Does the inclusion of rare variants improve risk prediction?
Every known link between a genetic variant and blood pressure improves the understanding and potentially the risk assessment of related diseases such as hypertension. Genetic data have become increasingly comprehensive and available for an increasing number of samples. The availability of whole-genome sequencing data means that statistical genetic models must evolve to meet the challenge of using both rare variants (RVs) and common variants (CVs) to link previously unidentified genome loci to disease-related traits. Penalized regression has two features, variable selection and proportional coefficient shrinkage, that allow researchers to build models tailored to hypothesized characteristics of the genotype-phenotype map. The following work uses the Genetic Analysis Workshop 18 data to investigate the performance of a spectrum of penalized regressions using at first only CVs or only RVs to predict systolic blood pressure (SBP). Next, combinations of CVs and RVs are used to model SBP, and the impact on prediction is quantified. The study demonstrates that penalized regression improves blood pressure prediction for any combination of CVs and RVs compared with maximum likelihood estimation. More significantly, models using both types of variants provide better predictions of SBP than those using only CVs or only RVs. The predictive mean squared error was reduced by up to 11.5% when RVs were added to CV-only penalized regression models. Elastic net regression with equally weighted LASSO and ridge components, in particular, can use large numbers of single-nucleotide polymorphisms to improve prediction.


What is the real number of Lyme disease cases in Canada?
Lyme disease is emerging in Canada due to expansion of the range of the tick vector Ixodes scapularis from the United States. National surveillance for human Lyme disease cases began in Canada in 2009. Reported numbers of cases increased from 144 cases in 2009 to 2025 in 2017. It has been claimed that few (< 10%) Lyme disease cases are reported associated with i) supposed under-diagnosis resulting from perceived inadequacies of serological testing for Lyme disease, ii) expectation that incidence in Canadian provinces and neighbouring US states should be similar, and iii) analysis of serological responses of dogs to the agent of Lyme disease, Borrelia burgdorferi. We argue that performance of serological testing for Lyme disease is well studied, and variations in test performance at different disease stages are accounted for in clinical diagnosis of Lyme disease, and in surveillance case definitions. Extensive surveillance for tick vectors has taken place in Canada providing a clear picture of the emergence of risk in the Canadian environment. This surveillance shows that the geographic scope of I. scapularis populations and Lyme disease risk is limited but increasing in Canada. The reported incidence of Lyme disease in Canada is consistent with this pattern of environmental risk, and the differences in Lyme disease incidence between US states and neighbouring Canadian provinces are consistent with geographic differences in environmental risk. Data on serological responses in dogs from Canada and the US are consistent with known differences in environmental risk, and in numbers of reported Lyme disease cases, between the US and Canada. The high level of consistency in data from human case and tick surveillance, and data on serological responses in dogs, suggests that a high degree of under-reporting in Canada is unlikely. We speculate that approximately one third of cases are reported in regions of emergence of Lyme disease, although prospective studies are needed to fully quantify under-reporting. In the meantime, surveillance continues to identify and track the ongoing emergence of Lyme disease, and the risk to the public, in Canada.


Evaluation of the effectiveness of an incentive strategy on the questionnaire response rate in parents of premature babies: a randomised controlled Study Within A Trial (SWAT) nested within SIFT.
Loss to follow-up resulting in missing outcomes compromises the validity of trial results by reducing statistical power, negatively affecting generalisability and undermining assumptions made at analysis, leading to potentially biased and misleading results. Evidence that incentives are effective at improving response rates exists, but there is little evidence regarding the best approach, especially in the field of perinatal medicine. The NIHR-funded SIFT trial follow-up of infants at 2 years of age provided an ideal opportunity to address this remaining uncertainty. Participants: parents of infants from participating neonatal units in the UK and Ireland followed up for SIFT (multicentre RCT investigating two speeds of feeding in babies with gestational age at birth < 32 weeks and/or birthweight < 1500 g). parents were randomly allocated to receive incentives (£15 gift voucher) before or after questionnaire return. The objective was to establish whether offering an unconditional incentive in advance or promising an incentive on completion of a questionnaire (conditional) improved the response rate in parents of premature babies. The primary outcome was questionnaire response rate. Permuted block randomisation was performed (variable size blocks), stratified by SIFT allocation (slower/faster feeds) and single/multiple birth. Multiple births were given the same incentives allocation. Parents were unaware that they were in an incentives SWAT; SIFT office staff were not blinded to allocation. Parents of 923 infants were randomised: 459 infants allocated to receive incentive before, 464 infants allocated to receive incentive after; analysis was by intention to treat. Allocation to the incentive before completion led to a significantly higher response rate, 83.0% (381/459) compared to the after-completion group, 76.1% (353/464); adjusted absolute difference of 6.8% (95% confidence interval 1.6% to 12.0%). Giving an incentive in advance is the more costly approach, but the mean difference of ~£3 per infant is small given the higher return. An unconditional incentive in advance led to a significantly higher response rate compared to the promise of an incentive on completion. Against a backdrop of falling response rates to questionnaires, incentives can be an effective way to increase returns. SIFT ( ISRCTN76463425 ). Registered on March 5, 2013.; SWAT registration (SWAT 69 available from http://www.qub.ac.uk/sites/TheNorthernIrelandNetworkforTrialsMethodologyResearch/FileStore/Filetoupload,864297,en.pdf ). Registered on June 27, 2016.


The human SNF5/INI1 protein facilitates the function of the growth arrest and DNA damage-inducible protein (GADD34) and modulates GADD34-bound protein phosphatase-1 activity.
The growth arrest and DNA damage-inducible protein (GADD34) mediates growth arrest and apoptosis in response to DNA damage, negative growth signals, and protein malfolding. GADD34 binds to protein phosphatase-1 (PP1) and can attenuate translational elongation of key transcriptional factors through dephosphorylation of eukaryotic initiation factor-2alpha. We reported previously that the human trithorax leukemia fusion protein (HRX) can bind to GADD34 and abrogate GADD34-mediated apoptosis in response to UV irradiation. We found that hSNF5/INI1, a component of the hSWI/SNF chromatin remodeling complex, also binds to GADD34 and can coexist with GADD34 and HRX fusion proteins as a trimolecular complexes in vivo. In the present report, we demonstrate that hSNF5/INI1 binds to GADD34 in part through the PP1 docking site within a domain homologous to herpes simplex virus-1 ICP34.5. We found that hSNF5/INI1 can bind PP1 independently and weakly stimulate its phosphatase activity in solution and in complex with GADD34. hSNF5/INI1 and PP1 do not compete for binding to GADD34 but rather form a stable heterotrimeric complex with GADD34. We also show that Epstein-Barr nuclear protein 2, which binds hSNF5/INI1, can disrupt hSNF5/INI1 binding to GADD34 and partially reverse the GADD34-mediated growth suppression function in Ha-ras expressing HIH-3T3 (3T3-ras) cells. These results implicate hSNF5/INI1 in the function of GADD34 and suggest that hSNF5/INI1 may regulate PP1 activity in vivo.


Cell differentiation in benign cutaneous fibrous histiocytomas. An immunohistochemical study with antibodies to histiomonocytic cells and intermediate filament proteins.
Seven benign cutaneous fibrous histiocytomas (BFHs) were investigated immunohistochemically by using a panel of antibodies to histiomonocytic cells and intermediate filament proteins. Immunoreactivity with antimacrophage antibodies was observed in all tumors in a significant but varying proportion of the tumor cells. All tumors were also positive for vimentin. In addition, two of the BFHs were positive for cytokeratin and one for desmin. The results suggest that BFHs either display a true histiomonocytic trait or, alternatively, contain a prominent histiomonocytic infiltration. Some BFHs may be related to smooth muscle cells as indicated by desmin positivity. The occasional occurrence of cytokeratin in BFHs could also be explained by smooth muscle cell differentiation.


Intrinsic Sensing and Evolving Internal Model Control of Compact Elastic Module for a Lower Extremity Exoskeleton.
To achieve strength augmentation, endurance enhancement, and human assistance in a functional autonomous exoskeleton, control precision, back drivability, low output impedance, and mechanical compactness are desired. In our previous work, two elastic modules were designed for human-robot interaction sensing and compliant control, respectively. According to the intrinsic sensing properties of the elastic module, in this paper, only one compact elastic module is applied to realize both purposes. Thus, the corresponding control strategy is required and evolving internal model control is proposed to address this issue. Moreover, the input signal to the controller is derived from the deflection of the compact elastic module. The human-robot interaction is considered as the disturbance which is approximated by the output error between the exoskeleton control plant and evolving forward learning model. Finally, to verify our proposed control scheme, several experiments are conducted with our robotic exoskeleton system. The experiment shows a satisfying result and promising application feasibility.


[Diagnostic scintigraphy and effectiveness of 131I radioiodine therapy in differentiated thyroid carcinoma (DTC)].
Since the effect of pre-therapeutic scintigraphy on the outcome of DTC treatment is debated, we evaluated factors affecting the effectiveness of (131)I therapy with respect to the delay between diagnostic scintigraphy and the application of radioiodine. In the studied group of 60 patients with DTC, mean age 54.6 +/- 13.0 years, four weeks prior to the planned diagnostics, L-thyroxine was withdrawn and the following tests performed: (131)I (4 MBq) uptake above the neck, thyroid volume by USG, TSH and hTg level. Wholebody scintigraphy (37 MBq) was performed. The time between this diagnostic scintigraphy and application of (131)I (3657 MBq) was calculated. Based on whole-body 131I scintigraphy (74 MBq) performed 1 year after radioiodine treatment, the patients were divided into: group I - 42 patients with no tracer accumulation, and group II--18 patients who continued to accumulate (131)I in the neck. The differences between the median values of (131)I uptake and of thyroid volumes, and between the TSH and hTg median values in the two groups of patients were found not to be statistically significant. The average times between diagnostic scintigraphy and (131)I treatment in group I and II (9.4 vs. 8.3 weeks, respectively) were not significantly different either. Despite the different effectiveness of supplementary (131)I treatment, patients in group I and group II showed no statistically significant differences in the studied parameters. It appears that the diagnostic (131)I activity of 37 MBq and the time between diagnostic scintigraphy and application of (131)I did not have any effect on the results of the treatment in our group of patients.


Facial Asymmetry in Unilateral Condylar Hyperplasia: Comparing Treatment for Active versus Burnt-Out Disease.
Facial asymmetry caused by unilateral condylar hyperplasia requires treatment to address facial and occlusal imbalances. There is no definitive evidence to suggest that a single intervention strategy (during either active condylar overgrowth or the burnt-out phase) results in better/more symmetric correction. This study sought to quantify preoperative and postoperative facial asymmetry in unilateral condylar hyperplasia patients comparing treatment for active versus burnt-out disease. Preoperative and postoperative three-dimensional photographs were obtained. Images were compared to those of unaffected controls as a standard for normal facial symmetry. Facial asymmetry was assessed using root-mean-square deviation. Paired t tests were performed to compare the root-mean-square deviations of preoperative and postoperative images between the unilateral condylar hyperplasia groups and against controls. Forty patients were included (11 active, nine burnt-out, and 20 controls) and 60 three-dimensional images were evaluated. Preoperatively, patients in the burnt-out group had worse asymmetry than those with active unilateral condylar hyperplasia (p = 0.011). Both groups demonstrated significantly improved symmetry postoperatively (active, p = 0.0069; burnt-out, p = 1.74E-4). However, burnt-out patients remained with some residual asymmetry (p = 4.75E-4), whereas their active counterparts showed no significant difference compared to unaffected controls (p = 0.089). Patients with end-stage unilateral condylar hyperplasia have more severe facial asymmetry that is more difficult to normalize compared to earlier intervention during active unilateral condylar hyperplasia. These findings suggest that, if possible, corrective intervention is preferable during active unilateral condylar hyperplasia. Risk, II.


Chronic traumatic encephalopathy-neuropathologic change in a routine neuropathology service: 7-year follow-up.
To follow our 2016 study of chronic traumatic encephalopathy neuropathologic change (CTE-NC) in our forensic autopsy service, we prospectively screened all cases with clinical histories of multiple concussions, persistent post-head injury symptoms, or ≥3 hospital investigations for head injuries from 2016 to 2022 inclusive using hyperphosphorylated tau (p-tau) immunostaining. The cases had routine brain sampling plus 4-6 additional lateral hemisphere samples. When "pathognomonic" CTE-NC lesions were identified, additional p-tau immunostaining was done for CTE-NC staging. Of ∼1100 adult brains aged 18-65 years examined, 85 were screened, and 16 were positive for CTE-NC (2 women, 14 men, ages 35-61 years, median 47 years). Alcohol abuse was documented in 14 of 16 (8 in combination with other substances); 5 had developmental brain anomalies (2 presumed genetic, 3 from acquired perinatal insults). Widespread p-tau deposits (high CTE-NC) were found in 7 of 16. Old brain contusions were present in 9 of 16, but CTE-NC did not colocalize. Of particular interest were (1) a man with FGFR3 mutation/hypochondroplasia and life-long head banging, (2) a woman with cerebral palsy and life-long head banging, and (3) a man with bilateral peri-Sylvian polymicrogyria, alcohol abuse, and multiple head injuries. Thus, CTE-NC occurs in association with repeated head trauma outside contact sports. Substance abuse is a common determinant of risk behavior. The utility of diagnosing mild-/low-stage CTE-NC in this population remains to be determined.


Renal Oxygenation in the Pathophysiology of Chronic Kidney Disease.
Chronic kidney disease (CKD) is a significant health problem associated with high morbidity and mortality. Despite significant research into various pathways involved in the pathophysiology of CKD, the therapeutic options are limited in diabetes and hypertension induced CKD to blood pressure control, hyperglycemia management (in diabetic nephropathy) and reduction of proteinuria, mainly with renin-angiotensin blockade therapy. Recently, renal oxygenation in pathophysiology of CKD progression has received a lot of interest. Several advances have been made in our understanding of the determinants and regulators of renal oxygenation in normal and diseased kidneys. The goal of this review is to discuss the alterations in renal oxygenation (delivery, consumption and tissue oxygen tension) in pre-clinical and clinical studies in diabetic and hypertensive CKD along with the underlying mechanisms and potential therapeutic options.


The outcome of bacterial arthritis: a prospective community-based study.
To assess the outcome and adverse prognostic factors of bacterial arthritis (BA). In a prospective community survey of BA, data were collected at the time of diagnosis and at a mean of 2 years later. A poor patient outcome was defined as death due to BA or severe overall functional deterioration. A poor joint outcome was defined as amputation, arthrodesis, prosthetic surgery, or severe functional deterioration. Possible prognostic factors were analyzed by univariate analysis. BA was diagnosed in 154 patients, 121 adults and 33 children. One-half of the adults had a preexisting joint disease and 29% of the infected joints contained synthetic material. The patient outcome was poor in 21% of all patients, and the joint outcome was poor in 33% of the surviving patients. Adverse prognostic factors were an older age, preexisting joint disease, and an infected joint containing synthetic material. These factors were interrelated. There was no association between a poor outcome and young age, comorbidity, immunosuppressive medication, functional class, multiple infected joints, type of microorganism, or treatment delay. BA had a poor outcome in almost one-half of the patients. Patients who were older, had a preexisting joint disease, and/or had an infected joint containing synthetic material had the poorest prognosis.


Effects on plasma amino acid concentrations and hepatic branched-chain alpha-keto acid dehydrogenase activity of feeding rats diets containing 9 or 50% casein.
Plasma concentrations of amino acids and alpha-ketoisocaproate and alpha-keto-gamma- methiolbutyrate decarboxylation activities in livers of rats trained to eat 9 or 50% casein diets for 5 hours/day, were measured one-half hour before and one-half and 3 hours after the start of the feeding period. Decarboxylation of both alpha-ketoisocaproate and alpha-keto-gamma- methiolbutyrate by liver increased significantly within one-half hour after rats had ingested either the 9 or the 50% casein diet. Liver decarboxylation activity of rats fed the 50% casein diet was from two- to fivefold higher than that of rats fed the 9% casein diet. The greatest difference was observed when calcium, NAD and coenzyme A were included in the decarboxylation assay medium. Although the activity of the branched-chain alpha-keto acid dehydrogenase increased in response to food ingestion, plasma concentrations of branched-chain amino acids also increased greatly after the ingestion of food. The similarity in the responses of alpha-ketoisocaproate and alpha-keto-gamma- methiolbutyrate decarboxylation in rats fed diets differing in protein content and subjected to different feeding regimens allows us to suggest that the branched-chain alpha-keto acid dehydrogenase is responsible, in part, for the oxidative decarboxylation of the alpha-keto acid analog of methionine. J. Nutr . 114: 1025-1034, 1984.


Critical behavior of non-order-parameter fields.
We show that all of the relevant features of a phase transition can be determined using a non-order-parameter field which is a physical state of the theory. This fact allows us to describe the deconfining transition of the pure Yang-Mills theory via the physical excitations rather than using the Polyakov loop.


ATIC Gene Polymorphism and Histologic Response to Chemotherapy in Pediatric Osteosarcoma.
Accumulating evidence indicates that polymorphisms in folate pathway genes play a role in response to methotrexate (MTX) treatment in various diseases. This study explored the influence of these genetic polymorphisms on treatment outcome in pediatric osteosarcoma. Blood and tissue samples from 48 osteosarcoma patients were obtained, and the following polymorphisms were analyzed; SLC19A1 80G>A, DHFR 829C>T, MTHFR 677C>T, MTHFR 1298A>C, and ATIC 347C>G. We evaluated associations between these candidate gene polymorphisms and treatment outcome, including histologic response and event-free and overall survival, of patients treated with high-dose MTX. Patients with ATIC 347C>G exhibited a good histologic response to chemotherapy (odds ratio, 0.13; 95% confidence interval, 0.017-0.978; P=0.048). However, none of these single nucleotide polymorphisms we examined affected event-free survival or overall survival rates of the patients. Even though the role of single nucleotide polymorphisms of ATIC in chemotherapy-induced tumor necrosis has not been investigated yet, the ATIC 347C>G polymorphism may influence the levels of adenosine after MTX treatment, which may affect the histologic response of osteosarcoma. This relationship warrants validation in a larger, prospective cohort study.


Identification of repetitive, genome-specific probes in crucifer oilseed species.
Direct amplification of minisatellite DNA by PCR (DAMD PCR) was used to amplify and subsequently clone several fragments of DNA from crucifer species. The PCR-derived fragments of DNA were generated using known minisatellite core sequences as PCR primers. Southern hybridization of these putative minisatellite DNA fragments revealed that many were genome-specific; they hybridized with high affinity only to the genomic DNA of the species from which they were cloned. The DNA fragments were believed to be dispersed in the genome, based on smear-like hybridization signals on EcoRI-, BamHI-, and HindIII-digested genomic DNA. Genome-specific probes were specifically isolated from Brassica rapa (A genome), Brassica nigra (B genome), and Sinapis alba in addition to several other crucifer species. The sequence of a B. rapa specific probe (pBr17.1.3A) contained a minisatellite region that could be divided into three tandem repeats; each repeat contained between two and five subrepeats and each subrepeat shared a highly conserved core region of 29 bp. This minisatellite sequence also hybridized with high affinity to the A genome species B. napus and B. juncea. This research showed that dispersed, genome-specific probes can be isolated using DAMD PCR and that these probes could be used to detect and quantify alien DNA present in progeny from intergeneric or interspecific crosses.


Maladaptive Schemas as Mediators in the Relationship Between Child Sexual Abuse and Displaced Aggression.
Child sexual abuse is one of the most serious forms of abuse due to the psychological consequences that persist even into adulthood. Expressions of anger among child sexual abuse survivors remain common even years after the event. While child sexual abuse has been extensively studied, the expression of displaced aggression has been studied less. Some factors, such as the maladaptive early schemas, might account for this deficiency. The objective of this study was to analyze the relationships between child sexual abuse, displaced aggression, and these schemas according to gender and determine if these early schemas mediate the relationship between child sexual abuse and displaced aggression. A total of 168 Spanish subjects who were victims of child sexual abuse completed measures of childhood trauma, displaced aggression, and early maladaptive schemas. The results depict the relationship between child sexual abuse, displaced aggression, and early maladaptive schemas. Women scored higher than men in child sexual abuse, emotional abuse, disconnection or rejection and impaired autonomy. Mediational analysis found a significant mediation effect of disconnection or rejection on the relationship between child sexual abuse and displaced aggression; however, impaired autonomy did not mediate significantly.


Sympathetic orchidopathia.
Subfertility has recently been shown to follow unilateral torsion of the spermatic cord in more than half the patients studied. Since the anatomical anomaly that predisposes to torsion (a high investment of the tunica vaginalis) is commonly bilateral, there could be an associated congenital defect in spermatogenesis on each side. Alternatively, autoantigens escaping from the ischaemic or 'exciting' testis could trigger an immunological response which damages the contralateral or 'sympathising' testis. Demonstration of an autoallergic (sympathetic) orchidopathia, analogous to sympathetic ophthalmia, would fundamentally alter the management of testicular torsion.


A comparison of simian rotavirus SA11 preparations maintained in different laboratories.
Preparations of simian rotavirus SA11 maintained in different laboratories were compared with each other by polyacrylamide gel electrophoresis of genomic RNA. Differences in the migration of genome segments 4, 5 and 7 allowed the classification of eight virus preparations into four electrophoretic types.


[Molecular mechanisms of individual platelet reactivity in hematuria secondary to lithotripsy].
To investigate the mechanisms of individual platelet reactivity to ADP and adrenaline associated with the variability of hematuria after lithotripsy in patients with chronic obstructive pyelonephritis (COPN). The study included 41 COPN patients admitted to the Department of Urology for lithotripsy (LT). The contact ultrasonic LT was performed using the Karl Storz Calcuson Ultrasonic Lithotripsy System. Postoperative hematuria was assessed by microscopic red blood cell count. Platelets were separated from the citrated peripheral blood by centrifugation. Platelet aggregation was measured by Chrono-log aggregometer using agonists (ADP, adrenaline) at a concentration of EC50 and EU10. There were three types of platelet functional response to ADP and adrenaline after LT (increased, unchanged and decreased aggregation), but the predominant type of individual response was increased platelet aggregation. Testing 24 hours after LT revealed 7 platelet phenotypes differing in functional activity of 2-adrenoceptor agonist and purine receptors (R2Y1 and R2Y12). Normal purine receptor activity was associated with the ability of platelets to respond to adrenaline by increasing the functional activity aimed at limiting hematuria. Reduced platelet response to ADP after LT reaching the level of hyporesponsiveness may be viewed as a predictor of severe hematuria after surgery. Individual platelet reactivity, manifested by the interaction of ADP and adrenaline agonist, determines the effectiveness of the increase in pro-aggregation capacity of platelets in developing postoperative hematuria.


Evidence for Quinone Redox Chemistry Mediating Daytime and Nighttime NO2-to-HONO Conversion on Soil Surfaces.
Humic acid (HA) is thought to promote NO2 conversion to nitrous acid (HONO) on soil surfaces during the day. However, it has proven difficult to identify the reactive sites in natural HA substrates. The mechanism of NO2 reduction on soil surrogates composed of HA and clay minerals was studied by use of a coated-wall flow reactor and cavity-enhanced spectroscopy. Conversion of NO2 to HONO in the dark was found to be significant and correlated to the abundance of C-O moieties in HA determined from the X-ray photoelectron spectra of the C 1s region. Twice as much HONO was formed when NO2 reacted with HA that was photoreduced by irradiation with UV-visible light compared to the dark reaction; photochemical reactivity was correlated to the abundance of C═O moieties rather than C-O groups. Bulk electrolysis was used to generate HA in a defined reduction state. Electrochemically reduced HA enhanced NO2-to-HONO conversion by a factor of 2 relative to non-reduced HA. Our findings suggest that hydroquinones and benzoquinones, which are interchangeable via redox equilibria, contribute to both thermal and photochemical HONO formation. This conclusion is supported by experiments that studied NO2 reactivity on mineral surfaces coated with the model quinone, juglone. Results provide further evidence that redox-active sites on soil surfaces drive ground-level NO2-to-nitrite conversion in the atmospheric boundary layer throughout the day, while amphoteric mineral surfaces promote the release of nitrite formed as gaseous HONO.


Effect of tumor necrosis factor alpha and vascular permeability growth factor on albuminuria in rats.
The purposes of this study were to measure the serum levels of vascular permeability growth factor (VPGF) and tumor necrosis factor alpha (TNFalpha) in minimal lesion nephrotic syndrome (MLNS) patients and to assess their effect on albuminuria in rats. Serum for VPGF and TNFalpha was obtained during relapse and remission from 18 MLNS patients. Tumor necrosis factor alpha was infused at the rate of 10 and 20 ng/h and VPGF at the rate of 20 and 40 ng/h for 5 days into the left renal artery of rats. Urinary albumin (24-h collection) was measured prior to infusion and on days 2, 4 and 5. Rats infused with 1% bovine serum albumin served as controls. Serum VPGF and TNFalpha levels in MLNS patients in relapse were not different from those seen during remission. A significant increase in albuminuria was observed on day 4 and 5 only when rats were infused with TNFalpha at the rate of 20 ng/h as compared to the excretion seen in same animals prior to the infusion of cytokine and on days 4 and 5 of normal controls. Neither VPGF nor TNFalpha seems to be the circulating pathogenic cytokine for proteinuria in MLNS. However, TNFalpha may contribute to the increased albuminuria via a paracrine effect at the glomerulus.


[Psychopathology of expression in the German language, countries. Attempt at a summary].
The foundations of the modern psychopathology of pictorial expression were laid more than a half-century ago by a Frenchman, Marcel Réja (1907), à Swiss, Morgenthaler (1921), and a German, Prinzhorn (1922). In the early days, this was a matter of marginal interest for a handful of psychiatrists and it attracted little official attention. Since the last war however, and especially since the establishment of the S.I.P.E., this special branch of psychopathology has won the recognition to which it is entitled. In French-speaking and other Latin language countries, Volmat's book (1956) provided a powerful stimulus to research. Numerous studies were also undertaken in German-speaking countries. A Swiss psychiatrist, living in a polyglot country, surrounded by some of the world's major linguistic zones, is especially well situated to follow the evolution of ideas. He soon comes to realize that these language areas are sharply separated by very real barriers. In the past few years, the lack of communication between French and German-speaking investigators has become increasingly apparent. Within the limits of a single report, it is impossible to cover all of the work that has been published in German since the time of Prinzhorn. The author has restricted himself to a selection of studies which he personally regards as important. He has sought to retrace and bring into view a line of thought which has proved to be productive and which has not received the attention it deserves in the French-language literature.


Different effect of Helicobacter pylori on the human gastric antral and body mucosal intracellular mucin.
To elucidate the role of Helicobacter pylori infection in the pathogenesis of gastric ulcer, we investigated the intracellular mucin content by measuring the periodic acid-Schiff-Alcian blue (PAS-AB)-stained substances, by means of computer, in the biopsy sample of gastric mucosa from patients with and without H. pylori infection. In the antral mucosa the intracellular PAS-AB-stained mucin content was significantly smaller in patients with infection than in patients without infection, whereas in the oxyntic gland mucosa the intracellular mucin content showed no significant change between patients with and without infection. In an animal study we investigated the effect of ammonia, which might be produced by H. pylori in the presence of urea. The ammonia, administered orally, caused a greater decrease of intracellular PAS-AB-stained mucin content in the gastric antral mucosa than in the body mucosa, in a dose-dependent manner. The results suggested that H. pylori infection had a different effect on the gastric mucosal intracellular PAS-AB-stained mucin and lowered specifically the antral intracellular PAS-AB-stained mucin content, possibly due to generation of ammonia by H. pylori.


The contributions of language control to executive functions: From the perspective of bilingual comprehension.
Previous studies have suggested that bilingual production experience has beneficial effects on executive functions. In the current study, four experiments were conducted to investigate whether bilingual comprehension experience influences executive functions. In Experiments 1 and 2, Chinese-English bilinguals completed a flanker task interleaved with a language comprehension task (reading comprehension in Experiment 1 and listening comprehension in Experiment 2). There were three blocks distinguished by language context, with a Chinese (L1) block, an English (L2) block, and a mixed (L1 and L2) block. Results showed that performance in the mixed block was better on both congruent and incongruent flanker trials when compared with the L1 and L2 blocks, indicating better monitoring functions overall. In Experiments 3 and 4 (reading comprehension and listening comprehension, respectively), participants were also exposed to three language contexts (i.e., L1, L2, and mixed block) but performed a non-conflict control task that did not require any conflict resolution. The results of Experiments 3 and 4 showed similar performance under the three different language contexts. Taken together, these results indicate that language control mechanisms involved in bilingual comprehension contribute to domain-general executive control performance. The results suggest a monitoring mechanism establishes a bridge connecting executive functions and bilingual language control during comprehension.


Hermeneutic notions augment cultural safety education.
Nurses are beginning to demand educational approaches that confront racism, rather than teach cultural diversity. One example of the latter approach is the introduction of kawa whakaruruhau, or cultural safety, in nursing and midwifery education in New Zealand. In the nursing and midwifery context of kawa whakaruruhau, nurses and midwives recognize, respect, and nurture the unique cultural identity of New Zealand's indigenous people, the tangata whenua, and safely meets their needs, expectations, and rights. In this article, I integrate literature pertaining to the implementation of cultural safety with the findings of a hermeneutic project that described the experience of nursing people from cultures other than one's own, and argue that the Gadamerian notions of "horizon," "prejudice," and "play" can be used to facilitate understanding of the tensions and contradictions inherent in cross-cultural practice. In addition, I recommend strategies that enable students to explore the prejudices, paradoxes, and possibilities experienced personally and professionally. As Gadamer noted, the art is in seeing what is questionable. There is also art in knowing how to question in a manner that makes new understanding possible.


Detailed comparison between StochSim and SSA.
Morton-Firth and Bray's stochastic simulator (StochSim) and Gillespie's stochastic simulation algorithm (SSA) are two important methods for stochastic modelling and simulation of biochemical systems. They have been widely applied to different biological problems. A key question is discussed here: Are these two methods equivalent? These two methods are compared using fundamental probability analysis. The analysis clearly shows that, when the time step in the StochSim is chosen very small, the StochSim can be viewed as a first-order approximation to the SSA. The analysis also explains why the SSA is usually much more efficient than the StochSim for biochemical systems. However, when multistate species present in a system, the StochSim clearly shows its advantage. The Complexity analysis is used to explain this advantage. The hybrid SSA (HSSA) is proposed to combine the advantages of both the StochSim and SSA. When the populations of the multistate species are small, the HSSA is very efficient. Numerical experiments are presented to verify the analysis.


Thrombophilia in Korean patients with arterial or venous thromboembolisms.
To determine the prevalence of thrombophilia in Korean patients with an arterial thromboembolism (ATE) or a venous thromboembolism (VTE), and to evaluate the characteristic of VTE in patients with thrombophilia. Hospital records of 294 patients (228 with VTE, 66 with ATE) including two foreign ones (mean age, 51.4 years) who underwent thrombophilia testing between August 2006 and March 2015 were reviewed retrospectively. In general, such screening was performed according to the guidelines of the international consensus statement for VTE. Thrombophilia testing included evaluations of the factor V Leiden and prothrombin G20210A mutations, levels of proteins C and S and antithrombin, and antiphospholipid antibody syndrome (APLS). A factor V Leiden mutation was not found in the 292 Korean patients. A prothrombin G21210A mutation was investigated in 33 patients but none was found. Among 226 Korean patients with VTE, 130 demonstrated no thrombophilia and 55 patients did after exclusion of 41 patients without confirmatory test. The most common form was protein S deficiency (31 of 55, 56%) followed by protein C deficiency, antithrombin deficiency, and APLS. When comparing patients with a VTE or deep vein thrombosis (DVT) according to the presence of thrombophilia, thrombophilia was associated with younger age (P = 0.001 for VTE; P < 0.001 for DVT) and a family history (P < 0.001 for VTE and DVT). We did not find any factor V Leiden mutation in Korean subjects at high risk for thrombophilia. Therefore, this testing is not warranted. Thrombophilia was associated with VTE in younger age and a family history.


Endotoxemia and bacteremia in patients with sepsis syndrome in the intensive care unit.
To study circulatory endotoxin (ET) in patients with sepsis syndrome (SS) in order to answer three questions: (a) How often and at which concentration is ET present in the plasma of patients with SS and is the presence of ET a prognostic marker in this situation? (b) Is detection of ET helpful in predicting Gram-negative bacterial infections with or without bacteremia? (c) What are the kinetics of clearance of ET concentrations in plasma? Prospective study of consecutive patients fulfilling Bone's criteria for SS. Medical ICU in a teaching hospital. The study included 93 patients. The simplified acute physiologic score was 19 +/- 6, 49 percent were in shock, and 54 percent were mechanically ventilated. The mortality at day 28 was 53 percent. Endotoxin determinations and blood cultures were performed simultaneously at the onset (day 1) of SS. Samples were collected on several days from 48 patients. Endotoxin concentration was determined using an end point chromogenic Limulus assay. For the first ET determination, the mean circulatory level (mean +/- SEM) was calculated among patients with detectable ET, thus excluding patients with a null value for ET. On day 1, ET was detected in 44 patients (47 percent; 60.2 +/- 16.5 pg/ml) and was statistically more frequent in patients with shock, elevated plasma lactate, and organ failure. There was no statistical difference for age, gender, ratio of PaO2 to fraction of inspired oxygen. Among patients with proven Gram-negative bacterial infection (n = 46), ET was detected in 67 percent as compared with 28 percent without Gram-negative bacterial infection (p = 0.0001). On day 1, among 19 patients who had positive blood cultures with Gram-negative bacteria (GNB), 15 had detectable ET (79 percent, 61 +/- 22 pg/ml). In 14 other patients whose blood cultures were positive for GNB but became negative on day 1, 9 had detectable ET (64 percent; 36 +/- 6.5 pg/ml). Endotoxin declined linearly between days 1 and 4. In our study, the plasma ET concentration predicts neither Gram-negative infection, with or without bacteremia, nor the outcome. However, when ET is present in the plasma of patients with SS it remains detectable for a long period of time as compared to its rapid disappearance from plasma of animals or healthy human volunteers receiving ET intravenously. This slow clearance of ET suggests either a continuous release or a defect in its clearance.


The ADRA2B gene in the production of false memories for affective information in healthy female volunteers.
False memories are common memory distortions in everyday life and seem to increase with affectively connoted complex information. In line with recent studies showing a significant interaction between the noradrenergic system and emotional memory, we investigated whether healthy volunteer carriers of the deletion variant of the ADRA2B gene that codes for the α2b-adrenergic receptor are more prone to false memories than non-carriers. In this study, we collected genotype data from 212 healthy female volunteers; 91 ADRA2B carriers and 121 non-carriers. To assess gene effects on false memories for affective information, factorial mixed model analysis of variances (ANOVAs) were conducted with genotype as the between-subjects factor and type of memory error as the within-subjects factor. We found that although carriers and non-carriers made comparable numbers of false memory errors, they showed differences in the direction of valence biases, especially for inferential causal errors. Specifically, carriers produced fewer causal false memory errors for scripts with a negative outcome, whereas non-carriers showed a more general emotional effect and made fewer causal errors with both positive and negative outcomes. These findings suggest that putatively higher levels of noradrenaline in deletion carriers may enhance short-term consolidation of negative information and lead to fewer memory distortions when facing negative events.


Increase in glycosylated and nonglycosylated serum ferritin in chronic alcoholism and their evolution during alcohol withdrawal.
Increase in serum ferritin, which occurs in 40 to 70% of chronic alcoholics, remains poorly understood. We tested the hypothesis which links hyperferritinemia in chronic alcoholism not only to ferritin release from damaged liver cells, but also to increased ferritin secretion. Fifty-eight chronic alcoholic patients hospitalized for alcohol withdrawal were subdivided into three groups according to liver damage. Their serum levels of ferritin and ferritin bound to concanavalin A (ferritin Con A, which represents glycosylated, i.e., secreted ferritin) were measured serially on days 1, 7, and 11 of withdrawal and compared with a control group. The results were: (1) Total serum ferritin increased in alcoholics. Both free and Con A ferritins increased in equal proportions, the ferritin Con A to total ferritin ratio remaining unchanged. The increase was dependent on liver disease, as both free and Con A ferritins increased significantly with the severity of liver illness. Serum ferritin levels were related to iron status: it correlated with hepatic iron concentration (obtained in 19 patients); however, high ferritin values were not related to the degree of iron overload, which remained low. Finally, there was no correlation between serum ferritin and the average of alcohol consumption. (2) Both free and Con A ferritin decreased by about 40% during alcohol withdrawal. In conclusion, we have demonstrated that (1) total serum ferritin is increased in chronic alcoholism and (2) that this ferritin increase is due in part to an increase in ferritin Con A, proof of the induction of ferritin secretion by alcohol in humans.


Partial liquid ventilation for the prevention of mortality and morbidity in paediatric acute lung injury and acute respiratory distress syndrome.
Acute lung injury and acute respiratory distress syndrome are syndromes of severe respiratory failure. Children with acute lung injury or acute respiratory distress syndrome have high mortality and the survivors have significant morbidity. Partial liquid ventilation is proposed as a less injurious form of respiratory support for these children. Uncontrolled studies in adults have shown improvements in gas exchange and lung compliance with partial liquid ventilation. A single uncontrolled study in six children with acute respiratory syndrome showed some improvement in gas exchange during three hours of partial liquid ventilation. This review was originally published in 2004, updated in 2009 and again in 2012. To assess whether partial liquid ventilation reduces mortality or morbidity, or both, in children with acute lung injury or acute respiratory distress syndrome. In this updated review, we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 11); CINAHL (Cumulative Index to Nursing & Allied Health Literature) via Ovid (1982 to November 2011); Ovid MEDLINE (1950 to November 2011); and Ovid EMBASE (1982 to November 2011). The search was last performed in August 2008. We included randomized controlled trials (RCTs) which compared partial liquid ventilation with other forms of ventilation in children (aged 28 days to 18 years) with acute lung injury or acute respiratory distress syndrome. Trials had to report one or more of the following: mortality; duration of mechanical ventilation, respiratory support, oxygen therapy, stay in the intensive care unit, or stay in hospital; infection; long-term cognitive impairment, neurodevelopmental progress, or other long-term morbidities. We independently evaluated the quality of the relevant studies and extracted the data from the included studies. Only one study enrolling 182 patients (reported as an abstract in conference proceedings) was identified and found eligible for inclusion; the authors reported only limited results. The trial was stopped prematurely and was, therefore, under-powered to detect any significant differences and at high risk of bias. The only available outcome of clinical significance was 28-day mortality. There was no statistically significant difference between groups, with a relative risk for 28-day mortality in the partial liquid ventilation group of 1.54 (95% confidence interval 0.82 to 2.9). There is no evidence from RCTs to support or refute the use of partial liquid ventilation in children with acute lung injury or acute respiratory distress syndrome. Adequately powered, high quality RCTs are still needed to assess its efficacy. Clinically relevant outcome measures should be assessed (mortality at discharge and later, duration of both respiratory support and hospital stay, and long-term neurodevelopmental outcomes). The studies should be published in full.


Catalase increases ethanol oxidation through the purine catabolism in rat liver.
Hepatic ethanol oxidation increases according to its concentration and is raised to near-saturation levels of alcohol dehydrogenase (ADH); therefore, re-oxidation of NADH becomes rate limiting in ethanol metabolism by the liver. Adenosine is able to increase liver ethanol oxidation in both in vivo and in vitro conditions; the enhancement being related with the capacity of the nucleoside to accelerate the transport of cytoplasmic reducing equivalents to mitochondria, by modifying the subcellular distribution of the malate-aspartate shuttle components. In the present study, we explored the putative effects of adenosine and other purines on liver ethanol oxidation mediated by non-ADH pathways. Using the model of high precision-cut rat liver slices, a pronounced increase of ethanol oxidation was found in liver slices incubated with various intermediates of the purine degradation pathway, from adenosine to uric acid (175-230%, over controls). Of these, urate had the strongest (230%), whereas xanthine had the less pronounced effect (178% over controls). The enhancement was not abolished by 4-methylpyrazole, indicating that the effect was independent of alcohol dehydrogenase. Conversely, aminotriazole, a catalase inhibitor, completely abolished the effect, pointing out that this enhanced ethanol oxidation is mediated by catalase activity. It is concluded that the H2O2 needed for catalase activity is derived from the oxidation of (hypo)xanthine by xanthine oxidase and the oxidation of urate by uricase. The present and previous data led us to propose that, depending on the metabolic conditions, adenosine might be able to stimulate the metabolism of ethanol through different pathways.


Energy requirement for liquid holding recovery from UV- and DEB-induced damage in rad mutants of Saccharomyces cerevisiae.
Respiratory deficient (rho o) strains respond to liquid holding in buffer alone with a sharp decrease of cell survival. In buffer with 0.02% glucose rho o strains behave similarly as rho+ strains. After UV or DEB inactivation rho o strains derived from rho+ rad mutants capable of LHR in buffer alone, manifest this capacity in glucose buffer. In some respiratory proficient rad mutants LHR is enhanced or induced by holding in glucose buffer, e.g. DEB inactivated rad3, rad6 and rad14. In such mutants the number of mitochondrial profiles was found to be 3 to 4 times lower than in the wild-type RAD or in rad mutants with LHR insensitive to glucose. This suggests that mutants with glucose-enhanced LHR are defective in energy metabolism and require exogenous energy supply for initiation of liquid holding repair capacity. In UV-irradiated JG-1 (rad1-1), rad3 and rad11 as well as in DEB-inactivated rad7, rad11, rad19 and rad20 the inability of LHR is a constitutive phenomenon and cannot be overcome by exogenous energy supply.


Deep Neuromuscular Blockade Improves Laparoscopic Surgical Conditions: A Randomized, Controlled Study.
Sustained deep neuromuscular blockade (NMB) during laparoscopic surgery may facilitate optimal surgical conditions. This exploratory study assessed whether deep NMB improves surgical conditions and, in doing so, allows use of lower insufflation pressures during laparoscopic cholecystectomy. We further assessed whether use of low insufflation pressure improves patient pain scores after surgery. This randomized, controlled, blinded study (NCT01728584) compared use of deep (1-2 post-tetanic-counts) or moderate (train-of-four ratio 10%) NMB, and lower (8 mmHg) or higher (12 mmHg; 'standard') insufflation pressure in a 2 × 2 factorial design. Primary endpoint was surgeon's overall satisfaction with surgical conditions, rated at end of surgery using an 11-point numerical scale. Post-operative pain scores were also evaluated. Data were analyzed using analysis of covariance. Of 127 randomized patients, 120 had evaluable data for the primary endpoint. Surgeon's score of overall satisfaction with surgical conditions was significantly higher with deep versus moderate NMB indicated by a least-square mean difference of 1.1 points (95% confidence interval 0.1-2.0; P = 0.026). Furthermore, strong evidence of an effect was observed for standard versus low pressure: least-square mean difference of 3.0 points (95% confidence interval 2.1-4.0; P < 0.001). No significant difference was observed in average pain scores within 24 h post-surgery for low versus standard pressure [0.17 (95% confidence interval -0.67 to +0.33); P = 0.494]. Although associated with significantly improved surgical conditions, deep NMB alone was insufficient to promote use of low insufflation pressure during laparoscopic cholecystectomy. Furthermore, low insufflation pressure did not result in reduced pain, compared with standard pressure. ClinicalTrials.gov identifier, NCT01728584. Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.


Medical management of gastroesophageal reflux disease.
Antisecretory therapies that raise intragastric pH provide the best healing of the esophageal mucosal damage that occurs in gastroesophageal reflux disease. Continuous maintenance therapy is also effective to reduce the likelihood of recurrence of esophagitis and control symptoms in the long term. Proton pump inhibitor (PPI) therapy is an effective approach for healing esophagitis and controlling symptoms. Endoscopic and surgical treatments may provide an option for patients who are refractory to PPIs in whom reflux has been clearly demonstrated. Long-term antireflux medication is often needed after surgical treatment because of persisting or recurrent pathologic reflux and symptoms. An alternative approach to controlling transient lower esophageal sphincter relaxations, such as the GABA-B agonists, deserves further study.


The impact of military sexual trauma and warfare exposure on women veterans' perinatal outcomes.
In the general population, history of trauma is associated with a range of adverse perinatal outcomes, which have long-term negative consequences for both mother and child. Research examining the impact of trauma, particularly trauma occurring during military service, on perinatal outcomes among women veterans is still in its nascence. The current study examined if warfare exposure and military sexual trauma (MST) contributed unique variance to the prediction of a broad range of adverse perinatal outcomes (i.e., preterm birth, full-term birth, infant birth weight, postpartum depression and/or anxiety). Women veterans living across the U.S. (oversampled for veterans living in high crime communities) completed a mail-based survey, and reported information about all pregnancies that occurred since enlistment in the military. They also reported on warfare exposure and MST using the Deployment Risk and Resilience Inventory. A total of 911 women reported on 1,752 unique pregnancies. Results revealed that MST, but not warfare exposure, was associated with having a lower infant birth weight (B = -17.30, SE = 5.41), a slight decrease in the likelihood of having a full-term birth (OR = .97, 95% CI [.93, 1.00]), and an increased likelihood of experiencing postpartum depression and/or anxiety (OR = 1.09, 95% CI [1.10, 1.14]) above and beyond age at pregnancy, racial/ethnic minority status, childhood violence exposure, and warfare exposure. Findings highlight the importance of screening for MST during pregnancy and trauma-informed obstetric care. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


Theoretical and experimental studies of polarization mode dispersion of an electro-optic Mach-Zehnder modulator.
A theoretical model is developed to study the polarization mode dispersion effect in an electro-optic Mach-Zehnder interferometric (MZI) modulator. The Stokes parameters and differential group delay (DGD) of the output light of a MZI modulator can be analytically derived with the proposed model, which is based on a three-dimensional Maxwell's wave equation approach. The theoretical model is validated to the extent possible by comparing the theoretical results of the Stokes parameters and DGD with experimental measurements that are based on the wavelength-scanning method and the Jones matrix eigenanalysis method.


Nano-extrusion: a one-step process for manufacturing of solid nanoparticle formulations directly from the liquid phase.
This paper presents a novel one-step process for converting a liquid stabilized nano-suspension into a solid formulation via hot-melt extrusion combined with an internal devolatilization process (nano-extrusion, NANEX). A polymer (Soluplus®) was fed into the extruder and molten, after which a stable nano-suspension was added via side-feeding devices. The solvent (water) was removed by devolatilization and the polymer solidified at the outlet. The solid material can be tableted or filled in a capsule directly. The results showed that the obtained extrudates comprised nanocrystals in the de-aggregated form, confirming that a solid nano-formulation was prepared. This method is capable of overcoming many of the problems associated with other processes involving solid nano-dosage forms and poses a straightforward approach towards manufacturing such products.


Ultrasound to Detect Pressure-related Deep Tissue Injuries in Adults Admitted via the Emergency Department: A Prospective, Descriptive, Pilot Study.
Stage 4 pressure ulcers (PUs) start with tissue death at the level of the bone, also known as deep tissue injury (DTI). Studies have shown the appearance of DTI on the skin is delayed for several days after the original pressure-related injury to the deep soft tissues. Studies also suggest DTI can be seen using ultrasound (US) technology. A prospective, descriptive, correlational pilot study was conducted to evaluate the use of US technology to detect DTI in the soft tissues that are not visible on the skin upon hospital admission. Study participants included a convenience sample of 33 persons at risk for PUs (ie, Braden score <18) admitted through the emergency department. Each participant had US scans of 13 common PU body sites. All scans were documented in the radiologist report in the electronic medical record. Creatinine phosphokinase, calcium levels, and urine myoglobin levels also were assessed upon enrollment. Skin failure risk factors (SFRFs), including fever, hypotension, weight loss, coagulopathy, and acidosis/respiratory failure, also were documented. Patients were examined for skin PUs every day for 7 days after US scan. Twenty-three (23) patients completed the study. US scans identified pressure necrosis at 2 levels: bone (54 positive [US+]) and subcutaneous (SC); 79 US+, respectively). US+ bone sites resulted in 5 PUs appearing 6 to 7 days post-admission (sensitivity = 100%, specificity 84.7%, positive predictive value 10%, and negative predictive value 100%), indicating all DTI that later became purple skin DTI were detected by the US. US+ SC sites, located immediately under the skin, yielded 5 PUs appearing on day 2 after admission (sensitivity 100%, specificity 74.8%, positive predictive value 6.3%, and negative predictive value 100%). The participants with PU occurrence in both bone and SC groups had low Braden scores (bone group mean = 13.25, SC group mean = 11.2). Study patients who were positive for PU also had >4 SFRFs. Creatinine phosphokinase, calcium, and myoglobin levels were inconsistent and did not correlate with US+ scans. These observations warrant larger studies to confirm findings and optimize the validity of US screening for DTI in select populations, which may help improve protocols of care and PU admission documentation. The preliminary results suggest inclusion of the Braden Scale score and known PU risk factors may improve the positive predictive value of this test.


Pergolide mesylate form II.
A new polymorph of pergolide mesylate or 8beta-[(methylsulfanyl)methyl]-6-propylergoline methanesulfonate, C(19)H(27)N(2)S(+).CH(3)SO(3)(-), is reported. Pergolide mesylate form II crystallizes in the trigonal system, which is unique for ergot derivatives. Although the hydrogen-bond system in form II differs completely from that in form I, the conformation of the pergolide moiety in various related structures is very similar.


Gemcitabine as frontline treatment for cutaneous T-cell lymphoma: phase II study of 32 patients.
Based on the activity of gemcitabine in heavily pretreated patients with cutaneous T-cell lymphoma (CTCL), the objective of the current study was to determine the role of gemcitabine in the treatment of patients with advanced, untreated CTCL. Between June 2002 and February 2004, 32 untreated patients with mycosis fungoides (MF) (n = 26 patients); peripheral T-cell lymphoma, unspecified (PTCLU) with exclusive skin involvement (n = 5 patients); and Sezary syndrome (SS) (n = 1 patient) were enrolled in a 7-institution, Phase II trial and treated with gemcitabine. This drug was given on Days 1, 8, and 15 of a 28-day schedule at a dose of 1200 mg/m2 intravenously over 30 minutes for a total of 6 cycles. Of the 32 patients studied, 7 (22%) achieved a complete response (CR) and 17 (53%) achieved a partial response (PR), whereas the remaining 8 patients showed no benefit from the treatment. Five of the CRs were confirmed histologically. The CR and PR rates were found to be the same for patients with MF and PTCLU, respectively. The median duration of CR was 10 months (range, 4-22 mos). Treatment appeared to be well tolerated; hematologic toxicity was mild and no nausea/emesis or organ toxicity was noted. The results of the current Phase II study demonstrate the activity of gemcitabine as a single agent in untreated CTCL patients. Further studies using gemcitabine in combination, either contemporary or sequentially, with other drugs in patients with advanced stage, untreated CTCL are needed.


Fritz Vögtle (1939-2017).
Fritz Vögtle, Professor Emeritus of Organic Chemistry and former Director of the Kekulé Institute of Organic Chemistry and Biochemistry at the University of Bonn passed away on January 3, 2017. He was significantly involved in the development of supramolecular chemistry as a new and seminal research field, and his outstanding achievements, including dendrimer, catenane, rotaxane, and knot synthesis, brought this area to both national and international attention.


Treatment with cholesterol just after thawing maintains the fertility of bull sperm.
Freezing and thawing diminish sperm motility and fertility by disrupting the cholesterol balance in sperm plasma and organelle membranes. The aim of this study was to elucidate the mechanisms through which exogeneous cholesterol treatment enhances the quality of frozen-thawed bull sperm. The incorporation of cholesterol was investigated using boron-dipyrromethene (BODIPY)-cholesterol, and BODIPY signals were detected not only in the plasma membrane but also in the midpiece region immediately after thawing. The positive signal of cholesterol in the midpiece region was inhibited by a scavenger receptor class B Type I (SR-BI) inhibitor, block lipid transport 1 (BLT-1). To comprehend the role of exogenous cholesterol in the functions of the plasma membrane, propidium iodide (PI)/Annexin V and peanut agglutinin lectin (PNA) staining were performed. The results showed that treatment with exogenous cholesterol increased the number of acrosome-intact sperm and decreased the number of sperm with damage to the plasma membrane. Moreover, since BODIPY signals were also observed in the midpiece region, mitochondrial function was evaluated using a flux analyzer and a flow cytometer with 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolyl carbocyanine iodide (JC-1) staining, revealing an increase in the number of sperm with high-mitochondrial activity and oxygen consumption. Finally, to assess sperm fertility, computer-assisted sperm analysis (CASA) and IVF were carried out. Sperm velocities and fertilization rates in IVF were significantly enhanced by the addition of cholesterol just after thawing. Thus, the treatment with cholesterol after thawing protected the plasma membrane from the stress of thawing and maintained mitochondrial function, thereby preserving the fertilization ability of frozen-thawed bull sperm for conventional IVF and artificial insemination (AI). Therefore, the application of cholesterol just after thawing is a promising option for improving the fertility of frozen-thawed sperm.


Prenatal diagnosis of the Meckel syndrome.
Sixteen pregnancies of 12 women with a previous child affected with the Meckel syndrome were monitored by ultrasonic scanning and amniotic fluid alpha-fetoprotein (AFP) assay. Second-trimester AFP testing in 14 pregnancies detected 1 of 2 affected fetuses, and was normal in all 12 pregnancies in which the child was normal. It is concluded that measurement of amniotic fluid AFP is helpful for Meckel syndrome only when there is an associated open neural tube defect. The importance of extremely careful ultrasonography is emphasized.


High-Throughput Purification in Drug Discovery: Scaling New Heights of Productivity.
With the "low hanging fruit" of early drug discovery gone, pharmaceutical companies are increasingly turning to developing high-throughput synthetic platforms capable of greatly shortening the design-make-test cycle of new drugs. Purification has long been considered the bottleneck of this procedure; however, new technologies and systems are now being integrated into these high-throughput synthetic workflows, providing compounds of high purity capable of being used directly in biological screening.


Impaired orienting of attention in left unilateral neglect: a componential analysis.
Twenty-six patients suffering from damage to the right side of the brain, 19 of whom exhibited signs of left neglect, as well as 32 matched controls, ran 3 spatial cuing tasks. Patients were also tested with 2 cancellation tests, a line-bisection test, the copy of a complex drawing, and a visual extinction procedure. Results first showed correlations between extinction and cancellation tests performance on one hand, and between line bisection and copy on the other hand. Second, results demonstrated that an engagement deficit toward contralesional targets appeared to be the most striking feature of neglect, and the engagement score was correlated with the cancellation score and extinction. Most patients with neglect also presented a deficit in disengagement, a deficit of inhibition of return, and probably a deficit of alertness. Deficits in engagement and in disengagement, as well as poor scores in cancellation tests, seemed to be related with posterior cortical and subcortical lesions. Most important, even if an endogenous deficit (frequently related with a thalamic lesion) could aggravate the neglect behavior, neglect syndrome was mainly explained by a deficit of exogenous attention.


Ultrafast electron transfer in the recognition of different DNA sequences by a DNA-binding protein with different dynamical conformations.
Ultrafast electron transfer (ET) phenomenon in protein and protein-DNA complex is very much crucial and often leads to the regulation of various kinds of redox reactions in biological system. Although, the conformation of the protein in protein-DNA complex is concluded to play the key role in the ET process, till date very little evidences exist in the literature. λ-repressor-operator DNA interaction, particularly O(R)1 and O(R)2, is a key component of the λ-genetic switch and is a model system for understanding the chemical principles of the conformation-dependent ET reaction, governed by differential protein dynamics upon binding with different DNA target sequences. Here, we have explored the photoinduced electron transfer from the tryptophan moieties of the protein λ-repressor to two operators DNA of different sequences (O(R)1 and O(R)2) using picosecond-resolved fluorescence spectroscopy. The enhanced flexibility and different conformation of the C-terminal domain of the repressor upon complexation with O(R)1 DNA compared to O(R)2 DNA are found to have pronounced effect on the rate of ET. We have also observed the ET phenomenon from a dansyl chromophore, bound to the lysine residue, distal from the DNA-binding domain of the protein to the operator DNA with a specific excitation at 299 nm wavelength. The altered ET dynamics as a consequence of differential protein conformation upon specific DNA sequence recognition may have tremendous biological implications.


Access to Perfluoroalkyl-Substituted Enones and Indolin-2-ones via Multicomponent Pd-Catalyzed Carbonylative Reactions.
A simple method for accessing perfluoroalkyl-substituted enones is described applying a four-component palladium-catalyzed carbonylative coupling of aryl boronic acids together with terminal alkynes and perfluoroalkyl iodides in the presence of carbon monoxide. A wide range of highly functionalized enones can thus be prepared in a single operation in good yields. With 2-aminophenylalkynes, an intramolecular aminocarbonylation event overrules providing the indolin-2-one framework. Finally, adaptation of the two-chamber technology expands the method to the synthesis of the aforementioned structures with 13C-isotope labeling.


[Experimental study on inhibitory effect of GFW on transplantable tumor cell metastasis in S180 tumor-bearing mices].
To detect the effect of GFW on tumor cell metastasis in S180 tumor-bearing mice. S180 tumor-bearing mice model were replicated and divided randomly into 4 groups: the model group, the GFW group, the cyclophosphamide group and the combination administration group. VEGF in serum on each group was detected by ELISA, and the expression of metastasis suppressor gene nm23H1 and cell adhesion molecule CD44 in Sarcoma were detected by SABC immunohistochemical assay. Compared with the model group, the GFW group showed a significant decrease in VEGF in serum (P < 0.01). From their statistically significant difference, GFW was proved to promote the expression of metastasis suppressor gene nm23H1 and inhibit the expression of cell adhesion molecule CD44 (P < 0.05). GFW has an effect on inhibiting tumor metastasis to some extent.


Fatalities from non-use of seat belts and helmets in Greece: a nationwide appraisal. Hellenic Road Traffic Police.
It has been established that seat belt use by car occupants and helmet use by motorcycle riders substantially reduces the risk of serious and fatal injuries following accidents. No study, however, has evaluated the motor vehicle deaths that could be prevented in Greece by general use of these devices, even though this country has the highest mortality from motor vehicle accidents in the European Union. We have estimated the odds ratios (OR) for death rather than injury in a motor vehicle accident by seat belt use among occupants of passenger cars or helmet use among motorcycle riders, using a nationwide database in which persons killed or injured in road traffic accidents in 1985 and 1994 were recorded. The study base included 910 dead and 19,511 injured persons for 1985 and 1203 dead and 22,186 injured persons for 1994. The OR and 95% confidence intervals (CI) for death rather than injury was 0.69 (CI: 0.58 to 0.81, p < 10(-5)) for seat belt users versus non-users and 0.64 (CI: 0.51 to 0.81; p < 10(-3)) for helmet users versus non-users. There was evidence that the protective effect of these passive safety devices increased from 1985 to 1994 probably reflecting technological improvements. The proportion of all deaths that could have been avoided if all car occupants used seat belts was estimated to 27%, whereas 38% of motorcycle deaths could have been avoided if all motorcycle riders used helmets. These proportions translate to about 500 deaths per year, mostly deaths among young men.


DENSITY DEPENDENCE AND UNPREDICTABLE SELECTION IN A HETEROGENEOUS ENVIRONMENT: COMPROMISE AND POLYMORPHISM IN THE ESS REACTION NORM.
In quantitative genetic models of the evolution of reaction norms, an individual is selected in the habitat in which it develops; as a consequence, selection leads to the optimum phenotype in each habitat. Here, individuals are assumed to experience unpredictable habitat change between development and selection, so that the environment in which an individual is selected may differ from the environment in which it developed. The model reveals that unpredictability of the selection an individual actually faces leads to the evolutionarily stable bet-hedging reaction norm constituting a compromise between the phenotypic optima in the different patches. We also examine the effect of local density regulation before selection, in the patches in which the individuals develop, and after selection, in the patches in which they are selected. Density regulation before selection has a much lower influence on the evolution of the reaction norm than density regulation after selection. The source-sink structure of the environment caused by differential productivity of patches strongly affects how the compromise bet-hedging strategy weighs the different phenotypic optima and might compromise the local evolutionary stability of the evolved reaction norm. If the strength and variability among patches of density regulation after selection is sufficiently large, no single reaction norm is evolutionary stable: Polymorphic reaction norms constitute the evolutionarily stable population. We also show that a polymorphic reaction norm is more likely to be observed in a less productive habitat. The relations between the present model and the Dempster and the Levene models are discussed.


Infanticide in prairie dogs: lactating females kill offspring of close kin.
Infanticide, although common in a wide range of species including humans and other primates, is poorly understood. A 7-year study under natural conditions reveals that infanticide within colonies of black-tailed prairie dogs (Cynomys ludovicianus) is striking for three reasons. It is the major source of juvenile mortality, accounting for the total or partial demise of 51 percent of all litters born. The most common killers are resident lactating females. The most common victims are the offspring of close kin.


Clinical Predictors of Preeclampsia in Pregnant Women with Chronic Kidney Disease.
Background and Objectives: Pregnant women with chronic kidney disease (CKD) are at high risk of adverse maternal and fetal outcomes. Preeclampsia (PE) superimposed on CKD is estimated to occur in 21%-79% of pregnancies. Both conditions share common features such as proteinuria and hypertension, making differential diagnosis difficult. Objective: The aim of this study was to evaluate the incidence and the clinical-biological predictors of preeclampsia in pregnant women with CKD. Material and Methods: We retrospectively analyzed 34 pregnant women with pre-existing CKD admitted to our department between 2008 and 2017. Results: Among the 34 patients, 19 (55.8%) developed PE and the mean time of occurrence was 31.26 ± 2.68 weeks of gestation. The median value of 24-h proteinuria at referral was 0.87 g/day (interquartile range 0.42-1.50) and 47.1% of patients had proteinuria of ≥1 g/day. Patients with PE tended to be more hypertensive, with a more decreased renal function at referral and had significantly higher proteinuria (1.30 vs 0.63 g/day, p = 0.02). Cox multivariate analysis revealed that proteinuria ≥1 g/day at referral and pre-existing hypertension were independently associated with PE (adjusted hazard ratio = 4.10, 95% confidence interval: 1.52-11.02, p = 0.005, adjusted hazard ratio = 2.62, 95% confidence interval: 1.01-6.77, p = 0.04, respectively). The cumulative risk of PE was significantly higher in pregnant women with proteinuria ≥1 g/day at referral (log-rank, p = 0.003). Proteinuria ≥ 1 g/day at referral and pre-exiting hypertension predicted PE development with accuracies of 73.5% and 64.7%, respectively. Conclusions: Pregnant patients with pre-existing CKD are at high risk of developing preeclampsia, while proteinuria ≥ 1 g/day at referral and pre-existing hypertension were independent predictors of superimposed preeclampsia.


Myths, fallacies and practical pearls in GI lab.
Many prevalent practices and guidelines related to Gastrointestinal endoscopy and procedural sedation are at odds with the widely available scientific-physiological and clinical outcome data. In many institutions, strict policy of pre-procedural extended fasting is still rigorously enforced, despite no evidence of increased incidence of aspiration after recent oral intake prior to sedation. Supplemental oxygen administration in the setting of GI procedural sedation has been increasingly adopted as reported in the medical journals, despite clear evidence that supplemental oxygen blunts the usefulness of pulse oximetry in timely detection of sedation induced hypoventilation, leading to increased number of adverse cardiopulmonary outcomes. Use of Propofol by Gastroenterologist-Nurse team is erroneously considered dangerous and often prohibited in various institutions, at the same time worldwide reports of remarkable safety and patient satisfaction continue to be published, dating back more than a decade. Of patient monitoring practices that have been advocated to be standard, many merely add cost, not value. Advances in the technology often are not incorporated in a timely manner in guidelines or clinical practices, e.g., Capsule endoscopy or electrocautery during GI procedures do not interfere with proper functioning of the current pacemakers or defibrillators. Orthopedic surgeons have continued to recommend prophylactic antibiotics for joint replacement patients prior to GI procedures, without any evidence of need. These myths are explored for a succint review to prompt a change in clinical practices and institutional policies.


Selenium (Se) Does Not Reduce Cadmium (Cd) Uptake and Translocation in Rice (Oryza sativa L.) in Naturally Occurred Se-Rich Paddy Fields with a High Geological Background of Cd.
This study examined the selenium (Se) and cadmium (Cd) uptake by rice from soil and analyzed the relationship between Se and Cd in naturally occurred Se-rich paddy fields with a high geological background of Cd. Significant correlations were observed between soil Se and plant biomass Se, but not between soil Cd and plant biomass Cd. High concentrations of Cd were detected in rice plants and particularly in rice grains, suggesting potential health risks to human. Contrary to results from other previous studies, our results showed that high soil Se did not reduce Cd uptake by rice, although it decreased the availability of Cd in soil. Rather, soil Se and internal Se pool in rice were positively correlated to the transfer of Cd from root to straw. The effect of Se on the uptake and translocation of Cd in rice in field is therefore different from those in pot experiments.


Spontaneous prediction error generation in schizophrenia.
Goal-directed human behavior is enabled by hierarchically-organized neural systems that process executive commands associated with higher brain areas in response to sensory and motor signals from lower brain areas. Psychiatric diseases and psychotic conditions are postulated to involve disturbances in these hierarchical network interactions, but the mechanism for how aberrant disease signals are generated in networks, and a systems-level framework linking disease signals to specific psychiatric symptoms remains undetermined. In this study, we show that neural networks containing schizophrenia-like deficits can spontaneously generate uncompensated error signals with properties that explain psychiatric disease symptoms, including fictive perception, altered sense of self, and unpredictable behavior. To distinguish dysfunction at the behavioral versus network level, we monitored the interactive behavior of a humanoid robot driven by the network. Mild perturbations in network connectivity resulted in the spontaneous appearance of uncompensated prediction errors and altered interactions within the network without external changes in behavior, correlating to the fictive sensations and agency experienced by episodic disease patients. In contrast, more severe deficits resulted in unstable network dynamics resulting in overt changes in behavior similar to those observed in chronic disease patients. These findings demonstrate that prediction error disequilibrium may represent an intrinsic property of schizophrenic brain networks reporting the severity and variability of disease symptoms. Moreover, these results support a systems-level model for psychiatric disease that features the spontaneous generation of maladaptive signals in hierarchical neural networks.


Pathological complete response rates following different neoadjuvant chemotherapy regimens for operable breast cancer according to ER status, in two parallel, randomized phase II trials with an adaptive study design (ECTO II).
Sequential doxorubicin/paclitaxel (AT) followed by CMF treatment was shown to be an active neoadjuvant chemotherapy regimen in the first European Cooperative Trial in Operable Breast Cancer (ECTO I trial). The aim of the current study (ECTO II) is to assess the complete pathological response (pCR) rate following three different anthracycline and taxane-containing neoadjuvant chemotherapy regimens, with or without capecitabine (X). Patients with operable, invasive breast cancer > 2.0 cm in diameter, were randomized to AT→CMF, AT→CMX or AC→TX regimens in two parallel, randomized, open-label, phase II trials (within a single study) in patients with estrogen receptor negative (ER-) and estrogen receptor positive (ER+) diseases, respectively. Exemestane was delivered concomitantly with neoadjuvant chemotherapy in ER+ tumors. Achievement of pCR was more common in ER- than ER+ women (45.3 vs. 10.4%). Capecitabine was only associated with a higher frequency of pCR in ER+ patients receiving AT→CMX. Overall response rates (ORR) ranged from 88 to 97%, and this translated into high rates of breast-conserving surgery (67% of ER- patients and 72% of ER+ patients). All three regimens were well tolerated. Febrile neutropenia and gastrointestinal effects were the most common grade ≥ 3 adverse events. As expected, the ECTO II study showed higher pCR rates in patients with ER- disease. Substituting capecitabine for fluorouracil (± methotrexate) in anthracycline/taxane-containing regimens appeared to be beneficial only in ER+ tumors. Translational studies investigating interactions between therapeutic agents and tumor biology are warranted to refine patient selection and improve the results of neoadjuvant chemotherapy.


Predictors of Outcome in Modern Surgery for Lung Abscess.
Background Surgery for lung abscess is a challenging task. Timing and indications for surgery are not well established. Identification of predictors of outcome could help to clarify the role of surgery. Methods Patients who underwent major thoracic surgery for infectious lung abscess were identified at six centers for general thoracic surgery in Germany, Spain, the United Kingdom, and the United States. Study period was 2000 to 2016. Results There were 91 patients. Pulmonary sepsis (48), pleural empyema (43), persistent air leakage (25), acute renal failure (12), and respiratory failure with mechanical ventilation (25) were already preoperatively present. The mean Charlson index of comorbidity was 3.0 (median: 2.0; interquartile range: 3). Procedures were segmentectomy (18), lobectomy (58), and pneumonectomy (15). The 30-day mortality following surgery was 13/91.Preoperative sepsis (odds ratio [OR]: 13.69; 95% confidence interval [CI]: 1.86-610.53; p < 0.01), preoperative persistent air leak (OR: 13.46, 95% CI: 3.00-85.37, p < 0.01), respiratory failure (OR: 5.60; 95% CI: 1.41-24.84; p < 0.01), acute renal failure (OR: 6.15 ; 95% CI: 1.24-29.56 ; p = 0.01), and Charlson index of comorbidity ≥ 3 (OR: 7.19 ; 95% CI: 1.43-71.21 ; p < 0.01) are associated with higher mortality, whereas age > 70 years (p = 0.46) and the extent of pulmonary resection (segmentectomy, lobectomy, pneumonectomy) have no significant influence on mortality. Patients with fatal outcome have significantly higher Charlson index of comorbidity (p < 0.01). Conclusions Delayed referral for surgery is common. Significant predictors for fatal outcome are pulmonary sepsis, septic complications (air leak, pleural empyema), septic organ failure (respiratory, acute renal failure), and preexisting comorbidity (Charlson index of comorbidity ≥ 3). The extent of surgical resection shows no significant influence.


Meticillin-resistant Staphylococcus aureus in elderly residents of care homes: colonization rates and molecular epidemiology.
Meticillin-resistant Staphylococcus aureus (MRSA) is a significant cause of mortality and morbidity in healthcare and community settings; however, there is a paucity of large-scale, longitudinal studies monitoring the occurrence of MRSA in the care home setting. To determine the molecular epidemiology of MRSA colonizing elderly residents of care homes. Residents in 65 care homes in Leeds, UK, were screened for MRSA nasal colonization in four consecutive years (2006-2009). Isolates were characterized using antibiotic susceptibility testing, detection of the Panton-Valentine leucocidin (PVL) locus, accessory gene regulator allotyping, characterization of the staphylococcal cassette chromosome mec element, spa-typing and pulsed-field gel electrophoresis. MRSA was recovered from 888 nasal swabs of 2492 residents and prevalence was similar (19-22%) throughout the study. Resistance to ≥3 antibiotic classes was common (34%), but resistance to only β-lactam agents was rare (3%); no PVL-positive isolates were identified. Most isolates were related to healthcare-associated epidemic-MRSA type 15 (EMRSA-15, ST22-IV); such isolates decreased in prevalence during the study (86-72%; P < 0.0001, χ(2)-test). The remainder belonged to five different multi-locus sequence type clonal complexes (CC). Most notably, CC59 strains increased in prevalence (10-25%; P < 0.0001, χ(2)-test) and were associated with high-level mupirocin resistance. The molecular epidemiology of MRSA in care homes is complex and dynamic. There was a high, consistent prevalence of MRSA nasal colonization, dominated by healthcare-associated strains. Vigilance is recommended; however, as high-level mupirocin resistance was associated with a single clonal group (CC59) that significantly increased in prevalence during the study.


FT-Raman investigation of alkaloids in the liana Ancistrocladus heyneanus.
The applicability of the micro-FT-Raman technique for studying alkaloids in vitro and for observing alkaloids in plant cells is demonstrated. This technique is examined using fresh plant material of Ancistrocladus heyneanus, a tropical liana known to produce pharmacologically interesting naphthylisoquinoline alkaloids as secondary metabolites. It will be shown that it is possible to localize and identify some of these alkaloids in different parts of the plant by means of Raman microspectroscopic studies. Data on the in situ structure and the spatial distribution can be obtained, which could provide information about the biosynthesis of the alkaloids in the plant.


Effectiveness of a novel serotonin blocker, sarpogrelate, for patients with angina pectoris.
We have recently demonstrated that a single oral administration of sarpogrelate, a 5-HT(2A) receptor antagonist, may improve exercise capacity in anginal patients with well-developed collaterals. The aim of the current study was to investigate the effectiveness of 2-week treatment with sarpogrelate on anginal symptoms and exercise capacity in anginal patients. A treadmill exercise test was repeated after a 2-week period with or without sarpogrelate (100 mg 3 times a day) in 20 patients with angiographically proven stable angina. Anginal symptoms and daily physical activity by the specific activity scale (SAS) were also evaluated. Treatment with sarpogrelate significantly increased the SAS score and prolonged exercise time to the onset of 0.1-mV ST depression. When data were analyzed in a subgroup of patients (n = 8) with well-developed collaterals, the treatment with sarpogrelate decreased the number of anginal attacks (control vs sarpogrelate, 3.0 +/- 2.8 vs 0.9 +/- 1.1/2 weeks, P <.05), increased the SAS score (5.2 +/- 1.6 vs 6.2 +/- 1.3 METS, P <.05), and increased the time to the onset of 0.1-mV ST depression (235 +/- 84 vs 295 +/- 127 seconds, P <.05). In addition, the double product at the onset of 0.1-mV ST depression increased by 15% (P <.05) after sarpogrelate. In contrast, all parameters were not significantly changed after sarpogrelate treatment in patients (n = 12) without well-developed collaterals. These findings indicate the therapeutic effectiveness of sarpogrelate for anginal patients, especially for patients with well-developed collaterals.


Glial activation positron emission tomography imaging in radiation treatment of breast cancer brain metastases.
Brain metastases affect more breast cancer patients than ever before due to increased overall patient survival with improved molecularly targeted treatments. Approximately 25-34% of breast cancer patients develop brain metastases in their lifetime. Due to the blood-brain barrier (BBB), the standard treatment for breast cancer brain metastases (BCBM) is surgery, stereotactic radiosurgery (SRS) and/or whole brain radiation therapy (WBRT). At the cost of cognitive side effects, WBRT has proven efficacy in treating brain metastases when used with local therapies such as SRS and surgery. This review investigated the potential use of glial activation positron emission tomography (PET) imaging for radiation treatment of BCBM. In order to put these studies into context, we provided background on current radiation treatment approaches for BCBM, our current understanding of the brain microenvironment, its interaction with the peripheral immune system, and alterations in the brain microenvironment by BCBM and radiation. We summarized preclinical literature on the interactions between glial activation and cognition and clinical studies using translocator protein (TSPO) PET to image glial activation in the context of neurological diseases. TSPO-PET is not employed clinically in assessing and guiding cancer therapies. However, it has gained traction in preclinical studies where glial activation was investigated from primary brain cancer, metastases and radiation treatments. Novel glial activation PET imaging and its applications in preclinical studies using breast cancer models and glial immunohistochemistry are highlighted. Lastly, we discuss the potential clinical application of glial activation imaging to improve the therapeutic ratio of radiation treatments for BCBM.


Compliance in quality of life data: a Norwegian experience.
Compliance is of extreme importance in assessing quality of life since lost data never can be retrieved. In order to assess this issue in various studies, a cross-sectional study in cured cancer patients, three prospective trials and a normative study were explored. In the cross-sectional study 82 per cent of the patients completed the questionnaires after one reminder. More females than males answered the questionnaires. The compliance rate varied from 99 per cent to 62 per cent in the prospective studies depending upon time after inclusion. It seems that compliance decreases during follow up, primarily because of disease progression. In one of the prospective studies low compliance rate (approximately 30 per cent) was found in the questionnaire assessing religious issues. In the normative study 68 per cent of the population completed the questionnaire. No gender differences were found, but younger males and elderly women were poor compliers. In conclusion, our data support that most patients complete quality of life questionnaires. It seems that patients with inferior education, reduced physical function and with progressive/terminal disease are low compliers. Introduction of the first quality of life questionnaires to the patients is of great importance. Detailed information about the study should be given and the importance of completing the questionnaires should be underlined.


Understanding premarital pregnancies among adolescents and young women in Ouagadougou, Burkina Faso.
In developing countries, young women between 15 and 24 years of age account for more than 40% of unsafe abortions due to the high number of unwanted and/or out-of-wedlock pregnancies. However, much about the profile of adolescents and young women who usually experience premarital pregnancies remains unknown. This study sought to understand the risk of pregnancy before marriage among adolescents and young women in Ouagadougou, Burkina Faso. By using longitudinal data from a demographic surveillance system, we tested the explanatory power of two theoretical assumptions on premarital childbearing in sub-Saharan Africa, which assumptions are the cultural inheritance model and the social capital model. The results confirmed the explanatory power of the cultural inheritance model on the one hand and partially confirmed the power of the social capital model on the other hand. These results highlight the need for a multipronged approach to sexual and reproductive health for young people. Efforts against premarital pregnancies among adolescents and young women would be more effective if they were based on participatory approaches, incorporating actions at both community and institutional levels, as suggested by the recent Global Accelerated Action for the Health of Adolescents logical framework.


Early Tumor Marker Response Predicts Treatment Outcomes in Patients with Unresectable Hepatocellular Carcinoma Receiving Combined Lenvatinib, Immune Checkpoint Inhibitors, and Transcatheter Arterial Chemoembolization Therapy.
Few reliable biomarkers for predicting the efficacy of triple therapy (lenvatinib + immune checkpoint inhibitors + transarterial chemoembolization) exist for patients with unresectable hepatocellular carcinoma (uHCC). This study explored the prognostic role of alpha-fetoprotein (AFP) and des-gamma-carboxyprothrombin (DCP) levels in patients with uHCC receiving triple therapy. This retrospective study included 93 patients with uHCC who received triple therapy at Fujian Provincial Hospital between August 2020 and November 2022. Depending on the respective baseline levels, the patients were divided into high-AFP and high-DCP groups. An early response was defined as an AFP or DCP concentration >50% less than the baseline concentration after 6 weeks of triple therapy. The primary endpoint was the objective response rate (ORR). The secondary endpoints were progression-free survival (PFS) and overall survival (OS). After 6 weeks of triple therapy, 75.3% (58/77) and 78.9% (60/76) of patients in the high-AFP and high-DCP groups achieved an objective response. Early AFP and DCP responses were positively associated with ORR (high-AFP group: odds ratio [OR]: 13.542; 95% confidence interval [CI]: 3.991-45.950, p<0.001; high-DCP group: OR: 17.853; 95% CI: 4.478-71.179, p<0.001). In the high-AFP group, the 6-month, 12-month, and 18-month PFS and OS rates were higher in the AFP responders than those in the non-responders (PFS: 66.4%, 59.6%, 48.2% vs 42.3%, 19.3%, 0%, p<0.001; OS: 94.5%, 90.4%, 77.3% vs 75.6%, 66.2%, 49.6%, p=0.006). In the high-DCP group, the 6-month, 12-month, and 18-month PFS and OS rates were higher in the DCP responders than those in the non-responders (PFS: 67.4%, 57.7%, 39.0% vs 38.9%, 8.1%, 0%, p<0.001; OS: 94.7%, 94.7%, 83.3% vs 77.0%, 53.9%, 36.0%, p<0.001). After 6 weeks of triple therapy, an AFP or DCP reduction of >50% predicts better treatment outcomes in uHCC patients.


Maternal age, parity, and reproductive outcome in captive chimpanzees (Pan troglodytes).
As early as the 1970s, it was suggested that nonhuman primates may serve as models of human reproductive senescence. In the present study, the reproductive outcomes of 1,255 pregnancies in captive chimpanzees (Pan troglodytes) were examined in relation to parity and its covariate, maternal age. The results show that the percentage of positive pregnancy outcomes was negatively correlated with increasing parity. In addition, spontaneous abortions, stillbirths, and caesarian sections (C-sections) were positively correlated with increasing parity. Maternal age, rather than parity, was found to be the most important predictor of negative birth outcome. This study supports research demonstrating reproductive decline and termination in nonhuman primates, and is the first to quantitatively account for this phenomenon in captive female chimpanzees.


A current view of the role of epigenetic changes in the aetiopathogenesis of endometriosis.
The purpose of the study was to examine the role of epigenetic changes in the aetiopathogenesis of endometriosis. The analysis and review of the relevant current literature in English language related to the role of epigenetic changes in the aetiopathogenesis of endometriosis. Epigenetic changes are common denominators for hormonal, immunological and inflammatory aberrations which play a key role in the aetiopathogenesis of endometriosis. Many internal and external factors may cause the different running of the epigenetic mechanism. As yet fully unknown genetic factors may increase the sensitivity of the epigenetic mechanism to various internal and external factors. The breakdown of epigenetic regulation is the main factor initiating the pathogenetic mechanisms for endometriosis formation.


Visualizing protein interactions by bimolecular fluorescence complementation in Xenopus.
Bimolecular fluorescence complementation (BiFC) provides a simple and direct way to visualise protein-protein interactions in vivo and in real-time. In this article, we describe methods by which one can implement this approach in embryos of the South African claw-toed frog Xenopus laevis. We have made use of Venus, an improved version of yellow fluorescent protein (YFP), so as to achieve rapid detection of protein interactions. To suppress spontaneous interactions between the N- and C-terminal fragments of Venus, a point mutation (T153M) was introduced into the N-terminal fragment. We have used this reagent to monitor signalling by members of the transforming growth factor type beta family in cells of the Xenopus embryo.