designs are still advised by most manufacturers. The purpose of this in vitro study was to investigate the ability of a CAD/CAM machine (Cerec) to produce minimal preparation designs and identify limiting parameters. Crown preparations based on the proposed minimal design were made using phantom teeth. Gauged burs (Intensiv SA; Meissinger, Germany) and a paralleling device were used to standardize preparations. Cerec Scan/Cerec 3D was used for scanning and designing. The materials tested were a resin composite (Paradigm MZ100, 3M ESPE) and two ceramic materials (ProCAD, Ivoclar Vivadent, and VITA Mark II, Vita). The morphology, marginal integrity, and materials' integrity were examined. The design was subjected to an interactive process as material property limitations and constraints imposed by the system became apparent. SEM, optical microscopy, and transillumination were used for the qualitative control of the crowns. The results of this study showed that only the composite material produced acceptable crowns with intact margins for the minimal design initially proposed. The ceramic materials required a wider preparation design in order to produce acceptable crowns. Within the limitations of this study, the null hypothesis was partially rejected as it was found that only the composite material could produce acceptable crowns based on the proposed minimal design. It was also found that the materials' properties, the milling mode, and cutting instruments are determining factors in establishing the extent of the minimal preparation.


A deformable surface model for real-time water drop animation.
A water drop behaves differently from a large water body because of its strong viscosity and surface tension under the small scale. Surface tension causes the motion of a water drop to be largely determined by its boundary surface. Meanwhile, viscosity makes the interior of a water drop less relevant to its motion, as the smooth velocity field can be well approximated by an interpolation of the velocity on the boundary. Consequently, we propose a fast deformable surface model to realistically animate water drops and their flowing behaviors on solid surfaces. Our system efficiently simulates water drop motions in a Lagrangian fashion, by reducing 3D fluid dynamics over the whole liquid volume to a deformable surface model. In each time step, the model uses an implicit mean curvature flow operator to produce surface tension effects, a contact angle operator to change droplet shapes on solid surfaces, and a set of mesh connectivity updates to handle topological changes and improve mesh quality over time. Our numerical experiments demonstrate a variety of physically plausible water drop phenomena at a real-time rate, including capillary waves when water drops collide, pinch-off of water jets, and droplets flowing over solid materials. The whole system performs orders-of-magnitude faster than existing simulation approaches that generate comparable water drop effects.


Hexokinase II partial knockout impairs exercise-stimulated glucose uptake in oxidative muscles of mice.
Muscle glucose uptake (MGU) is distributively controlled by three serial steps: delivery of glucose to the muscle membrane, transport across the muscle membrane, and intracellular phosphorylation to glucose 6-phosphate by hexokinase (HK). During states of high glucose fluxes such as moderate exercise, the HK activity is of increased importance, since augmented muscle perfusion increases glucose delivery, and increased GLUT4 at the cell membrane increases glucose transport. Because HK II overexpression augments exercise-stimulated MGU, it was hypothesized that a reduction in HK II activity would impair exercise-stimulated MGU and that the magnitude of this impairment would be greatest in tissues with the largest glucose requirement. To this end, mice with a HK II partial knockout (HK+/-) were compared with their wild-type control (WT) littermates during either sedentary or moderate exercise periods. Rg, an index of glucose metabolism, was measured using 2-deoxy-[3H]glucose. No differences in glucose metabolism were detected between sedentary groups. The increase in Rg due to exercise was impaired in the highly oxidative heart and soleus muscles of HK+/- compared with WT mice (7 +/- 10 vs. 29 +/- 9 and 8 +/- 3 vs. 25 +/- 7 micromol. 100 g-1. min-1, respectively). However, the increase in Rg due to exercise was not altered in gastrocnemius and superficial vastus lateralis muscles in HK+/- and WT mice (8 +/- 2 vs. 12 +/- 3 and 5 +/- 2 vs. 8 +/- 2 micromol. 100 g-1. min-1, respectively). In conclusion, MGU is impaired by reductions in HK activity during exercise, a physiological condition characterized by high glucose flux. This impairment is critically dependent on the tissue's glucose metabolic rate and correlates with tissue oxidative capacity.


Surface plasmon resonance biosensor chips integrated with MoS2-MoO3 hybrid microflowers for rapid CFP-10 tuberculosis detection.
This study reports on the modification of surface plasmon resonance (SPR) chips with molybdenum disulfide-molybdenum trioxide (MoS2-MoO3) microflowers to detect the tuberculosis (TB) markers of CFP-10. The MoS2-MoO3 microflowers were prepared by hydrothermal methods with variations in the pH and amount of trisodium citrate (Na3Ct), which were projected to influence the shape and size of microflower particles. The analysis shows that optimum MoS2-MoO3 hybrid microflowers were obtained at neutral pH using 0.5 g Na3Ct. The modified SPR biosensor exhibits a ten times higher response than the bare Au. Moreover, increasing MoS2-MoO3 thickness results in a higher detection response, sensitivity, and a smaller limit of detection (LOD). Using the optimized material composition, the Au/MoS2-MoO3-integrated SPR sensor can demonstrate sensitivity and LOD of 1.005 and 3.45 ng mL-1, respectively. This biosensor also has good selectivity, stability, and reproducibility based on cross-sensitivity characterization with other analytes and repeated measurements on several chips with different storing times and fabrication batch. Therefore, this proposed SPR biosensor possesses high potential to be further developed and applied as a detection technology for CFP-10 in monitoring and diagnosing TB.


Selection and Characterization of Specific Nanobody Against Human Immunoglobulin G.
Nanobodies (or VHHs) are the smallest antigen-binding domain of heavy chain antibodies, which naturally occur in camelidae. The small size, monomeric nature, low immunogenicity, high solubility and stability, as well as high affinity to target in nanomolar range, makes nanobodies a promising tool for diagnostic and therapeutic application. In the present study, we developed and identified the nanobody against human IgG from an immune library using phage display technique. For this goal, we performed four rounds of selection procedures on immobilized human IgG through biopanning. A clone named R1Nb was selected and expressed as His-tagged protein, and purified by nickel affinity chromatography. In addition, R1Nb was further characterized for binding specificity and affinity. Results demonstrated that R1Nb was highly specific for human IgG and its constant affinity was about 7.5 nM. Taken together, our achieved results indicate the potential of R1Nb as a promising tool in research and may be used for therapeutic purposes as a fusion part of target-specific nanobody.


Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine among children aged 6-18 years with immunocompromising conditions: recommendations of the Advisory Committee on Immunization Practices (ACIP).
On February 20, 2013, the Advisory Committee on Immunization Practices (ACIP) recommended routine use of 13-valent pneumococcal conjugate vaccine (PCV13; Prevnar 13, Wyeth Pharmaceuticals, Inc., a subsidiary of Pfizer, Inc.) for children aged 6-18 years with immunocompromising conditions, functional or anatomic asplenia, cerebrospinal fluid (CSF) leaks, or cochlear implants who have not previously received PCV13. PCV13 should be administered to these children regardless of whether they received the 7-valent pneumococcal conjugate vaccine (PCV7) or the 23-valent pneumococcal polysaccharide vaccine (PPSV23). Recommendations for PPSV23 use for children in this age group remain unchanged. The evidence for the benefits and risks associated with PCV13 vaccination of children with immunocompromising conditions was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework. This recommendation reflects a policy change from permissive and off-label recommendation of PCV13 in the pediatric immunocompromised population to a category A recommendation. This report summarizes the evidence considered by ACIP to make this recommendation and reviews the recommendations for use of PCV13 and PPSV23 for children aged 6-18 years.


Dexamethasone-Induced Sarcopenia and Physical Frailty in Children With Acute Lymphoblastic Leukemia: Protocol for a Prospective Cohort Study.
During treatment for pediatric acute lymphoblastic leukemia (ALL), children receive high doses of dexamethasone for its apoptotic effect on leukemia cells; however, muscle atrophy is a well-known serious side effect. Muscle atrophy (loss of muscle mass) accompanied by a decreased muscle strength may lead to a generalized impaired skeletal muscle state called sarcopenia. Loss of muscle mass is also an indicator of physical frailty, which is defined as a state of increased vulnerability that is characterized by co-occurrence of low muscle mass, muscle weakness, fatigue, slow walking speed, and low physical activity. Both sarcopenia and physical frailty are related to an increased risk of infections, hospitalizations, and decreased survival in children with chronic diseases. This study aims to (1) estimate the occurrence of sarcopenia and physical frailty in children during ALL maintenance therapy, (2) evaluate the effect of administering dexamethasone, and (3) explore determinants associated with these outcomes. This prospective study is being pursued within the framework of the DexaDays-2 study: a randomized controlled trial on neurobehavioral side effects in pediatric patients with ALL. A total of 105 children (3-18 years) undergoing ALL maintenance treatment at the Princess Máxima Center for Pediatric Oncology are included in this study. Sarcopenia/frailty assessments are performed before and just after a 5-day dexamethasone course. A subset of 50 children participating in the DexaDays-2 trial because of severe dexamethasone-induced neurobehavioral problems were assessed at 3 additional timepoints. The sarcopenia/frailty assessment consists of bioimpedance analysis (skeletal muscle mass [SMM]), handheld dynamometry (handgrip strength), Pediatric Quality of Life Inventory Multidimensional Fatigue Scale (fatigue), Timed Up and Go Test (TUG; walking speed), and physical activity questionnaires. To evaluate potential change in sarcopenia/frailty components after a 5-day dexamethasone administration, a paired Student t test or Mann-Whitney U test will be used. Because of the presence of repeated measurements, generalized linear mixed models will be used to estimate the effect of dexamethasone on sarcopenia and frailty outcomes. Multivariable regression models will be estimated to investigate associations between the assessment scores and patient and treatment-related factors. Patient accrual started in 2018 and was finalized in spring 2021. From autumn 2021 onward final data analyses will be performed. This first study combining parameters of sarcopenia and physical frailty is of importance because these conditions can seriously complicate continuation of ALL therapy, independence in physical functioning, reaching motor milestones, and participating in daily life activities. The results will provide knowledge about these complications, the association between dexamethasone treatment and muscle loss and other components of frailty, and therefore insights into the severity of this side effect. By exploring potential determinants that may be associated with sarcopenia and physical frailty, we may be able to identify children at risk at an earlier stage and provide timely interventions. DERR1-10.2196/33517.


Interim payment system and risk management.
Agencies need to be aware of the legal implications of the Medicare reimbursement system changes in the high-risk areas of patient care. Agencies must take deliberate steps to manage the risks that are sure to ensue under the new system of restricted payments and to minimize liability concerns.


Gap junctions in the differentiated neural retinae of newly hatched chickens.
Gap junctions in the neural retinae of newly hatched chickens were examined in thin section and by freeze cleaving. Unusual gap junctions containing linear arrays of intramembrane particles are found between principal and accessory cones which form a double cone at the region of the outer limiting membrane. These unusual gap junctions are often continuous with macular aggregates of hexagonally packed intramembrane particles which are characteristic of a typical gap junction. Typical gap junctions are also found in both the outer and the inner plexiform layers and in the outer nuclear layer, but are not so abundant as in the outer limiting membrane region. The sizes of intramembrane particles and their centre-to-centre spacing within the macular aggregate of a gap junction in differentiated neural retinae are slightly larger than those in undifferentiated neural retinae. Tight junctions are not found in differentiated neural retinae.


Effect of novel stressors on gene expression of tyrosine hydroxylase and monoamine transporters in brainstem noradrenergic neurons of long-term repeatedly immobilized rats.
Responses of central noradrenergic (NE) neurons to stressors like immobilization (IMO), cold exposure, insulin-induced hypoglycemia, and cellular glucoprivation caused by 2-deoxy-D-glucose (2-DG) were investigated in intact and long-term repeatedly immobilized (LTR, 2 h daily IMO for 41 days) rats. Expression of tyrosine hydroxylase (TH), norepinephrine transporter (NET) and vesicular monoamine transporter (VMAT2) genes were determined by using in situ hybridization histochemistry in brainstem A1, A2, A5 and locus coeruleus (LC) neurons. TH mRNA levels were increased by single IMO or 2-DG administration in all areas studied. Cold was effective only in LC and A2 neurons while insulin had no effect. LTR immobilization elevated TH mRNA levels in all investigated cell groups. These elevations were equally high to those elicited by a single IMO in each noradrenergic group, except the LC where LTR IMO was less effective than the single IMO. The levels of NET and VMAT2 mRNAs were elevated only in the A1 and A2 cell groups of LTR IMO rats. A newly applied IMO in LTR rats did not alter TH, NET, and VMAT2 mRNA levels in any NE cell group investigated. Novel stressors like cold and 2-DG exaggerated the increased TH mRNA levels only in the LC of LTR IMO rats, unlike in the other NE cell groups. The present data indicate that repeated exposure of rats to homotypic stressor induces an adaptation of NE neurons, whereas single exposure of such animals to heterotypic novel stressor produces an exaggerated response of the system at the level of TH (in LC) and NET (in A1, A2) gene expression.


A pilot, first-in-human, pharmacokinetic study of 9cUAB30 in healthy volunteers.
9cUAB30 is a synthetic analog of 9-cis-retinoic acid with chemopreventive activity in cell lines and in animal models. The purpose of this first-in-human evaluation of 9cUAB30 was to evaluate the single-dose pharmacokinetic profile and toxicity of the compound in healthy volunteers at 3 dose levels. This study enrolled 14 patients to receive a single dose of 5, 10, or 20 mg of 9cUAB30. Plasma and urine samples were collected to assess 9cUAB30 concentrations by a validated LC/MS MS method. 9cUAB30 was well tolerated, with 1 patient experiencing grade 2 toxicity and no grade 3 or 4 toxicities reported. T(max) occurred approximately 3 hours after dose administration with the plasma half-life ranging from 2.79 to 7.21 hours. AUC increased linearly across the examined dose range of 5 to 20 mg; C(max) was proportional to the log of the dose. The plasma clearance ranged from 25 to 39 L/h compared to the renal clearance which ranged from 0.018 to 0.103 L/h. 9cUAB30 has a favorable toxicity and pharmacokinetic profile, with oral availability and primarily hepatic metabolism. Further dose ranging studies with once a day dosing are underway.


Is obesity an inflammatory illness? Role of low-grade inflammation and macrophage infiltration in human white adipose tissue.
There are at least two scientific evidences of human obesity as a chronic inflammatory illness: first, the well-described moderate increase of inflammatory factors in the circulation in obese subjects, and second, the recent identification of macrophage cells infiltrating the white adipose tissue (WAT). These observations led to a revision of the physiopathology of obesity and its co-morbidities. It has been suggested that the 'low-grade' inflammatory state associates with metabolic and cardiovascular complications of obesity. Weight loss is able to improve this inflammatory state by both significantly decreasing circulating inflammatory molecules and macrophage cell infiltration in WAT depots. However, the mechanisms of WAT macrophage recruitment into the adipose tissue and their role in obesity complications have not been defined. This review aims to point out the knowledge on inflammatory cytokines associated with obesity and focuses on macrophage infiltration in human WAT, discussing their recruitment and role. The interactions of macrophages with adipocytes will certainly be the subject of intense investigations in the future.


Automatic Swimming Activity Recognition and Lap Time Assessment Based on a Single IMU: A Deep Learning Approach.
This study presents a deep learning model devoted to the analysis of swimming using a single Inertial Measurement Unit (IMU) attached to the sacrum. Gyroscope and accelerometer data were collected from 35 swimmers with various expertise levels during a protocol including the four swimming techniques. The proposed methodology took high inter- and intra-swimmer variability into account and was set up for the purpose of predicting eight swimming classes (the four swimming techniques, rest, wallpush, underwater, and turns) at four swimming velocities ranging from low to maximal. The overall F1-score of classification reached 0.96 with a temporal precision of 0.02 s. Lap times were directly computed from the classifier thanks to a high temporal precision and validated against a video gold standard. The mean absolute percentage error (MAPE) for this model against the video was 1.15%, 1%, and 4.07%, respectively, for starting lap times, middle lap times, and ending lap times. This model is a first step toward a powerful training assistant able to analyze swimmers with various levels of expertise in the context of in situ training monitoring.


Clustering of Cx43 cell-to-cell channels into gap junction plaques: regulation by cAMP and microfilaments.
Cell-to-cell channels are often seen clustered at cell-cell contacts into the so-called gap junction plaques. The mechanism of this clustering is unknown. We show that the clustering of cell-to-cell channels composed of connexin43 is induced by elevation of cyclic AMP. The cAMP-induced clustering is enhanced by inhibition of glycosylation and abolished by disruption of microfilaments. Channel clustering thus seems to be regulated by cAMP and glycosylation and to involve microfilaments.


Effect of nanotube coupling on exciton transport in polymer-free monochiral semiconducting carbon nanotube networks.
Semiconducting single-walled carbon nanotubes (s-SWCNTs) are attractive light-harvesting components for solar photoconversion schemes and architectures, and selective polymer extraction has emerged as a powerful route to obtain highly pure s-SWCNT samples for electronic applications. Here we demonstrate a novel method for producing electronically coupled thin films of near-monochiral s-SWCNTs without wrapping polymer. Detailed steady-state and transient optical studies on such samples provide new insights into the role of the wrapping polymer on controlling intra-bundle nanotube-nanotube interactions and exciton energy transfer within and between bundles. Complete removal of polymer from the networks results in rapid exciton trapping within nanotube bundles, limiting long-range exciton transport. The results suggest that intertube electronic coupling and associated exciton delocalization across multiple tubes can limit diffusive exciton transport. The complex relationship observed here between exciton delocalization, trapping, and long-range transport, helps to inform the design, preparation, and implementation of carbon nanotube networks as active elements for optical and electronic applications.


A rare case of metastatic ductal type prostate adenocarcinoma presenting with syndrome of inappropriate secretion of antidiuretic hormone: a case report and review.
Ductal adenocarcinoma of the prostate is a rare malignancy and it accounts for less than 1% of prostatic adenocarcinomas as a predominant pattern. In general, the prognosis for these patients is worse than those with typical adenocarcinoma of the prostate. SIADH is a rare paraneoplastic syndrome associated with classic and poorly differentiated acinar prostate adenocarcinoma. To our knowledge, this is the first case of paraneoplastic SIADH associated with ductal type prostate adenocarcinoma. The case highlights once again that the patients with metastatic prostate cancer who present with hyponatremia should get a diagnostic workup for SIADH done due to the potential fatal consequences of this paraneoplastic syndrome.


Pyracene-linked bis-imidazolylidene complexes of palladium and some catalytic benefits produced by bimetallic catalysts.
Two new palladium complexes with a pyracene-linked bis-imidazolylidene (pyrabim) group have been obtained and fully characterized. The related monometallic analogues were obtained from the coordination of an acetanaphthene-supported N-heterocyclic carbene (NHC). The catalytic properties of all complexes were studied in the acylation of aryl halides with hydrocinnamaldehyde, and in the Suzuki-Miyaura coupling of aryl halides and aryl boronic acids. The results show that the presence of a second metal in the dimetallic complexes induces some benefits in the catalytic behavior of the complexes. This effect is more pronounced in the Suzuki-Miyaura coupling, for which the dimetallic complexes exhibit significantly higher activity than their monometallic counterparts.


Cost-effectiveness evidence of mental health prevention and promotion interventions: A systematic review of economic evaluations.
The prevention of mental disorders and promotion of mental health and well-being are growing fields. Whether mental health promotion and prevention interventions provide value for money in children, adolescents, adults, and older adults is unclear. The aim of the current study is to update 2 existing reviews of cost-effectiveness studies in this field in order to determine whether such interventions are cost-effective. Electronic databases (including MEDLINE, PsycINFO, CINAHL, and EconLit through EBSCO and Embase) were searched for published cost-effectiveness studies of prevention of mental disorders and promotion of mental health and well-being from 2008 to 2020. The quality of studies was assessed using the Quality of Health Economic Studies Instrument (QHES). The protocol was registered with PROSPERO (# CRD42019127778). The primary outcomes were incremental cost-effectiveness ratio (ICER) or return on investment (ROI) ratio across all studies. A total of 65 studies met the inclusion criteria of a full economic evaluation, of which, 23 targeted children and adolescents, 35 targeted adults, while the remaining targeted older adults. A large number of studies focused on prevention of depression and/or anxiety disorders, followed by promotion of mental health and well-being and other mental disorders. Although there was high heterogeneity in terms of the design among included economic evaluations, most studies consistently found that interventions for mental health prevention and promotion were cost-effective or cost saving. The review found that targeted prevention was likely to be cost-effective compared to universal prevention. Screening plus psychological interventions (e.g., cognitive behavioural therapy [CBT]) at school were the most cost-effective interventions for prevention of mental disorders in children and adolescents, while parenting interventions and workplace interventions had good evidence in mental health promotion. There is inconclusive evidence for preventive interventions for mental disorders or mental health promotion in older adults. While studies were of general high quality, there was limited evidence available from low- and middle-income countries. The review was limited to studies where mental health was the primary outcome and may have missed general health promoting strategies that could also prevent mental disorder or promote mental health. Some ROI studies might not be included given that these studies are commonly published in grey literature rather than in the academic literature. Our review found a significant growth of economic evaluations in prevention of mental disorders or promotion of mental health and well-being over the last 10 years. Although several interventions for mental health prevention and promotion provide good value for money, the varied quality as well as methodologies used in economic evaluations limit the generalisability of conclusions about cost-effectiveness. However, the finding that the majority of studies especially in children, adolescents, and adults demonstrated good value for money is promising. Research on cost-effectiveness in low-middle income settings is required. PROSPERO registration number: CRD42019127778.


The Effect of Aging on Memory for Recent and Remote Egocentric and Allocentric Information.
The present study explores recent and well-consolidated spatial memory within the egocentric and allocentric frames of reference in young and elderly people. The research included young and old participants, within the range of normality. All the participants were tested on four spatial tasks requiring allocentric and egocentric judgments, based on recent as well as remote spatial information, using a Multivariate Regression Analysis. An age effect on both egocentric and allocentric tasks was present in recently learned spatial information. The age effect was not present in tasks regarding well-consolidated spatial information. Finally, sex influenced the performance in allocentric tasks regarding both recent and well-consolidated memory. These data were discussed according to the Multiple Trace Theory, supporting the idea that the magnitude of difference between egocentric and allocentric judgments in aging is somewhat attributable to the characteristic of spatial tasks. In general, a lower difference between the performance of young and elderly participants is shown in tasks based on well-consolidated information when compared with tasks based on episodic information. Well-consolidated information seemed to be better preserved in memory and less prone to the impairment.


Computational identification and experimental characterization of substrate binding determinants of nucleotide pyrophosphatase/phosphodiesterase 7.
Nucleotide pyrophosphatase/phosphodiesterase 7 (NPP7) is the only member of the mammalian NPP enzyme family that has been confirmed to act as a sphingomyelinase, hydrolyzing sphingomyelin (SM) to form phosphocholine and ceramide. NPP7 additionally hydrolyzes lysophosphatidylcholine (LPC), a substrate preference shared with the NPP2/autotaxin(ATX) and NPP6 mammalian family members. This study utilizes a synergistic combination of molecular modeling validated by experimental site-directed mutagenesis to explore the molecular basis for the unique ability of NPP7 to hydrolyze SM. The catalytic function of NPP7 against SM, LPC, platelet activating factor (PAF) and para-nitrophenylphosphorylcholine (pNPPC) is impaired in the F275A mutant relative to wild type NPP7, but different impacts are noted for mutations at other sites. These results are consistent with a previously described role of F275 to interact with the choline headgroup, where all substrates share a common functionality. The L107F mutation showed enhanced hydrolysis of LPC, PAF and pNPPC but reduced hydrolysis of SM. Modeling suggests this difference can be explained by the gain of cation-pi interactions with the choline headgroups of all four substrates, opposed by increased steric crowding against the sphingoid tail of SM. Modeling also revealed that the long and flexible hydrophobic tails of substrates exhibit considerable dynamic flexibility in the binding pocket, reducing the entropic penalty that might otherwise be incurred upon substrate binding. Substrate recognition by NPP7 includes several important contributions, ranging from cation-pi interactions between F275 and the choline headgroup of all substrates, to tail-group binding pockets that accommodate the inherent flexibility of the lipid hydrophobic tails. Two contributions to the unique ability of NPP7 to hydrolyze SM were identified. First, the second hydrophobic tail of SM occupies a second hydrophobic binding pocket. Second, the leucine residue present at position 107 contrasts with a conserved phenylalanine in NPP enzymes that do not utilize SM as a substrate, consistent with the observed reduction in SM hydrolysis by the NPP7-L107F mutant.


Synovial Cysts Confounding Access to the Dorsal S1 Neural Foramen in Transforaminal Epidural Steroid Injections.
The S1 dorsal foramen is the route for 30% of lumbar transforaminal epidural injections; it is therefore important to identify structures impeding S1 foraminal access. The study objective was to characterize the imaging findings, prevalence, and anatomic origin of synovial cysts presenting within the S1 neural foramen. A case series (N = 14) established imaging characteristics of S1 synovial cysts. Imaging studies of 400 patients undergoing epidural injections were reviewed for lesions compromising S1 foraminal access. Cadaveric dissections defined the relationship of the inferior recess of the L5-S1 facet to the S1 dorsal foramen. Elderly patients (mean age = 76) exhibited S1 synovial cysts. Synovial cysts were typically 1-2 cm in diameter, hyperintense on sagittal T2 weighted magnetic resonance images (MRIs), fluid-density on computed tomography, and dorsal to the S1 spinal nerve. Sixty percent of cysts exhibited complex MRI signal characteristics (thick wall, internal structure). Tarlov cysts, in contrast, were larger, lobular, and exhibited pure fluid intensity. Lesions impeded access to the S1 dorsal foramina in 5% of reviewed imaging studies (16 Tarlov cysts, three synovial cysts, one conjoint S1-S2 nerve root). The multifidus muscle was interposed between the L5-S1 facet inferior recess and the S1 dorsal foramen on dissection specimens; severe atrophy of the ipsilateral multifidus was noted on imaging in 17/18 synovial cysts. The S1 neural foramina should be inspected on sagittal MRI, when available, for confounding lesions before performing S1 epidural injections. Tarlov cysts are more common than synovial cysts; the latter are seen in elderly patients with severe multifidus atrophy.


NanoCluster Itraconazole Formulations Provide a Potential Engineered Drug Particle Approach to Generate Effective Dry Powder Aerosols.
Itraconazole (ITZ), a triazole antifungal agent, is a poorly water-soluble drug that is orally administered for treatment of fungal infections such as allergic bronchopulmonary aspergillosis (ABPA) and invasive aspergillosis (IA). ABPA is relatively well controlled but IA can be fatal, especially in immunosuppressed patients. Aerosolized ITZ delivered to the lung may provide a local treatment and prophylaxis against IA at the primary site of infection in the lungs. Variations of the percent fine particle fraction (FPF), the percent emitted dose, and the physical properties of the aerosol (e.g., crystallinity) can confound consistent delivery. ITZ NanoClusters were formulated via milling (top-down process) or precipitation (bottom-up process) without using any excipients. Itraconazole formulations (ITZ) were prepared by milling 1 gram of micronized itraconazole in 300 mL of fluid. The suspension was collected at 0.5, 1, and 2 hours milling time. Milled ITZ was compared to ITZ prepared by anti-solvent precipitation and to the stock micronized itraconazole. The aerosolization performance of ITZ formulations was determined using an Andersen Cascade Impactor (ACI). The physicochemical properties and aerosol performance of different ITZ NanoClusters suggested an optimized wet milling was the preferred process compared to precipitation. ITZ NanoClusters prepared by wet milling showed better aerosol performance compared to micronized ITZ as received and ITZ NanoClusters prepared by precipitation. ITZ NanoClusters prepared by precipitation methods also showed an amorphous state, while ITZ milled in 10% EtOH maintained the crystalline character of ITZ throughout a 2 hour milling time. The aerosol performance of milled ITZ NanoClusters was dramatically improved compared to micronized ITZ as received due to the difference of drug particle structures. ITZ NanoCluster formulations represent a potential engineered drug particle approach for inhalation therapy, providing effective aerosol properties and stability due to the crystalline state of the drug powders.


A typical case study correcting color deficiency.
Within one month after visiting his optometrist, a 14-year-old color deficient vocational high school student was able to sufficiently improve his color discrimination and his perception of objects which blend with their background, so as to continue with his study in electronics. The three prescribed sessions were adequate and the student was very pleased with his color improvement.


Incorporation of bioactive glass in calcium phosphate cement: material characterization and in vitro degradation.
Calcium phosphate cements (CPCs) have been widely used as an alternative to biological grafts due to their excellent osteoconductive properties. Although degradation has been improved by using poly(D,L-lactic-co-glycolic) acid (PLGA) microspheres as porogens, the biological performance of CPC/PLGA composites is insufficient to stimulate bone healing in large bone defects. In this context, the aim of this study was to investigate the effect of incorporating osteopromotive bioactive glass (BG; up to 50 wt %) on setting properties, in vitro degradation behavior and morphological characteristics of CPC/BG and CPC/PLGA/BG. The results revealed that the initial and final setting time of the composites increased with increasing amounts of incorporated BG. The degradation test showed a BG-dependent increasing effect on pH of CPC/BG and CPC/PLGA/BG pre-set scaffolds immersed in PBS compared to CPC and CPC/PLGA equivalents. Whereas no effects on mass loss were observed for CPC and CPC/BG pre-set scaffolds, CPC/PLGA/BG pre-set scaffolds showed an accelerated mass loss compared with CPC/PLGA equivalents. Morphologically, no changes were observed for CPC and CPC/BG pre-set scaffolds. In contrast, CPC/PLGA and CPC/PLGA/BG showed apparent degradation of PLGA microspheres and faster loss of integrity for CPC/PLGA/BG pre-set scaffolds compared with CPC/PLGA equivalents. Based on the present in vitro results, it can be concluded that BG can be successfully introduced into CPC and CPC/PLGA without exceeding the setting time beyond clinically acceptable values. All injectable composites containing BG had suitable handling properties and specifically CPC/PLGA/BG showed an increased rate of mass loss. Future investigations should focus on translating these findings to in vivo applications.


How many joints in the hands and wrists should be included in a score of radiologic abnormalities used to assess rheumatoid arthritis?
Numerous methods for reading abnormalities of rheumatoid arthritis in hand and wrist radiographs have been proposed over the past several decades. There are many differences among these methods, one of the more striking of which is the variation in the number of joints that are scored. In this study, we tested the number of joints that need to be read in order to represent abnormalities accurately and reproducibly, using the scores of multiple observers. Thirteen rheumatologists and radiologists each read a set of 41 hand and wrist films from patients with rheumatoid arthritis. Ten of 13 readers scored 27 joints in each hand and wrist; the other 3 readers scored fewer areas. Fourteen combinations of joints were selected based on the frequency of involvement and the technical adequacy of routine films in assessing a given area. After testing these 14 different combinations, 1 scheme, which included 17 areas read for erosions and 18 areas read for joint space narrowing, was tested further. The correlation coefficients for 10 intraobserver scores derived from this modified scheme compared with the original scores were between 0.981 and 0.997. Seventy-one of 78 interobserver comparisons were better using the new scheme than using the original scheme. These data indicate that the simplified scheme, using a combination of 17 joints to score erosions and 18 to score joint space narrowing, more accurately reflects the extent of abnormalities perceived by a panel of experts than does the original scheme. This abbreviated number of joints shortens the amount of time required to read a set of films and simplifies the scoring of films, since a number of areas that are difficult to read are eliminated from radiographic assessment.


Loss and gain of FUS function impair neuromuscular synaptic transmission in a genetic model of ALS.
Amyotrophic lateral sclerosis (ALS) presents clinically in adulthood and is characterized by the loss of motoneurons in the spinal cord and cerebral cortex. Animal models of the disease suggest that significant neuronal abnormalities exist during preclinical stages of the disease. Mutations in the gene fused in sarcoma (FUS) are associated with ALS and cause impairment in motor function in animal models. However, the mechanism of neuromuscular dysfunction underlying pathophysiological deficits causing impairment in locomotor function resulting from mutant FUS expression is unknown. To characterize the cellular pathophysiological defect, we expressed the wild-type human gene (wtFUS) or the ALS-associated mutation R521H (mutFUS) gene in zebrafish larvae and characterized their motor (swimming) activity and function of their neuromuscular junctions (NMJs). Additionally, we tested knockdown of zebrafish fus with an antisense morpholino oligonucleotide (fus AMO). Expression of either mutFUS or knockdown of fus resulted in impaired motor activity and reduced NMJ synaptic fidelity with reduced quantal transmission. Primary motoneurons expressing mutFUS were found to be more excitable. These impairments in neuronal function could be partially restored in fus AMO larvae also expressing wtFUS (fus AMO+wtFUS) but not mutFUS (fus AMO+mutFUS). These results show that both a loss and gain of FUS function result in defective presynaptic function at the NMJ.


[Coronary circulation and left ventricular function in patients with transmural myocardial infarct].
Hemodynamics and left-ventricular segmental contractility were examined in 72 patients, subjected to selective coronarography and ventriculography. Forty-six patients had a history of anterior, and 26, posterior, transmural myocardial infarction (MI). Atherosclerotic stenosis of coronary arteries (more than 75% of vascular diameter) was revealed in 67 of 72 patients. Residual occlusion was shown to occur more commonly in the right coronary artery. Collateral flow was more commonly associated with a history of myocardial infarction affecting the posterior wall of the left ventricle, while segmental contractility disorders, even aneurysms, and generalized disturbance of left-ventricular contractility, as manifested in reduced mean rate of myocardial circular fibre shortening, were more typical for the affection of the anterior wall of the left ventricle.


Selected reaction monitoring applied to proteomics.
Selected reaction monitoring (SRM) performed on triple quadrupole mass spectrometers has been the reference quantitative technique to analyze small molecules for several decades. It is now emerging in proteomics as the ideal tool to complement shotgun qualitative studies; targeted SRM quantitative analysis offers high selectivity, sensitivity and a wide dynamic range. However, SRM applied to proteomics presents singularities that distinguish it from small molecules analysis. This review is an overview of SRM technology and describes the specificities and the technical aspects of proteomics experiments. Ongoing developments aiming at increasing multiplexing capabilities of SRM are discussed; they dramatically improve its throughput and extend its field of application to directed or supervised discovery experiments.


Correlation between coronavirus conspiracism and antisemitism: a cross-sectional study in the United Kingdom.
This article presents the findings of a survey of UK-resident adults ([Formula: see text] = 1790) carried out in December 2021 and designed to test for a relationship between antisemitism and coronavirus conspiracism. Antisemitism was measured using the Generalised Antisemitism (GeAs) scale, and coronavirus conspiracism was measured using a version of the Flexible Inventory of Conspiracy Suspicions (FICS). Hypotheses and methodology were pre-registered, and all data and code are open. There was found to be a positive correlation between coronavirus conspiracy suspicions and Generalised Antisemitism, robust to demographic controls. This correlation appears to be entirely accounted for by older forms of antisemitism: antisemitism as expressed in relation to Israel and its supporters was found to be associated with coronavirus conspiracism only because both of these variables were associated with antisemitism as expressed in relation to Jews identified as Jews. Statistical analysis suggests that these findings may be generalised from the sample to the UK adult population with some confidence, although no data were collected in other national contexts, such that generalisation to other national contexts must remain speculative.


The biosphere theory of V. I. Vernadsky and the Gaia theory of James Lovelock: a comparative analysis of the two theories and traditions.
James Hutton (1726-1797) regarded Earth as a super-organism and physiology the science to study it. A strong line of evidence for an intimate relationship of biological and abiotic processes on Earth leads from Hutton to the Gaia theory of J. Lovelock. A less known in the West but important approach to the biosphere as a self-regulating system (the biosphere theory) was proposed V.I. Vernadsky (1863-1945). The main concern of this paper revolves around the question: What is the difference between Gaia and the biosphere? To approach the problem of Earth as a super-organism one can use also the biosphere theory of V. N. Beklemishev (1890-1962), who examined the biosphere from a morphological viewpoint.


Electronic properties of pure and p-type doped hexagonal sheets and zigzag nanoribbons of InP.
Unlike graphene, a hexagonal InP sheet (HInPS) cannot be obtained by mechanical exfoliation from the native bulk InP, which crystallizes in the zinc blende structure under ambient conditions. However, by ab initio density functional theory calculations we found that a slightly buckled HInPS is stable both in pristine form and when doped with Zn atoms; the same occurred for hydrogen-passivated zigzag InP nanoribbons (ZInPNRs), quasi-one-dimensional versions of the quasi-two-dimensional material. We investigated the electronic properties of both nanostructures, in the latter case also in the presence of an external transverse electric field, and the results are compared with those of hypothetical planar HInPS and ZInPNRs. The band gaps of planar ZInPNRs were found to be tunable by the choice of strength of this field, and to show an asymmetric behavior under weak electric fields, by which the gap can either be increased or decreased depending on their direction; however, this effect is absent from slightly buckled ZInPNRs. The binding energies of the acceptor impurity states of Zn-doped HInPS and ZInPNRs were found to be similar and much larger than that of Zn-doped bulk InP. These latter findings show that the reduction of the dimensionality of these materials limits the presence of free carriers.


Is language a barrier to the use of preventive services?
To isolate the effect of spoken language from financial barriers to care, we examined the relation of language to use of preventive services in a system with universal access. Cross-sectional survey. Household population of women living in Ontario, Canada, in 1990. Subjects were 22,448 women completing the 1990 Ontario Health Survey, a population-based random sample of households. We defined language as the language spoken in the home and assessed self-reported receipt of breast examination, mammogram and Pap testing. We used logistic regression to calculate odds ratios for each service adjusting for potential sources of confounding: socio-economic characteristics, contact with the health care system, and measures reflecting culture. Ten percent of the women spoke a non-English language at home (4% French, 6% other). After adjustment, compared with English speakers, French-speaking women were significantly less likely to receive breast exams or mammography, and other language speakers were less likely to receive Pap testing. Women whose main spoken language was not English were less likely to receive important preventive services. Improving communication with patients with limited English may enhance participation in screening programs.


Partial purification and characterization of ADP-ribosyltransferase produced by Legionella pneumophila.
A scheme for the partial purification of a Legionella pneumophila product possessing ADP-ribosyl-transferase and NAD-glycohydrolase activities is presented. The purification steps consisted of gel chromatography, ion-exchange, hydrophobic interaction chromatography, and chromatofocusing. The partially purified preparation modified eukaryotic components of molecular mass 20-25 kDa, which it is proposed are GTP-binding proteins. Addition of bivalent cations as well as ATP to the reaction buffer was necessary for ADP-ribosylation. NAD (50 microM) and nicotinamide (16 mM) greatly inhibited incorporation of ADP-ribose into acceptor proteins.


Incidence of pediatric traumatic brain injury and associated hospital resource utilization in the United States.
The goal was to examine the influence of sociodemographic characteristics and health care system factors on the utilization of hospital resources by US children < or = 17 years of age with a diagnosis of traumatic brain injury. A retrospective analysis of data from the Healthcare Cost and Utilization Project Kids' Inpatient Database, from January 1, 2000, to December 31, 2000, was performed. National estimates of traumatic brain injury-associated hospitalization rates and resource use were calculated with Kids' Inpatient Database sample weighting methods. Of 2,516,833 encounters between January 1, 2000, and December 31, 2000, 25,783 cases involved patients < or = 17 years of age with a recorded diagnosis of traumatic brain injury. On the basis of these data, there were an estimated 50,658 traumatic brain injury-associated hospitalizations among children < or = 17 years of age in the United States in 2000. The traumatic brain injury-associated hospitalization rate was 70 cases per 100,000 children < or = 17 years of age per year; 15- to 17-year-old patients had the highest hospitalization rate (125 cases per 100,000 children per year). Pediatric inpatients accrued more than $1 billion in total charges for traumatic brain injury-associated hospitalizations in this study. In the multivariate regression models, older age, Medicaid insurance status, and admission to any type of children's hospital were associated with a longer length of stay for pediatric traumatic brain injury-associated hospitalizations. Older age, longer length of stay, and in-hospital death predicted higher total charges for traumatic brain injury-associated hospitalizations. Pediatric traumatic brain injury is a substantial contributor to the health resource burden in the United States, accounting for more than $1 billion in total hospital charges annually.


Identification of cholesterol-assimilating actinomycetes strain and application of statistical modeling approaches for improvement of cholesterol oxidase production by Streptomyces anulatus strain NEAE-94.
Cholesterol oxidase biosensors have been used to determine the level of cholesterol in different serum and food samples. Due to a wide range of industrial and clinical applications of microbial cholesterol oxidase, isolation and identification of a new microbial source (s) of cholesterol oxidase are very important. The local isolate Streptomyces sp. strain NEAE-94 is a promising source of cholesterol oxidase. It was identified based on cultural, morphological and physiological characteristics; in addition to the 16S rRNA sequence. The sequencing product had been deposited in the GenBank database under the accession number KC354803. Cholesterol oxidase production by Streptomyces anulatus strain NEAE-94 in shake flasks was optimized using surface response methodology. The different process parameters were first screened using a Plackett-Burman design and the parameters with significant effects on the production of cholesterol oxidase were identified. Out of the 15 factors screened, agitation speed, cholesterol and yeast extract concentrations had the most significant positive effects on the production of cholesterol oxidase. The optimal levels of these variables and the effects of their mutual interactions on cholesterol oxidase production were determined using Box-Behnken design. Cholesterol oxidase production by Streptomyces anulatus strain NEAE-94 was 11.03, 27.31 U/mL after Plackett-Burman Design and Box-Behnken design; respectively, with a fold of increase of 6.06 times compared to the production before applying the Plackett-Burman design (4.51 U/mL). Maximum cholesterol oxidase activity was obtained at the following fermentation conditions: g/L (cholesterol 4, yeast extract 5, NaCl 0.5, K2HPO4 1, FeSO4.7H2O 0.01, MgSO4.7H2O 0.5), pH 7, inoculum size 4% (v/v), temperature 37°C, agitation speed of 150 rpm, medium volume 50 mL and incubation time 5 days.


[Endemic goiter in school children of Salta Province, Argentina].
The Province of Salta, located in the northwest of Argentina, showed severe endemic goiter-cretinism. The purpose of our work, therefore, was to evaluate the results of the iodized salt prophylaxis measure implemented since 1963. In 1980-1981 the prevalence of goiter was determined in 16,935 school children whose ages ranged from four to 15 years. The urinary iodine/creatinine index was also determined in a subsample of 401 children. Findings revealed that the goiter prevalence in the Province was 16.1%. In 10 Departments of the Province, those with greater socioeconomic development and denser population, the prevalences found were below 10%, limit established as endemic. In the remaining 13 Departments, especially in those less developed--where mountainous regions make their access difficult and hence, their populations consume non-iodized salt obtained from natural salt basins--values exceeded this limit. The average ioduria was 104.0 micrograms I/g Cr, with 4.5% presenting values below 25 micrograms. After 20 years of prophylaxis, endemic goiter has therefore been partially eradicated. It is suggested, however, that consumption of iodized salt and, even the supply of iodized oil in those areas where prevalence is high, be recommended.


[Posttraumatic stress disorder in patients after stroke].
Objective. To assess the frequency of main symptoms of posttraumatic stress disorder (PTSD) in post stroke patients. Material and methods. Forty-eight patients took part in the study. We used the Impact of Events Scale (IES) and other scales to assess the severity of posttraumatic stress. Results and conclusion. Thirty three percent of patients experienced posttraumatic stress, 12.5% suffered from PTSD. We found an association between the severity of posttraumatic stress after stroke and the level of anxiety, sleep disturbances and decrease of quality of life. Symptoms of posttraumatic stress are often observed after stroke, this needs to be taken into account during planning of rehabilitation programs.


Experience with liver dialysis in acetaminophen induced fulminant hepatic failure: a preliminary report.
Our aim was to assess the efficacy of the liver dialysis unit (LDU) in the treatment of patients with acetaminophen-induced fulminant hepatic failure. Seventeen patients with acetaminophen-induced fulminant hepatic failure between January 1996 and December 2001 were retrospectively studied. A liver dialysis unit became available in our Unit in July 2000, and as of December 2001, four of these 17 patients had undergone treatment with liver dialysis. Mean age was 29 years (range: 14-47) and 76% were women. Four of 17 patients underwent a total of 12 (range: 1-4) LDU sessions. Ammonia level tended to be lower following the LDU and all four patients recovered without a need for orthotopic liver transplantation (OLT). Prior to July 2000, eight of 13 patients survived with supportive therapy, three expired and two underwent OLT. No major bleeding episodes were observed during the LDU course. A significant difference was found between the three cases who died and the cases that survived with respect to the grade of encephalopathy (p<0.001). There was significant difference in the admission serum creatinine among survivors (p<0.05). In conclusion, the Liver Dialysis Unit treatment appeared to benefit patients with acetaminophen-induced fulminant hepatic failure by reverse of the encephalopathy and spontaneous recovery of the damaged liver in selected patients.


Modulation of interleukin-6 by beta2-adrenoceptor in endotoxin-stimulated renal macrophage cells.
Activation of the cAMP signaling pathway by means of beta2-adrenoceptor agonists has been shown to up-regulate interleukin-6 (IL-6) gene expression and to stimulate IL-6 production in macrophage cells. However, whether beta2-adrenoceptor activation can also modify the rate of IL-6 production in macrophage cells activated by the bacterial endotoxins has not yet been determined. Using renal resident macrophage cells treated with endotoxin, lipopolysaccharide (LPS), and beta2-adrenoceptor agonist, terbutaline, we investigated the role of cAMP pathway, tumor necrosis factor (TNF)-alpha and mitogen-activated protein kinase (MAPK) pathway (p42/p44) in regulating IL-6 production. IL-6 protein, mRNA, and promoter activity were measured in these cells exposed to LPS (1 microg/ml) and/or terbutaline (10(-9) to 10(-6) M). Furthermore, the time course effects of terbutaline on cAMP, MAPK (p42/p44), and TNF-alpha release were evaluated in the cells. Terbutaline at high concentrations (10(-6) M) significantly up-regulated IL-6 by approximately 25% (P<0.05), whereas at a lower concentration (10(-8) M), it down-regulated IL-6 production by 42% (P<0.05). Terbutaline (10(-8) and 10(-6) M) caused a concentration- and time-dependent stimulation of cAMP (P<0.05) and TNF production (P<0.05) and a time-dependent decrease in MAPK activity (P<0.05). Following the addition of a cAMP inhibitor, IL-6 promoter activity was correlated with TNF-alpha levels and MAPK activity. A biphasic effect of beta2-adrenoceptor agonist on IL-6 production in renal resident macrophage cells became apparent when LPS was exposed to the cells. The terbutaline-induced down-regulation of IL-6 gene production was mediated by an inhibitory effect of terbutaline on TNF-alpha, which was exerted through the MAPK and cAMP pathways, whereas the up-regulation appeared to be due to a direct action of intracellular cAMP.


Differential expression and localization of insulin-like growth factors I and II in cutaneous wounds of diabetic and nondiabetic mice.
Insulin-like growth factor (IGF)-I has profound effects on tissue repair. IGF-II is felt to exert its influence predominately during fetal development. The purpose of this study was to localize and quantify the expression of IGF-I and IGF-II mRNA and protein during early wound healing in diabetic and nondiabetic mice. The hypothesis is that IGF-I and IGF-II are up-regulated in the healing wound, but their expression is inhibited in diabetics. Full-thickness cutaneous wounds were made on genetically diabetic (C57BL/ KsJ-db/db) mice and their nondiabetic littermates. At various times after wounding, one-half of each wound was fixed and paraffin embedded for immunohistochemistry and in situ hybridization. The other half was flash-frozen for quantification of IGF mRNA by competitive reverse transcriptase polymerase chain reaction and protein by radioimmunoassay. IGF-I mRNA rose sharply in nondiabetics at day 3. Expression in diabetic wounds was significantly delayed until 14 days after wounding. Even then, diabetic IGF-I mRNA levels were 50% less than those in the nondiabetics at their peak. Although not usually considered active in adult life, IGF-II mRNA expression was augmented after wounding, peaking at 3 days in nondiabetics. As with IGF-I, diabetic wounds exhibited a delay in IGF-II mRNA expression, with maximal levels at 10 days after wounding. Interestingly, peak concentrations of IGF-II mRNA were four times greater in diabetics versus nondiabetics. Trends in IGF-I protein expression followed the patterns of mRNA expression. IGF-I levels in nondiabetics were initially double those in diabetics and peaked at 5 days. Diabetic wound concentrations of IGF-I did not peak until 21 days after wounding, at which time they rose to nondiabetic levels. IGF-I and IGF-II proteins were localized to the advancing epithelial edge, to the epithelial cells of adjacent hair follicles, and to the granulation tissue of the wounds. IGF-I and IGF-II mRNA expression was noted in the epithelial edge and in the hair follicles adjacent to the wound, paralleling protein expression. Both IGF-I and IGF-II are up-regulated in the healing wound. A delay in IGF-I and -II presence is noted in the diabetic wound. The impairment in tissue repair in diabetic animals is at least partially due to a deficiency in the production of the IGFs.


On the development of psychoneuroimmunology.
Psychoneuroimmunology, the study of interactions among behavioral, neural and endocrine, and immune processes, coalesced as an interdisciplinary field of study in the late 1970s. Some of the early research that was critical in establishing neuroanatomical, neurochemical and neuroendocrine pathways and functional relationships between the brain and the immune system is outlined here. These and subsequent studies have led to the general acknowledgment that the nervous and immune systems are components of an integrated system of adaptive processes, and that immunoregulatory processes can no longer be studied as the independent activity of an autonomous immune system. This paradigm shift in the study of immunoregulatory processes and the elaboration of the mechanisms underlying behaviorally induced alterations of immune function promise a better understanding and a new appreciation of the multi-determined etiology of pathophysiological states.


Validation of an improved reversed-phase high-performance liquid chromatography assay with reductive electrochemical detection for the determination of artemisinin derivatives in man.
For the determination of artemisinin (ART) and analogs, a reversed-phase high-performance liquid chromatography method using reductive electrochemical detection (ED) was set up with some important modifications as compared to previously published assays. A different technique of deoxygenating resulted in a factor 2-3 lower background current. A Spectroflow 400 liquid chromatograph in combination with a Triathlon autoinjector coupled to a Decade electrochemical detector was used. The detector was operated in the reductive mode as a closed system under chromatography grade helium to exclude any access of oxygen. The Decade has a glassy carbon electrode and a reference Ag/AgCl electrode. Infrequent electropolishing was required implicating a very stable system. By increasing acetonitril or lowering the pH of the mobile phase, the various derivatives could be determined in the same chromatogram. The assay was validated using artemether (ATM) and dihydroartemisinin (DHA) as test substances. In the concentration range seen in people after usual doses (5 to 220 ng/ml), the assay performs with adequate accuracy and precision. The interassay and intraassay precision are < 6% for ATM. For DHA, the interassay and intraassay precision are < 9%. The accuracy expressed as the deviation from the expected concentration varies from -1% to +4.5% for the intraassay ATM-determinations and from +1% to +6.3% for the interassay measurements. For DHA, the accuracy is somewhat less, varying from -0.3% to -9.5% for the intraassay measurements and -0.6% to +2.6% for the interassay measurements. The reproducibility of the assay, measured over a time period of 3 months, is good for ATM and DHA with an interassay precision of < 18% in 70 repetitive samples and an accuracy varying from -0.6% to +7.6%. In a cross-check with two other reference laboratories who used comparable methods of determination, a strong correlation (correlation coefficient > 0.98) was achieved. The method was applied in a study in which artemether was administered orally to healthy white subjects. We consider high-performance liquid chromatography with electrochemical detection an accurate and precise method for quantitative determination of artemisinin derivatives in pharmacokinetic studies.


Lactosylceramide recruits PKCalpha/epsilon and phospholipase A2 to stimulate PECAM-1 expression in human monocytes and adhesion to endothelial cells.
Despite the importance of platelet/endothelial cell adhesion molecule-1 (PECAM-1, CD31) in the adhesion and diapedesis of monocytes/lymphocytes, little is known about the mechanisms by which it is regulated. We explored the role of a glycosphingolipid, lactosylceramide (LacCer), in modulating PECAM-1 expression and cell adhesion in human monocytes. We observed that LacCer specifically exerted a time-dependent increase in PECAM-1 expression in U-937 cells. Maximal increase in PECAM-1 protein occurred after incubation with LacCer for 60 min. LacCer activated PKCalpha and -epsilon by translocating them from cytosol to membrane. This was accompanied by the activation of phospholipase A(2) (PLA(2)) and the increase of cell adhesion, which were abrogated by chelerythrine chloride, 2-[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl)-maleimide and 12-(2-cyanoethyl)-6,7,12,13-tetrahydro-13-methyl-5-oxo-5H-indolo(2,3-a)pyrrolo(3,4-c)-carbazole (GO 6976) (PKC inhibitors). Similarly, bromoenol lactone (a Ca(2+)-independent PLA(2) inhibitor) and methyl arachidonyl fluorophosphonate (an inhibitor of cytosolic PLA(2) and Ca(2+)-independent PLA(2)) inhibited LacCer-induced PLA(2) activity. Bromophenacyl bromide (a PLA(2) inhibitor) abrogated LacCer-induced PECAM-1 expression, and this was bypassed by arachidonic acid. Furthermore, the arachidonate-induced up-regulation of PECAM-1 was abrogated by indomethacin [a cyclooxygenase (COX)-1 and -2 inhibitor] or N-[2-(cyclohexyloxy)-4-nitrophenyl]-methanesulfonamide (a COX-2 inhibitor) but not nordihydroguaiaretic acid (a lipoxygenase inhibitor). In sum, PKCalpha/epsilon are the primary targets for the activation of LacCer. Downstream activation of intracellular Ca(2+)-independent PLA(2) and/or cytosolic PLA(2) results in the production of arachidonic acid, which in turn serves as a precursor for prostaglandins that subsequently stimulate PECAM-1 expression and cell adhesion. These findings may be relevant in explaining the role of LacCer in the regulation of PECAM-1 and related pathophysiology.