Propranolol for the Treatment of Lymphatic Malformations in a Neonate - A Case Report and Review of Literature.
Lymphatic malformations in neonates often manifest as a chylothorax, and although rare, morbidity and mortality can be significant. First-line treatment with medium-chain triglyceride-enriched formulas, or enteric rest with total parenteral nutrition, are not always successful. We describe the case of a premature neonate with trisomy 21 who presented with bilateral pleural effusions and a pericardial effusion that worsened with the initiation of enteral nutrition. Clinical improvement was not seen until the initiation of treatment with oral propranolol at a maximum dosage of 0.5 mg/kg/day divided every 8 hours with extubation 8 days after propranolol initiation. Two case reports have described the use of propranolol in similar patients receiving 2 mg/kg/day; however, our experience is the first to report treatment success at a much lower dose. A review of the literature for alternative medication treatments uncovered numerous case reports and series documenting variable results with incongruent definitions of treatment success in a diverse patient population. The rarity of this disease state makes accrual of patients difficult and more robust treatment data unlikely. Therefore, selection of the optimal adjunctive treatment must be based on individual patient and disease state characteristics as well as safety and efficacy profile of the medication.


Prevalence of dyslipidemia and the association with levels of TSH and T4 hormones among patients in south region of Jordan.
Glycolipid metabolism disorders (dysglycolipidemia) are characterized by elevated levels of glycolipid profile components and fasting blood glucose. Dysglycolipidemia are major threats to human health and life. Therefore, the aim of this cross-sectional study is to estimate the prevalence of dysglycolipidemia and the existence of association of TSH and T4 and glycolipid profiles. Cross-sectional data were obtained from the medical laboratory of Ma'an Governmental Hospital. A total of 141 patients' results were collected (18-60 years). Differences in the glycolipidemic profiles according to age and sex and TSH and T4 were compared. Different statistical analyses were used to analyze the prevalence of dysglycolipidemia and the correlation with the levels of TSH and T4. The study involved results of 141 patients (54.7% males and 45.3% females) in Ma'an Province (Jordan), who visited the internal medicine clinic at Ma'an Governmental Hospital. Patients have overweight and BMI of more than 25 kg/m2. The overall results of the prevalence of dyslipidemia indicated that patients have 42.5% of hypercholesterolemia, 48.2% of high LDL-C, 34.1% of hypertriglyceridemia, and 41.8% of low HDL-C. The prevalence of isolated lipid profiles showed that 10 patients have mixed dyslipidemia. The association of dyslipidemia with age indicated a positive significance between triglyceride and older people (≥40 years), while HDL levels have a significance with gender (p=0.025). The overall ANOVA model yielded non-statistical significant results between levels of any components of lipid profile and levels of TSH and T4 hormones. Welch test (p=0.036) showed positive significance between levels of fasting blood glucose and triglyceride levels. Our results showed and confirmed the presence of a high percentage of hyperlipidemia in Ma'an province and there was no relationship with levels of TSH and T4. A relationship exists between levels of triglycerides and blood glucose concentrations.


Acute exacerbation of interstitial lung disease after radical surgery for lung cancer: a case report.
A 69-year-old male patient underwent a left upper lobectomy for lung cancer, showing slight interstitial changes in the lung before surgery. He suffered fever with cough and expectoration postoperatively, and high-resolution computed tomography (HRCT) of the thorax indicated that the interstitial lesion in the lung was aggravated. The course of the disease progressed rapidly, and treatment that included anti-infection and steroid pulse therapy was ineffective. We conducted a retrospective analysis of the clinical data and the process of diagnosis and treatment of this patient with acute exacerbation of interstitial lung disease (AE-ILD) after radical surgery for lung cancer. Patients with ILD should be given very careful consideration when selecting a therapeutic approach because interventions may aggravate AE-ILD, leading to a poor prognosis.


Response of superoxide dismutase isoenzymes in tomato plants (Lycopersicon esculentum) during thermo-acclimation of the photosynthetic apparatus.
Seedlings of Lycopersicon esculentum Mill. var. Amalia were grown in a growth chamber under a photoperiod of 16 h light at 25 degrees C and 8 h dark at 20 degrees C. Five different treatments were applied to 30-day-old plants: Control treatment (plants maintained in the normal growth conditions throughout the experimental time), heat acclimation (plants exposed to 35 degrees C for 4 h in dark for 3 days), dark treatment (plants exposed to 25 degrees C for 4 h in dark for 3 days), heat acclimation plus heat shock (plants that previously received the heat acclimation treatment were exposed to 45 degrees C air temperature for 3 h in the light) and dark treatment plus heat shock (plants that previously received the dark treatment were exposed to 45 degrees C air temperature for 3 h in the light). Only the heat acclimation treatment increased the thermotolerance of the photosynthesis apparatus when the heat shock (45 degrees C) was imposed. In these plants, the CO(2) assimilation rate was not affected by heat shock and there was a slight and non-significant reduction in maximum carboxylation velocity of Rubisco (V(cmax)) and maximum electron transport rate contributing to Rubisco regeneration (J(max)). However, the plants exposed to dark treatment plus heat shock showed a significant reduction in the CO(2) assimilation rate and also in the values of V(cmax) and J(max). Chlorophyll fluorescence measurements showed increased thermotolerance in heat-acclimated plants. The values of maximum chlorophyll fluorescence (F(m)) were not modified by heat shock in these plants, while in the dark-treated plants that received the heat shock, the F(m) values were reduced, which provoked a significant reduction in the efficiency of photosystem II. A slight rise in the total superoxide dismutase (SOD) activity was found in the plants that had been subjected to both heat acclimation and heat shock, and this SOD activity was significantly higher than that found in the plants subjected to dark treatment plus heat shock. The activity of Fe-SOD isoenzymes was most enhanced in heat-acclimated plants but was unaltered in the plants that received the dark treatment. Total CuZn-SOD activity was reduced in all treatments. Darkness had an inhibitory effect on the Mn-SOD isoenzyme activity, which was compensated by the effect of a rise in air temperature to 35 degrees C. These results show that the heat tolerance of tomatoplants may be increased by the previous imposition of a moderately high temperature and could be related with the thermal stability in the photochemical reactions and a readjustment of V(cmax) and J(max). Some isoenzymes, such as the Fe-SODs, may also play a role in the development of heat-shock tolerance through heat acclimation. In fact, the pattern found for these isoenzymes in heat-acclimated Amalia plants was similar to that previously described in other heat-tolerant tomato genotypes.


Investigation of Tactile Sensory System Configuration for Construction Hazard Perception.
The application of tactile-based wearable devices to assist in navigation for people with low sight/low memory has demonstrated the feasibility of using such devices as a means of communication. Accordingly, a previous study in construction research investigated various parameters of tactile signals to develop a communicable system for potential application in construction hazard communication. However, the nature of construction limits the application of such devices to the body of construction workers, and it is important to understand sensor design parameters for improved communication, which has not been given significant attention yet. Therefore, this study aims to determine key design factors such as the number of motors, spacing between sensors and the layout of a tactile sensory system to be used for communicating construction hazards to workers. For this purpose, this study focused on identifying the number of motors based on extensive literature and the problem of construction safety as to hazard communication, determining the arrangement that allowed for effective delivery and perception of information with minimum effort. The researchers conducted two experimental studies: First, to determine the minimum spacing between vibration motors that allows for the identification of each individual motor with high accuracy; and second, to determine the layout of motors that is suitable for effective communication of multiple types of information. More importantly, the tactile-sensor configuration identified from this study allows the workers to learn the signal patterns easily in order to identify multiple types of information related to hazards. Using such a communication system on construction sites will assist in transmitting hazard-related information to workers, and thus, protect the lives of workers. Such wearable technologies enable the detection of individual-level hazards and prevent worker fatalities and severe injuries.


Prediction of response to pegylated interferon plus ribavirin by IL28B gene variation in patients coinfected with HIV and hepatitis C virus.
Variation in the IL28B gene is associated with sustained virologic response (SVR) to pegylated interferon plus ribavirin in hepatitis C virus (HCV)-monoinfected patients with genotype 1. Data on other genotypes and on patients coinfected with human immunodeficiency virus (HIV) and HCV are more limited. We aimed to assess the predictive ability of variations in the single-nucleotide polymorphism rs12979860 for SVR in HIV/HCV-coinfected patients, regardless of HCV genotype. The rs12979860 genotype was determined by polymerase chain reaction in 154 patients who had received therapy against HCV with pegylated interferon plus ribavirin. rs12979860 genotype was TT in 20 patients (13%), TC in 66 patients (43%), and CC in 68 patients (44%). Rates of SVR in patients with genotype CC and in those with genotype TC or TT, according to HCV genotype, were, respectively, 50% and 17% (P < .001) in patients with genotype 1, 80% and 25% (P = .027) in patients with genotype 4, and 93% and 77% (P = .115) in patients with genotype 3. The median (interquartile range) low-density lipoprotein cholesterol level in patients with rs12979860 CC was 89 mg/dL (73-120 mg/dL) versus 75 mg/dL (55-91 mg/dL) (P = .001) in those with TC or TT. Independent predictors of SVR were HCV genotype 2-3 (odds ratio [OR], 13.98; 95% confidence interval [CI], 4.87-40.1; P < .001), rs12979860 CC (OR, 5.05; 95% CI, 2.04-12.5; P < .001), baseline plasma HCV RNA load of < or =600,000 IU/mL (OR, 1.99; 95% CI, 1.18- 3.34; P = .009), and female sex (OR, 4.28; 95% CI, 1.08-16.96; P = .039). IL28B gene variations independently predict SVR in HIV/HCV-coinfected patients with HCV genotype 1 and non-genotype 1 HCV infection. The association between rs12979860 and plasma low-density lipoprotein cholesterol suggests that the system low-density lipoprotein ligand/receptor might be involved in the effect of this genotype.


Characterization of human cytochrome P450s involved in the bioactivation of tri-ortho-cresyl phosphate (ToCP).
Tri-ortho-cresyl phosphate (ToCP) is a multipurpose organophosphorus compound that is neurotoxic and suspected to be involved in aerotoxic syndrome in humans. It has been reported that not ToCP itself but a metabolite of ToCP, namely, 2-(ortho-cresyl)-4H-1,2,3-benzodioxaphosphoran-2-one (CBDP), may be responsible for this effect as it can irreversibly bind to human butyrylcholinesterase (BuChE) and human acetylcholinesterase (AChE). The bioactivation of ToCP into CBDP involves Cytochrome P450s (P450s). However, the individual human P450s responsible for this bioactivation have not been identified yet. In the present study, we aimed to investigate the metabolism of ToCP by different P450s and to determine the inhibitory effect of the in vitro generated ToCP-metabolites on human BuChE and AChE. Human liver microsomes, rat liver microsomes, and recombinant human P450s were used for that purpose. The recombinant P450s 2B6, 2C18, 2D6, 3A4 and 3A5 showed highest activity of ToCP-bioactivation to BuChE-inhibitory metabolites. Inhibition experiments using pooled human liver microsomes indicated that P450 3A4 and 3A5 were mainly involved in human hepatic bioactivation of ToCP. In addition, these experiments indicated a minor role for P450 1A2. Formation of CBDP by in-house expressed recombinant human P450s 1A2 and 3A4 was proven by both LC-MS and GC-MS analysis. When ToCP was incubated with P450 1A2 and 3A4 in the presence of human BuChE, CBDP-BuChE-adducts were detected by LC-MS/MS which were not present in the corresponding control incubations. These results confirmed the role of human P450s 1A2 and 3A4 in ToCP metabolism and demonstrated that CBDP is the metabolite responsible for the BuChE inactivation. Interindividual differences at the level of P450 1A2 and 3A4 might play an important role in the susceptibility of humans in developing neurotoxic effects, such as aerotoxic syndrome, after exposure to ToCP.


Lateral diffusion and retrograde movements of individual cell surface components on single motile cells observed with Nanovid microscopy.
A recently introduced extension of video-enhanced light microscopy, called Nanovid microscopy, documents the dynamic reorganization of individual cell surface components on living cells. 40-microns colloidal gold probes coupled to different types of poly-L-lysine label negative cell surface components of PTK2 cells. Evidence is provided that they bind to negative sialic acid residues of glycoproteins, probably through nonspecific electrostatic interactions. The gold probes, coupled to short poly-L-lysine molecules (4 kD) displayed Brownian motion, with a diffusion coefficient in the range 0.1-0.2 micron2/s. A diffusion coefficient in the 0.1 micron2/s range was also observed with 40-nm gold probes coupled to an antibody against the lipid-linked Thy-1 antigen on 3T3 fibroblasts. Diffusion of these probes is largely confined to apparent microdomains of 1-2 microns in size. On the other hand, the gold probes, coupled to long poly-L-lysine molecules (240 kD) molecules and bound to the leading lamella, were driven rearward, toward the boundary between lamelloplasm and perinuclear cytoplasm at a velocity of 0.5-1 micron/min by a directed ATP-dependent mechanism. This uniform motion was inhibited by cytochalasin, suggesting actin microfilament involvement. A similar behavior on MO cells was observed when the antibody-labeled gold served as a marker for the PGP-1 (GP-80) antigen. These results show that Nanovid microscopy, offering the possibility to observe the motion of individual specific cell surface components, provides a new and powerful tool to study the dynamic reorganization of the cell membrane during locomotion and in other biological contexts as well.


Online Sales of Unscheduled Pharmaceutical Agents: A Case Report of Tianeptine Use in the United States.
: Tianeptine is a tricyclic antidepressant that stimulates mu-opioid receptors at high doses. It is marketed and used across Europe and Latin America as an antidepressant, but is not approved by the Food and Drug Administration for use in the United States. In the United States, tianeptine is sold through online health stores as a cognition enhancer, dietary supplement, or as research chemical. We report the case of a 36-year-old man with a history of major depressive disorder, responsive to sertraline, who turned to the unmonitored use of tianeptine purchased online to treat residual feelings of apathy and boredom. His use of tianeptine was marked by rapidly escalating doses and a significant withdrawal syndrome that made discontinuation of this substance difficult. This case serves as a reminder that unscheduled pharmaceutical agents are available for misuse by the general population and have the potential to cause significant harm. Therefore, medical providers must be aware of and screen for the use of such products amongst their patients.


Coxsackievirus B4 as a Causative Agent of Diabetes Mellitus Type 1: Is There a Role of Inefficiently Treated Drinking Water and Sewage in Virus Spreading?
This study proposed to detect the enterovirus (EV) infection in children with type 1 diabetes mellitus (T1D) and to assess the role of insufficiently treated water and sewage as sources of viral spreading. Three hundred and eighty-two serum specimens of children with T1D, one hundred serum specimens of children who did not suffer from T1D as control, and forty-eight water and sewage samples were screened for EV RNA using nested RT-PCR. The number of genome copies and infectious units of EVs in raw and treated sewage and water samples were investigated using real-time (RT)-PCR and plaque assay, respectively. T1D markers [Fasting blood glucose (FBG), HbA1c, and C-peptide], in addition to anti-Coxsackie A & B viruses (CVs A & B) IgG, were measured in control, T1D-negative EV (T1D-EV-), and T1D-positive EV (T1D-EV+) children specimens. The prevalence of EV genome was significantly higher in diabetic children (26.2%, 100 out of 382) than the control children (0%, 0 out of 100). FBG and HbA1c in T1D-EV- and T1D-EV+ children specimens were significantly higher than those in the control group, while c-peptide in T1D-EV- and T1D-EV+ children specimens was significantly lower than that in the control (n = 100; p < 0.001). Positivity of anti-CVs A & B IgG was 70.7, 6.7, and 22.9% in T1D-EV+, T1D-EV-, and control children specimens, respectively. The prevalence of EV genome in drinking water and treated sewage samples was 25 and 33.3%, respectively. The prevalence of EV infectious units in drinking water and treated sewage samples was 8.5 and 25%, respectively. Quantification assays were performed to assess the capabilities of both wastewater treatment plants (WWTPs) and water treatment plants (WTPs) to remove EV. The reduction of EV genome in Zenin WWTP ranged from 2 to 4 log10, while the reduction of EV infectious units ranged from 1 to 4 log10. The reduction of EV genome in El-Giza WTP ranged from 1 to 3 log10, while the reduction of EV infectious units ranged from 1 to 2 log10. This capability of reduction did not prevent the appearance of infectious EV in treated sewage and drinking water. Plaque purification was performed for isolation of separate EV isolates from treated and untreated water and sewage samples. Characterization of the EV amplicons by RT-PCR followed by sequencing of these isolates revealed high homology (97%) with human coxsackievirus B4 (CV B4) in 60% of the isolates, while the rest of the isolates belonged to poliovirus type 1 and type 2 vaccine strains. On the other hand, characterization of the EV amplicons by RT-PCR followed by sequencing for T1D-EV+ children specimens indicated that all samples contained CV B4 with the same sequence characterized in the environmental samples. CV B4-contaminated drinking water or treated sewage may play a role as a causative agent of T1D in children.


Studies on coumarins and coumarin-related compounds to determine their therapeutic role in the treatment of cancer.
The Benzopyrones are a group of compounds whose members include coumarins and flavonoids. Dietary exposure to benzopyrones is quite significant, as these compounds are found in vegetables, fruit, seeds, nuts, coffee, tea and wine. It is estimated that the average western diet contains approximately 1 g/day of mixed benzopyrones. It is, therefore, not difficult to see why extensive research into their pharmacological and therapeutic properties is underway over many years. Coumarin is a natural substance that has shown anti-tumour activity in vivo, with the effect believed to be due to its metabolites (e.g. 7-hydroxycoumarin). This review is based on recent studies of coumarins and coumarin related compounds. Therefore, the focus will be on these relevant compounds and their therapeutic importance. A recent study has shown that 7-hydroxycoumarin inhibits the release of Cyclin D1, which is overexpressed in many types of cancer. This knowledge may lead to its use in cancer therapy. Esculetin inhibits growth and cell cycle progression by inducing arrest of the G(1) phase in HL-60 leukaemia cells, resulting from the inhibition of retinoblastoma protein phosphorylation. Recent studies investigating the potential of flavonoids as therapeutic agents have suggested they may have use in various therapeutic settings ranging from leukaemia treatment to the treatment of patients with HIV. Genistein is a well-known isoflavone and is a tyrosine kinase inhibitor. Studies have indicated that genistein elicits inhibitory effects on cell growth of various carcinoma cell-lines and may be a potential candidate for cancer therapy. In our research, we have investigated the effects of coumarins and coumarin-related compounds on a panel of cell-lines. The most recent work involves two cell-lines, MCF-7 a breast carcinoma and A549 a lung carcinoma. Microtitre assays were performed along with real-time analysis of cell viability using a biosensor called the Cytosensor microphysiometer. These studies suggest that both genistein and esculetin exerted the most potent inhibitory effect on cell growth in comparison to the other two compounds.


Calibrating models in economic evaluation: a comparison of alternative measures of goodness of fit, parameter search strategies and convergence criteria.
The importance of assessing the accuracy of health economic decision models is widely recognized. Many applied decision models (implicitly) assume that the process of identifying relevant values for a model's input parameters is sufficient to prove the model's accuracy. The selection of infeasible combinations of input parameter values is most likely in the context of probabilistic sensitivity analysis (PSA), where parameter values are drawn from independently specified probability distributions for each model parameter. Model calibration involves the identification of input parameter values that produce model output parameters that best predict observed data. An empirical comparison of three key calibration issues is presented: the applied measure of goodness of fit (GOF); the search strategy for selecting sets of input parameter values; and the convergence criteria for determining acceptable GOF. The comparisons are presented in the context of probabilistic calibration, a widely applicable approach to calibration that can be easily integrated with PSA. The appendix provides a user's guide to probabilistic calibration, with the reader invited to download the Microsoft® Excel-based model reported in this article. The calibrated models consistently provided higher mean estimates of the models' output parameter, illustrating the potential gain in accuracy derived from calibrating decision models. Model uncertainty was also reduced. The chi-squared GOF measure differentiated between the accuracy of different parameter sets to a far greater degree than the likelihood GOF measure. The guided search strategy produced higher mean estimates of the models' output parameter, as well as a narrower range of predicted output values, which may reflect greater precision in the identification of candidate parameter sets or more limited coverage of the parameter space. The broader convergence threshold resulted in lower mean estimates of the models' output, and slightly wider ranges, which were closer to the outputs associated with the non-calibrated approach. Probabilistic calibration provides a broadly applicable method that will improve the relevance of health economic decision models, and simultaneously reduce model uncertainty. The analyses reported in this paper inform the more efficient and accurate application of calibration methods for health economic decision models.


Signals of selection in conditionally expressed genes in the diversification of three horned beetle species.
Species radiations may be facilitated by phenotypic differences already present within populations, such as those arising through sex-specific development or developmental processes biased towards particular reproductive or trophic morphs. We sought to test this hypothesis by utilizing a comparative transcriptomic approach to contrast among- and within-species differentiation using three horned beetle species in the genus Onthophagus. These three species exhibit differences along three phenotypic axes reflective of much of the interspecific diversity present within the genus: horn location, polarity of sexual dimorphism and degree of nutritional sensitivity. Our approach combined de novo transcript assembly, assessment of amino acid substitutions (dN/dS) across orthologous gene pairs and integration of gene function and conditional gene expression data. We identified 17 genes across the three species pairs related to axis patterning, development and metabolism with dN/dS > 1 and detected elevated dN/dS in genes related to metabolism and biosynthesis in the most closely related species pair, which is characterized by a loss of nutritional polyphenism and a reversal of sexual dimorphism. Further, we found that genes that are conditionally expressed (i.e. as a function of sex, nutrition or body region) within one of our focal species also showed significantly stronger signals of positive or relaxed purifying selection between species divergent along the same morphological axis (i.e. polarity of sexual dimorphism, degree of nutritional sensitivity or location of horns). Our findings thus reveal a positive relationship between intraspecific differentiation due to condition-specific development and genetic divergences among species.


Xanthohumol attenuates collagen synthesis in scleroderma skin fibroblasts by ROS/Nrf2/TGFβ1/Smad3 pathway.
Skin fibrosis, the most obvious clinical manifestation of systemic sclerosis (SSc), has a high unmet need for treatment. Xanthohumol (Xn) has been shown to have beneficial effects on fibrotic diseases, but its efficacy in SSc remains unreported. This study aims to elucidate the effects and mechanisms of Xn on collagen synthesis in SSc skin fibroblasts (SScF). We found increased collagen production in SScF cultured in vitro, accompanied by dysregulated levels of oxidative stress. Cell experiments showed that Xn inhibited cell proliferation and promoted apoptosis. In addition, Xn was shown for the first time to upregulate reactive oxygen species (ROS) and nuclear factor erythroid 2-related factor 2 (Nrf2)levels in SScF, and when combined with the ROS scavenger N-acetylcysteine (NAC), Nrf2 expression was decreased. Importantly, we demonstrated that Xn significantly attenuated collagen synthesis by blocking the fibrotic classical transforming growth factor beta 1 (TGFβ1)/Smad3 pathway, which interestingly was upregulated when combined with the Nrf2 inhibitor 385. Taken together, Xn suppressed the TGFβ1/Smad3 pathway to ameliorate collagen overproduction by promoting ROS-induced oxidative stress damage and activating Nrf2, suggesting that Xn administration may be an emerging therapeutic strategy for skin fibrosis in SSc.


Laparoscopic prophylactic total gastrectomy with limited lymphadenectomy for CDH1 gene carriers.
CDH1 gene mutations are the leading etiology of hereditary diffuse gastric cancer with cumulative lifetime risk ranging up to 83%. Prophylactic total gastrectomy (PTG) is, therefore, recommended for CDH1 carriers. A laparoscopic approach may reduce operative risk versus an open operation, thus leading more patients with CDH1 mutations to pursue PTG prior to cancer development. However, more experience and oncologic outcome data are needed for a laparoscopic approach and indicated lymphadenectomy. A retrospective descriptive cohort study of adult patients with CDH1 mutations who underwent laparoscopic PTG with D1 lymphadenectomy between 2012 and 2022 was conducted at a single institution. All patients had preoperative EGD screening, and those with visible tumor lesions on surveillance EGD were excluded and not considered prophylactic. Demographics, family history, pathology, and operative course were obtained. Outcomes included complications, readmission, and postoperative weight change. Among 23 patients, median age was 48 years (IQR 37, 53) and 15 (65%) were female. Family history for gastric and/or lobular breast cancer was present in 22 (96%) patients. The median [IQR] time from positive genetic testing to PTG was 347 days [140, 625]. Pathologic evaluation showed five (22%) patients with foci of gastric cancer on pre-operative EGD biopsies, 10 (44%) in resected stomach specimens. All lymph nodes were negative. To address early postoperative complications, EJ anastomotic technique changed from EEA to GIA over the course of the study and feeding jejunostomy was no longer placed during PTG with minimal change in postoperative weight loss. This is the largest series, spanning 10 years at a single institution, dedicated solely to a laparoscopic approach for risk-reducing PTG. A laparoscopic approach with limited lymphadenectomy resulted in acceptable surgical and oncologic outcomes. Despite no visible cancer, over half of our patients had foci of early gastric cancer. Therefore, CDH1 carriers should consider laparoscopic PTG.


Sporadic versus Radiation-Associated Angiosarcoma: A Comparative Clinicopathologic and Molecular Analysis of 48 Cases.
Angiosarcomas are aggressive tumors of vascular endothelial origin, occurring sporadically or in association with prior radiotherapy. We compared clinicopathologic and biologic features of sporadic angiosarcomas (SA) and radiation-associated angiosarcomas (RAA). Methods. From a University of Michigan institutional database, 37 SA and 11 RAA were identified. Tissue microarrays were stained for p53, Ki-67, and hTERT. DNA was evaluated for TP53 and ATM mutations. Results. Mean latency between radiotherapy and diagnosis of RAA was 11.9 years: 6.7 years for breast RAA versus 20.9 years for nonbreast RAA (P = 0.148). Survival after diagnosis did not significantly differ between SA and RAA (P = 0.590). Patients with nonbreast RAA had shorter overall survival than patients with breast RAA (P = 0.03). The majority of SA (86.5%) and RAA (77.8%) were classified as high-grade sarcomas (P = 0.609). RAA were more likely to have well-defined vasoformative areas (55.6% versus 27%, P = 0.127). Most breast SA were parenchymal in origin (80%), while most breast RAA were cutaneous in origin (80%). TMA analysis showed p53 overexpression in 25.7% of SA and 0% RAA, high Ki-67 in 35.3% of SA and 44.4% RAA, and hTERT expression in 100% of SA and RAA. TP53 mutations were detected in 13.5% of SA and 11.1% RAA. ATM mutations were not detected in either SA or RAA. Conclusions. SA and RAA are similar in histology, immunohistochemical markers, and DNA mutation profiles and share similar prognosis. Breast RAA have a shorter latency period compared to nonbreast RAA and a significantly longer survival.


Repeated exposure to Lutzomyia intermedia sand fly saliva induces local expression of interferon-inducible genes both at the site of injection in mice and in human blood.
During a blood meal, Lutzomyia intermedia sand flies transmit Leishmania braziliensis, a parasite causing tegumentary leishmaniasis. In experimental leishmaniasis, pre-exposure to saliva of most blood-feeding sand flies results in parasite establishment in absence of any skin damages in mice challenged with dermotropic Leishmania species together with saliva. In contrast, pre-immunization with Lu. intermedia salivary gland sonicate (SGS) results in enhanced skin inflammatory exacerbation upon co-inoculation of Lu. intermedia SGS and L. braziliensis. These data highlight potential unique features of both L. braziliensis and Lu. intermedia. In this study, we investigated the genes modulated by Lu. intermedia SGS immunization to understand their potential impact on the subsequent cutaneous immune response following inoculation of both SGS and L. braziliensis. The cellular recruitment and global gene expression profile was analyzed in mice repeatedly inoculated or not with Lu. intermedia. Microarray gene analysis revealed the upregulation of a distinct set of IFN-inducible genes, an immune signature not seen to the same extent in control animals. Of note this INF-inducible gene set was not induced in SGS pre-immunized mice subsequently co-inoculated with SGS and L. braziliensis. These data suggest the parasite prevented the upregulation of this Lu. intermedia saliva-related immune signature. The presence of these IFN-inducible genes was further analyzed in peripheral blood mononuclear cells (PBMCs) sampled from uninfected human individuals living in a L. braziliensis-endemic region of Brazil thus regularly exposed to Lu. intermedia bites. PBMCs were cultured in presence or absence of Lu. intermedia SGS. Using qRT-PCR we established that the IFN-inducible genes induced in the skin of SGS pre-immunized mice, were also upregulated by SGS in PBMCs from human individuals regularly exposed to Lu. intermedia bites, but not in PBMCs of control subjects. These data demonstrate that repeated exposure to Lu. intermedia SGS induces the expression of potentially host-protective IFN-inducible genes.


Some mutant phages produced directly by Bacillus megatherium 899a with their rate of occurrence.
The rate at which cultures of B. megatherium 899a produce certain mutants of its phage T (wild type) has been investigated in two media; one (peptone) in which reinfection of sensitive cells, if present, is virtually certain, and one (asparagine) in which reinfection is extremely unlikely. Little difference either in the number or types of mutants produced has been detected. It is concluded that phage mutants are produced directly by B. megatherium 899a and that no intermediate passage through a sensitive cell is necessary for the mutation. 396 individual mutant plaques have been isolated and classified into at least 18 types of plaque-forming mutants of B. megatherium 899a. The over-all mutant ratio found was in the order of 1:2000 while individual mutants appeared with rates between 1:7000 and less than 1:100,000.


Enhanced Energy Storage Performance of Sodium Niobate-Based Relaxor Dielectrics by a Ramp-to-Spike Sintering Profile.
Sodium niobate (NaNbO3)-based lead-free ceramics have been actively studied for energy storage applications because of their antiferroelectric and/or relaxor features achieved in modified systems. The P-E loops of NaNbO3-based ceramics are usually hysteretic because of the existence of a metastable ferroelectric phase at room temperature. In this study, by introducing aliovalent cations and A-site vacancies, the relaxor characteristics are greatly enhanced in (Na1-2xBix)(Nb1-xZrx)O3 ceramics, leading to a high energy storage efficiency of above 90%. In addition, sintering aid CuO and a special ramp-to-spike sintering profile were employed to decrease the sintering temperature and reduce the grain size. The modified ceramic exhibits improved insulating properties and hence a higher breakdown strength, leading to a high recoverable energy density of 4.9 J/cm3 and a high energy efficiency of 88% at 430 kV/cm. The ceramic also exhibits satisfactory temperature stability over a wide temperature range from 25 to 125 °C and charge-discharge performance, making it a promising candidate for high-power dielectric energy storage applications.


[Role of kidney prostaglandins, kinins and dopamine receptors in the natriuretic effect of ethacrynic acid].
It was found in experiments on anesthetized rats that ethacrynic acid (3 mg/kg intravenously) exerted no effect on the blood flow in the internal zone of the cortical layer but significantly increased the blood supply to the median zone of this region of the kidneys. A pronounced natriuretic reaction produced by inhibition of this ion develops. An inhibitor of cyclooxygenase indomethacin (3 mg/kg orally, 5 days) completely eliminated an increase of the blood flow in the cortical median zone but failed to prevent an increase of diuresis and urinary excretion of sodium in response to the diuretic administration. An inhibitor of kallikrein contrykal (5000 U/kg subcutaneously) produced no effect on diuretic and natriuretic effects of the drug but prevented the hemodynamic shift in the renal cortex. A blocker of dopaminergic receptors haloperidol (3 mg/kg subcutaneously) caused no changes in the rat kidney response to ethacrynic acid. Prostaglandins and kinins formed in the kidneys under the influence of the diuretic are thought to be involved in the mechanism of dilatation of vessels of the cortical layer median zone but play no significant role in the formation of its natriuretic effect.


The origins of the Irish travellers and the genetic structure of Ireland.
Ireland's unique and well-documented history provides insight into the formation and origins of population subdivisions. Of particular interest, is the controversial ethnogenesis of an itinerant population of Ireland: the Travellers. The objectives of this study were: (1) to determine the genetic affinity of the Travellers to the general Irish population based on gene frequency data, subdivided by county, and (2) to explore the relationship between subpopulations of Ireland, given its turbulent history. The gene frequencies of standard genetic markers collected from populations residing in counties of Ireland and the Travellers were calculated and analysed using several multivariate methods. First, a relationship (R) matrix was used to ascertain the scaled variance covariance matrix of population similarity. Second, mean per locus heterozygosity (H) was regressed on distance of the region from the gene frequency centroid (r(ii)). The results of this study include: (1) the confirmation of Crawford's (1975, in Biosocial Interrelations in Population Adaptations, E. S. Watts et al. (eds), pp. 93-103) conclusions concerning the origins and genetic affinity of the Travellers; (2) based on several multivariate analyses, the major influence on population structure was unique historical events; and (3) Relethford and Crawford's (1995, American Journal of Physical Anthropology, 96, 25-38) hypothesis concerning the distinctiveness of the midland counties was verified by this study.


Protein hydration dynamics in solution: a critical survey.
The properties of water in biological systems have been studied for well over a century by a wide range of physical techniques, but progress has been slow and erratic. Protein hydration--the perturbation of water structure and dynamics by the protein surface--has been a particularly rich source of controversy and confusion. Our aim here is to critically examine central concepts in the description of protein hydration, and to assess the experimental basis for the current view of protein hydration, with the focus on dynamic aspects. Recent oxygen-17 magnetic relaxation dispersion (MRD) experiments have shown that the vast majority of water molecules in the protein hydration layer suffer a mere twofold dynamic retardation compared with bulk water. The high mobility of hydration water ensures that all thermally activated processes at the protein-water interface, such as binding, recognition and catalysis, can proceed at high rates. The MRD-derived picture of a highly mobile hydration layer is consistent with recent molecular dynamics simulations, but is incompatible with results deduced from intermolecular nuclear Overhauser effect spectroscopy, dielectric relaxation and fluorescence spectroscopy. It is also inconsistent with the common view of hydration effects on protein hydrodynamics. Here, we show how these discrepancies can be resolved.


Intravenous regional ketorolac and lidocaine in the treatment of complex regional pain syndrome of the lower extremity: a randomized, double-blinded, crossover study.
Intravenous regional blocks (IVRBs) with ketorolac and lidocaine have been reported to be useful in the treatment of complex regional pain syndrome (CRPS). This is the first controlled prospective study of IVRB with lidocaine and ketorolac for treatment of pain and edema in CRPS of the lower extremity in adults. A prospective, randomized, double-blinded, crossover design was used. The primary outcome was overall pain numeric rating scale (NRS) at 1 week postinjection; secondary outcomes included pain with motion, allodynia, joint pain score, edema, range of ankle motion, skin temperature, and short-term pain relief. Ten of 12 adult patients diagnosed with unilateral lower extremity CRPS (type I) completed the study. Four IVRBs were performed 1 week apart in a random sequence with 50 mL lidocaine 0.5% and 0, 30, 60, and 120 mg ketorolac. Only 1 outcome achieved significant improvement; there was 1 day of significant pain reduction in the ketorolac groups (median NRS 6 to 4, P=0.002). Overall pain NRS (10-point scale, mean±SE) at 1 week was 6.2±0.53, 6.5±0.89, 6.0±0.88, 5.9±0.82, and 5.8±0.9 at baseline, 0, 30, 60, and 120 mg, respectively (P=0.8). Pain with movement was 7.15±0.69, 5.7±1.07, 6.1±0.86, 5.0±0.97, and 5.6±0.86, (P=0.059). Edema was not significantly reduced (2% reduction, P=0.6). IVRB with ketorolac and lidocaine produced only short-term pain reduction in patients with CRPS involving the lower extremity after 4 serial injections in our study group. Prospective study is warranted, particularly in the pediatric population.


[Further development of the International Pneumoconiosis Classification--from ILO 1980 to ILO 2000 and to ILO 2000/German Federal Republic version].
The ILO (1980) Classification has been revised during recent years. The new version is now available as the International Classification of Radiographs of Pneumoconioses (Revised edition 2000). The Guidelines booklet is currently available only in English. Those involved felt it was important to maintain continuity with the ILO (1980) edition, in particular to retain the standard radiographs, despite their restricted quality, so as to ensure comparability with earlier national and international data sets. The standard films illustrating pleural abnormalities, and 'u'-shadows, have been modified and reconstituted. The most important changes relate to assessment of film quality, pleural abnormalities, and additional symbols. In Germany, film quality is characterised as "+", "+-", "+--" and "u" according to whether the ability to assess pneumoconiosis is judged to be unimpeachable ("+") to unusable ("u"). If a film is not classified as "+", then written comments regarding defects are required. For "diffuse" pleural thickening, the ILO (2000) edition now requires the presence also of obliteration of the costophrenic angle. This was not required in the earlier (1980) edition and, as previously, is also not stipulated in the German version. A minimum width of 3 mm (previously 0-5 mm), coded "a", is required both for plaques as well as for the margin to the lateral chest wall. Congruence is thus achieved for criteria, which, in German practice, lead to an indication of suspect occupational disease. Plaques on the diaphragm are not considered for measurement of extent; they are only coded as present or absent. If calcification is identified, then this must also be classified and measured as a localised plaque. Extent of calcification on its own, previously coded "0" to "3", is no longer specified. The following new symbols, illustrated by new diagrams, have been introduced: aa = atherosclerotic aorta; at = apical thickening; cg = calcified granuloma (or other non-pneumocononiotic nodules); me = mesothelioma (already previously differentiated from "ca" on the German record sheet); pa = plate atelectasis; pb= parenchymal bands; ra = rounded atelectasis; od = other disease. (Examples of the latter are illustrated diagrammatically by lobar pneumonia, aspergilloma, goiter and hiatal hernia.) Earlier national differences (ILO 1980/German Federal Republic) on particular issues have also been agreed among German "double-readers" ["Zweitbeurteiler"]. However, conformity between the original (ILO 2000) text and the national (German) modified text has been retained in large measure. The detailed descriptions of the standard films differ in certain respects from the German (1980) definitions. Some revision of individual descriptions of the films are proposed. Except for a few differences, agreement was reached here too. The definitive date for the change in Germany is expected to be in early 2004. The standard films are already available now through ILO offices in Geneva or Bonn (addresses in appendix.)


Estrogen replacement therapy induces functional asymmetry on an odor memory/discrimination test.
The secondary afferents of the olfactory system largely project to the ipsilateral cortex without synapsing in the thalamus, making unilateral olfactory testing a useful probe of ipsilateral hemispheric activity. In light of evidence that lateralized performance on some perceptual tasks may be influenced by estrogen, we assessed left:right nostril differences in two measures of olfactory function in 14 post-menopausal women receiving estrogen replacement therapy (ERT) and 48 post-menopausal women receiving no such therapy. Relative to women not taking ERT, those receiving ERT exhibited better performance in the left nostril and poorer performance in the right nostril on an odor memory/discrimination test. Similar laterality effects were not observed for an odor detection threshold test employing phenyl ethyl alcohol. These results suggest that estrogen influences the lateralization of an odor memory/discrimination task and that hormone replacement therapy in the menopause may be an excellent paradigm for understanding lateralizing effects of hormones on some sensory processes.


A study on the precursors of the acetyl moiety of acetylcholine in brain slices. Observations on the compartmentalization of the acetyl-coenzyme A pool.
1. A method was devised for the determination of the specific radioactivity of the acetyl moiety of acetylcholine synthesized from various (14)C-labelled substrates. 2. The precursor for the acetyl moiety of acetylcholine was studied in slices of striatum and cerebral cortex from rat and guinea-pig brain. Incorporation of radioactivity into acetylcholine was determined after incubating the slices in the presence of [2-(14)C]acetate, [(14)C]bicarbonate, [1,5-(14)C]citrate, dl-[1- or 5-(14)C]glutamate or [1- or 2-(14)C]pyruvate. 3. After incubation for 1h, acetylcholine was accumulated significantly in both striatum slices (4.1nmol/mg of protein) and cerebral-cortex slices (0.57nmol/mg of protein) from the rat. Final concentrations were about 11 and 5 times respectively the initial values. 4. With slices from rat striatum, rat cerebral cortex and guinea-pig cerebral cortex, the specific radioactivity of acetylcholine derived from [2-(14)C]pyruvate was very high, reaching approx. 30, 20 and 6% respectively of the initial specific radioactivity of added pyruvate in the medium. With the striatum slices this high value was reached after incubation for 15min. Incorporation of radioactivity from [2-(14)C]acetate was only 1.25, 5.3 and 19.7% of that from [2-(14)C]pyruvate in rat striatum, rat cerebral-cortex and guinea-pig cerebral-cortex slices respectively. A small but definite incorporation was found from [5-(14)C]glutamate. No incorporation was found from the other substrates. The findings suggest that pyruvate is the most important precursor for the synthesis of the acetyl moiety of acetylcholine in brain slices. 5. The specific radioactivity of acetylcholine relative to that of citrate when [2-(14)C]pyruvate was used compared with that obtained when [2-(14)C]acetate was used. A marked difference was found in all slices, suggesting metabolic compartmentation of the acetyl-CoA pool.


On the roles of form systematicity and sensorimotor effects in language processing.
Grounded or embodied cognition research has employed body-object interaction (BOI; e.g., Pexman et al., 2019) ratings to investigate sensorimotor effects during language processing. We investigated relationships between BOI ratings and nonarbitrary statistical mappings between words' phonological forms and their syntactic category in English; i.e., form systematicity. In Study 1, principal components analysis revealed that BOI and form systematicity measures load on a common component, indicating they convey similar information about the probability of a word belonging to a particular syntactic category. In Studies 2, 3, and 4, form systematicity measures were stronger predictors of English Lexicon Project (ELP; Balota et al., 2007), Auditory English Lexicon Project (AELP; Goh et al., 2020), and English Crowdsourcing Project (ECP; Mandera et al., 2020) performance than BOI. In Study 5, BOI was a stronger predictor of performance from the Calgary Semantic Decision Project (CSDP; Pexman et al., 2017) than form systematicity. In Study 6, only form systematicity significantly predicted performance from the LinguaPix object naming megastudy (Krautz & Keuleers, 2022). Together, these results demonstrate that nonarbitrary statistical relationships in the form of mappings between ortho-phonological information and meaning are accessed automatically during language processing; i.e., even when syntactic category is not relevant to the task, and that sensorimotor simulation mechanisms are only strongly engaged when explicitly demanded by the task. We discuss the implications of these findings for proposals of embodied or grounded cognition and interpretations of neuroimaging data from word recognition tasks. (PsycInfo Database Record (c) 2023 APA, all rights reserved).


Stable inhibition-related inferior frontal hypoactivation and fronto-limbic hyperconnectivity in obsessive-compulsive disorder after concentrated exposure therapy.
Response inhibition has previously been suggested as an endophenotype for obsessive-compulsive disorder (OCD), evidenced by studies showing worse task performance, and altered task-related activation and connectivity. However, it's unclear if these measures change following treatment. In this study, 31 OCD patients and 28 healthy controls performed a stop signal task during 3 T functional magnetic resonance imaging before treatment, while 24 OCD patients and 17 healthy controls were rescanned one week and three months after concentrated exposure and response prevention over four consecutive days using Bergen 4-Day Format. To study changes over time we performed a longitudinal analysis on stop signal reaction time and task-related activation and amygdala connectivity during successful and failed inhibition. Results showed that there was no group difference in task performance. Before treatment, OCD patients compared to controls showed less inhibition-related activation in the right inferior frontal gyrus, and increased functional connectivity between the right amygdala and the right inferior frontal gyrus and pre-supplementary motor area. During error-processing, OCD patients versus controls showed less activation in the pre-SMA before treatment. These group differences did not change after treatment. Pre-treatment task performance, brain activation, and connectivity were unrelated to the degree of symptom improvement after treatment. In conclusion, inferior frontal gyrus hypoactivation and increased fronto-limbic connectivity are likely trait markers of OCD that remain after effective exposure therapy.


Discriminating analysis of atypical squamous cells of undetermined significance of the uterine cervix using nuclear three-dimensional analysis.
The Bethesda System (TBS) of uterine cervical cytology is a classification method that can improve accuracy in management and it includes descriptions on adequate specimens, human papillomavirus (HPV) involvement and estimated lesions. However, the judgment of atypical squamous cells of undetermined significance (ASC-US) using TBS features complicated diagnostic criteria and poor reproducibility due to the definition of ASC-US. Of patients diagnosed with ASC-US in the initial cytology, cervical intraepithelial neoplasia (CIN)1-2 cases positive for high-risk HPV (CIN+) and benign cases in histology negative for high-risk HPV (B-) were selected for discriminant analysis based on Mahalanobis distance, in order to improve the accuracy of the ASC-US diagnosis. ASC-US cases featuring koilocytosis with little nuclear atypia (koilocytosis) and squamous epithelial cells with nuclear atypia (SC with atypia), morphologically diagnosed with liquid-based cytology specimens prepared using ThinPrep were included. The nuclei of koilocytosis cases (CIN+, 8 cases, and B-, 10 cases) and SC with atypia (CIN+, 19 cases, and B-, 15 cases) were three-dimensionally analyzed to conduct a discriminant analysis based on Mahalanobis distance. Discrimination rates were 78.9% for CIN+ and 66.7% for B- in koilocytosis, and 50.7% for CIN+ and 72.1% for B- in SC with atypia. The present method allows the objective analysis of nuclear chromatin, providing effective cytology regarding CIN+ in koilocytosis and B- in SC with atypia of ASC-US cases.


Mutation analysis of hereditary multiple exostoses in the Chinese.
Hereditary multiple exostoses (EXT; MIM 133700) is an autosomal dominant bone disorder. It is genetically heterogeneous with at least three chromosomal loci: EXT1 on 8q24.1, EXT2 on 11p11, and EXT3 on 19p. EXT1 and EXT2, the two genes responsible for EXT1 and EXT2, respectively, have been cloned. Recently, three other members of the EXT gene family, named the EXT-like genes (EXTL: EXTL1, EXTL2, and EXTL3), have been isolated. EXT1, EXT2, and the three EXTLs are homologous with one another. We have identified the intron-exon boundaries of EXTL1 and EXTL3 and analyzed EXT1, EXT2, EXTL1, and EXTL3, in 36 Chinese families with EXT, to identify underlying disease-related mutations in the Chinese population. Of the 36 families, five and 12 family groups have mutations in EXT1 and EXT2, respectively. No disease-related mutation has been found in either EXTL1 or EXTL2, although one polymorphism has been detected in EXTL1. Of the 15 different mutations (three families share a common mutation in EXT2), 12 are novel. Most of the mutations are either frameshift or nonsense mutations (12/15). These mutations lead directly or indirectly to premature stop codons, and the mutations generate truncated proteins. This finding is consistent with the hypothesis that the development of EXT is mainly attributable to loss of gene function. Missense mutations are rare in our families, but these mutations may reflect some functionally crucial regions of these proteins. EXT1 is the most frequent single cause of EXT in the Caucasian population in Europe and North America. It accounts for about 40% of cases of EXT. Our study of 36 EXT Chinese families has found that EXT1 seems much less common in the Chinese population, although the frequency of the EXT2 mutation is similar in the Caucasian and Chinese populations. Our findings suggest a possibly different genetic spectrum of this disease in different populations.


Validation of a childhood eating disorder outcome scale.
We developed and validated a childhood eating disorder outcome scale based on outcomes associated with body mass index standard deviation score (BMI-SDS). This prospective observational study included 131 children with eating disorders (aged 5-15 years). Participants' outcomes scales were completed at the first visit and at 1, 3, 6, and 12 months. The scale evaluated 12 outcomes: body weight change (BW), eating attitude (EA), fear of being fat (FF), body image distortion (BD), menstruation (ME), perceived physical condition (PC), attending school (AS), disease recognition by school (RS), family function (FA), disease recognition by parent (RP), social adaptation (SA), and relationships with friends (RF). Responses to all items were on a four-point Likert scale. Exploratory factor analysis was used to determine the number of factors based on the 12 outcomes. The relation between outcome scale scores and BMI-SDS over the 12-month follow-up period was analyzed. Two types of factors were extracted: disease-specific factors (EA, FF, BD) and biopsychosocial factors (BW, PC, AS, FA, SA, RF). Three items (ME, RS, RP) were excluded because they showed no significant loading effect. There was a significant negative correlation between the outcome scale and BMI-SDS, and changes in outcome scale scores from baseline to 12 months were significantly associated with improvement in BMI-SDS. We developed a childhood eating disorder outcome scale characterized by disease-specific and biopsychosocial factors. Biopsychosocial management combined with a therapeutic approach for disease-specific symptoms may support body weight recovery for children with eating disorders.


Accelerated partial breast irradiation for pure ductal carcinoma in situ.
To report outcomes for ductal carcinoma in situ (DCIS) treated with breast-conserving therapy using accelerated partial breast irradiation (APBI). From March 2001 to February 2009, 53 patients with Stage 0 breast cancer were treated with breast conserving surgery and adjuvant APBI. Median age was 62 years. All patients underwent excision with margins negative by ≥1 mm before adjuvant radiotherapy (RT). A total of 39 MammoSite brachytherapy (MS) patients and 14 three-dimensional conformal external beam RT (3DCRT) patients were treated to the lumpectomy bed alone with 34 Gy and 38.5 Gy, respectively. Of the DCIS cases, 94% were mammographically detected. All patients with calcifications had either specimen radiography or postsurgical mammography confirmation of clearance. Median tumor size was 6 mm, and median margin distance was 5 mm. There were no statistically significant differences according to APBI method for race/ethnicity, tumor detection method, tumor grade, estrogen receptor (ER) status, or use of tamoxifen (p = NS). Recurrence and survival were calculated using the Kaplan-Meier method. Cosmesis was scored by the Harvard criteria. With a median follow-up of 3.6 years (range, 0.4-6.3 years), the overall and cause-specific survival rates were 98% and 100%, respectively. Three-year actuarial ipsilateral breast tumor recurrence was 2%. One failure was observed at the resection bed 11 months post-RT. No other elsewhere breast failures, regional recurrences, or distant metastases were noted. Cosmesis was excellent or good in 92.4% of cases, with no statistically significant differences according to the APBI method (92.3% with MammoSite and 92.8% with 3DCRT; p = 0.649). APBI as part of breast-conserving therapy for pure DCIS was associated with excellent local control and survival rates, with the vast majority of patients having good to excellent cosmesis. This finding supports the recent analysis by the American Society of Breast Surgeons on a subset of DCIS patients treated efficaciously with APBI.


Critical analysis of spirometric patterns in correlation to chest computed tomography among adult Indigenous Australians with chronic airway diseases.
Background: There is sparse literature evidence in the spirometric patterns of adult Indigenous Australians with and without chest computed tomography (CT)-proven chronic airway diseases (CADs).Methods: Participants spirometry testing graded as acceptable for quality and had a chest CT scan showing radiographic evidence of CADs were included for analysis.Results: Of the 1350 spirometric tests performed between 2012 and 2020, a total of 212 patients with a mean age of 53 years and 54% females were eligible to be included. One-third (30%) had normal chest CT (without CADs), 35% had predominant COPD, 19% bronchiectasis and 16% combined COPD and bronchiectasis. Percentage predicted values for forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) both pre- and post- bronchodilator were significantly reduced for all participants - FVC: CT-normal 64%, 65%; COPD 58%, 62%; bronchiectasis 54%, 54%; combined COPD and bronchiectasis 50%, 53%. FEV1: CT-normal 62%, 65%; COPD 46%, 49%; bronchiectasis 48%,51%; combined COPD and bronchiectasis 36%,40%. FEV1/FVC was only reduced for CT abnormality patients - CT-normal 96%,98%; COPD 77%,77%; bronchiectasis 87%,89%; combined COPD and bronchiectasis 71%,72%.Conclusions: Restrictive spirometric pattern is common and an obstructive pattern with COPD, in isolation or when COPD coexists with bronchiectasis.


New ℓ2 - ℓ0 algorithm for single-molecule localization microscopy.
Among the many super-resolution techniques for microscopy, single-molecule localization microscopy methods are widely used. This technique raises the difficult question of precisely localizing fluorophores from a blurred, under-resolved, and noisy acquisition. In this work, we focus on the grid-based approach in the context of a high density of fluorophores formalized by a ℓ2 least-square term and sparsity term modeled with ℓ0 pseudo-norm. We consider both the constrained formulation and the penalized formulation. Based on recent results, we formulate the ℓ0 pseudo-norm as a convex minimization problem. This is done by introducing an auxiliary variable. An exact biconvex reformulation of the ℓ2 - ℓ0 constrained and penalized problems is proposed with a minimization algorithm. The algorithms, named CoBic (Constrained Biconvex) and PeBic (Penalized Biconvex) are applied to the problem of single-molecule localization microscopy and we compare the results with other recently proposed methods.


Revisiting the video stethoscope: an application of digital signal processing software (Goldwave) to monitoring ventilation in intubated patients.
Problems with tracheal intubation and mechanical ventilation are potentially important causes of perioperative morbidity and mortality. We have developed a method of monitoring the ventilation of both lungs during general anesthesia that is an advanced digital version of a more primitive analog technique developed over two decades ago. We used two miniature electret microphones connected to regular chest pieces, placing the assemblies on the anterior chest wall about 4 inches below the clavicle in the midclavicular line. After amplification and 16-bit analog-to-digital conversion, the digital signal processing software package Goldwave (Version 5.12, www.goldwave. com) was used to produce real-time X-Y plots of the signals, with sounds from the right side plotted on the horizontal axis and sounds from the left side plotted on the vertical axis. Recognizing that when two signals are identical, their X-Y plot should form a 45 degree line, we hypothesized that X-Y plots obtained under endobronchial conditions would be recognizably different to plots reflecting normal bilateral lung ventilation. We also hypothesized that as a result of noise and anatomical variations that under conditions of bilateral mechanical ventilation the obtained plot would be very different from a simple 45 degree line. The data obtained supports these hypotheses. This preliminary study suggests that our technique may help provide a practical real-time warning system for detecting endotracheal tube malpositions, and may help build on the work of other investigators.


Phase III clinical trial comparing the efficacy and safety of adamgammadex with sugammadex for reversal of rocuronium-induced neuromuscular block.
Preliminary clinical trials of adamgammadex, a new cyclodextrin-based selective reversal agent, have demonstrated its efficacy in reversing neuromuscular block by rocuronium. This multicentre, randomised, double-blind, positive-controlled, non-inferiority phase III clinical trial compared the efficacy and safety of adamgammadex and sugammadex. We randomised 310 subjects to receive adamgammadex (4 mg kg-1) or sugammadex (2 mg kg-1) at reappearance of the second twitch of the train-of-four (TOF), and standard safety data were collected. For the primary outcome, the proportion of patients with TOF ratio ≥0.9 within 5 min was 98.7% in the adamgammadex group vs 100% in the sugammadex group, with a point estimate and 95% confidence interval (CI) of 1.3% (-4.6%, +1.3%); the lower limit was greater than the non-inferiority margin of -10%. For the key secondary outcome, the median (inter quartile range) time from the start of administration of adamgammadex or sugammadex to recovery of TOF ratio to 0.9 was 2.25 (1.75, 2.75) min and 1.75 (1.50, 2.00) min, respectively. The difference was 0.50 (95% CI: 0.25, 0.50); the upper limit was lower than the non-inferiority margin of 5 min. In addition, there were no inferior results observed in secondary outcomes. Adamgammadex had a lower incidence of adverse drug reactions compared with sugammadex (anaphylactic reaction, recurarisation, decreased heart rate, and laryngospasm; P=0.047). Adamgammadex was non-inferior to sugammadex with a possible lower incidence of adverse drug reactions compared with sugammadex. Adamgammadex may have a potential advantage in terms of its overall risk-benefit profile. Chinese Clinical Trial Registry, ChiCTR2000039525. Registered October 30, 2020. https://www.chictr.org.cn/showproj.html?proj=56825.


Specific Induction of Double Negative B Cells During Protective and Pathogenic Immune Responses.
Double negative (DN) (CD19+CD20lowCD27-IgD-) B cells are expanded in patients with autoimmune and infectious diseases; however their role in the humoral immune response remains unclear. Using systematic flow cytometric analyses of peripheral blood B cell subsets, we observed an inflated DN B cell population in patients with variety of active inflammatory conditions: myasthenia gravis, Guillain-Barré syndrome, neuromyelitis optica spectrum disorder, meningitis/encephalitis, and rheumatic disorders. Furthermore, we were able to induce DN B cells in healthy subjects following vaccination against influenza and tick borne encephalitis virus. Transcriptome analysis revealed a gene expression profile in DN B cells that clustered with naïve B cells, memory B cells, and plasmablasts. Immunoglobulin VH transcriptome sequencing and analysis of recombinant antibodies revealed clonal expansion of DN B cells that were targeted against the vaccine antigen. Our study suggests that DN B cells are expanded in multiple inflammatory neurologic diseases and represent an inducible B cell population that responds to antigenic stimulation, possibly through an extra-follicular maturation pathway.


Children's Oncology Group's 2023 blueprint for research: Surgery.
Surgery plays a crucial role in the treatment of children with solid malignancies. A well-conducted operation is often essential for cure. Collaboration with the primary care team is important for determining if and when surgery should be performed, and if performed, an operation must be done in accordance with well-established standards. The long-term consequences of surgery also need to be considered. Indications and objectives for a procedure vary. Providing education and developing and analyzing new research protocols that include aims relevant to surgery are key objectives of the Surgery Discipline of the Children's Oncology Group. The critical evaluation of emerging technologies to ensure safe, effective procedures is another key objective. Through research, education, and advancing technologies, the role of the pediatric surgeon in the multidisciplinary care of children with solid malignancies will continue to evolve.


Interim Estimates of COVID-19 Vaccine Effectiveness Against COVID-19-Associated Emergency Department or Urgent Care Clinic Encounters and Hospitalizations Among Adults During SARS-CoV-2 B.1.617.2 (Delta) Variant Predominance - Nine States, June-August 2021.
Data on COVID-19 vaccine effectiveness (VE) since the B.1.617.2 (Delta) variant of SARS-CoV-2, the virus that causes COVID-19, became the predominant circulating strain in the United States are limited (1-3). CDC used the VISION Network* to examine medical encounters (32,867) from 187 hospitals and 221 emergency departments (EDs) and urgent care (UC) clinics across nine states during June-August 2021, beginning on the date the Delta variant accounted for >50% of sequenced isolates in each medical facility's state. VISION Network methods have been published (4).


Climate and society: lessons from the past 10,000 years.
This paper distinguishes three major "revolutions" in the socio-environmental interactions that reflect growth in the extent to which human beings invest in and modify their environments. As people settled in villages during the Neolithic, interactions between more people became an important element in survival strategies, shifting the emphasis in survival strategies from mobility to sociality. The emergence of cities changed human societies by: i) creating dependencies between more and more distant regions, ii) increasing the degree of aggregation of human populations, iii) narrowing the range of subsistence resources on which people depended, and iv) increasing further their investment in the natural environment and in material culture. Altogether, urbanization drove human social systems further and further away from flexibility and rapid adaptation to environmental change, while increasing the demands on the social system, including major increases in energy and matter to support urban populations. This was achieved by linking together larger and larger hinterlands for these cities, in effect creating Empires. The fundamental change is one from humans responding to environmental change and disruption by migration to humans investing in the environment, and therefore responding to environmental change by problem solving. One therefore needs to look at the combined socio-environmental systems over the longer term that reflect the buildup and culmination of the shifts in the social and environmental risk spectra due to the human-environmental interactions in periods before the "crisis" occurs, which are a fact of life in any society's interaction with its environment, and should be seen as "social" challenges rather than "environmental" ones. These are generally due to the fact that the society in question has invested so much in a particular way of life that it cannot innovate itself out of difficulty before time runs out. This implies that we have to shift our thinking about socio-environmental issues, from "population thinking" to "organization thinking." In this perspective, a crisis does not imply the disappearance of the people involved, but a transformation of the organization that links them.


Lung cancer: microRNA and target database.
MicroRNAs (miRNAs) are a class of non-coding RNAs that hybridize to mRNAs and induce either translation repression or mRNA cleavage. Recently, it has been reported that miRNAs could possibly play a critical role in cellular processes like regulation of cell growth, differentiation, and apoptosis, emphasizing their role in tumorigenesis. Likewise, several miRNA's are involved in lung cancer tumorigenesis. The present review puts forth a database of human miRNA's involved in lung cancer along with their target genes. It also provides sequences of miRNA's and their chromosomal locations retrieved from different databases like microCosm (218 microRNAs), PhenomiR (293 microRNAs), and mir2Disease (90 microRNAs) and target gene information such as the pathways like cell cycle regulation, angiogenesis, apoptosis etc. Though miRNA's are still to be explored, they hold a promise as therapeutic targets and diagnostic markers of cancer.


European Code against Cancer 4th Edition: Diet and cancer.
Lifestyle factors, including diet, have long been recognised as potentially important determinants of cancer risk. In addition to the significant role diet plays in affecting body fatness, a risk factor for several cancers, experimental studies have indicated that diet may influence the cancer process in several ways. Prospective studies have shown that dietary patterns characterised by higher intakes of fruits, vegetables, and whole-grain foods, and lower intakes of red and processed meats and salt, are related to reduced risks of death and cancer, and that a healthy diet can improve overall survival after diagnosis of breast and colorectal cancers. There is evidence that high intakes of fruit and vegetables may reduce the risk of cancers of the aerodigestive tract, and the evidence that dietary fibre protects against colorectal cancer is convincing. Red and processed meats increase the risk of colorectal cancer. Diets rich in high-calorie foods, such as fatty and sugary foods, may lead to increased calorie intake, thereby promoting obesity and leading to an increased risk of cancer. There is some evidence that sugary drinks are related to an increased risk of pancreatic cancer. Taking this evidence into account, the 4th edition of the European Code against Cancer recommends that people have a healthy diet to reduce their risk of cancer: they should eat plenty of whole grains, pulses, vegetables and fruits; limit high-calorie foods (foods high in sugar or fat); avoid sugary drinks and processed meat; and limit red meat and foods high in salt.


Inhibition of human platelet adenylate cyclase by collagen fibres. Effect of collagen is additive with that of adrenaline, but interactive with that of thrombin.
Collagen fibres in suspension have been shown to inhibit adenylate cyclase in human platelet preparations. Direct inhibition by collagen fibres was observed when intact platelets were used, although secondary events such as ADP secretion or prostanoid formation were important contributors to the inhibition of adenylate cyclase after treatment of platelets with collagen. The nature of the direct inhibition caused by collagen has been investigated in platelet membrane preparations, with the following results. (1) Collagen fibres inhibit platelet membrane adenylate cyclase in a dose-dependent manner. (2) Inhibition of adenylate cyclase by thrombin, adrenaline or collagen fibres could be abolished in the presence of guanosine 5'-[beta-thio]diphosphate; half-maximal inhibition was obtained at about 100 microM for the inhibitory action of thrombin, and at about 500 microM for that of either adrenaline or collagen. (3) The action of each ligand was blocked to a similar extent by pertussis-toxin treatment of the platelet membranes. Taken together, these results indicate that the action of collagen, like that of thrombin and adrenaline, is G-protein-dependent. (4) inhibition of adenylate cyclase by collagen fibres was additive with that caused by adrenaline, but co-operative with that caused by thrombin, suggesting that inhibitory pathways exists for collagen and adrenaline which are distinct from, but interactive with, that for thrombin. (5) Modification of the collagen fibres by pepsin treatment attenuated the effects of collagen, whereas heat-denaturation of the collagen fibres completely abolished their effects. These data suggest that the effects of collagen are specific, and depend on the detailed structure of the collagen fibres.


Anxiety disorders and all-cause mortality: systematic review and meta-analysis.
The purpose of this study was to perform a systematic review and meta-analysis of prospective cohort studies that examined the relationship between anxiety disorders, or clinically significant anxiety symptoms, at baseline and all-cause mortality at follow-up relative to control participants without clinically significant anxiety. PubMed, EMBASE, PsycInfo, and CINAHL were searched through July 2015, along with manual searches of published reviews and forward and backward snowball searches of included studies. Studies were excluded if anxiety was not defined with a standardized instrument, or if participants were followed-up for 1 year or less. The initial search yielded 7901 articles after the removal of duplicates, of which 328 underwent full-text screening. Forty-two estimates from 36 articles were included in the meta-analysis with a total sample of 127,552 participants and over 11,573 deaths. The overall hazard ratio (HR) estimate of mortality in clinically anxious participants relative to controls was 1.09 (95 % CI 1.01-1.16); however, this was reduced after adjusting for publication bias (1.03; 95 % CI 0.95-1.13). There was no evidence of increased mortality risk among anxious participants derived from community samples (0.99; 95 % CI 0.96-1.02) and in studies that adjusted for a diagnosis of depression (1.01; 95 % CI 0.96-1.06). These findings suggest that positive associations in the literature are attributable to studies in smaller samples, comorbid depression (or other psychiatric conditions) among participants, and possible confounding in medical patient samples followed-up for short durations.


Familial longevity is marked by better cognitive performance at middle age: the Leiden Longevity Study.
Decline in cognitive performance is a highly prevalent health condition in elderly. We studied whether offspring of nonagenarian siblings with a familial history of longevity, perform better on cognitive tests compared to their partners as controls. This is relevant since it could provide insights into determinants underlying decline in cognitive performance. Cross-sectional analysis within the longitudinal cohort of the Leiden Longevity Study consisting of middle-aged offspring of nonagenarian siblings together with their partners (n = 500, mean age (SD) 66.3 (6.1) and 65.7 (7.2) years, respectively) as controls. Memory function, attention and processing speed were tested using the 15-Picture Learning Test, Stroop test and Digit Symbol Substitution Test. Data were analyzed with regression adjusted for age, gender, years of education and additionally for diabetes mellitus, cardiovascular diseases, alcohol use, smoking, inflammatory markers and apolipoprotein E genotype. Robust standard errors were used to account for familial relationships among the offspring. Cognitive performance was worse at higher calendar age (p<0.001, all except Stroop test part 1). The offspring performed better compared to their partners on trial 3 (p = 0.005), the immediate (p = 0.016) and delayed (p = 0.004) recall of the 15-Picture Learning Test as well as on the interference and combined interference score of the Stroop test (p = 0.014 and p = 0.036, respectively) in the fully adjusted model. The difference between offspring and partners was estimated to be more than three years according to the observed difference in calendar age. Offspring of nonagenarian siblings with a familial history of longevity have better cognitive performance compared to the group of their partners of comparable age. This effect is independent of age-related diseases and known possible confounders. Possible explanations might be differences in subclinical vascular pathology between both groups.


The effect of prayer on physical health: Experimental evidence.
There has been enough published scientific work on the direct effects of prayer upon physical health in the past thirty years to merit review. While experimental evidence has yet to reveal large direct effects of prayer on physical health, the effects which have been found are notable and encourage further study. In this article the authors review the major studies, discuss problems in their interpretation, and suggest considerations for future experimental study of prayer.


[Antimicrobial susceptibility and serotyping of Pseudomonas aeruginosa isolated from HIV/AIDS patients].
Sixty-eight strains from seropositive patients seen at "Pedro Kouri" Tropical Medicine Hospital from October 1996 to September 1997 were analyzed in this study. Antimicrobial susceptibility tests by the Kirby-Bauer method and antigenic study through slide agglutination of the somatic antigen were performed in such strains. The most frequent isolated serogroups were 01(27.9%), 011(10%), 06(8.8%) and 05(7.3%); twenty-one strains of 68 isolates (30.9%) could not be serotyped. All the strains were susceptible to gentamycin and azlocylin; most of isolates were susceptible to ceftazidime (n = 66), and ciprofloxacin (n = 62). On the other hand, 25 of the 68 isolates (35.7%) showed resistance to cefotaxime. No direct relation between antibiotic resistance and serologic results could be proved. According to these results, gentamycin is highly effective for treating analyzed strains. In the forthcoming years, beta-lactams and quinolones should be more rationally used so as to prevent the emergence of multi-resistant strains in Cuba.


[Drug-therapy: misunderstanding and omission, in patientdoctor communication].
Patient-doctor communication is fraught with misunderstanding and omission, especially around the drug therapy. In this article we mobilize health anthropology to illustrate this phenomenon. Beyond the biomedical effect, the drug is also an object of meaning: it objectifies the disease and is appealing but also raising uncertainities. It simultaneously promises a certain autonomy and a dependency on the doctor. Drug prescription also serves as a communication tool between the suffering patient and the caring doctor. If the prescription can be source of disagreement, it could present an opportunity for the doctor to explore the patient's illness representation, and the potential obstacles to negotiated therapeutic adherence between the partners of the therapeutic relationship.


Exercise-induced syncope associated with QT prolongation and ephedra-free Xenadrine.
The Food and Drug Administration recently banned the sale of ephedra alkaloids because of their association with arrhythmic sudden death, myocardial infarction, and stroke. This has resulted in the emergence of formulations marketed for weight loss and performance enhancement that are "ephedra free" but contain other sympathomimetic substances, the safety of which has not been established. We report a case of exercise-induced syncope in a healthy 22-year-old woman that occurred 1 hour after she took the second dose of Xenadrine EFX, an ephedra-free weight-loss supplement. Electrocardiography revealed prolongation of the QT interval (corrected QT, 516 milliseconds); this resolved in 24 hours. Results of echocardiography and exercise stress testing were normal. Nine months of monitoring with an implanted loop recorder revealed no arrhythmias in the absence of Xenadrine EFX. Although this product contains a number of compounds whose pharmacologic effect is poorly characterized, notable quantities of phenylephrine are present, and the proarrhythmic potential of this compound in the setting of exercise is discussed.


The industrial hygiene audit: purposes and implementation.
The increased implementation of industrial hygiene programs in industry, with the associated increase in funds allocated to safety and health programs, has introduced the concept of evaluative measures for program performance. The audit is a frequently used and valuable tool for the safety specialist, but it has been infrequently used by the hygienist. We differentiate the audit from 1) program guidelines and 2) program evaluation. The latter implies relating program activities to articulated measures of effectiveness. The audit, in contrast, utilizes widely accepted industrial hygiene program structural elements. In an audit a qualitative or numerical rating scale is assigned each audit program element to indicate the extent to which the element is present. The audit is an essential tool for the manager of an industrial hygiene program. Audits are not a substitute for program evaluation, but program evaluation is a very uncertain matter because the industrial hygiene profession has yet to focus on measures of program progress in terms similar to those of the safety field, i.e. accident frequencies and severities. Program elements and qualitative and quantitative rating scales are described. Preparation, conduct and reporting of the audit are discussed.


Factors confounding assessment of ambulatory blood pressure monitors, studied during formal evaluation of the Tycos Quiet-Trak.
The credibility of studies assessing ambulatory blood pressure monitoring (ABPM) devices will be enhanced by minimizing opportunities to manipulate the outcome through biased selection of patient volunteers, and by insuring that participants are representative of the target patient population. While subjecting the Welch Allyn Quiet-Trak to the British Hypertension Society (BHS) protocol, we examined the extent to which certain candidate characteristics might influence device assessment. The Quiet-Trak achieved an A grade overall. During its field testing, daytime physical activity measured with a wrist-mounted, piezoelectric accelerometer, influenced significantly the rate of measurement rejection. The tertiles of subjects with highest and lowest levels of daytime physical activity (64 +/- 16 and 35 +/- 10 activity units; P < .001) exhibited significantly different measurement rejection rates (10 +/- 3 and 3 +/- 2 daytime rejects; P < .001)). Most rejected readings occurred during episodes of high physical activity. During static evaluation (Phase V), the level of systolic BP influenced the accuracy of diastolic BP estimation; above 190 mm Hg systolic BP, estimates of diastolic BP differed significantly from manual measurements. Subjects' age and arm circumference influenced neither field nor static evaluation. Retrospective comparison of the study subjects with 120 consecutive ABPM clinic attenders revealed (1) that participants in field testing were younger, had lower BP but were equally active compared with clinic patients; and (2) that Phase V participants exhibited higher systolic (155 +/- 42 v 135 +/- 15 mm Hg; P < .001) but similar diastolic BP levels compared to controls. The reliability of ABPM validation protocols would be enhanced by: (a) incorporation of objective measurement of physical activity during field testing, demonstrating normal levels of activity; (b) requiring that field testing be conducted in representative patients rather than normal volunteers; and (c) a greater focus in both static and field testing on those levels of blood pressure that are relevant in clinical practice.


Dietary Intake of 91 Individual Polyphenols and 5-Year Body Weight Change in the EPIC-PANACEA Cohort.
Polyphenols are bioactive compounds from plants with antioxidant properties that may have a protective role against body weight gain, with adipose tissue and systemic oxidative stress as potential targets. We aimed to investigate the dietary intake of individual polyphenols and their association with 5-year body weight change in a sub-cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC). This study included 349,165 adult participants from nine European countries. Polyphenol intake was estimated through country-specific validated dietary questionnaires and the Phenol-Explorer database. Body weight was obtained at recruitment and after a mean follow-up time of 5 years. Associations were estimated using multilevel mixed linear regression models. From 91 polyphenols included, the majority (n = 67) were inversely associated with 5-year body weight change after FDR-correction (q < 0.05). The greatest inverse associations were observed for quercetin 3-O-rhamnoside (change in weight for doubling in intake: −0.071 (95% CI: −0.085; −0.056) kg/5 years). Only 13 polyphenols showed positive associations with body weight gain, mainly from the subclass hydroxycinnamic acids (HCAs) with coffee as the main dietary source, such as 4-caffeoylquinic acid (0.029 (95% CI: 0.021; 0.038) kg/5 years). Individual polyphenols with fruit, tea, cocoa and whole grain cereals as the main dietary sources may contribute to body weight maintenance in adults. Individual HCAs may have different roles in body weight change depending on their dietary source.


The Extent of Human Apolipoprotein A-I Lipidation Strongly Affects the β-Amyloid Efflux Across the Blood-Brain Barrier in vitro.
Much evidence suggests a protective role of high-density lipoprotein (HDL) and its major apolipoprotein apoA-I, in Alzheimer's disease (AD). The biogenesis of nascent HDL derived from a first lipidation of apoA-I, which is synthesized by the liver and intestine but not in the brain, in a process mediated by ABCA1. The maturation of nascent HDL in mature spherical HDL is due to a subsequent lipidation step, LCAT-mediated cholesterol esterification, and the change of apoA-I conformation. Therefore, different subclasses of apoA-I-HDL simultaneously exist in the blood circulation. Here, we investigated if and how the lipidation state affects the ability of apoA-I-HDL to target and modulate the cerebral β-amyloid (Aβ) content from the periphery, that is thus far unclear. In particular, different subclasses of HDL, each with different apoA-I lipidation state, were purified from human plasma and their ability to cross the blood-brain barrier (BBB), to interact with Aβ aggregates, and to affect Aβ efflux across the BBB was assessed in vitro using a transwell system. The results showed that discoidal HDL displayed a superior capability to promote Aβ efflux in vitro (9 × 10-5 cm/min), when compared to apoA-I in other lipidation states. In particular, no effect on Aβ efflux was detected when apoA-I was in mature spherical HDL, suggesting that apoA-I conformation, and lipidation could play a role in Aβ clearance from the brain. Finally, when apoA-I folded its structure in discoidal HDL, rather than in spherical ones, it was able to cross the BBB in vitro and strongly destabilize the conformation of Aβ fibrils by decreasing the order of the fibril structure (-24%) and the β-sheet content (-14%). These data suggest that the extent of apoA-I lipidation, and consequently its conformation, may represent crucial features that could exert their protective role in AD pathogenesis.


[Importance of microcirculatory disorders in combined treatment of acute pleural empyema and pyopneumothorax].
To investigate responses to application of quick-frozen or cryosupernatant plasma, heparin and proteinases inhibitors of DIC-syndrome in patients with pleural empyema and pyopneumothorax. Transfusions of quick-frozen or cryosupernatant plasma, injections of heparin and inhibitors of proteinases were used as an adjuvant to conventional treatment in 548 patients with acute pleural empyema and pyopneumothorax. The addition of cryoplasm-antienzyme complex to conventional treatment of acute pleural empyema resulted in reduced number of lethal outcomes compared to the conventional treatment alone (5.9 vs 14.4%, respectively). Transfusion of quick-frozen or cryosupernatant plasma, injection of heparin and inhibitors of proteinases improve microcirculation around the inflammatory focus. In addition to antibiotic therapy and evacuation of the pus from the pleural cavity, the above methods contribute to better outcomes of pleural empyema and pyopneumothorax.


Improvement and Evaluation of the TOPCOP Taxonomy of Patient Portals: Taxonomy-Evaluation-Delphi (TED) Approach.
Patient portals have been introduced in many countries over the last 10 years, but many health information managers still feel they have too little knowledge of patient portals. A taxonomy can help them to better compare and select portals. This has led us to develop the TOPCOP taxonomy for classifying and comparing patient portals. However, the taxonomy has not been evaluated by users. This study aimed to evaluate the taxonomy's usefulness to support health information managers in comparing, classifying, defining a requirement profile for, and selecting patient portals and to improve the taxonomy where needed. We used a modified Delphi approach. We sampled a heterogeneous panel of 13 health information managers from 3 countries using the criterion sampling strategy. We conducted 4 anonymous survey rounds with qualitative and quantitative questions. In round 1, the panelists assessed the appropriateness of each dimension, and we collected new ideas to improve the dimensions. In rounds 2 and 3, the panelists iteratively evaluated the taxonomy that was revised based on round 1. In round 4, the panelists assessed the need for a taxonomy and the appropriateness of patient engagement as a distinguishing concept. Then, they compared 2 real portals with the final taxonomy and evaluated its usefulness for comparing portals, creating an initial requirement profile, and selecting patient portals. To determine group consensus, we applied the RAND/UCLA Appropriateness Method. The final taxonomy consists of 25 dimensions with 65 characteristics. Five new dimensions were added to the original taxonomy, with 8 characteristics added to already existing dimensions. Group consensus was achieved on the need for such a taxonomy to compare portals, on patient engagement as an appropriate distinguishing concept, and on the comprehensibility of the taxonomy's form. Further, consensus was achieved on the taxonomy's usefulness for classifying and comparing portals, assisting users in better understanding portals, creating a requirement profile, and selecting portals. This allowed us to test the usefulness of the final taxonomy with the intended users. The TOPCOP taxonomy aims to support health information managers in comparing and selecting patient portals. By providing a standardized terminology to describe various aspects of patient portals independent of clinical setting or country, the taxonomy will also be useful for advancing research and evaluation of patient portals.


Erythropoiesis- and thrombopoiesis-characterizing parameters in adenosine A3 receptor knock-out mice.
Influence of the regulatory system mediated by adenosine A(3) receptors on the functioning of erythropoiesis and thrombopoiesis was studied by means of evaluation of the numbers and attributes of peripheral blood erythrocytes and platelets, as well as of erythroid bone marrow progenitor cells in adenosine A(3) receptor knock-out (Adora3(tm1Jbsn)/Adora3(tm1Jbsn), A(3)AR((-/-))) mice and their wild-type C57BL/6 counterparts, both males and females. Minor but statistically significant disturbances in the properties of erythrocytes, namely in the parameters of mean erythrocyte volume and mean erythrocyte hemoglobin were observed in A(3)AR((-/-)) mice. In addition, adenosine A(3) receptor knock-out mice were found to exhibit an expressive, statistically significant decrease of their blood platelet count, amounting to 17 % and 21 % in males and females, respectively. This decrease in platelet levels was accompanied by a significant 17 % decline in the plateletcrit in both sexes. The obtained data can help to define therapeutic applications based on the principle of adenosine receptor signaling.


Association Between Inflammatory Cytokines, Executive Function, and Substance Use in Patients With Opioid Use Disorder and Amphetamine-Type Stimulants Use Disorder.
Long-term opioid and amphetamine-type stimulants (ATS) abuse may affect immunological function and impair executive function. We aimed to determine whether biomarkers of inflammation and executive function were associated with substance use in individuals with opioid use disorder (OUD) and ATS use disorder (ATSUD). The interactions between these biomarkers were also explored. We assessed plasma cytokines [tumor necrosis factor (TNF)-α, C-reactive protein (CRP), interleukin (IL)-8, IL-6, transforming growth factor (TGF)-β1, brain-derived neurotrophic factor (BDNF), and executive function in terms of the Wisconsin Card Sorting Test (WCST) and Continuous Performance Test (CPT) in OUD and ATSUD patients and healthy controls (HC). OUD and ATSUD patients were followed for 12 weeks, and their urine morphine and amphetamine tests, cytokine levels, and executive function were repeatedly measured. We enrolled 483 patients and 145 HC. Plasma TNF-α, CRP, IL-8, IL-6, and BDNF levels and most subscale scores on the WCST and CPT significantly differed between OUD and ATSUD patients and HC. Increased TNF-α levels and more perseveration error on the WCST were significantly associated with more urine drug-positive results and less abstinence. Plasma IL-6 and CRP levels were significantly negatively correlated with WCST and CPT performance. OUD and ATSUD patients had more inflammation and worse executive function than HC. Inflammatory markers and WCST performance were associated with their urinary drug results, and higher inflammation was associated with poor executive function. Studies on regulating the inflammatory process and enhancing executive function in OUD and ATSUD are warranted.


Impact of activated charcoal on the mineralisation of 14C-phenanthrene in soils.
The development of phenanthrene catabolism in four soils amended with varying concentrations of activated charcoal (AC) (0%, 0.1%, 1% and 5%), a type of black carbon, was investigated. Mineralisation of (14)C-phenanthrene was monitored after 1, 25, 50 and 100 d soil-PAH contact time; lag phases, rates and extents of mineralisation of the (14)C-phenanthrene to (14)CO(2) were determined. At concentrations >0.1% AC rates and extents of mineralisation were reduced by more than 99%. This revealed that the presence of >0.1% AC in soils may substantially diminish the rate at which the catabolic activity of indigenous soil microflora develops in contaminated soil. Soil C, which had the highest organic carbon (OC) content, consistently exhibited the highest extents of degradation. It is suggested that, in accordance with other researchers, OC may have blocked available phenanthrene sorption sites. This enhanced phenanthrene availability ultimately facilitated a greater level of catabolic activity within this soil. Such results reflect the complex nature of interactions between soil, biota and contaminants and their influence on the degradation of contaminants in the environment.