Regulation of protein synthesis in mammary glands of lactating dairy cows by starch and amino acids.
The objective of this study was to evaluate local molecular adaptations proposed to regulate protein synthesis in the mammary glands. It was hypothesized that AA and energy-yielding substrates independently regulate AA metabolism and protein synthesis in mammary glands by a combination of systemic and local mechanisms. Six primiparous mid-lactation Holstein cows with ruminal cannulas were randomly assigned to 4 treatment sequences in a replicated incomplete 4 x 4 Latin square design experiment. Treatments were abomasal infusions of casein and starch in a 2 x 2 factorial arrangement. All animals received the same basal diet (17.6% crude protein and 6.61 MJ of net energy for lactation/kg of DM) throughout the study. Cows were restricted to 70% of ad libitum intake and abomasally infused for 36 h with water, casein (0.86 kg/d), starch (2 kg/d), or a combination (2 kg/d starch+0.86 kg/d casein) using peristaltic pumps. Milk yields and composition were assessed throughout the study. Arterial and venous plasma samples were collected every 20 min during the last 8h of infusion to assess mammary uptake. Mammary biopsy samples were collected at the end of each infusion and assessed for the phosphorylation state of selected intracellular signaling molecules that regulate protein synthesis. Animals infused with casein had increased arterial concentrations of AA, increased mammary extraction of AA from plasma, either no change or a trend for reduced mammary AA clearance rates, and no change in milk protein yield. Animals infused with starch had increased milk and milk protein yields, increased mammary plasma flow, reduced arterial concentrations of AA, and increased mammary clearance rates and net uptake of some AA. Infusions of starch increased plasma concentrations of glucose, insulin, and insulin-like growth factor-I. Starch infusions increased phosphorylation of ribosomal protein S6 and endothelial nitric oxide synthase, consistent with changes in milk protein yields and plasma flow, respectively. Phosphorylation of the mammalian target of rapamycin was increased in response to starch only when casein was also infused. Thus, cell signaling molecules involved in the regulation of protein synthesis differentially responded to these nutritional stimuli. The hypothesized independent effects of casein and starch on animal metabolism and cell signaling were not observed, presumably because of the lack of a milk protein response to infused casein.


Bedside ultrasound diagnosis of nonangulated distal forearm fractures in the pediatric emergency department.
Ultrasound (US) may be a useful tool for rapidly diagnosing fractures. Our objective was to determine the accuracy of US as compared with radiographs in the detection of nonangulated distal forearm fractures. Distal forearm US was performed and interpreted at the bedside by a pediatric emergency medicine physician before radiography in a prospective sample of children with possible nonangulated distal forearm fractures. A second pediatric emergency medicine physician with extensive US experience gave a final interpretation of the images. This second reviewer was blinded to both clinical and radiographic findings. The primary outcome was accuracy in the detection of fracture via the blinded reviewer's US interpretation when compared with the radiologist's clinical radiography results. Patient-reported FACES pain scores (range, 0-5) associated with both US and radiography were compared. Of 101 enrolled patients, 46 had a fracture detected by the radiologist. When compared with radiographs, the blinded US interpretation had an overall accuracy of 94% (95% confidence interval [CI], 88%-99%). Sensitivity and specificity were 96% (95% CI, 85%-99%) and 93% (95% CI, 82%-98%), respectively. Positive predictive value was 92%, and negative predictive value was 96%. Mean FACES pain scores were higher following radiography than US (1.7 vs 1.2, respectively; P = 0.004). For the diagnosis of nonangulated distal forearm fractures in children, bedside US holds promise as a diagnostic modality, particularly with appropriate training. Ultrasound is at least no more painful that traditional radiographs. Pediatric emergency medicine physicians should consider becoming proficient in this application.


[A. Weismann's germ-plasma theory: a new methodological approach to the problems of general biology].
A. Weismann's theory of germ plasm is of special importance in the history of theoretical biology. Its meaning was not confined by presenting of neoperformistic ideas on the new level of science. In fact it predicted reduction division, the continuing of germ plasm and the significance of chromosomes in heredity. For the first time it brought a new methodology to the experimental genetics and the idea of interdisciplinary synthesis.


Association analysis of HLA-DRA in Chinese patients with sporadic Parkinson's disease.
Our aim is to explore the linkage between single nucleotide polymorphisms (SNPs) in human leukocyte antigen (HLA)-DRA and Parkinson's disease (PD). 542 sporadic PD patients and 674 healthy controls were recruited to investigate this association in the Chinese population by the screening of 15 SNPs in HLA-DRA, and the association of rs3129882 was further re-evaluated by performing meta-analysis and meta-regression analysis. No SNPs in HLA-DRA were significantly associated with PD in the Chinese patients. Although the rs3129882 allele-G frequency in the Caucasian population was lower than that in Chinese population, meta-analysis showed no association of rs3129882 allele-G with PD in the Chinese or Caucasian population. In consideration of the heterogeneity (I(2)=78.6%, Q=66.33, p<0.000), subgroup analysis was performed, revealing a significant association between rs3129882 and PD in the Caucasian patients from the genome-wide association studies (OR=1.22, 95% CI: 1.16, 1.27); however, this association was not consistently observed in the studies performed using other DNA sequencing techniques. Meta-regression analysis, which accounted for 58.3% of the heterogeneity, revealed that the impact of the sequencing technique used was significant (p=0.027) compared with ethnicity. Regression analysis of the Caucasian population further showed that the sequencing technique used contributed to 71.2% of the heterogeneity (p=0.033). Our data support the absence of a linkage between the risk loci in HLA-DRA and PD in Chinese patients. The different DNA sequencing techniques used in PD studies may largely account for the controversial conclusions concerning rs3129882.


What influences Indonesian medical educators' intentions to teach public health? A qualitative study.
Medical educators are central in ensuring future doctors have sufficient public health skills. Attitudes, norms, and perceived control about the significance of teaching a subject determines whether or not it is taught and how well. This qualitative study aims to explore medical educators' perceptions about what factors influence their intention to teach public health in Indonesian undergraduate medical schools. Semi-structured interviews were conducted with eighteen medical educators from different Indonesian medical schools. Interviews were analyzed thematically using the Theory of Planned Behavior domains: attitudes, subjective norms, and perceived behavioral control. Five subthemes emerged under these domains: attitudes (defining public health); subjective norms (room in the medical curricula; teaching and assessment); and perceived behaviour control (medical educator confidence; institutional support). Most participants had a limited understanding about the scope of public health. This coupled with an already overcrowded medical curriculum made it challenging for them to incorporate public health into the medical curriculum dominated by clinical and biomedical content. Although believing that public health is important, medical educators were reluctant to incorporate public health because they were not confident incorporating or assessing content. Strong institutional support is to improve public health quality and content in the medical curriculum. Including public health educators in discussions is critical.


Diet, the gut microbiome, and epigenetics.
Increasingly, the gut microbiome is implicated in the etiology of cancer, not only as an infectious agent but also by altering exposure to dietary compounds that influence disease risk. Whereas the composition and metabolism of the gut microbiome is influenced by diet, the gut microbiome can also modify dietary exposures in ways that are beneficial or detrimental to the human host. The colonic bacteria metabolize macronutrients, either as specialists or in consortia of bacteria, in a variety of diverse metabolic pathways. Microbial metabolites of diet can also be epigenetic activators of gene expression that may influence cancer risk in humans. Epigenetics involves heritable changes in gene expression via post-translational and post-transcriptional modifications. Microbial metabolites can influence epigenetics by altering the pool of compounds used for modification or by directly inhibiting enzymes involved in epigenetic pathways. Colonic epithelium is immediately exposed to these metabolites, although some metabolites are also found in systemic circulation. In this review, we discuss the role of the gut microbiome in dietary metabolism and how microbial metabolites may influence gene expression linked to colon cancer risk.


[A trial to improve operative results of coronary artery bypass grafting (CABG); off-pump CABG (OPCAB) as standard procedure].
To improve operative results of coronary artery bypass grafting (CABG), off-pump CABG (OPCAB) was performed as standard procedure in 220 cases at Toho University Omori Medical Center between 1999 and 2008. In the early group, OPCAB was performed in 94 cases, minimally invasive direct coronary artery bypass (MIDCAB) in 5 cases (off-pump rate of was 81.1%), on-pump beating coronary artery bypass (CAB) in 4 cases, and on-pump arrest CAB in 19 cases. In the late group, OPCAB was done in 79 cases (80.6%), on-pump beating CAB in 8 cases, and on-pump arrest CAB in 11 cases. One patient died because of multiple organ failure after OPCAB for acute coronary syndrome (ACS) in the early group. There was no surgical death in the late group. The overall surgical mortality rate was 0.45%. In the late group, 69 PAS x Port systems were used in 53 cases for proximal anastomosis of the saphenous vein graft (SVG). The patency rate was 97.8% which was confirmed by CAG and or 3-dimensional computed tomography (3D-CT) between 10 days to 23 months after operation. OPCAB could be performed for over 80% of CABG candidates with very low mortality. To improve clinical results, on-pump beating CAB and on-pump arrest CAB should be selected in cases of poor cardiac performance or ischemic condition at the pre- and during operation. The use of proximal anastomosis device reduces the stress of surgeon and the time of anastomosis, those benefits make the excellent postoperative course with reduced postoperative cerebral infarction.


Orthopaedic conditions in the newborn.
The occasional consultation on a neonate can be unfamiliar territory for many orthopaedic surgeons. Just as children are not little adults, newborns are not just little children; rather, they have a unique physiology that affects the presentation of their orthopaedic concerns. Careful physical examination with appropriate understanding of neonatal development is essential to making the proper diagnosis. A flail extremity in the newborn is most commonly attributed to fracture or brachial plexus palsy; however, infection must also be considered and ruled out to prevent long-term morbidity. Metatarsus adductus is the most common foot abnormality, but clubfoot, calcaneovalgus deformity, and congenital vertical talus may also be encountered. Joint contractures that spontaneously improve are normal in the newborn, but it is important to identify and institute proper treatment for early developmental dysplasia of the hip, congenital knee dislocation, and torticollis. Clavicular pseudarthrosis and periosteal reactions may be discovered on radiographic examination. A basic understanding of the relevant conditions will help the orthopaedist with the initial diagnosis and management of orthopaedic issues in the newborn.


Motor neuron apoptosis and neuromuscular junction perturbation are prominent features in a Drosophila model of Fus-mediated ALS.
Amyotrophic lateral sclerosis (ALS) is progressive neurodegenerative disease characterized by the loss of motor function. Several ALS genes have been identified as their mutations can lead to familial ALS, including the recently reported RNA-binding protein fused in sarcoma (Fus). However, it is not clear how mutations of Fus lead to motor neuron degeneration in ALS. In this study, we present a Drosophila model to examine the toxicity of Fus, its Drosophila orthologue Cabeza (Caz), and the ALS-related Fus mutants. Our results show that the expression of wild-type Fus/Caz or FusR521G induced progressive toxicity in multiple tissues of the transgenic flies in a dose- and age-dependent manner. The expression of Fus, Caz, or FusR521G in motor neurons significantly impaired the locomotive ability of fly larvae and adults. The presynaptic structures in neuromuscular junctions were disrupted and motor neurons in the ventral nerve cord (VNC) were disorganized and underwent apoptosis. Surprisingly, the interruption of Fus nuclear localization by either deleting its nuclear localization sequence (NLS) or adding a nuclear export signal (NES) blocked Fus toxicity. Moreover, we discovered that the loss of caz in Drosophila led to severe growth defects in the eyes and VNCs, caused locomotive disability and NMJ disruption, but did not induce apoptotic cell death. These data demonstrate that the overexpression of Fus/Caz causes in vivo toxicity by disrupting neuromuscular junctions (NMJs) and inducing apoptosis in motor neurons. In addition, the nuclear localization of Fus is essential for Fus to induce toxicity. Our findings also suggest that Fus overexpression and gene deletion can cause similar degenerative phenotypes but the underlying mechanisms are likely different.


Bird pollination in an angraecoid orchid on Reunion Island (Mascarene Archipelago, Indian Ocean).
Although numerous angraecoid orchids in Madagascar display typical sphingophilous syndrome (i.e. white, nectariferous, long-spurred flowers, producing a strong scent at the crepuscule that is attractive to moths), three species of Angraecum in Reunion, belonging to the endemic section Hadrangis, have atypical unscented and short-spurred flowers. The aim of the study was to investigate the implication of plant-pollinator interaction on the evolution of floral morphology of these peculiar island floral forms. The flower morphology of A. striatum (one of the three section Hadrangis species) was investigated by performing a set of floral measures, and the reproductive biology was investigated by a set of hand pollination experiments. Natural pollinators were observed by means of a digital video camera. Pollinator efficiency (pollen removal and deposition) and reproductive success (fruit set) were quantified once a week in natural field conditions during the 2005 flowering season (i.e. from January to March). The orchid is self-compatible but requires a pollinator to achieve fruit set. Only one pollinator was observed, the endemic white-eye Zosterops borbonicus (Zosteropidae). These birds perched on inflorescences, and probed most fresh-looking flowers on each plant for nectar. Nectar was both abundant (averaging 7.7 microL) and dilute (averaging 9.7 % sugar in sucrose equivalents). Birds were mostly active between 0830 and 0930 h. Visits to plants were extremely short, lasting from 9 to 27 s. At the study site, 60.9 % of flowers had pollen removed, and 46.4 % had pollinia deposited on stigmas. The proportion of flowers that initiated a fruit averaged 20.6 % in natural conditions. For the first time, a bird-pollinated orchid is described from a sub-tribe that is mainly specialized for moth pollination. This study documents a morphological shift in flowers in response to pollinator adaptations in the insular context of the Mascarene Archipelago.


The tumor suppressor TMEM127 regulates insulin sensitivity in a tissue-specific manner.
Understanding the molecular components of insulin signaling is relevant to effectively manage insulin resistance. We investigated the phenotype of the TMEM127 tumor suppressor gene deficiency in vivo. Whole-body Tmem127 knockout mice have decreased adiposity and maintain insulin sensitivity, low hepatic fat deposition and peripheral glucose clearance after a high-fat diet. Liver-specific and adipose-specific Tmem127 deletion partially overlap global Tmem127 loss: liver Tmem127 promotes hepatic gluconeogenesis and inhibits peripheral glucose uptake, while adipose Tmem127 downregulates adipogenesis and hepatic glucose production. mTORC2 is activated in TMEM127-deficient hepatocytes suggesting that it interacts with TMEM127 to control insulin sensitivity. Murine hepatic Tmem127 expression is increased in insulin-resistant states and is reversed by diet or the insulin sensitizer pioglitazone. Importantly, human liver TMEM127 expression correlates with steatohepatitis and insulin resistance. Our results suggest that besides tumor suppression activities, TMEM127 is a nutrient-sensing component of glucose/lipid homeostasis and may be a target in insulin resistance.


Weathering storms: a cohort study of how participation in a mindfulness-based stress reduction program benefits women after breast cancer treatment.
A growing number of psychosocial interventions are being offered to cancer patients during and after their medical treatment. Here, we examined whether Mindfulness-Based Stress Reduction (MBSR), a stress management course, helps women to cope better with stress and illness once their breast cancer treatment is completed. Our aim was to understand how MBSR may benefit those who participate in the course. Our cohort study enrolled 59 women in an 8-week MBSR program. They completed "before and after" questionnaires pertaining to outcomes (stress, depression, medical symptoms) and process variables (mindfulness, coping with illness, sense of coherence). Paired t-tests examined changes from before to after the MBSR course. Changes in mindfulness were correlated with changes in post-MBSR variables, and a regression analysis examined which variables contributed to a reduction in stress after program participation. Adherence to the program was 91%. Participants reported significant reductions in stress (p < 0.0001), depression (p < 0.0001), and medical symptoms (p < 0.0001), and significant improvements in mindfulness (p < 0.0001), coping with illness (p < 0.0001), and sense of coherence (p < 0.0001). Changes in mindfulness were significantly related to changes in depression, stress, emotional coping, and sense of coherence. Increases in mindfulness and sense of coherence predicted reductions in stress. It appears that learning how to be mindful is beneficial for women after their treatment for breast cancer.


Frontal theta activity in humans increases with memory load in a working memory task.
Recent theoretical work has suggested that brain oscillations in the theta band are involved in active maintenance and recall of working memory representations. To test this theoretical framework we recorded neuromagnetic responses from 10 subjects performing the Sternberg task. Subjects were required to retain a list of 1, 3, 5 or 7 visually presented digits during a 3-s retention period. During the retention period we observed ongoing frontal theta activity in the 7-8.5-Hz band recorded by sensors over frontal brain areas. The activity in the theta band increased parametrically with the number of items retained in working memory. A time-frequency analysis revealed that the task-dependent theta was present during the retention period and during memory scanning. Following the memory task the theta activity was reduced. These results suggest that theta oscillations generated in frontal brain regions play an active role in memory maintenance.


The use of time-averaged concentrations of metals to predict the toxicity of pulsed complex effluent exposures to a freshwater alga.
Intermittent, fluctuating and pulsed contaminant discharges may result in organisms receiving highly variable toxicant exposures. This study investigated the toxicity of continuous and pulsed exposures of a complex, neutralised drainage water (NDW) and dissolved copper-spiked dilute NDW to the green alga, Pseudokirchneriella subcapitata. The effects of single pulses of between 1 and 48 h duration and continuous exposures (72 h) on algal growth rate inhibition were compared on a time-averaged concentration (TAC) basis. Algal growth rates generally recovered to control levels within 24-48 h of the pulse removal. Continuous exposures to NDW resulted in similar or marginally higher toxicity to the algae when compared to pulsed exposures of equivalent TAC (% NDW). The toxicity of the NDW was attributed mostly to the metals, with the major cations potentially causing effects that are both additive (direct toxicity) and antagonistic (lower bioavailability of trace metals). For dissolved copper in dilute NDW, the pulsed exposures caused slightly higher toxicity than continuous exposures of equivalent dissolved copper TAC, with much of the difference explained by differences in labile copper concentrations between treatments. The results indicate that water quality guideline values for toxicants derived from continuous chronic exposures may be relaxed for pulsed exposures by a factor related to the TAC with the intent to provide an adequately protective but not overly-conservative outcome. The study highlights the influence that natural water quality parameters such as water hardness and DOC can have metal speciation and toxicity, and indicates that these parameters are particularly important for site-specific water quality guideline value derivation where, on a TAC basis, pulsed exposures may be more toxic than continuous exposures typically used in guideline value derivation.


Insulin-like growth factor-1 potentiates platelet activation via the IRS/PI3Kalpha pathway.
As insulin-like growth factor-1 (IGF-1) is present in the alpha granules of platelets and its receptor is expressed on the platelet surface, it may contribute to the amplification of platelet responses and pathogenesis of cardiovascular disease. The functional and signaling pathways that are involved in IGF-1 modulation of platelet function, however, are presently unknown. Here, I report that IGF-1 stimulation of platelets results in dose-dependent phosphorylation of the IGF receptor in the range of 1 to 100 nM. Phosphorylation of the IGF receptor is rapid and sustained, with maximal phosphorylation reached within 1 minute. Furthermore, IGF-1 stimulates tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-2 and their association with the p85 subunit of phosphoinositide-3 kinase (PI3K). IGF-1-stimulated tyrosine phosphorylation of IRS-1 and IRS-2 and subsequent p85 binding is transient and precedes phosphorylation of protein kinase B (PKB) on Ser473. PAR-1-mediated platelet aggregation is potentiated by IGF-1 and this potentiation, together with PKB phosphorylation, is abolished by the PI3Kalpha inhibitors PI-103 and PIK-75. Importantly, the IGF receptor inhibitor NVP-AEW541 and the neutralization antibody alphaIR3 inhibit SFLLRN-stimulated aggregation, implicating IGF-1 in autocrine regulation of platelet function. These results demonstrate that IGF-1 activates the IGF receptor/IRS/PI3K/PKB pathway, and that PI3Kalpha is essential for the potentiatory effect of IGF-1 on platelet responses.


p53 isoforms can regulate p53 transcriptional activity.
The recently discovered p53-related genes, p73 and p63, express multiple splice variants and N-terminally truncated forms initiated from an alternative promoter in intron 3. To date, no alternative promoter and multiple splice variants have been described for the p53 gene. In this study, we show that p53 has a gene structure similar to the p73 and p63 genes. The human p53 gene contains an alternative promoter and transcribes multiple splice variants. We show that p53 variants are expressed in normal human tissue in a tissue-dependent manner. We determine that the alternative promoter is conserved through evolution from Drosophila to man, suggesting that the p53 family gene structure plays an essential role in the multiple activities of the p53 family members. Consistent with this hypothesis, p53 variants are differentially expressed in human breast tumors compared with normal breast tissue. We establish that p53beta can bind differentially to promoters and can enhance p53 target gene expression in a promoter-dependent manner, while Delta133p53 is dominant-negative toward full-length p53, inhibiting p53-mediated apoptosis. The differential expression of the p53 isoforms in human tumors may explain the difficulties in linking p53 status to the biological properties and drug sensitivity of human cancer.


Audit and feedback of antibiotic use: utilising electronic prescription data.
There is now little doubt that improving antimicrobial use is necessary for the containment of resistance. To determine whether providing individualised feedback to doctors about their recent compliance with the hospital's antibiotic policy improves compliance with the policy. This study was conducted at a teaching hospital in Sydney, Australia. Computerised alerts integrated into the electronic prescribing system (ePS) inform prescribers of the local antibiotic policy. We utilised prescribing data extracted from the ePS for 'audit and feedback'. Thirty-six prescribers were sent feedback letters via email. We also interviewed doctors who had received letters to explore their views of the feedback and the policy in general. There was no significant change in compliance with the policy following implementation of the feedback intervention (0% compliant vs 11.9%; p = 0.07). Several problems with the policy and the approval process were identified by researchers during auditing and by prescribers during interviews. Some problems identified made it difficult to accurately assess compliance and for doctors to comply with the policy. Our intervention did not result in improved compliance with the antibiotic policy but revealed practical problems with the policy and approval process that had not been identified prior to the trial. Greater support for the policy by senior doctors and the assignment of more clearly defined roles and responsibilities associated with antibiotic use and approval may result in improved compliance. Harnessing the full potential of technology would streamline the antimicrobial approval process and allow more efficient and reliable monitoring of antibiotic use and compliance. Many of the problems we identified are generic issues of importance to all organisations seeking to integrate antimicrobial stewardship into ePS.


[Mechanism of the membrane stabilizing action of vitamins K and E under conditions of chronic phenol poisoning in albino rats].
In experiment with white male-rats the influence of membranotropic phenol-poison on the qualitative composition of phospholipids of liver, kidneys, heart, skeletal muscles as well as biomembranes of erythrocytes and mitochondria of liver was investigates. Along with these investigations the possibility of preventing from supposed changes of qualitative composition of phospholipids has also been studied by additional injection K and K vitamins as minor lipid components. As the result of this research it was stated that when phenol (per, os) was repeatedly injected the content of lysophospholipids, phosphatidic acids in phospholipid composition increased and the content of phosphatidylcholine, phosphatidylethanolamine and sphingomyelin simultaneous decreased. Additional injection E and K vitamins (50 mg/kg by weight and 20 mg/kg accordingly) prevented to a greater extent the changes of fractional composition of the lipid phase of biomembranes. The mechanism of protective action of K and E vitamins is probably connected with spatial screening of pi-bonds in the radicals of polyunsaturated fatty acids in phospholipid composition from reoxidation and on the hand the competitive interrelations may exist between minor lipid components and on the other hand between the ethers of cholesterol. These conclusions agree with hypothesis that K and E vitamins are the natural modifiers of the membranes of different types of structure.


TRPA1 mediates the antinociceptive properties of the constituent of Crocus sativus L., safranal.
Safranal, contained in Crocus sativus L., exerts anti-inflammatory and analgesic effects. However, the underlying mechanisms for such effects are poorly understood. We explored whether safranal targets the transient receptor potential ankyrin 1 (TRPA1) channel, which in nociceptors mediates pain signals. Safranal by binding to specific cysteine/lysine residues, stimulates TRPA1, but not the TRP vanilloid 1 and 4 channels (TRPV1 and TRPV4), evoking calcium responses and currents in human cells and rat and mouse dorsal root ganglion (DRG) neurons. Genetic deletion or pharmacological blockade of TRPA1 attenuated safranal-evoked release of calcitonin gene-related peptide (CGRP) from rat and mouse dorsal spinal cord, and acute nociception in mice. Safranal contracted rat urinary bladder isolated strips in a TRPA1-dependent manner, behaving as a partial agonist. After exposure to safranal the ability of allyl isothiocyanate (TRPA1 agonist), but not that of capsaicin (TRPV1 agonist) or GSK1016790A (TRPV4 agonist), to evoke currents in DRG neurons, contraction of urinary bladder strips and CGRP release from spinal cord slices in rats, and acute nociception in mice underwent desensitization. As previously shown for other herbal extracts, including petasites or parthenolide, safranal might exert analgesic properties by partial agonism and selective desensitization of the TRPA1 channel.


Liver Fibrosis and Inflammation under the Control of ERK2.
Chronic liver injury could lead the formation of liver fibrosis, eventually some would develop to hepatocellular carcinoma (HCC), one of the leading malignancies worldwide. The aim of the study is to dissect the role of extracellular signal-regulated kinase 2 (ERK2) signaling in liver fibrosis and inflammation. The choline-deficient, ethionine-supplemented (CDE) diet could lead to fatty livers and generate oval cells, activate hepatocyte stellate cell (HSC) and recruit immune cells as the liver fibrosis model mice. WT and ERK2 deficient (ERK2-/-) mice were compared in terms of liver weight/body weight, liver function, liver fibrosis markers and the differential gene expression in hepatotoxicity. ERK2-/- mice display the less degree of liver fibrosis when compared to WT mice. The protein level of alpha smooth muscle (α-SMA) was reduced and several hepatocellular carcinoma-related genes such as MMP9, FoxM1 were down-regulated. In addition, the cell proliferation and the percentages of activated T cells were reduced in ERK2-/- mice upon liver injury. Therefore, ERK2 plays an important role in regulating liver cirrhosis and inflammation.


Corneal epithelial cell biocompatibility to silicone hydrogel and conventional hydrogel contact lens packaging solutions.
Although all contact lenses (CLs) are applied initially to the eye directly from a packaging solution, little is known about the effects of these solutions on human corneal epithelial cells (HCECs). Due to the porous nature of CL materials, they have the potential to sorb components of the packaging solution during storage, which could then be subsequently released upon insertion of the CL on the eye. The purpose of this study was to investigate the effect of various packaging solutions on HCECs, using an in vitro model. An in vitro assay was developed whereby various silicone hydrogels and conventional, poly-2-hydroxyethylmethacrylate (polyHEMA)-based lens materials were removed directly from their packaging and then incubated for up to 24 h with HCECs. The effect of the retained and released packaging solution components on HCECs was assessed by measuring cell viability, adhesion phenotype, and apoptosis. Incubation of HCECs with CLs stored in borate-buffered packaging solutions resulted in a significant reduction in cell viability. Adherent cells incubated with these CLs also exhibited reduced levels of beta(1) and alpha(3) integrin. Soaking borate-buffered packaged CLs in PBS before cell incubation resolved viability and integrin expression in all cases, with the exception of galyfilcon A and balafilcon A, from which a 20% reduction in cell viability was still observed. In comparison, CLs stored in phosphate-buffered packaging solutions had cellular viability and expression of integrins similar to control cells (cells incubated in the absence of a lens). When incubated with cells at a 10% concentration in serum-free medium, borate-buffered packaging solutions and borate-containing saline (Unisol 4) significantly reduced cell viability and integrin expression. Neither caspase activation nor annexin V binding was observed on cells following exposure to borate buffer solution. However, a significant decrease in reactive oxygen species was observed at 24 h. These latter results suggest that in vitro exposure to low concentration of borate/boric acid results in cell dysfunction, leading to necrosis rather than apoptosis. Borate-buffered packaging solutions were shown to adversely affect the viability and integrin expression of HCECs in vitro. When used in ophthalmic packaging solutions, the antimicrobial properties of borate buffer may be outweighed by its relatively cytotoxic effects on cells.


Nitrous oxide attenuates pressor but augments norepinephrine response to laryngoscopy and endotracheal intubation.
Nitrous oxide (N(2)O) exerts a sympathomimetic action. We investigated whether N(2)O modifies the cardiovascular responses to tracheal intubation during general anesthesia. One-hundred healthy patients were assigned randomly to receive one of four concentrations (0%, 25%, 50%, or 75%; n = 25 each) of N(2)O in oxygen throughout the study beginning 3 min before tracheal intubation. Anesthesia was induced with IV thiopental (5-7 mg/kg) whereas patients were ventilated with designated concentrations of N(2)O. Tracheal intubation was facilitated with IV vecuronium (0.12 mg/kg). After intubation, all received 2% sevoflurane in oxygen via a semiclosed anesthesia circuit. Systolic arterial blood pressure, heart rate and rhythm, and plasma catecholamine concentrations were measured. The intubation significantly increased arterial blood pressure and heart rate. The maximum pressure changes were 46 +/- 21 and 65 +/- 24 mm Hg in 75% N(2)O and control groups, respectively (P < 0.05), being attenuated by N(2)O without affecting the tachycardiac response. Norepinephrine concentrations were increased at 1 min after the intubation, the magnitude of which was augmented by N(2)O. N(2)O did not affect the incidence of arrhythmias. It was shown that N(2)O suppressed the pressor response to endotracheal intubation, despite the augmented increase of norepinephrine concentrations. We examined whether nitrous oxide modifies the cardiovascular response to endotracheal intubation because it activates the sympathetic nervous system. Nitrous oxide attenuated the pressor response, whereas it augmented the norepinephrine response to laryngoscopy and endotracheal intubation.


alpha beta T cell regulation and CD40 ligand dependence in murine systemic autoimmunity.
To explore the mechanisms by which alpha beta T cells and gamma delta T cells regulate systemic autoimmunity, lupus-prone mice were rendered deficient in CD40 ligand and/or alpha beta T cells by intercrossing CD40L -/- and TCR-alpha -/- knockouts, generating CD40L-intact or -deficient (CD40L+ or CD40L-), alpha beta T cell-intact or -deficient (alpha beta+ or alpha beta-) MRL-lpr/lpr animals. As expected, CD40L+ alpha beta+ mice developed high titer autoantibodies along with severe renal and cutaneous disease. CD40L+ alpha beta- animals developed lower levels of autoantibodies, accompanied by less severe or delayed renal and cutaneous disease. CD40L- alpha beta+ mice developed even lower titers of autoantibodies and less severe renal disease yet developed cutaneous lesions indistinguishable from those of CD40L+ alpha beta+ disease. Most surprisingly, CD40L- alpha beta- animals developed higher levels of some autoantibodies than did CD40L- alpha beta+ mice and developed renal disease similar in severity to CD40L+ alpha beta- counterparts; however, they failed to develop skin disease. Thus, disruption of CD40L and alpha beta T cells provides a novel dissection of the physiology and pathology of murine lupus; while these data confirm previous findings demonstrating a role for CD40L-dependent, alpha beta T cell-dependent mechanisms in autoantibody production and renal disease in murine lupus, they also: 1) establish that alpha beta T cells may drive autoimmune skin disease by a CD40L-independent mechanism; 2) identify a role for CD40L in non-alpha beta T cell-dependent autoantibody production and autoimmune skin disease; and 3) suggest a role for alpha beta T cells in the down-regulation of autoimmunity driven by other T cells. Thus, both alpha beta and non-alpha beta T cells, such as gamma delta T cells, regulate systemic autoimmunity by CD40L-dependent and -independent mechanisms.


Shear localization in a model glass.
Using molecular dynamics simulations, we show that a simple model of a glassy material exhibits the shear localization phenomenon observed in many complex fluids. At low shear rates, the system separates into a fluidized shear band and an unsheared part. The two bands are characterized by a very different dynamics probed by a local intermediate scattering function. Furthermore, a stick-slip motion is observed at very small shear rates. Our results, which open the possibility of exploring complex rheological behavior using simulations, are compared to recent experiments on various soft glasses.


New approaches to robotics.
In order to build autonomous robots that can carry out useful work in unstructured environments new approaches have been developed to building intelligent systems. The relationship to traditional academic robotics and traditional artificial intelligence is examined. In the new approaches a tight coupling of sensing to action produces architectures for intelligence that are networks of simple computational elements which are quite broad, but not very deep. Recent work within this approach has demonstrated the use of representations, expectations, plans, goals, and learning, but without resorting to the traditional uses of central, abstractly manipulable or symbolic representations. Perception within these systems is often an active process, and the dynamics of the interactions with the world are extremely important. The question of how to evaluate and compare the new to traditional work still provokes vigorous discussion.


Heterogeneous reaction between Li and anatase TiO2 nanoparticles under ultra-high vacuum.
We demonstrate heterogeneous chemistry between Li and anatase TiO2 nanoparticles under UHV. The reduction of TiO2 upon formation of lithium oxide proceeds via two different schemes: one that reduces Ti(4+) to Ti(3+) and one that reduces Ti(4+) directly to Ti(2+). The second scheme sets in only after a critical degree of reduction (i.e. Li amount) has been reached (Li/Ti = 0.28) and is associated with restructuring of the film. Two films with different morphologies were compared and the results demonstrate that the reaction between Li and larger TiO2 structures (30-50 nm) is kinetically restricted while such effects were significantly less prominent for small particles (10 nm).


Zygomycosis mimicking paranasal malignancy.
A case of zygomycosis involving the maxillary sinus in a normal host and mimicking paranasal malignancy is presented. Computed tomographic images showing destruction of adjoining bony structures and histologic features of fungi are described and presented. A successful outcome was achieved with amphotericin B irrigation and parenteral amphotericin B. Nasal biopsy should be advised by both radiologists and clinicians in all cases of lesions that look like malignancy in the sinus areas before a treatment modality is initiated.


Expression and protein-binding studies of the EEN gene family, new interacting partners for dynamin, synaptojanin and huntingtin proteins.
EEN, identified initially as a fusion partner to the mixed-lineage leukaemia gene in human leukaemia, and its related members, EEN-B1 and EEN-B2, have recently been shown to interact with two endocytic molecules, dynamin and synaptojanin, as well as with the huntingtin protein. In the present study, we show that the expression of the EEN gene-family members is differentially regulated. Multiple-spliced variants were identified for EEN-B2. In the brain, EEN-B1 and EEN-B2 mRNA are preferentially expressed in the cerebellar Purkinje and granule cells, dentate gyrus cells, hippocampal pyramidal neurons and cerebral granule cells. The expression patterns of EEN-B1 and EEN-B2 mRNA in the brain overlap with those of dynamin-I/III, synaptojanin-I and huntingtin, whereas the ubiquitous expression of EEN is consistent with that of dynamin-II. In testes, members of the EEN family are co-expressed with testis-type dynamin and huntingtin in Sertoli cells and germ cells respectively. Our results on the overlapping expression patterns are consistent with the proposed interaction of EEN family members with dynamin, synaptojanin and huntingtin protein in vivo. Although all three EEN family members bind to dynamin and synaptojanin, EEN-B1 has the highest affinity for binding, followed by EEN and EEN-B2. We also demonstrate that amphiphysin, a major synaptojanin-binding protein in brain, can compete with the EEN family for binding to synaptojanin and dynamin. We propose that recruitment of the EEN family by dynamin/synaptojanin to clathrin-coated pits can be regulated by amphiphysin.


Controlled compression and liposuction treatment for lower extremity lymphedema.
In 1987 we noticed excess adipose tissue in a patient with arm lymphedema and later, objective studies confirmed this clinical finding in patients with non-pitting arm lymphedema following breast cancer. A prospective study was begun in 1993, and its long-term results (15 years) shows overall complete reduction of the excess volume in patients with non-pitting arm lymphedema and that adipose tissue dominates the excess volume. Encouraged by these results we operated on a patient with primary and secondary elephantiasis of the leg. The edema was first transferred from a pitting to a non-pitting state by controlled compression therapy. Then liposuction was performed to remove the remaining excess adipose tissue, and complete reduction was finally achieved. The patient wears compression garments continuously and during the 11 years of followup, no recurrence has occurred. This paper explains our philosophical approach: a pitting lymphedema first should be treated conservatively to remove excess fluid, then liposuction can be performed to remove remaining excess volume bothersome to the patient.


Molecular and Mechanical Mechanisms Regulating Ductus Arteriosus Closure in Preterm Infants.
Failure of ductus arteriosus closure after preterm birth is associated with significant morbidities. Ductal closure requires and is regulated by a complex interplay of molecular and mechanical mechanisms with underlying genetic factors. In utero patency of the ductus is maintained by low oxygen tension, high levels of prostaglandins, nitric oxide and carbon monoxide. After birth, ductal closure occurs first by functional closure, followed by anatomical remodeling. High oxygen tension and decreased prostaglandin levels mediated by numerous factors including potassium channels, endothelin-1, isoprostanes lead to the contraction of the ductus. Bradykinin and corticosteroids also induce ductal constriction by attenuating the sensitivity of the ductus to PGE2. Smooth muscle cells of the ductus can sense oxygen through a mitochondrial network by the role of Rho-kinase pathway which ends up with increased intracellular calcium levels and contraction of myosin light chains. Anatomical closure of the ductus is also complex with various mechanisms such as migration and proliferation of smooth muscle cells, extracellular matrix production, endothelial cell proliferation which mediate cushion formation with the interaction of blood cells. Regulation of vessel walls is affected by retinoic acid, TGF-β1, notch signaling, hyaluronan, fibronectin, chondroitin sulfate, elastin, and vascular endothelial cell growth factor (VEGF). Formation of the platelet plug facilitates luminal remodeling by the obstruction of the constricted ductal lumen. Vasa vasorum are more pronounced in the term ductus but are less active in the preterm ductus. More than 100 genes are effective in the prostaglandin pathway or in vascular smooth muscle development and structure may affect the patency of ductus. Hemodynamic changes after birth including fluid load and flow characteristics as well as shear forces within the ductus also stimulate closure. Current pharmacological treatment for the closure of a patent ductus is based on the blockage of the prostaglandin pathway mainly through COX or POX inhibition, albeit with some limitations and side effects. Further research for new agents aiming ductal closure should focus on a clear understanding of vascular biology of the ductus.


[Sedation during noninvasive mechanical ventilation].
Noninvasive mechanical ventilation (NIMV) is an effective technique that can avert side effects and complications associated with endotracheal intubation. The tolerance of NIMV is crucial for its success. Mask intolerance because of pain or discomfort, or claustrophobia, may lead the patient to refuse ongoing NIMV prompting its discontinuation. After considering all factors known to improve adaptation of the patients to NIMV, the implementation of sedation-based strategy to rescue patients with poor cooperation and/or adaptation to NIMV is remaining attaractive to enlarge its rate of success. Pilot studies suggest that continuous infusion of a single different sedative and analgesic agent titrated to obtain "conscious sedation" may decrease patient discomfort, with no significant effects on respiratory drive, respiratory pattern, or hemodynamic; in addition, gas exchange improve under NIMV plus sedation. Despite these encouraging findings, the level of the evidence in favor of a large application of sedation during NIMV is still limited and further larger and controlled trials are needed to clarify the indications of sedation during NIMV and better select the patients who are mostly likely to benefit from this practice. In this review, indications of sedation during NIMV, the timing, sedative drugs, the level of sedation as well as clinical studies on this subject have been summarized.


[Angiogram-negative subarachnoid hemorrhage. Should the procedure be repeated?].
Most cases of non-traumatic subarachnoid hemorrhage are caused by rupture of an arterial aneurysm or an arteriovenous malformation. The first angiogram performed is normal nearly 20% of the time. To review the need to repeat angiography if the first study is negative. Review of patients admitted to our hospital with subarachnoid hemorrhage in recent years. All had had high quality angiography performed, that was repeated if the first study was negative. We analyzed 112 cases of subarachnoid hemorrhage, of which 27 (24.1%) had angiographic studies of the four main cerebral vessels that failed to reveal the origin of the hemorrhage. An aneurysm that had not previously been seen was detected in 2 patients (7.4%), whether or not there had been vasospasm in the first study. Given our findings, the low incidence of complications in the first study and the seriousness of the pathology under consideration, we suggest that angiography should be repeated unless there are major contraindications.


Deep infection after hip arthroplasty: staying current with change.
Periprosthetic joint infection (PJI) complicates between 0.5% and 1.2% primary total hip arthroplasties (THAs) and may have devastating consequences. The traditional assessment of patients suffering from PJI has involved the serological study of inflammatory markers and microbiological analysis of samples obtained from the joint space. Treatment has involved debridement and revision arthroplasty performed in either one or two stages. We present an update on the burden of PJI, strategies for its diagnosis and treatment, the challenge of resistant organisms and the need for definitive evidence to guide the treatment of PJI after THA.


The preference of the most appropriate radical-based regeneration process for spent activated carbon by the PROMETHEE approach.
In this study, regeneration of spent granular activated carbon (GAC) with reactive dye by hydroxyl and sulfate radical-based advanced oxidation processes (microwave (MW) +persulfate (PS)), (Fe(II)+ PS), and (O3 + H2O2) were evaluated. The adsorption of the dye to the GAC surface was characterized by chemisorption and Langmuir isotherm. Regeneration processes have been optimized by the response surface methodology to determine the operating conditions that will provide the highest adsorptive capacity. The optimum conditions of (MW + PS), (Fe (II) + PS), and (O3 + H2O2) processes were process PS anion of 45.52 g/L, pH of 11.4, MW power of 126 W, and duration of 14.56 min; Fe (II) of 3.58 g/L, PS anion of 73.5 g/L, duration of 59.8 min, and pH of 10.9; and H2O2 of 2.8 mole/L, flow rate of 8.14 mg ozone/L, duration of 32.8 min, and pH of 5.3, respectively. For (MW + PS), (Fe (II) + PS), and (O3 + H2O2) processes, the adsorptive capacity under optimum conditions was found as 4.36, 8.89, and 8.12 mg dye/g GAC, respectively. For (Fe (II) + PS) and (O3 + H2O2) processes, these values are approximately equal to the adsorptive capacity of raw GAC (8.01 mg dye/g GAC). The predicted values of the adsorption capacities by the obtained models were in good agreement with the actual experimental results. Preference Ranking Organization Method for Enrichment Evaluation approach was used in the preference of the appropriate regeneration process. The adsorptive capacity of regenerated GAC, operating cost of the regeneration process, change in the adsorptive capacity during the regeneration cycle, and carbon mass loss criteria were taken into account. The order of preference of regeneration processes was determined as (Fe (II) + PS)> (MW + PS)> (O3 + H2O2) considering all criteria.


Biomimetic studies on polyenes.
The crispatenes and SNF4435 C&D are complex polypropionate derived natural products. The core structures of these compounds along with a complex unnatural structure can be easily prepared from a common polyene precursor simply by variation of the reaction conditions. The reaction pathways provide insight into the biosynthesis of these complex natural products.


Macronuclear division with and without microtubules in Tetrahymena.
The effects of cold shocks (0 degrees C) and colchicine (4 mg/ml) on macronuclear microtubules and macronuclear division have been investigated in Tetrahymena. Macronuclear division was affected by both treatments, but loss of microtubules occurred only in the presence of colchicine. When colchicine was applied immediately prior to macronuclear elongation, the nuclei underwent a partial elongation without microtubules, but were unable to constrict and separate into daughter nuclei. Such nuclei were cut in two by the advancing cytoplasmic fission furrow. When colchicine was applied to macronuclei in the fully elongated state, that maintained their elongation in the absence of microtubules, and were subsequently separated into daughter nuclei by the cytoplasmic furrow. It is suggested that macronuclear microtubules, most probably the membrane-associated microtubules, are required for the terminal stages of nuclear elongation and separation. However, the considerable macronuclear elongation which takes place in the absence of microtubules serves to focus attention on molecular mechanisms of force production which must reside elsewhere in the macronucleus.


Darwin, artificial selection, and poverty.
This paper argues that the processes of evolutionary selection are becoming increasingly artificial, a trend that goes against the belief in a purely natural selection process claimed by Darwin's natural selection theory. Artificial selection is mentioned by Darwin, but it was ignored by Social Darwinists, and it is all but absent in neo-Darwinian thinking. This omission results in an underestimation of probable impacts of artificial selection upon assumed evolutionary processes, and has implications for the ideological uses of Darwin's language, particularly in relation to poverty and other social inequalities. The influence of artificial selection on genotypic and phenotypic adaptations arguably represents a substantial shift in the presumed path of evolution, a shift laden with both biological and political implications.


Pancreatic triacylglycerol lipase in a hibernating mammal. I. Novel genomic organization.
Pancreatic triacylglycerol lipase (PTL) is expressed in novel locations during hibernation in the thirteen-lined ground squirrel (Spermophilus tridecemlineatus). PTL cDNAs isolated from two of these locations, heart and white adipose tissue (WAT), contain divergent 5'-untranslated regions (5'-UTRs) suggesting alternative promoter usage or the possibility of multiple PTL genes in the ground squirrel genome. In addition, cDNAs isolated from WAT contain tracts of retroviral sequence in their 5'-UTRs. Our examination of PTL genomic clones isolated from a thirteen-lined ground squirrel genomic DNA library, coupled with genomic Southern blot analysis, enabled us to conclude that PTL mRNAs expressed in heart and WAT are the products of the same single-copy gene. The 5' portion of this gene spans 9.2 kb, is composed of 6 exons, and contains a full-length endogenous retroviral genome with conserved long terminal repeats (LTRs). Alignment of the ground squirrel PTL gene with the mouse, rat, and human PTL genes indicates that this retrovirus inserted into the ground squirrel genome approximately 200 bases upstream of the original PTL transcriptional start site. The insertion is a relatively recent event based on largely intact open-reading frames containing minimal frame-shift and nonsense mutations. The high-percentage identity (99.2%) shared between the 5'- and 3'-LTRs of this endogenous retrovirus suggests that the insertion occurred as recently as 300,000 years ago.


Prognostic utility of preoperative and postoperative KRAS-mutated circulating tumor DNA (ctDNA) in resected pancreatic ductal adenocarcinoma: A systematic review and meta-analysis.
Pancreatic ductal adenocarcinoma (PDAC) is a challenging disease, with surgery being the only possible cure. However, despite surgery, the majority of patients experience recurrence. Recent evidence suggests that perioperative KRAS-mutated circulating tumor DNA (ctDNA) may have prognostic value. Therefore, we conducted a systematic review and meta-analysis to explore the prognostic significance of preoperative and postoperative KRAS-mutated ctDNA testing in resected PDAC. We searched PubMed/MEDLINE, Embase, and Cochrane Central Register of Controlled Trials databases for studies that reported the effect of preoperative and postoperative KRAS-mutated ctDNA on overall survival (OS) and/or relapse-free survival (RFS) in resected PDAC. We used a random-effects model to determine the pooled OS and RFS hazard ratios (HR) and their corresponding 95 % confidence intervals (CI). We identified 15 studies (868 patients) eligible for analysis. In the preoperative setting, positive ctDNA correlated with worse RFS in 8 studies (HR, 2.067; 95 % CI, 1.346-3.174, P < 0.001) and worse OS in 10 studies (HR, 2.170; 95 % CI, 1.451-3.245, P < 0.001) compared to negative ctDNA. In the postoperative setting, positive ctDNA correlated with worse RFS across 9 studies (HR, 3.32; 95 % CI, 2.19-5.03, P < 0.001) and worse OS in 6 studies (HR, 6.62; 95 % CI, 2.18-20.16, P < 0.001) compared to negative ctDNA. Our meta-analysis supports the utility of preoperative and postoperative KRAS-mutated ctDNA testing as a prognostic marker for resected PDAC. Further controlled studies are warranted to confirm these results and to investigate the potential therapeutic implications of positive KRAS-mutated ctDNA.


A comprehensive review of dengue with a focus on emerging solutions for precision and timely detection.
Dengue is a global health problem, caused by the dengue virus (DENV), which belongs to the Flaviviridae family of viruses. The transmission of DENV occurs through vectors, Ae. aegypti and Ae. Albopictus mosquitoes, to the human host, classifying it as a vector-borne disease. The disease incidence is increasing at an alarming rate and needs to be tackled to reduce the morbidity and mortality caused by the disease. Environmental and clinical surveillance, detection of the virus, and diagnostics are critical tools to address this issue. In this comprehensive review, we explore various diagnostic techniques and the associated challenges within the context of dengue. While we briefly touch upon dengue's epidemiology, serotypes, and pathogenesis, our primary emphasis remains on diagnostics. We delve into the intricacies of these diagnostic methods, considering both the challenges they entail and the potential they hold in terms of accuracy and accessibility. It's important to note that the review does not extensively cover clinical aspects or regional variations of the disease.


24-hour ECG frequency-domain measures in preeclamptic and healthy pregnant women during and after pregnancy.
The aim of the present study was to evaluate the autonomic balance in women with preeclampsia and in healthy women during and after pregnancy by means of a 24-h ECG Holter recording combined with power spectral analysis. Fifteen preeclamptic and 15 healthy women underwent 24-h Holter monitoring in the 32nd-36th week of gestation and 3-6 months postpartum. The power spectrum of the maternal electrocardiogram was analyzed with an autoregressive algorithm. The power spectrum contains two major components: a low-frequency peak, primarily attributed to sympathetic tone, and a high-frequency peak, reflecting vagal tone. The power spectrum of maternal heart rate variability did not differ between preeclamptic and normal women during pregnancy. After delivery, the amplitude of all components became significantly higher than those during pregnancy, with one exception: the high-frequency component in the patients who had been preeclamptic. In a comparison of the two groups, the high-frequency component after delivery was significantly lower in women who had preeclampsia than in normal healthy women (p = 0.03). During pregnancy, the power spectrum is reduced and cannot be used to distinguish between patients with preeclampsia and normal healthy women. Three to 6 months after delivery, the high-frequency component is still reduced in the preeclamptic group of women. This indicates an impaired vagal modulation even in the nonpregnant state in this group of women, unlike those who had a normotensive pregnancy.


[Publishing in biomedical journals in the year 2000 and after; report of a symposium].
On the occasion of the oration by prof. dr. A.J.P.M. Overbeke, executive editor of the Nederlands Tijdschrift voor Geneeskunde, a symposium was organized on 16 June 2000. The lecturers were (chief) editors of medical journals. Many changes in medical publishing are to be expected in the next 10 years. The new technology will play an important part in this, but the details remain to be seen. Scientific journals can continue to exist in the electronic era if they produce legible, i.e. brief and clear articles in the printed version and offer extra information on the internet: details of methods used and statistical analyses and extensive tables. Also, the contributions of the various authors are printed. Not all, but only a few authors should make certain that the work described has indeed been performed and these would be responsible for the contents of the entire article. It appeared that the main part played by physicians in mass media is that of occasional informants. There still exist possibilities to use the media in distributing and supporting the messages of medicine and in elucidating the dilemmas. While 'archivist' journals mostly record scientific work presented, the task of the 'newspaper journals' consists of informing, interpreting, criticizing and stimulating. In this 'colouring' of the contents of the journal, the independence of the chief editors is of great importance. The innovations in medicine of the past century appear to be based mostly on the work of predecessors, of research physicians opposing established authorities, and on coincidence. The interval between discovery and publication has grown much shorter.


Phase and morphology changes in lipid monolayers induced by SP-B protein and its amino-terminal peptide.
Both human lung surfactant protein, SP-B, and its amino-terminal peptide, SP-B1-25, inhibit the formation of condensed phases in monolayers of palmitic acid, resulting in a new fluid phase. This fluid phase forms a network, separating condensed-phase domains at coexistence. The network persists to high surface pressures, altering the nucleation, growth, and morphology of monolayer collapse structures, leading to lower surface tensions on compression and more reversible respreading on expansion. The network is stabilized by the low line tension between the fluid phase and the condensed phase as confirmed by the formation of "stripe" phases.


Radio-guided localization of clinically occult breast lesions: current modalities and future directions.
The extensive availability of breast cancer screening programs and improvement in diagnostic imaging have led to more frequent detection of suspicious and clinically occult breast lesions. Early detection of tumor is important for breast-conserving treatment. Incomplete excision is a major risk factor for local recurrence. Following precise localization and removing the entire lesion while achieving adequate clear margins is the key factor for successful management of non-palpable breast lesions. For this purpose, several techniques such as wire-guided localization, intra-operative ultrasound guided resection, radio-guided occult lesion localization and radioactive seed localization have been described and applied. In this article, we overview the two commonly used localization techniques, radio-guided occult lesion localization and wire-guided localization, particularly describing their advantages and drawbacks.


Heritabilities and genetic correlations for litter size and semen traits in Czech Large White and Landrace pigs.
The objective of the present study was to estimate heritabilities and genetic correlations for semen and litter size traits using full animal model analyses. Litter size data were available from 28,485 Czech Large White and 10,410 Czech Landrace sows farrowing between 1995 and 2008. The number of litter records was 91,922 and 30,937, respectively. Records on semen traits (37,137 ejaculates from 778 Large White boars and 51,341 ejaculates from 841 Landrace boars) were available from 22 AI centers in the Czech Republic from 2000 to 2009. All calculations were carried out separately for each breed. Number of functional sperm was defined as total number of sperm times the fraction of motile sperm times (1 - the fraction of abnormal sperm). Among the semen traits, semen volume showed the greatest heritability (0.20 +/- 0.019 in Large White and 0.25 +/- 0.018 in Landrace), followed by sperm concentration with a heritability of 0.18 (SE = 0.012 and 0.014) in both breeds. The heritabilities of the remaining 4 traits (motility, percentage of abnormal sperm, total number of sperm, and number of functional sperm) were around 0.10 (SE = 0.016 to 0.031). Large negative genetic correlations were observed between semen volume and sperm concentration and between motility and percentage of abnormal sperm, especially in Large White. Positive and negative correlations among remaining semen traits were mostly of small magnitude. There was a tendency for increasing litter size to be associated with slight decreases in the total number of sperm and in the number of functional sperm, especially in the Large White breed (genetic correlations of -0.08 to -0.14 and -0.16 to -0.31, respectively, with SE between 0.100 and 0.114). Some of the correlations between semen and litter size traits (especially with the percentage of abnormal sperm) were breed-specific (positive up to 0.63 +/- 0.062 for Large White and negative until -0.41 +/- 0.106 in Landrace). Furthermore, parity-specific correlations were observed in the Large White breed.


[Characteristics of the hormonal-immunologic status in inflammatory disorders of the female reproductive system].
The presence of cooperative hormonal-immunologic reactions in the female reproductive tract is substantiated. The features of their regional morphologic manifestations in menarche, hormonal pregnancy and non-complicated delivery are described. The importance of specific hormonal factors in the pathogenesis of ascending genital infections at various stages of the gestational period is shown. The possibilities of a pathomorphologic method in the evaluation of the hormonal -- immunological status when examining a gynecological-obstetrical material are determined.


Onset of efficacy of long-acting psychostimulants in pediatric attention-deficit/hyperactivity disorder.
Attention-deficit/hyperactivity disorder (ADHD) adversely impacts the educational achievement, mood and emotion processing, and interpersonal relationships of children and adolescents. Effective treatments include a number extended-release (ER) methylphenidate-(MPH) and amphetamine-based drugs. Some formulations release a comparatively larger bolus after dosing and can result in different onset and duration of efficacy. Provide an evidence-based description of the time course of efficacy of psychostimulant medications used in ADHD treatment of children and adolescents. A literature search from 1998 to 2008 was conducted using a MEDLINE database and the keywords "attention-deficit/hyperactivity disorder," "extended-release," "sustained-release," "methylphenidate," "amphetamine," "randomized," "controlled," "placebo," "efficacy," "time course," and "classroom study." Selection criteria included randomized, blinded, placebo- or active comparator-controlled clinical studies that evaluated an ER formulation of a psychostimulant treatment for ADHD in at least 30 children and adolescents aged 6 to 17 years. Eighteen clinical trials met the chosen criteria and evaluated: d, l-MPH, long-acting (d, l-MPH-LA); d, l-MPH-OR; d, l-MPH-CD (MCD); d-MPH-ER; MPH transdermal system (MTS); mixed amphetamine salts, ER (MAS-XR); and lisdexamfetamine dimesylate (LDX). Onset of efficacy was earliest for d-MPH-ER at 0.5 hours, followed by d, l-MPH-LA at 1 to 2 hours, MCD at 1.5 hours, d, l-MPH-OR at 1 to 2 hours, MAS-XR at 1.5 to 2 hours, MTS at 2 hours, and LDX at approximately 2 hours. Duration of efficacy for each treatment was: MCD 7.5 hours; d, l-MPH-LA 8 to 12 hours; and 12 hours for MTS, d-MPH-ER, d, l-MPH-OR, MAS-XR, and LDX. However, data should be interpreted with caution given the different trial designs and assessment time points. d-MPH-ER has the earliest onset of efficacy at 0.5 hours postdose, and MTS, d-MPH-ER, d, l-MPH-OR, MAS-XR, and LDX have a long duration of action at 12 hours postdose. Clinicians should consider differences in the onset of efficacy of each drug in the context of individual patient needs.


The GluN2B-Containing NMDA Receptor Alleviates Neuronal Apoptosis in Neonatal Hypoxic-Ischemic Encephalopathy by Activating PI3K-Akt-CREB Signaling Pathwa.
Neonatal hypoxic-ischemic encephalopathy (HIE) is a disease caused by insufficient blood supply in the brain in newborns during the perinatal period. Severe HIE leads to patient death, and patients with mild HIE are at increased risk of cognitive deficits and behavioral abnormalities. The NMDA receptor is an important excitatory receptor in the central nervous system, and in adult hypoxic-ischemic injury both subtypes of the NMDA receptor play important but distinct roles. The GluN2A-containing NMDA receptor (GluN2A-NMDAR) could activate neuronal protective signaling pathway, while the GluN2B-NMDAR subtype is coupled to the apoptosis-inducing signaling pathway and leads to neuronal death. However, the expression level of GluN2B is higher in newborns than in adults, while the expression of GluN2A is lower. Therefore, it is not clear whether the roles of different NMDA receptor subtypes in HIE are consistent with those in adults. We investigated this issue in this study and found that in HIE, GluN2B plays a protective role by mediating the protective pathway through binding with PSD95, which is quite different to that in adults. The results of this study provided new theoretical support for the clinical treatment of neonatal hypoxic ischemia.


Three-dimensional shoulder kinematics: Upright four-dimensional computed tomography in comparison with an optical three-dimensional motion capture system.
Although shoulder kinematics have been analyzed by various methods, dynamic shoulder motion is difficult to track. This study aimed to validate the shoulder kinematic analysis using upright four-dimensional computed tomography (4DCT) and to compare the results with optical three-dimensional motion capture. During active elevation, bilateral shoulders of 10 healthy volunteers were tracked using 4DCT and motion capture. The scapulothoracic and glenohumeral rotations and the scapulohumeral rhythm (SHR) at each position were calculated, and the differences between 4DCT and motion capture were compared. During 10-140° of humerothoracic elevation, the scapulothoracic joint showed upward rotation, internal rotation, and posterior tilting, and the glenohumeral joint showed elevation, external rotation, and anterior plane of elevation in both analyses. In scapulothoracic rotations, the mean differences between the two analyses were -2.6° in upward rotation, 13.9° in internal rotation, and 6.4° in posterior tilting, and became significant with humerothoracic elevation ≥110° in upward rotation, ≥50° in internal rotation, and ≥100° in posterior tilting. In glenohumeral rotations, the mean differences were 3.7° in elevation, 9.1° in internal rotation, and -8.8° in anterior plane of elevation, and became significant with humerothoracic elevation ≥110° in elevation, ≥90° in internal rotation, and ≥100° in anterior plane of elevation. The mean overall SHRs were 1.8 in 4DCT and 2.4 in motion capture, and the differences became significant with humerothoracic elevation ≥100°. The 4DCT analysis of in vivo shoulder kinematics using upright computed tomography scanner is feasible, but the values were different from those by skin-based analysis at the elevated arm positions.


[Alterations of auriculoventricular valves in single ventricles and similar abnormalities].
The morphologic changes of the atrio-ventricular valve in 30 cases of lone ventricle or similar anomalies have been: 1. Common atrio-ventricular valve (8 cases); 2. Abnormally small left atrio-ventricular valve (15 cases) 3. Parachute-like left atrio-ventricular valve (5 cases); 4. Atresia of one of the atrio-ventricular valves (2 cases); 5. Atrio-ventricular valves corresponding to a tricuspid valve which were bicuspid (6 cases); 6. Accessory valvular orifices (5 cases); 7. Valvular clefts (3 cases); 8. Insufficient valvular tissue (4 cases); 9. Accessory valvular tissue (7 cases); 10. Anomalies of orientation of the anterior in relation with the posterior mitral valve leaflet (7 cases); 11. Peculiar orientation of the valve in relation with the outflow tract, resulting in a "functional overlap" (1 case); 12. Muscle column on the posterior wall of the main ventricular chamber (18 cases); 13. Papillary muscle distribution alterations (29 cases). The embryologic, diagnostic and surgical signification of all these anomalies were considered.


Immunocytochemical localization of DNA double-strand breaks in human and rat brains.
Post-mitotic neurons are particularly susceptible to DNA double-strand breaks during their relatively long lifespan. Here, we report the anatomical distribution and subcellular localization of a molecule first identified as a DNA damage checkpoint protein. Immunocytochemical analysis of 53BP1 showed that this nuclear molecule is widely expressed in adult human and rat brains. Further, we showed that 53BP1 routinely co-clusters with γ-aminobutyric acid neurons throughout the rat neuraxis. Notably, 53BP1 is only expressed in neuronal cells as the DNA damage checkpoint protein was virtually absent from glial cells. Finally, we found that human neural progenitors showed a differential index of DNA fragmentation at different stages of cellular differentiation. These data provide additional and important anatomical findings for the distribution and phenotype of DNA double-strand breaks in the mammalian brain, and suggest that DNA fragmentation is a spontaneous event routinely occurring in neural progenitors and adult neurons.


Secretive eating among youth with overweight or obesity.
Secretive eating, characterized by eating privately to conceal being seen, may reflect eating- and/or body-related shame, be associated with depression, and correlate with binge eating, which predicts weight gain and eating disorder onset. Increasing understanding of secretive eating in youth may improve weight status and reduce eating disorder risk. This study evaluated the prevalence and correlates of secretive eating in youth with overweight or obesity. Youth (N = 577) presented to five research/clinical institutions. Using a cross-sectional design, secretive eating was evaluated in relation to eating-related and general psychopathology via linear and logistic regression analyses. Secretive eating was endorsed by 111 youth, who were, on average, older than youth who denied secretive eating (mean age = 12.07 ± 2.83 versus 10.97 ± 2.31). Controlling for study site and age, youth who endorsed secretive eating had higher eating-related psychopathology and were more likely to endorse loss of control eating and purging than their counterparts who did not endorse secretive eating. Groups did not differ in excessive exercise or behavioral problems. Dietary restraint and purging were elevated among adolescents (≥13y) but not children (<13y) who endorsed secretive eating; depression was elevated among children, but not adolescents, who endorsed secretive eating. Secretive eating may portend heightened risk for eating disorders, and correlates of secretive eating may differ across pediatric development. Screening for secretive eating may inform identification of problematic eating behaviors, and understanding factors motivating secretive eating may improve intervention tailoring.


Epidermal growth factor receptor (EGFR) signaling regulates global metabolic pathways in EGFR-mutated lung adenocarcinoma.
Genetic mutations in tumor cells cause several unique metabolic phenotypes that are critical for cancer cell proliferation. Mutations in the tyrosine kinase epidermal growth factor receptor (EGFR) induce oncogenic addiction in lung adenocarcinoma (LAD). However, the linkage between oncogenic mutated EGFR and cancer cell metabolism has not yet been clearly elucidated. Here we show that EGFR signaling plays an important role in aerobic glycolysis in EGFR-mutated LAD cells. EGFR-tyrosine kinase inhibitors (TKIs) decreased lactate production, glucose consumption, and the glucose-induced extracellular acidification rate (ECAR), indicating that EGFR signaling maintained aerobic glycolysis in LAD cells. Metabolomic analysis revealed that metabolites in the glycolysis, pentose phosphate pathway (PPP), pyrimidine biosynthesis, and redox metabolism were significantly decreased after treatment of LAD cells with EGFRTKI. On a molecular basis, the glucose transport carried out by glucose transporter 3 (GLUT3) was downregulated in TKI-sensitive LAD cells. Moreover, EGFR signaling activated carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD), which catalyzes the first step in de novo pyrimidine synthesis. We conclude that EGFR signaling regulates the global metabolic pathway in EGFR-mutated LAD cells. Our data provide evidence that may link therapeutic response to the regulation of metabolism, which is an attractive target for the development of more effective targeted therapies to treat patients with EGFR-mutated LAD.


STIM1 and STIM2 cooperatively regulate mouse neutrophil store-operated calcium entry and cytokine production.
Neutrophils are key effector cells of the innate immune system. Calcium-dependent signaling pathways initiated by store-operated calcium entry (SOCE) are known to regulate neutrophil activation; however, the precise mechanism of this process remains unclear. STIM1 and STIM2 are calcium-sensing molecules that link calcium depletion of the endoplasmic reticulum with opening of plasma membrane calcium channels. Although a role for STIM1 in neutrophil SOCE and activation has been established, the function of STIM2 is unknown. Here we use mice with conditional ablation of Stim1 and/or Stim2 to investigate the role of STIM2 in neutrophil activation. We demonstrate that loss of STIM2 results in decreased SOCE, particularly at lower doses of agonists. Reactive oxygen species (ROS) production, degranulation, and phagocytosis are normal in the absence of STIM2, suggesting STIM1 is the dominant calcium sensor required for classical short-term neutrophil responses. However, neutrophil cytokine production required STIM2, but not STIM1, at least in part as a result of redox regulation of cytokine gene expression. In vivo loss of STIM2 results in lower cytokine levels and protection from mortality in a mouse model of systemic inflammatory response syndrome. These data, combined with previous studies focusing on STIM1, define distinct but cooperative functions for STIM1 and STIM2 in modulating neutrophil bactericidal and cytokine responses.


[Particularities of epileptic women's care].
Development on the epileptic women's care. A research in the medical literature on PubMed and an exhaustive review of the published summaries and reports of Epileptology International Meetings, in the last five years. We included cohort studies, reviews and randomized double blinded therapeutic trials. Case reports and fundamental research studies have been excluded. sensitizing of the epileptic women starts with adolescence with an education and a preparation to sexual life and available contraceptive methods, in order to avoid undesired pregnancies and the serious consequences which they are likely to generate. Approximately 1/3 of the epileptic women have variations of their disease related to the menstrual cycle, probably because of a neurotoxic effect of estrogens (not counterbalanced by progestational hormones). Antiepileptic teratogenicity issue is not, yet, solved, in spite of new molecules commercialisation. The upkeep of a register concerning the use of AED during pregnancy makes it possible to better identify the problems and to establish an optimal therapeutic control for the mother and the child. Epilepsy impact on women's life is very different compared to men, because it interferes with the fields of sexuality, reproduction, menstrual cycle and contraception, in addition of AED teratogenicity. A close cooperation between obstetricians and neurologist and a sensitizing of health professionals are essential for the global care of the epileptic pregnant women or in age of procreation.


Cytomegalovirus infections following renal transplantation--effects on antiviral prophylaxis: a report of the North American Pediatric Renal Transplant Cooperative Study.
Post-transplant cytomegalovirus (CMV) infections are a source of significant morbidity. However, the extent of the problem and the benefits of various antiviral prophylactic therapies remain incompletely understood. The North American Pediatric Renal Transplant Cooperative Study registry was screened to identify patients hospitalized for CMV infections during the 1st post-renal transplant year between 1987 and 1993. Using a control group of transplant recipients, we performed a retrospective analysis of risk factors for CMV disease among these hospitalized patients and studied the effects of various viral prophylactic strategies on CMV risk, clinical manifestations, and outcome. We identified 142 patients hospitalized with CMV infections, the majority of which included major organ involvement. A CMV-positive kidney donor was the most significant risk factor for hospitalization [odds ratio (OR) = 5.2, P<0.0001] irrespective of recipient age or CMV immune status. As opposed to antiviral agents (acyclovir, ganciclovir) or pooled IgG, prophylaxis with enriched anti-CMV IgG significantly reduced the risk of CMV hospitalization (OR = 0.31, P = 0.03). The prophylactic use of antiviral agents was associated with a decreased risk of major organ involvement during the CMV infection (OR = 0.34, P<0.005). Among the patients with CMV, the 3-year graft survival was significantly better for those who received any form of prophylaxis compared with those who received none (88% vs. 52%, P<0.001). Our findings suggest a role for combined CMV-enriched IgG and antiviral agent prophylaxis for post-transplant CMV disease. Such an approach could diminish the incidence and severity of CMV infection and appears to have an independent favorable effect on graft outcome.


A cluster-randomised controlled trial comparing school and community-based deworming for soil transmitted helminth control in school-age children: the CoDe-STH trial protocol.
Current guidelines and targets for soil-transmitted helminth (STH) control focus on school-based deworming for school-age children, given the high risk of associated morbidity in this age group. However, expanding deworming to all age groups may achieve improved STH control among both the community in general and school-age children, by reducing their risk of reinfection. This trial aims to compare school-based targeted deworming with community-wide mass deworming in terms of impact on STH infections among school-age children. The CoDe-STH (Community Deworming against STH) trial is a cluster-randomised controlled trial (RCT) in 64 primary schools in Dak Lak province, Vietnam. The control arm will receive one round of school-based targeted deworming with albendazole, while in the intervention arm, community-wide mass deworming with albendazole will be implemented alongside school-based deworming. Prevalence of STH infections will be measured in school-age children at baseline and 12 months following deworming. The primary outcome is hookworm prevalence in school-age children at 12 months, by quantitative PCR. Analysis will be intention-to-treat, with outcomes compared between study arms using generalised linear and non-linear mixed models. Additionally, cost-effectiveness of mass and targeted deworming will be calculated and compared, and focus group discussions and interviews will be used to assess acceptability and feasibility of deworming approaches. Individual based stochastic models will be used to predict the impact of mass and targeted deworming strategies beyond the RCT timeframe to assess the likelihood of parasite population 'bounce-back' if deworming is ceased due to low STH prevalence. The first large-scale trial comparing mass and targeted deworming for STH control in South East Asia will provide key information for policy makers regarding the optimal design of STH control programs. ACTRN12619000309189 .


Angiokeratoma of the vulva.
Angiokeratomas are benign tumors characterized by ectasia of blood vessels in the papillary dermis associated with acanthosis and hyperkeratosis of the epidermis. Dermatological examination of angiokeratomas of Fordyce is characterized by papular keratotic lesions of erythematous-violet color. They are more common in the scrotum, and vulvar involvement is rarely reported. Histopathology is particularly important to distinguish them from other benign and malignant tumors. The article reports the case of a middle-aged black woman with a history of chronic constipation, varicose veins of the lower limbs and cesarean section performed 20 years ago who had had multiple vulvar angiokeratomas for three months.


Serum/glucocorticoid-regulated kinase 1 (SGK1) is a prominent target gene of the transcriptional response to cytokines in multiple myeloma and supports the growth of myeloma cells.
Multiple myeloma (MM) is a paradigm for a malignant disease that exploits external stimuli of the microenvironment for growth and survival. A thorough understanding of the complex interactions between malignant plasma cells and their surrounding requires a detailed analysis of the transcriptional response of myeloma cells to environmental signals. We determined the changes in gene expression induced by interleukin (IL)-6, tumor necrosis factor-α, IL-21 or co-culture with bone marrow stromal cells in myeloma cell lines. Among a limited set of genes that were consistently activated in response to growth factors, a prominent transcriptional target of cytokine-induced signaling in myeloma cells was the gene encoding the serine/threonine kinase serum/glucocorticoid-regulated kinase 1 (SGK1), which is a down-stream effector of PI3-kinase. We could demonstrate a rapid, strong and sustained induction of SGK1 in the cell lines INA-6, ANBL-6, IH-1, OH-2 and MM.1S as well as in primary myeloma cells. Pharmacologic inhibition of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway abolished STAT3 phosphorylation and SGK1 induction. In addition, small hairpin RNA (shRNA)-mediated knock-down of STAT3 reduced basal and induced SGK1 levels. Furthermore, downregulation of SGK1 by shRNAs resulted in decreased proliferation of myeloma cell lines and reduced cell numbers. On the molecular level, this was reflected by the induction of cell cycle inhibitory genes, for example, CDKNA1/p21, whereas positively acting factors such as CDK6 and RBL2/p130 were downregulated. Our results indicate that SGK1 is a highly cytokine-responsive gene in myeloma cells promoting their malignant growth.


Nucleotide sequence of the genomic RNA of hepatitis C virus isolated from a human carrier: comparison with reported isolates for conserved and divergent regions.
The complete nucleotide sequence of a hepatitis C virus derived from plasma of a human carrier in Japan was determined. The cDNA of the isolate (HC-J6) contained 9481 nucleotides and an additional T stretch of 30 to 108 nucleotides at the 3' end, and had one large open reading frame coding for a polyprotein of 3033 amino acids. It differed by 31.8 to 32.1% in the nucleotide sequence and by 27.4 to 27.7% in the amino acid sequence from an American isolate and two Japanese isolates previously reported. Among these four isolates, the 5' non-coding region of 329 to 341 nucleotides was well conserved (greater than 93% identity), whereas the 3' non-coding region of 39 to 45 nucleotides (T stretches not included) was more variable (greater than 30% identity). An excellent degree of conservation of the 5' non-coding region would reflect its pivotal role in replication, and primers deduced from this region could be applied for the sensitive and specific detection of viral RNA by polymerase chain reaction. Due to a high degree of similarity in the amino acid sequence of the putative core protein (greater than 90%), antigen probes deduced from it would be suitable for the serological diagnosis of HCV infection. Low sequence similarity in the putative envelope protein (greater than 53% identity), however, would have to be taken into account in considering the immunoprophylaxis of HCV infection.


Renal excretion of ascorbic acid in the rat: a micropuncture study.
Ascorbate concentration was measured by high-performance liquid chromatography and amperometry in plasma, tubular fluid, and urine from rats infused with ascorbic acid to steady-state levels. At a low concentration of ascorbate in plasma (Pasc = 0.2 mM) reabsorption occurred along the proximal convoluted tubule (PCT). The fractional delivery (FD) of ascorbate [(TF/P)asc/(TF/P)polyfructosan] to the late proximal convoluted tubule was 0.64 +/- 0.04, and the fractional excretion of ascorbate (FEasc) was 0.56 +/- 0.01. At higher Pasc (0.9 mM) net secretion occurred in the PCT, while the FDasc was 1.5 +/- 0.2 to the early and 1.8 +/- 0.2 to the late PCT. At still higher Pasc the secretory and the reabsorptive transports were saturated and the FDasc and FEasc approached unity, indicating that reabsorptive as well as secretory transport occurs in the proximal tubule. In clearance experiments the reabsorptive transport and secretory transport were inhibited by 2-nitroprobenecid. The drug induced a fall of FEasc when infused at a low rate (0.9 mumol X kg body wt-1 . min-1), which was followed by an increase in FEasc when the rate of infusion of 2-nitroprobenecid was increased to 3 mumol . kg body wt-1 X min-1.


[Intervention effects of qingre jiangya capsule on brain hippocampus of spontaneously hypertensive rats based on metabonomic research].
Thirty SHRs were obtained randomly to hypertension, model group, captopril group and Qingre jiangya capsule group. Ten Wistar rats were used as control group. The hippocampus tissue was removed to explore the damage of spontaneously hypertensive rats (SHR) and the protective effect of Qingre jiangya capsule after continuously administered for 14 days. And then the data were processed by principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA). The research results revealed captopril group was significantly different from the other three groups. The classification of other three groups is also very clear after captopril group removed. This suggested that Qingre jiangya capsule could improve the overall metabolism compared with captopril. Four metabolites were identified: dimethylglycine, glycerophosphocholine, aldosterone and noradrenaline. Hypertension hippocampus damage may mainly be expressed in tyrosine metabolism, aldosterone-regulated sodium, vascular smooth muscle contraction reabsorption, and Qingre jiangya capsule could reverse the hippocampus tissue damage of SHR.


Genetic influences on cognitive endophenotypes in schizophrenia.
Cognitive deficits are prominent in schizophrenia and represent promising endophenotypes for genetic research. The current study investigated the importance of two conceptually distinct genetic aggregates, one based on copy number variations (uncommon deletion burden), and one based on single nucleotide polymorphisms identified in recent risk studies (genetic risk score). The impact of these genetic factors, and their interaction, was examined on cognitive endophenotypes defined by principal component analysis (PCA) in a multi-center sample of 50 patients with schizophrenia and 86 controls. PCA was used to identify three different types of executive function (EF: planning, fluency, and inhibition), and in separate analyses, a measure general cognitive ability (GCA). Cognitive deficits were prominent among individuals with schizophrenia, but no group differences were evident for either genetic factor. Among patients the deletion burden measures predicted cognitive deficits across the three EF components and GCA. Further, an interaction was noted between the two genetic factors for both EF and GCA and the observed patterns of interaction suggested antagonistic epistasis. In general, the set of genetic interactions examined predicted a substantial portion of variance in these cognitive endophenotypes. Though adequately powered, our sample size is small for a genetic study. These results draw attention to genetic interactions and the possibility that genetic influences on cognition differ in patients and controls.


Evaluating Radiation Exposure in Patients with Stable Chest Pain in the SCOT-HEART Trial.
Background In the Scottish Computed Tomography of the Heart (SCOT-HEART) trial in individuals with stable chest pain, a treatment strategy based on coronary CT angiography (CTA) led to improved outcomes. Purpose To assess 5-year cumulative radiation doses of participants undergoing investigation for suspected angina due to coronary artery disease with or without coronary CTA. Materials and Methods This secondary analysis of the SCOT-HEART trial included data from six of 12 recruiting sites and two of three imaging sites. Participants were recruited between November 18, 2010, and September 24, 2014, with follow-up through January 31, 2018. Study participants had been randomized (at a one-to-one ratio) to standard care with CT (n = 1466) or standard care alone (n = 1428). Imaging was performed on a 64-detector (n = 223) or 320-detector row scanner (n = 1466). Radiation dose from CT (dose-length product), SPECT (injected activity), and invasive coronary angiography (ICA; kerma-area product) was assessed for 5 years after enrollment. Effective dose was calculated using conversion factors appropriate for the imaging modality and body region imaged (using 0.026 mSv/mGy · cm for cardiac CT). Results Cumulative radiation dose was assessed in 2894 participants. Median effective dose was 3.0 mSv (IQR, 2.6-3.3 mSv) for coronary calcium scoring, 4.1 mSv (IQR, 2.6-6.1 mSv) for coronary CTA, 7.4 mSv (IQR, 6.2-8.5 mSv) for SPECT, and 4.1 mSv (IQR, 2.5-6.8 mSv) for ICA. After 5 years, total per-participant cumulative dose was higher in the CT group (median, 8.1 mSv; IQR, 5.5-12.4 mSv) compared with standard-care group (median, 0 mSv; IQR, 0-4.5 mSv; P < .001). In participants who underwent any imaging, cumulative radiation exposure was higher in the CT group (n = 1345; median, 8.6 mSv; IQR, 6.1-13.3 mSv) compared with standard-care group (n = 549; median, 6.4 mSv; IQR, 3.4-9.2 mSv; P < .001). Conclusion In the SCOT-HEART trial, the 5-year cumulative radiation dose from cardiac imaging was higher in the coronary CT angiography group compared with the standard-care group, largely because of the radiation exposure from CT. Clinical trial registration no. NCT01149590 © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Dodd and Bosserdt in this issue.


Implementation fidelity of hospital based directly observed therapy for tuberculosis treatment in Bhutan: mixed-method study.
Direct observed treatment (DOT) has been implemented in Bhutan since 1997 and currently, it is offered in various model of delivery including a combination of hospital based, home based DOT and ambulatory DOT. Overall, treatment success rate for tuberculosis cases is higher than the global target; however, it is still need to be improved. Evaluation to the implementation fidelity of DOT is important to identify potential rooms for improvement. This study aimed to assess two major components of the program's implementation fidelity: to assess patient's adherence to DOT and explore factors for adherence; to assess provider's compliance with DOT guideline and explore factors for compliance. This research used a sequential explanatory mixed method. The conceptual framework of implementation fidelity was adopted to guide this study design. The cross-sectional study of TB patients was enrolled in two hospitals with highest TB load, between September to November 2017 in Bhutan. Interviewer assisted survey was conducted with 139 TB patients who visited the hospital in continuation phase. In-depth interview was then conducted with nine TB patients and four health staffs to explore the barriers and enablers of DOT. Total of 61.9% (86/139) of patients has received DOT at intensive phase. Proportion was higher among MDR-TB cases (100%), and smear sputum positive TB cases (84.7%). In the continuation phase, 5.8% of patients took medicine at hospital, 48.9% at home and the rest 45.3% no longer practiced DOT. More than 90% of patient received correct dosage and standard regimen of anti-TB drugs according to the guideline. The key factors affecting poor adherence to DOT as perceived by patients were; lack of willingness to visit the clinic on daily basis due to long distance, financial implications and family support. However, patient's satisfaction to the quality of TB treatment service delivery was high (98.6%). Providing incentives to the patient was most agreed enabler felt by both health workers and patients. In the selected hospital sites, the patient's adherence to DOT and provider's compliance with DOT guideline is partially implemented; the coverage and the duration of DOT is very low, therefore, need to revise and improve DOT model and structure.


Opposing levels of selection can cause neutrality: mating patterns and maternal-fetal interactions.
A biallelic viability model based on human data for maternal-fetal interactions reported by Hedrick (1997) gives the interesting result of neutral stability at all gene frequencies. I show that there are two levels of selection, within and among families, acting in opposing directions in this model and that the neutral stability occurs when the two levels of selection exactly balance one another, as they do in a randomly mating population. Deviations from random mating disrupt the balance and consequently destroy the neutral stability. However, with inbreeding avoidance, which characterizes the human histocompatibility loci, within-family selection is strengthened and among-family selection is weakened. This favors the invasion of new alleles and contributes to a high equilibrium level of genetic diversity at loci with maternal-fetal interactions affecting offspring viability in the pattern described by Hedrick. This pattern of selection is remarkably similar to that observed for the maternal effect selfish genes, Medea in flour beetles and scat in the mouse, and the Gp-9 gene in the fire ant.