[Infection and superior vena cava syndrome after pacemaker implantations: major consequences of a minor intervention].
Two men, aged 71 and 56 years, with pacemakers, developed the superior vena cava syndrome one and five years, respectively, after infection of the pacemaker pocket. They had been treated with antibiotics and partial removal of the foreign bodies. The conditions of both included occlusion of the superior vena cava and of both subclavian veins. The symptoms disappeared after removal of the total pacemaker system and venous reconstruction. The possibility of a superior vena cava syndrome occurring is increased if other complications have occurred previously, particularly infection. Prevention and treatment comprise on the one hand prevention and treatment of the infection (which is not always obvious) and on the other, earliest possible detection of thromboembolisms.


Toxicity of doxorubicin on pig liver after chemoembolization with doxorubicin-loaded microspheres: a pilot DNA-microarrays and histology study.
The potential mechanisms accounting for the hepatotoxicity of doxorubicin-loaded microspheres in chemoembolization were examined by combining histology and DNA-microarray techniques. The left hepatic arteries of two pigs were embolized with 1 mL of doxorubicin-loaded (25 mg; (DoxMS)) or non-loaded (BlandMS) microspheres. The histopathological effects of the embolization were analyzed at 1 week. RNAs extracted from both the embolized and control liver areas were hybridized onto Agilent porcine microarrays. Genes showing significantly different expression (p < 0.01; fold-change > 2) between two groups were classified by biological process. At 1 week after embolization, DoxMS caused arterial and parenchymal necrosis in 51 and 38 % of embolized vessels, respectively. By contrast, BlandMS did not cause any tissue damage. Up-regulated genes following embolization with DoxMS (vs. BlandMS, n = 353) were mainly involved in cell death, apoptosis, and metabolism of doxorubicin. Down-regulated genes (n = 120) were mainly related to hepatic functions, including enzymes of lipid and carbohydrate metabolisms. Up-regulated genes included genes related to cell proliferation (growth factors and transcription factors), tissue remodeling (MMPs and several collagen types), inflammatory reaction (interleukins and chemokines), and angiogenesis (angiogenic factors and HIF1a pathway), all of which play an important role in liver healing and regeneration. DoxMS caused lesions to the liver, provoked cell death, and disturbed liver metabolism. An inflammatory repair process with cell proliferation, tissue remodeling, and angiogenesis was rapidly initiated during the first week after chemoembolization. This pilot study provides a comprehensive method to compare different types of DoxMS in healthy animals or tumor models.


Postpartum thyroiditis presenting as a cold nodule and evolving to Graves' disease.
We describe the case of a 30-year-old woman who, five months after giving birth, was referred with a solitary nodule in her anterior neck. Laboratory analysis, ultrasonography, pertechnetate (Tc99m) thyroid scan and cytological examination of fine needle aspiration biopsy performed on the nodule led us to diagnose postpartum thyroiditis (PPT). Twenty-eight months after parturition, overt hyperthyroidism developed, with raised thyroperoxidase and thyroid stimulating hormone receptor antibody titres, diffuse high uptake of Tc99m at thyroid scan, and high vascular flow throughout the gland at Color-Power imaging. The diagnosis of Graves' disease (GD) was established. The differential diagnosis of thyrotoxicosis in the postpartum period, and the possible aetiological relationships between PPT and GD are discussed. To our knowledge, this is the first published report of a PPT presenting as a cold nodule, and evolving to GD.


Suppression of lymphocyte responses by tuberculous plasma and mycobacterial arabinogalactan. Monocyte dependence and indomethacin reversibility.
During tuberculosis, exposure of monocytes to circulating factors may induce the suppressor activity observed in some anergic patients. To explore this possibility, we examined the effects of plasma pooled from 28 untreated tuberculosis (TB) patients and the mycobacterial cell wall polysaccharide D-arabino-D-galactan (AG) on the in vitro function of peripheral blood mononuclear cells (PBMC) from healthy donors. In the [3H] thymidine incorporation assay, stimulated responses of PBMC incubated in culture medium supplemented with TB plasma or co-cultured with 3.0 microgram/ml AG were depressed significantly when compared with control responses. Cytotoxicity and altered kinetics of stimulated DNA synthesis did not contribute to the observed suppression. TB plasma and AG-induced suppression of the PBMC response to purified protein derivative was monocyte dependent and indomethacin reversible. In addition, TB plasma and AG directly inhibited the phytohemagglutinin-stimulated responses of T lymphocytes. In a quantitative assay of monocyte attachment to plastic, both TB plasma and AG significantly increased monocyte adherence from basal levels. These effects on monocyte adherence were reversed with indomethacin or antibody to mycobacterial polysaccharide. In addition, TB plasma passed over an immunoabsorbent column of Sepharose-linked antibody to mycobacterial polysaccharide was depleted of the suppressive and monocyte-adherence augmenting factors. 3.0 microgram/ml AG stimulated a fivefold increase in prostaglandin E2 production by cultured mononuclear cells. Our data suggest that AG circulating alone or bound in immune complexes may account for the observed effects of TB plasma. Similar in vivo exposure may contribute to the cell-mediated suppression of lymphocyte responses in tuberculosis.


ACR Appropriateness Criteria® Acute Nonlocalized Abdominal Pain.
The range of pathology in adults that can produce abdominal pain is broad and necessitates an imaging approach to evaluate many different organ systems. Although localizing pain prompts directed imaging/management, clinical presentations may vary and result in nonlocalized symptoms. This review focuses on imaging the adult population with nonlocalized abdominal pain, including patients with fever, recent abdominal surgery, or neutropenia. Imaging of the entire abdomen and pelvis to evaluate for infectious or inflammatory processes of the abdominal viscera and solid organs, abdominal and pelvic neoplasms, and screen for ischemic or vascular etiologies is essential for prompt diagnosis and treatment. Often the first-line modality, CT quickly evaluates the abdomen/pelvis, providing for accurate diagnoses and management of patients with abdominal pain. Ultrasound and tailored MRI protocols may be useful as first-line imaging studies, especially in pregnant patients. In the postoperative abdomen, fluoroscopy may help detect anastomotic leaks/abscesses. While often performed, abdominal radiographs may not alter management. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.


A new isomer of C20 and a way to a new C240.
Here we show that the dynamic simulation of a molecular collision can give insight into new molecular species. In this way, a new stable isomer of C(20) (IV) has been found. It is planar with pentagonal form. This isomer is high in energy compared to the three most stable previously known isomers of C(20): cage (I), bowl (II) and ring (III). Most interestingly, we show that using this new isomer it is possible to construct a macrobucky C(240) (V) that is also stable. The electronic structure of this new isomer of C(240) is very different from properties of the C(240) fullerene. Contrary to the C(240) fullerene, in the new isomer the π electrons are localized.


The translation initiation factor homolog eif4e1c regulates cardiomyocyte metabolism and proliferation during heart regeneration.
The eIF4E family of translation initiation factors bind 5' methylated caps and act as the limiting step for mRNA translation. The canonical eIF4E1A is required for cell viability, yet other related eIF4E families exist and are utilized in specific contexts or tissues. Here, we describe a family called Eif4e1c, for which we find roles during heart development and regeneration in zebrafish. The Eif4e1c family is present in all aquatic vertebrates but is lost in all terrestrial species. A core group of amino acids shared over 500 million years of evolution forms an interface along the protein surface, suggesting that Eif4e1c functions in a novel pathway. Deletion of eif4e1c in zebrafish caused growth deficits and impaired survival in juveniles. Mutants surviving to adulthood had fewer cardiomyocytes and reduced proliferative responses to cardiac injury. Ribosome profiling of mutant hearts demonstrated changes in translation efficiency of mRNA for genes known to regulate cardiomyocyte proliferation. Although eif4e1c is broadly expressed, its disruption had most notable impact on the heart and at juvenile stages. Our findings reveal context-dependent requirements for translation initiation regulators during heart regeneration.


Attentional biases in problem and non-problem gamblers.
From a cognitive perspective, attentional biases are deemed as factors responsible in the onset and development of gambling disorder. However, knowledge relating to attentional processes in gambling is scarce and studies to date have reported contrasting results. Moreover, no study has ever examined which component and what type of bias are involved in attentional bias in gambling. In the present study, 108 Italian participants, equally divided into problem and non-problem gamblers, were administered a modified Posner Task, an attentional paradigm in which - through the manipulation of stimuli presentation time - it is possible to measure both initial orienting and maintenance of attention. In addition to the experimental task, participants completed self-report measures involving (i) craving (Gambling Craving Scale), (ii) depression, anxiety and stress (Depression Anxiety Stress Scale) and (iii) emotional dysregulation (Difficulties in Emotion Regulation Scale). Analyses revealed facilitation in detecting gambling-related stimuli at the encoding level in problem gamblers but not in non-problem gamblers. Compared to non-problem gamblers, problem gamblers also reported higher levels of craving, emotional dysregulation, and negative mood states. Furthermore, all measures correlated with the gambling severity. The use of indirect measure of attentional bias could be less accurate compared to direct measures. The facilitation in detecting gambling-related stimuli in problem gamblers and the correlation between subjective craving and facilitation bias suggests that attentional bias could not be due to a conditioning process but that motivational factors such as craving could induce addicted-related seeking-behaviors.


Regulation of milk lipid secretion: effects of oxytocin, prolactin and ionomycin on triacylglycerol release from rat mammary gland slices.
A system for the study of the regulation of the release of triacylglycerols by mammary gland slices was developed. By prelabelling the triacylglycerol pool with [3H]oleate measurements of release of both mass of triacylglycerol and of newly synthesized triacylglycerol have been made. Oxytocin and ovine prolactin stimulated release of triacylglycerol and protein, but the former was 40-fold more effective. Recombinant bovine prolactin was even less active than ovine prolactin, suggesting that contamination of the latter with oxytocin and/or vasopressin was partly responsible for its stimulatory effect on release. The findings support the view that the major effect of oxytocin is to stimulate contraction of myoepithelial cells and thus release secreted lipid stored in the lumen of the mammary gland alveoli. Ionomycin, a Ca2+ ionophore, also stimulated lipid release, but probably not by the usual apocrine route. Parathyroid hormone-related protein, a peptide produced by the mammary gland, did not stimulate release or antagonize the effects of oxytocin. Release of lipid was also measured in mammary gland slices from late-pregnant, early- and mid-lactating rats and lactating rats made prolactin-deficient. Hormonal stimulation in vitro showed the maturation of response seen in vivo on transition from late pregnancy to peak lactation. Prolactin deficiency resulted in decreased release of newly synthesized lipid in response to oxytocin.


Primary hyperparathyroidism: diagnosis and management in 2017.
Primary hyperparathyroidism is a relatively common endocrine condition, which is being increasingly identified in its asymptomatic stage, following routine evaluation of serum calcium levels. Parathyroid hormone and calcium excess impact multiple organ systems. The greatest effects are seen on the skeleton and the kidney. This overview describes the current advances in the diagnosis, presentation, and management of primary hyperparathyroidism.


Gene expression patterns during intramuscular fat development in cattle.
Deposition of intramuscular fat, or "marbling," in beef cattle contributes significantly to meat quality variables, including juiciness, flavor, and tenderness. The accumulation of intramuscular fat is largely influenced by the genetic background of cattle, as well as their age and nutrition. To identify genes that can be used as early biomarkers for the prediction of marbling capacity, we studied the muscle transcriptome of 2 cattle crossbreeds with contrasting intramuscular fat content. The transcriptomes of marbling LM tissue of heifers from Wagyu x Hereford (WxH; n = 6) and Piedmontese x Hereford (PxH; n = 7) crosses were profiled by using a combination of complementary DNA microarray and quantitative reverse transcription-PCR. Five biopsies of LM were taken from each animal at approximately 3, 7, 12, 20, and 25 mo from birth. Tissue was also collected from the LM of each animal at slaughter (approximately 30 mo). Microarray experiments, conducted on the first 3 biopsies of 2 animals from each crossbreed, identified 97 differentially expressed genes. The gene expression results indicated that the LM transcriptome of animals with high marbling potential (WxH) could be reliably distinguished from less marbled animals (PxH) when the animals were as young as 7 mo of age. At this early age, one cannot reliably determine meaningful differences in intramuscular fat deposition. We observed greater expression of a set of adipogenesis- and lipogenesis-related genes in the LM of young WxH animals compared with their PxH contemporaries. In contrast, genes highly expressed in PxH animals were associated with mitochondrial oxidative activity. Further quantitative reverse transcription-PCR experiments revealed that the messenger RNA of 6 of the lipogenesis-related genes also peaked at the age of 20 to 25 mo in WxH animals. The messenger RNA expression of ADIPOQ, SCD, and THRSP was highly correlated with intramuscular fat content of an individual in WxH animals. Our study provides clear evidence of early molecular changes associated with marbling and also identifies specific time frames when intramuscular fat development in cattle muscle can be detected by using gene expression. This information could be used by animal scientists to design optimal nutrition for high marbling potential. In addition, the genes found to be highly expressed during development of marbling could be used to develop genetic markers or biomarkers to assist with beef production strategies.


A global barley panel revealing genomic signatures of breeding in modern Australian cultivars.
The future of plant cultivar improvement lies in the evaluation of genetic resources from currently available germplasm. Today's gene pool of crop genetic diversity has been shaped during domestication and more recently by breeding. Recent efforts in plant breeding have been aimed at developing new and improved varieties from poorly adapted crops to suit local environments. However, the impact of these breeding efforts is poorly understood. Here, we assess the contributions of both historical and recent breeding efforts to local adaptation and crop improvement in a global barley panel by analysing the distribution of genetic variants with respect to geographic region or historical breeding category. By tracing the impact that breeding had on the genetic diversity of Hordeum vulgare (barley) released in Australia, where the history of barley production is relatively young, we identify 69 candidate regions within 922 genes that were under selection pressure. We also show that modern Australian barley varieties exhibit 12% higher genetic diversity than historical cultivars. Finally, field-trialling and phenotyping for agriculturally relevant traits across a diverse range of Australian environments suggests that genomic regions under strong breeding selection and their candidate genes are closely associated with key agronomic traits. In conclusion, our combined data set and germplasm collection provide a rich source of genetic diversity that can be applied to understanding and improving environmental adaptation and enhanced yields.


Highly sensitive real-time detection of intracellular oxidative stress and application in mycotoxin toxicity evaluation based on living single-cell electrochemical sensors.
Single-cell electrochemical sensor is widely used in the local selective detection of single living cells because of its high spatial-temporal resolution and sensitivity, as well as its ability to obtain comprehensive cellular physiological states and processes with increased accuracy. Functionalized nanoprobes can detect the oxidative stress response of cells in single-cell electrochemical sensors. Moreover, the T-2 toxin is one of the most toxic mycotoxins and widely occurs in field crops. T-2 toxin can cause mitochondrial damage in cells and increase intracellular reactive oxygen species (ROS) in various cells. As the most representative free radical of intracellular ROS, H2O2 can effectively reflect the toxic effects of intracellular T-2 toxin. In this study, a functionalized gold nanoprobe was used to dynamically monitor the production of H2O2 in a single live human hepatoma cell HepG2 stimulated by mycotoxin T-2. The concentration of H2O2 produced by HepG2 cells stimulated by T-2 toxin at 1 ppb-1 ppm was linearly correlated, R2 = 0.99055, and LOD = 0.13807 ng mL-1. Sample spiking experiments were conducted, and the recovery rate of spiking was 81.19%-130.17%. A comparative analysis of differences in the current produced by multiple toxins, HT-29 cells, as well as single cells in cell populations, was performed. This method can be applied in real-time monitoring of mycotoxin toxicity during food processing in living cells and provides a novel idea for enhancing food quality and safety in a nanoenvironment.


What is new in pharmacological treatment for osteoarthritis?
Osteoarthritis (OA) is a degenerative joint disease in which structural changes of hyaline articular cartilage, subchondral bone, ligaments, capsule, synovium, muscles, and periarticular changes are involved. The knee is the most commonly affected joint, followed by the hand, hip, spine, and feet. Different pathological mechanisms are at play in each of these various involvement sites. Although systemic inflammation is more prominent in hand OA, knee and hip OA have been associated with excessive joint load and injury. As OA has varied phenotypes and the primarily affected tissues differ, treatment options must be tailored accordingly. In recent years, ongoing efforts have been made to develop disease-modifying options that halt or slow disease progression. Many are still in clinical trials, and as insights into the pathogenesis of OA evolve, novel therapeutic strategies will be developed. In this chapter, we provide an overview of the novel and emerging strategies in the management of OA.


Using a Naturalistic Store Laboratory for Clinical Trials of Point-of-Sale Nutrition Policies and Interventions: A Feasibility and Validation Study.
Point-of-sale policies such as warnings and taxes are promising tools for improving the nutritional quality of food purchases. Research studies conducted in naturalistic store laboratories could improve the quality of evidence about point-of-sale interventions by allowing for realistic exposure in a controlled setting. This study aimed to assess whether purchasing behavior in a naturalistic store laboratory setting was similar to real-life purchasing behavior and to evaluate participants' perceptions of store realism and the acceptability of research study protocols in this setting. In a longitudinal observational study in 2019, Latinx parents in North Carolina (n = 61) attended five weekly visits at the UNC Mini Mart, a naturalistic store laboratory that resembled a small convenience store. At each visit, participants purchased a week's supply of beverages. Purchases of beverages in the Mini Mart were compared to participants' purchases from receipts submitted the week prior to the study. Analyses compared the percentage of participants buying sugary drinks and non-sugary drinks in the Mini Mart vs. in real stores using Chi-Square tests with Fisher's p. The percentage of parents who purchased sugary drinks in the Mini Mart (93%) was not significantly different from the percentage who purchased sugary drinks during the week before the study (74%, p = 0.28). The percentage purchasing non-sugary drinks was similar in the two settings (85% in the Mini Mart vs. 85% from receipts, p = 0.33). Nearly all participants reported that their Mini Mart purchases were similar to real-life purchases (96%); the Mini Mart felt like a real store (94%); they could find all the beverages they were looking for (92%); and they could imagine doing their real-life beverage shopping in the Mini Mart (92%). Moreover, retention was high, with 97% of participants attending the final study visit. These results indicate that naturalistic store laboratories are a promising method for increasing the ecological validity of trials to evaluate point-of-sale interventions.


Effect of ovariectomy on hormone receptors and growth of N-nitrosomethylurea-induced mammary tumors in the rat.
Estrogen receptor(s) (ER), progesterone receptor(s) (PGR), androgen receptor(s) (ANR), and prolactin receptor(s) (PRLR) were measured in N-nitrosomethylurea-induced mammary tumors in intact female Sprague-Dawley rats and in rats 9 days after ovariectomy. Following ovariectomy, 12 of 15 tumors regressed to 47.7 +/- 5.5% of the original size (hormone-dependent tumors), while the remaining three had arrest of growth reaching 88.8 +/- 7.3% of their original sizes. Cytosol ER level was 50.3 +/- 6.6 fmol/mg protein in tumors of intact rats and was significantly lower (25.6 +/- 8.3 fmol/mg, p < 0.025) in the ovariectomized group. PGR was abundantly present in ten of 13 tumors of intact rats (mean, 144.5 +/- 46.8) but was undetectable in five of six hormone-dependent tumors after ovariectomy (p < 0.01). ANR ws detectable at low levels in only four of 13 tumors of intact rats but in none of six hormone-dependent tumors after ovariectomy. PRLR was not significantly different in tumors of intact and ovariectomized rats (20.6 +/- 2.4 and 15.6 +/- 1.8 fmol/mg, respectively). In three tumors that had arrest of growth after ovariectomy, the levels of ER, PGR, ANR, and PRLR were not significantly different from those of the hormone-dependent tumors. We conclude that the majority of N-nitrosomethylurea-induced rat mammary tumors are hormone dependent. ER, PGR, and PRLR were abundantly present in the majority of these tumors, while ANR was present in only four of 13 tumors. The levels of ER and PGR were significantly lower following ovariectomy, while PRLR was not significantly changed.


Bone tissue responses to Mg-incorporated oxidized implants and machine-turned implantsin the rabbit femur.
Previous studies have demonstrated a significant improvement in the bone response to oxidized titanium implants. Little is known about the effects of specific oxide properties on the bone tissue responses to titanium implants. This study in-vestigated the bone tissue responses to magnesium (Mg)-incorporated oxidized titanium implants and machine-turned titani-um implants in the rabbit femur. The oxidized implants were prepared using micro arc oxidation (MAO) methods. Surface oxide properties were characterized by using various surface analytic techniques, involving scanning electron microscopy (SEM) equipped with energy dispersive spectrometer (EDS), X-ray diffractometry (XRD), X-ray photoelectron spectroscopy (XPS) and optical interferometry. Screw shaped titanium implants, 10 machine-turned implants (controls) and 10 Mg-incorporated im-plants (tests) were inserted in the femoral condyles of 10 New Zealand white rabbits. After a 6-week healing period, resonance frequency analyses and removal torque measurements of the Mg-incorporated oxidized implants demonstrated significant im-provements in implant integration with bone in comparison to machine-turned implants, p=0.007 and p=0.017, respectively. Bone growth in the pores of the oxidized implants was probably incomplete at a follow-up of 6 weeks, as indicated by SEM and EDS measurements. Mg-incorporated titanium implants significantly improved bone responses as compared with machine-turned control implants. Considering the differences and similarities of the surface oxide properties of controls and test im-plants, the enhanced bone responses to Mg-incorporated implants could be explained by the Mg surface chemistry of the test im-plants. (Journal of Applied Biomaterials and Biomechanics 2005; 3: 18-28).


Alendronate increases bone density and bone strength at the distal radius in postmenopausal women.
In addition to the alendronate Osteoporosis Intervention Trial (FOSIT) core protocol 901-0A of 1908 enrolled patients, the use of peripheral quantitative computed tomography (pQCT) was explored for the assessment of response to therapy. Bone mineral and strength related parameters at two different sites at the distal radius were explored in a subset of the multicenter core study. One hundred and three patients were entered into the substudy and given either a daily dose of 10 mg of alendronate or placebo for 1 year. Measurements were done at months 0, 3, 6, and 12. Inclusion criteria were bone mineral density (BMD) measurements at the lumbar spine of -2 SD. The response to therapy was assessed by dual-energy X-ray absorptiometry in the lumbar spine and the hip, and by pQCT in the ultradistal and the shaft sites of the radius. In line with the FOSIT core study, alendronate increased BMD at the lumbar spine and the hip, and it decreased the serum biochemical markers of bone turnover. The substudy showed differences between the therapy and placebo group in trabecular bone density (8.4%, p = 0.095), in total density (6.8%, p = 0.009), and in the bone strength index (BSI) (15. 6 mm3, p = 0.037) at the ultradistal site due to treatment and no changes at the radius shaft. A significant correlation was observed between percentage changes from baseline in BMD of the lumbar spine, and in total density and bone strength at the ultradistal radius site in the treatment group, but not in the placebo group. Thus, the ultradistal radius site did respond to alendronate therapy. The increased bone density accompanied a significant gain in the BSI at the ultradistal site, a finding that might help explain the reduced wrist fractures in the alendronate Fracture Intervention Trial.


Atrophy of cholinergic basal forebrain neurons following excitotoxic cortical lesions is reversed by intravenous administration of an NGF conjugate.
Nerve growth factor (NGF) has been shown to sustain the viability and modulate the function of cholinergic basal forebrain neurons. However, under normal circumstances, NGF does not cross the blood-brain barrier (BBB) following systemic administration making this neurotrophin unavailable to NGF-responsive neurons within the central nervous system (CNS). Recently, a non-invasive method for delivering NGF to the brain was established in which NGF was conjugated to an antibody directed against the transferrin receptor (OX-26) [15, 16]. This conjugation facilitates the transfer of NGF from the systemic circulation to the CNS via the transferrin transport system. In the present study, we tested whether intravenous administration of an OX-26-NGF conjugate could reverse the atrophy of cholinergic basal forebrain neurons following removal of the target sites. Lesions of the left cerebral cortex were created by epidural application of N-methyl-D-aspartic acid (NMDA). Seventy-five days later, cholinergic nucleus basalis neurons were atrophic ipsilateral to the lesion relative to the contralateral side in control rats receiving intravenous injections of vehicle or a non-conjugated mixture of OX-26 and NGF. In contrast, intravenous injections of the OX-26-NGF conjugate restored the size of nucleus basalis perikarya to within normal limits relative to the unlesioned contralateral side. Immunohistochemical studies using rat serum albumen antisera indicated that the BBB was closed at the time of treatment indicating that this trophic effect did not result from NGF crossing through a compromised BBB at the site of the lesion. These data demonstrate that systemic administration of a neurotrophic factor-antibody conjugate, intended to circumvent the BBB, can provide trophic influences to degenerating cholinergic basal forebrain neurons. These data support the emerging concept that the conjugate method can facilitate the transfer of impermeable therapeutic compounds across the BBB.


Double D-π-A dye linked by 2,2'-bipyridine dicarboxylic acid: influence of para- and meta-substituted carboxyl anchoring group.
Starting from 2,2'-bipyridine dicarboxylic acid, two new (D-π-A)2 sensitizers, including m-DA with the carboxyl anchoring group substituted meta to the donor-bridge moiety and p-DA with a para-substituted anchoring group, were synthesized in order to evaluate the impact of the position of the anchoring group on the optical, electrochemical, and photovoltaic properties of dye-sensitized solar cells. p-DA exhibits red-shifted absorption behavior compared to m-DA, owing to the more efficiently extended π-conjugation with para substitution. Both m-DA and p-DA are adsorbed on the mesoporous TiO2 surface by using both of their carboxylic acid groups in a bianchoring mode, which is confirmed through attenuated total reflectance FTIR analysis. Red-shifted absorption of p-DA assists the achievement of a red-shifted incident photon-to-electron conversion efficiency and a higher short-circuit current density than m-DA. The photogenerated electron lifetime in TiO2 is also found to be higher for para substituted p-DA than the meta-substituted m-DA, which results in a higher open-circuit voltage. All of the results suggest that dicarboxyl-2,2'-bipyridine can be used as an acceptor for metal-free organic sensitizers. However, the anchoring segments should be adjusted to the favorable position of the corresponding donor-bridge moieties for better conjugation.


Brain and leptomeningeal metastases from cutaneous melanoma: survival outcomes based on clinical features.
Brain metastases (BM) are among the most devastating and debilitating complications of melanoma. This retrospective study was conducted to gain a better understanding of patient and disease characteristics that have the greatest impact on overall survival in melanoma patients with BM; therapeutic interventions were also assessed. The records of all patients diagnosed with cutaneous melanoma and BM who were seen at Memorial Sloan-Kettering Cancer Center between 1991 and 2001 were retrospectively reviewed. A variety of factors, including age at diagnosis of stage IV disease, gender, race, disease stage at diagnosis, presence of BM at diagnosis of stage IV disease, neurologic symptoms, radiographic findings, number of BM, status and site(s) of extracranial metastasis, and treatment modalities, were analyzed for correlation with overall survival using univariate and multivariate Cox regression models. The records of 355 patients with BM were included in the analysis. On univariate analysis, seven patient and disease characteristics were significantly associated with poorer survival: age > 65 years, extracranial metastases, BM at stage IV diagnosis, neurologic symptoms, four or more BM, hydrocephalus, and leptomeningeal metastases. Of these, age, extracranial metastasis, neurologic symptoms, and number of BM were significantly associated with poorer survival in a multivariate analysis. Multivariate analysis of treatment modalities suggested that patients who had surgery, radiosurgery, or chemotherapy with temozolomide had improved survival outcomes, although this analysis has limitations. The prognostic factors identified in this retrospective study should be considered when making treatment decisions for patients with BM and used as stratification factors in future clinical trials.


Peripheral blood IFN-gamma-secreting Valpha24+Vbeta11+ NKT cell numbers are decreased in cancer patients independent of tumor type or tumor load.
Natural killer T (NKT) cells are CD1d-restricted lymphoid cells and are characterized by an invariant T-cell receptor, which in humans consists of a Valpha24 chain paired with a Vbeta11 chain. These cells are known for their rapid production of large amounts of cytokines (e.g., IFN-gamma and IL-4), thereby modulating other cells of the immune system such as T cells, NK cells and dendritic cells. NKT cells have been reported to play important regulatory roles in many immune responses, including antitumor immune responses. Here, we demonstrate an age-dependent decrease in circulating Valpha24(+)Vbeta11(+) NKT cell numbers in both healthy controls and cancer patients and demonstrate that in both groups females have higher NKT cell levels compared to males. In a large group of 120 cancer patients, we show that circulating Valpha24(+)Vbeta11(+) NKT cell numbers are about 50% lower than in age- and gender-matched healthy controls and that this decrease is independent of tumor type or tumor load. This decrease was not restored upon tumor removal by means of surgery or radiotherapy. Even though the percentage of NKT cells that secrete IFN-gamma, as detected by ELISPOT, is normal in cancer patients, the absolute number of circulating IFN-gamma-secreting NKT cells is reduced. Together, our results suggest that the reduced circulating Valpha24(+)Vbeta11(+) NKT cell numbers in cancer patients are not affected by tumor load, but might actually reflect a risk factor for tumor development, e.g., by hampering efficient tumor immunosurveillance.


Single small enhancing CT lesion in Thai patients with acute symptomatic seizures: a clinico-radiological study.
To identify the frequency of single small enhancing CT lesion cases (SSECTL) in a provincial hospital in Thailand and verify a set of clinico-radiological criteria for the diagnosis of benign SSECTL. All patients who fulfilled the following criteria were recruited: acute symptomatic focal seizures with or without secondary generalization; minimal or no neurological deficit; no evidence of raised intracranial pressure; no evidence of systemic disease; CT scan showing SSECTL of < 20 mm diameter. After recruitment, patients received antiepileptic drugs and other symptomatic treatment. A CT scan of the brain was repeated every 2 weeks until the lesion had significantly resolved, which was defined as a 50% decrease in size. A CT scan was then taken every 4 weeks until the lesion had completely disappeared or turned into a calcified spot. The data from all other patients presenting with seizures and solitary enhancing lesion on the CT scan who did not fulfil the inclusion criteria were also reviewed. 972 patients with seizure disorder were recruited. 110 patients (11.3%) presented with seizure and solitary enhancing lesion on the CT scan, 22 of whom (20%) fulfilled the inclusion criteria. 20 of the 22 patients had SSECTL with a spontaneous resolution: 14 (70%) within 4 weeks and 18 (90%) within 8 weeks. Two patients had a progressive course. One patient with a solitary enhancing CT lesion > 20 mm had spontaneous resolution. 87 patients had another diagnoses. The diagnostic criteria for benign SSECTL were 95.23% sensitive, 97.75% specific, had a positive predictive value of 90.91% and a negative predictive value of 98.86%. SSECTL is not uncommon in our provincial hospital. The clinico-radiological criteria proposed by Rajshekhar (1991) are valid and reliable in predicting a benign outcome. CT follow-up within the first 4 weeks is critical.


Increases in placental nitric oxide, but not nitric oxide-mediated relaxation, underlie the improvement in placental efficiency and antihypertensive effects of hydrogen sulphide donor in hypertensive pregnancy.
Dysregulation of hydrogen sulphide (H2 S) producing enzymes has been related to hypertensive pregnancy, and H2 S donor, sodium hydrosulphide (NaHS) exerts antihypertensive effects, modulates angiogenic factors production and acts as an antioxidant. Moreover, reduction in nitric oxide (NO) bioavailability is related to hypertensive pregnancy and H2 S may interact with NO, modulating its production. We aimed to investigate the NaHS effects in hypertension-in-pregnancy and also in feto-placental parameters. Female Wistar rats (200-250 g) were mated and desoxycorticosterone acetate injections followed by replacement of water by 0.9% saline solution were used to induce hypertensive pregnancy. Rats were divided into four groups: normal pregnant (Norm-Preg), pregnant + NaHS (Preg+NaHS), hypertensive pregnant (HTN-Preg) and HTN-Preg+NaHS. Systolic blood pressure was increased in HTN-Preg and this increase was blunted in HTN-Preg+NaHS. Fetal and placental weights were decreased in HTN-Preg animals, while fetal growth restriction was improved in HTN-Preg+NaHS. Placental weight was lower in HTN-Preg+NaHS than in HTN-Preg; however, placental efficiency was re-established in HTN-Preg+NaHS rats. We observed that a partial contribution of placental NO, but not changes in anti-angiogenic factors may mediate the increases in placental efficiency in HTN-Preg+NaHS. HTN-Preg presented thoracic aorta hyperreactivity to phenylephrine while NaHS treatment blunted this hyperreactivity, which seems not to be related to NO-mediated relaxation induced by acetylcholine. Therefore, changes in vascular responsiveness promoted by NaHS treatment may underlie the beneficial effects in systolic blood pressure and feto-placental parameters in our study.


Evolution of drug-resistant viral populations during interruption of antiretroviral therapy.
Analysis of a large number of HIV-1 genomes at multiple time points after antiretroviral treatment (ART) interruption allows determination of the evolution of drug-resistant viruses and viral fitness in vivo in the absence of drug selection pressure. Using a parallel allele-specific sequencing (PASS) assay, potential primary drug-resistant mutations in five individual patients were studied by analyzing over 18,000 viral genomes. A three-phase evolution of drug-resistant viruses was observed after termination of ART. In the first phase, viruses carrying various combinations of multiple-drug-resistant (MDR) mutations predominated with each mutation persisting in relatively stable proportions while the overall number of resistant viruses gradually increased. In the second phase, viruses with linked MDR mutations rapidly became undetectable and single-drug-resistant (SDR) viruses emerged as minority populations while wild-type viruses quickly predominated. In the third phase, low-frequency SDR viruses remained detectable as long as 59 weeks after treatment interruption. Mathematical modeling showed that the loss in relative fitness increased with the number of mutations in each viral genome and that viruses with MDR mutations had lower fitness than viruses with SDR mutations. No single viral genome had seven or more drug resistance mutations, suggesting that such severely mutated viruses were too unfit to be detected or that the resistance gain offered by the seventh mutation did not outweigh its contribution to the overall fitness loss of the virus. These data provide a more comprehensive understanding of evolution and fitness of drug-resistant viruses in vivo and may lead to improved treatment strategies for ART-experienced patients.


Aggregation-induced emission of siloles.
Aggregation-induced emission (AIE) is a unique and significant photophysical phenomenon that differs greatly from the commonly acknowledged aggregation-caused emission quenching observed for many π-conjugated planar chromophores. The mechanistic decipherment of the AIE phenomenon is of high importance for the advance of new AIE systems and exploitation of their potential applications. Propeller-like 2,3,4,5-tetraphenylsiloles are archetypal AIE-active luminogens, and have been adopted as a core part in the design of numerous luminescent materials with diverse functionalities. In this review article, we elucidate the impacts of substituents on the AIE activity and shed light on the structure-property relationship of siloles, with the aim of promoting the judicious design of AIE-active functional materials in the future. Recent representative advances of new silole-based functional materials and their potential applications are reviewed as well.


Faceted structures in Langmuir monolayers of diethylene glycol mono-n-octadecyl ether at the air--water interface.
We have concurrently studied the surface pressure (pi) versus area (A) isotherms and microscopic surface morphological features of Langmuir monolayers of diethylene glycol mono-n-octadecyl ether (C18E2) by film balance and Brewster angle microscopy (BAM) over a wide range of temperature. At temperatures < or =10 degrees C, the monolayers exist in the form of condensed phase even just after the evaporation of the spreading solvent, suggesting that the melting point of the condensed phase is above this temperature. At > or =15 degrees C, the monolayers can exist as gas (G), liquid expanded (LE), and liquid condensed (LC) phases and undergo a pressure-induced first-order phase transition between LE and LC phases showing a sharp cusp point followed by a plateau region in the pi-A isotherms. A variety of 2-D structures, depending on the subphase temperature, are observed by BAM just after the appearance of the cusp point. It is interesting to note here that the domains attain increasingly large and compact shape as the subphase temperature increases and finally give faceted structures with sharp edges and corners at > or =30 degrees C. The BAM observations were coupled with polarization modulation infrared reflection absorption spectroscopy (PM-IRRAS) to gain better understanding regarding the conformational order and subcell packing of the molecules. The constancy of the methylene stretching modes over the studied temperature range suggests that the hydrocarbon chains do not undergo any conformational changes upon compression of the monolayer. However, the full width at half-maximum (fwhm) values of the asymmetric methylene stretching mode (nu(as)(CH(2))) are found to respond differently with changes in temperature. It is concluded that even though the trans/gauche ratio of the hydrocarbon chains remains virtually constant, the LE-LC phase transition upon compression of the monolayer is accompanied by a loss of the rotational freedom of the molecules.


Influence of Nutrition on Disease Severity and Health-related Quality of Life in Adults with Sickle Cell Disease: A Prospective Study.
Sickle cell disease (SCD), a genetic disorder resulting from the presence of a mutated hemoglobin S (HbS), has a worldwide distribution and causes significant morbidity and mortality in children and adults. Few studies addressed the determinants of SCD severity in adults; therefore, we investigated the impact of nutrition on the outcome of SCD and health-related quality of life (HRQoL) in adult patients. In this longitudinal study, we recruited and prospectively followed 62 adults with SCD (aged ≥18 years) for a median of 93 months. At entry and follow-up, patients provided medical and dietary history, had a physical examination and anthropometric measurements, assessed protein-energy intake, measurement of micronutrient levels, estimation of SCD severity score, and determination of the HRQoL (SF-26v2). The study outcome was a composite of hospitalization due to SCD crises or death. At baseline, 42 (67.74%) patients had macro and, or micro-undernutrition (Group A), and 20 (32.26%) were well nourished. (Group B). The BMI and most anthropometric measurements were significantly lower in SCD patients compared to control subjects. Seventy percent of SCD patients had vitamin D, vitamin B12, and zinc deficiencies. Thirty-six under-nourished patients (86%) had gastrointestinal disorders. During follow-up, 46 patients (74.19%) developed one or more vaso-occlusive pain crises or other SCD related complications that required hospitalization. Significant differences in most SF-36v2 domains existed between well-nourished and undernourished SCD patients. Protein-energy and micronutrient deficiencies were independent predictors of severe SCD and mortality. Correction of undernutrition and hydroxyurea therapy improved SCD severity scores and HRQoL. Patients with sickle cell disease have various degrees of macro and micro deficiencies, which increase SCD severity and hospitalizations and reduce the health-related quality of life. Early diagnosis and prompt correction of macro and micronutrient deficiencies need to be incorporated in the standard of care of SCD patients to improve the disease outcomes.


Primers for fourteen protein-coding genes and the deep phylogeny of the true yeasts.
The Saccharomycetales or 'true yeasts' consist of more than 800 described species, including many of scientific, medical and commercial importance. Considerable progress has been made in determining the phylogenetic relationships of these species, largely based on rDNA sequences, but many nodes for early-diverging lineages cannot be resolved with rDNA alone. rDNA is also not ideal for delineating recently diverged species. From published full-genome sequence data, we have identified 14 regions of protein-coding genes that can be PCR-amplified in a large proportion of a diverse collection of 25 yeast species using degenerate primers. Phylogenetic analysis of the sequences thus obtained reveals a well-resolved phylogeny of the Saccharomycetales with many branches having high bootstrap support. Analysis of published sequences from the Saccharomyces paradoxus species complex shows that these protein-coding gene fragments are also informative about genealogical relationships amongst closely related strains. Our set of protein-coding gene fragments is therefore suitable for analysing both ancient and recent evolutionary relationships amongst yeasts.


Effects of thiamin on vitamin B6 synthesis in yeasts.
The effects of exogenous thiamin on the growth yield and vitamin B6 content of 18 strains of yeasts and a few strains of bacteria were examined. The addition of thiamin hardly affected the growth yield of the yeasts tested, except for two strains Saccharomyces uvarum strain 4228 and Saccharomyces uvarum IFO 0751. In contrast, the vitamin B6 content of all the yeasts tested, except Pichia membranaefaciens IFO 0189, decreased markedly in the presence of thiamin. In S. uvarum IFO 1265, the synthesis of vitamin B6 was maximally inhibited by the addition of thiamin (1.5 nmol ml-1) to the growth medium without affecting cell growth, whereas the amounts of cellular vitamin B6 increased in the presence of the thiamin antagonist, pyrithiamin or oxythiamin, at concentrations that did not affect growth. When [4'-14C]pyridoxine. HCl (0.5 micrograms ml-1) was added to the growth medium at least 54% of the added isotope was incorporated into the cells during 24 h incubation. In the presence of thiamin (15 nmol ml-1), at least 32% of the added isotope was incorporated. The metabolism of [4'-14C]pyridoxine. HCl to inactive forms having no vitamin B6 activity was not stimulated by the addition of thiamin. Thus, vitamin B6 synthesis in many yeasts was affected by thiamin, whereas, in bacteria, growth yield and vitamin B6 content were not affected by thiamin.


Functional heterogeneity correlates with structural heterogeneity of breast carcinoma acid-soluble glycoproteins.
Patients with malignant tumors, specifically with metastatic breast carcinoma (BCa), are immunosuppressed and have defective lymphocyte responsiveness to antigenic and mitogenic stimulation. The present study examined the role of perchloric acid (PCA)-soluble glycoproteins and their oligosaccharide moieties from tumor cells and from sera of patients with metastatic BCa. Sera from 15 patients and from age-matched healthy adults were examined for immunoregulatory glycoproteins. BCa tissue was obtained from 9 of the 15 patients. The PCA extracts from tumor tissue were resolved into six (GP-I to GP-VI), and from serum into three (GP-II, GP-IV, and GP-V), BCa-associated glycoproteins. After alkaline borohydride treatment, six groups of BCa-associated oligosaccharides were obtained. Peripheral blood mononuclear (MNC) and natural killer (NK) cells were obtained from patients with metastatic BCa and from age-matched healthy adults. These were used as effector cells in the well-established 4-hr cytotoxicity assay. The results indicated that interleukin 2 (IL-2) significantly (P less than 0.001) enhanced the cytotoxic activities of MNC and NK cells from healthy adults, but it had a nonsignificant effect on MNC and NK cells from patients with metastatic BCa. The BCa-associated glycoproteins and their oligosaccharides varied in their effects on MNC and NK cells from both the healthy adults and the patients with metastatic BCa. IL-2 activated MNC cytotoxic activity against BCa cells. GP-I, GP-II, GP-III, and GP-IV inhibited MNC inherent cytotoxicity and blocked MNC stimulation by IL-2, GP-IV fraction had a statistically nonsignificant effect, whereas GP-V enhanced both MNC inherent and IL-2-activated cytotoxic activities. Oligosaccharides obtained from PCA extracts of BCa tissue and by alkaline borohydride treatment differentially bound and inhibited a series of monoclonal antibodies raised against BCa-associated glycoproteins. These results indicated that the oligosaccharide moieties of the BCa-associated glycoproteins modulate recognition of the BCa cells by the effector cells.


Design of a hybrid computational fluid dynamics-monte carlo radiation transport methodology for radioactive particulate resuspension studies.
There are numerous scenarios where radioactive particulates can be displaced by external forces. For example, the detonation of a radiological dispersal device in an urban environment will result in the release of radioactive particulates that in turn can be resuspended into the breathing space by external forces such as wind flow in the vicinity of the detonation. A need exists to quantify the internal (due to inhalation) and external radiation doses that are delivered to bystanders; however, current state-of-the-art codes are unable to calculate accurately radiation doses that arise from the resuspension of radioactive particulates in complex topographies. To address this gap, a coupled computational fluid dynamics and Monte Carlo radiation transport approach has been developed. With the aid of particulate injections, the computational fluid dynamics simulation models characterize the resuspension of particulates in a complex urban geometry due to air-flow. The spatial and temporal distributions of these particulates are then used by the Monte Carlo radiation transport simulation to calculate the radiation doses delivered to various points within the simulated domain. A particular resuspension scenario has been modeled using this coupled framework, and the calculated internal (due to inhalation) and external radiation doses have been deemed reasonable. GAMBIT and FLUENT comprise the software suite used to perform the Computational Fluid Dynamics simulations, and Monte Carlo N-Particle eXtended is used to perform the Monte Carlo Radiation Transport simulations.


Amniotic membrane diffusion chambers: a new possibility for pancreatic islet transplantation.
In order to avoid the host foreign-body reaction which is probably responsible for the long-term failure of the artificial membrane diffusion chambers currently used for protecting the implanted islet tissue from rejection, we tested the human amniotic membrane as a possible new tool for enclosing transplanted islets of Langerhans. Bag-shaped chambers were made with human amniotic membranes and the diffusion of 125 I-Insulin out and of D-glucose into the chambers was measured. The diffusion patterns of insulin and glucose were shown to be better than those described for the best artificial membranes, the 50% diffusion being reached at min 42 for 125 I-Insulin and at min 11 for D-glucose. Moreover, it was shown that no lymphocytes diffused into the amniotic membrane chambers. These results, together with the already known characteristics of the human amniotic membrane, induce us to propose it as a suitable material for further experimental work in islet tissue transplantation.


NEI-01-Induced Arginine Deprivation Has Potent Activity Against Acute Myeloid Leukemia Cells Both In Vitro and In Vivo.
Recent studies have revealed that targeting amino acid metabolic enzymes is a promising strategy in cancer therapy. Acute myeloid leukemia (AML) downregulates the expression of argininosuccinate synthase (ASS1), a recognized rate-limiting enzyme for arginine synthesis, and yet displays a critical dependence on extracellular arginine for survival and proliferation. This dependence on extracellular arginine, also known as arginine auxotrophy, suggests that arginine deprivation would be a treatment strategy for AML. NEI-01, a novel arginine-depleting enzyme, is capable of binding to serum albumin to extend its circulating half-life, leading to a potent anticancer activity. Here we reported the preclinical activity of NEI-01 in arginine auxotrophic AMLs. NEI-01 efficiently depleted arginine both in vitro and in vivo NEI-01-induced arginine deprivation was cytotoxic to arginine auxotrophic AML cells through induction of cell-cycle arrest and apoptosis. Furthermore, the potent anti-leukemia activities of NEI-01 were observed in three different types of mouse models including human cell line-derived xenograft, mouse cell line-derived homografts in syngeneic mice and patient-derived xenograft. This preclinical data provide strong evidence to support the potential use of NEI-01 as a therapeutic approach in AML treatment.


Inhibition of biliary cholesterol and phospholipid secretion by cefmetazole. The role of vesicular transport and of canalicular events.
A number of organic anions selectively inhibit the biliary secretion of cholesterol and phospholipids without affecting bile acid secretion. We studied the effect of cefmetazole, a third-generation cephalosporin, on biliary lipid secretion in the rat. Injection of cefmetazole at a dose of 200 mumol/kg body wt. induced a choleretic effect and a significant decrease in the biliary output of cholesterol and phospholipid, without changes in bile acid secretion. The decrease was more marked for cholesterol than for phospholipid secretion, with a significant decrease in their molar ratio in bile. The effects were apparently unrelated to an inhibition of intracellular vesicular transport because, after injection of horseradish peroxidase, both the time course and total amount secreted of the protein did not significantly differ between control animals and those receiving cefmetazole. The secretory rate of the lysosomal marker acid phosphatase was not affected by cefmetazole administration. Biliary outputs of the plasma-membrane enzymes alkaline phosphatase and gamma-glutamyltransferase were significantly decreased by the antibiotic. These results point to an effect of cefmetazole at the level of the canalicular membrane.


The seroprevalence of pandemic influenza H1N1 (2009) virus in China.
Mainland China experienced pandemic influenza H1N1 (2009) virus (pH1N1) with peak activity during November-December 2009. To understand the geographic extent, risk factors, and attack rate of pH1N1 infection in China we conducted a nationwide serological survey to determine the prevalence of antibodies to pH1N1. Stored serum samples (n = 2,379) collected during 2006-2008 were used to estimate baseline serum reactogenicity to pH1N1. In January 2010, we used a multistage-stratified random sampling method to select 50,111 subjects who met eligibility criteria and collected serum samples and administered a standardized questionnaire. Antibody response to pH1N1 was measured using haemagglutination inhibition (HI) assay and the weighted seroprevalence was calculated using the Taylor series linearization method. Multivariable logistic regression analyses were used to examine risk factors for pH1N1 seropositivity. Baseline seroprevalence of pH1N1 antibody (HI titer ≥40) was 1.2%. The weighted seroprevalence of pH1N1 among the Chinese population was 21.5%(vaccinated: 62.0%; unvaccinated: 17.1%). Among unvaccinated participants, those aged 6-15 years (32.9%) and 16-24 years (30.3%) had higher seroprevalence compared with participants aged 25-59 years (10.7%) and ≥60 years (9.9%, P<0.0001). Children in kindergarten and students had higher odds of seropositivity than children in family care (OR: 1.36 and 2.05, respectively). We estimated that 207.7 million individuals (15.9%) experienced pH1N1 infection in China. The Chinese population had low pre-existing immunity to pH1N1 and experienced a relatively high attack rate in 2009 of this virus. We recommend routine control measures such as vaccination to reduce transmission and spread of seasonal and pandemic influenza viruses.


Abnormal maternal body mass index and obstetric and neonatal outcome.
The objective of this study is to examine the effects of abnormal maternal body mass index (BMI), either underweight or severe or morbid obesity (BMI >35), on obstetrical and neonatal outcomes. A three-year period (2.007-2.009) observational retrospective study was carried out in Granada (Spain). Women were categorized by first ten weeks of pregnancy BMI, according to World Health Organization (WHO) into three groups: underweight (<18.5), normal (20-24.9), and severe or morbid obese (>35). Obstetrical and neonatal outcomes were evaluated using normal group as reference after suitable adjustments for confounding factors. 3.016 patients out of 12.781 single births were included. Maternal BMI classified 168 women (5.5 %) as underweight, 2.597 (86.1%) as normal, and 251 (8.3%) as severe or morbidly obese. As compared to normal women, underweight women were younger, and class II or III obese showed higher parity and higher incidence of hypertension disorders and Diabetes Mellitus. After controlling for these confounders, underweight women showed increased adjusted risk of oligohydramnios and low birth weight babies, and severe or morbidly obese women had an increased adjusted risk of Streptococcus Group B colonization, induction of labour, elective and emergency cesarean section, fetal macrosomia, fetal acidosis at birth, and perinatal mortality. Severe or morbid obesity were associated with an increased risk of adverse perinatal outcome and mortality and should be managed as high-risk pregnancies.


Remodeling of Liver and Plasma Lipidomes in Mice Lacking Cyclophilin D.
In recent years, several studies aimed to investigate the metabolic effects of non-functioning or absent cyclophilin D (CypD), a crucial regulatory component of mitochondrial permeability transition pores. It has been reported that the lack of CypD affects glucose and lipid metabolism. However, the findings are controversial regarding the metabolic pathways involved, and most reports describe the effect of a high-fat diet on metabolism. We performed a lipidomic analysis of plasma and liver samples of CypD-/- and wild-type (WT) mice to reveal the lipid-specific alterations resulting from the absence of CypD. In the CypD-/- mice compared to the WT animals, we found a significant change in 52% and 47% of the measured 225 and 201 lipid species in liver and plasma samples, respectively. The higher total lipid content detected in these tissues was not accompanied by abdominal fat accumulation assessed by nuclear magnetic resonance imaging. We also documented characteristic changes in the lipid composition of the liver and plasma as a result of CypD ablation with the relative increase in polyunsaturated membrane lipid species. In addition, we did not observe remarkable differences in the lipid distribution of hepatocytes using histochemistry, but we found characteristic changes in the hepatocyte ultrastructure in CypD-/- animals using electron microscopy. Our results highlight the possible long-term effects of CypD inhibition as a novel therapeutic consideration for various diseases.


Effects of range restriction and criterion contamination on differential validity of the SAT by race/ethnicity and sex.
We illustrate the effects of range restriction and a form of criterion contamination (individual differences in course-taking patterns) on the validity of SAT scores for predicting college academic performance. College data facilitate exploration of differential validity's determinants because they (a) permit the use multivariate range-restriction corrections to more accurately account for differential range restriction across subgroups and (b) allow for separate examinations of composite performance and specific performance episodes, the latter of which controls for ecological contamination of composite performance due to individuals' choices of performance opportunities. Using data from 363,004 students at 107 U.S. institutions, we found that controlling for course-taking patterns resulted in validity coefficients that were appreciably larger than predictors' correlations with obtained grade point averages (GPAs). The validities of SAT scores for predicting the first-year college performance of Black and Hispanic students were not significantly different from the validity for White students after correcting for both course-taking patterns and differential range restriction, but significant Black-White differences were detected for predicting 4-year cumulative performance. Validity estimates for predicting both first-year and 4-year cumulative performance were significantly smaller among Asian students than White students after making these corrections. The SAT's observed validity for predicting college GPAs was substantially lower for males than females and, unexpectedly, controlling for course-taking patterns increased male-female validity differences. Implications for personnel selection research are discussed. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


MODY1 mutation Q268X in hepatocyte nuclear factor 4alpha allows for dimerization in solution but causes abnormal subcellular localization.
Recent studies have shown that mutations in the hepatocyte nuclear factor (HNF)-4alpha gene give rise to maturity-onset diabetes of the young, type 1 (MODY1). HNF-4, an orphan member of the nuclear receptor superfamily, contains a DNA-binding domain (DBD) and a putative ligand-binding domain (LBD) that can act independently of each other. The first MODY1 mutation identified creates a stop codon at amino acid 268 in the LBD of HNF-4 (Q268X) that leaves the DBD intact, suggesting that the mutant protein may retain some of the properties of the wild-type protein. To determine the functional properties of this mutant, we constructed HNF4.Q268X and tested it in vitro and in vivo for DNA binding, protein dimerization, and transactivation activity. Results of an electrophoretic mobility shift assay showed that HNF4.Q268X neither binds DNA alone nor binds it as a dimer with wild-type HNF-4 (HNF4.wt). In contrast, a co-immunoprecipitation assay showed that HNF4.Q268X is capable of dimerizing in solution with HNF4.wt. Transient transfection assays, however, indicated that HNF4.Q268X does not affect transactivation by HNF4.wt in vivo, supporting the argument against a dominant negative effect. Additional results suggest that the lack of a dominant negative effect could be due to a striking differential subcellular localization of the HNF4.Q268X protein: HNF4.Q268X could be extracted from transfected cells only when treated with SDS. Taken together, our results suggest that the MODY1 phenotype is due to a loss of functional HNF-4 protein that is aggravated in tissues that express relatively low amounts of HNF-4, such as pancreas.


Design of peptide-based bolaamphiphiles exhibiting heat-set hydrogelation via retro-Diels-Alder reaction.
Supramolecular hydrogels have attracted much attention as smart soft materials. To install various stimuli-responsive functions in the supramolecular hydrogels, skilful utility of chemical reactions for triggering the change in molecular structure of hydrogelators or their precursor in response to external stimuli is a promising strategy. We have recently developed a unique heat-set supramolecular hydrogel, which was triggered by rationally designed molecular conversion of a glycolipid-based bolaamphiphile into a hydrogelator via retro-Diels-Alder reaction. Here we designed new bolaamphiphiles based on short peptide-based hydrogelators as a scaffold to accelerate the heat-set hydrogelation process and also demonstrated the flexible molecular design of such bolaamphiphiles.


Renal bioengineering with scaffolds generated from rat and pig kidneys.
Chronic kidney disease (CKD) is a global public health issue with an estimated prevalence of 8-16% worldwide. End-stage renal disease eventually develops every year in 0.15-0.2% of patients with overt CKD, and renal replacement therapy (RRT) with dialysis or transplantation is required. Although approximately 2 million people worldwide are currently on RRT to sustain life, this likely represents less than 10% of those who need it. The kidney transplant approach is also seriously impaired by limited graft survival and by the scarce availability of donors. Innovative tissue-engineering strategies have been recently proposed to overcome these challenges. It is anticipated that these novel approaches will also be cost-effective in the long term. Although the initial setup of these innovative technologies could be quite expensive, there would be a single application for each patient, with no additional costs thereafter, compared to the lifelong costs of dialysis or immunosuppressive medications required for transplantation. One of the most innovative tools currently being investigated in experimental models is based on the idea of using decellularized kidneys to engineer a new functional organ as a potential future treatment option for end-stage renal disease. In the last 5 years, several interesting observations have been reported regarding the possibility of using an acellular matrix from the whole kidney and the attempt to recellularize this scaffold using stem or differentiated cells. This review provides an overview of the decellularization methods tested so far and their effects on the resulting extracellular matrix structure and composition. In addition, we also discuss methods recently described by us and others for the perfusion of kidney scaffolds for recellularization. Despite difficulties in achieving the import goal of kidney engineering in the laboratory, we discuss the problems with and limits of the experimental results obtained so far and point out the strategies that need to be adopted in order for this line of research to advance.


Chemokine receptor CCR6 transduces signals that activate p130Cas and alter cAMP-stimulated ion transport in human intestinal epithelial cells.
Human colon epithelial cells express the G protein-coupled receptor CCR6, the sole receptor for the chemokine CCL20 (also termed MIP-3alpha). CCL20 produced by intestinal epithelial cells is upregulated in response to proinflammatory stimuli and microbial infection, and it chemoattracts leukocytes, including CCR6-expressing immature myeloid dendritic cells, into sites of inflammation. The aim of this study was to determine whether CCR6 expressed by intestinal epithelial cells acts as a functional receptor for CCL20 and whether stimulation with CCL20 alters intestinal epithelial cell functions. The human colon epithelial cell lines T84, Caco-2, HT-29, and HCA-7 were used to model colonic epithelium. Polarized intestinal epithelial cells constitutively expressed CCR6, predominantly on the apical side. Consistent with this, apical stimulation of polarized intestinal epithelial cells resulted in tyrosine phosphorylation of the p130 Crk-associated substrate (Cas), an adaptor/scaffolding protein that localizes in focal adhesions and has a role in regulating cytoskeletal elements important for cell attachment and migration. In addition, CCL20 stimulation inhibited agonist-stimulated production of the second messenger cAMP and cAMP-mediated chloride secretory responses by intestinal epithelial cells. Inhibition was abrogated by pertussis toxin, consistent with signaling through Galphai proteins that negatively regulate adenylyl cyclases and cAMP production. These data indicate that signaling events, occurring via the activation of the apically expressed chemokine receptor CCR6 on polarized intestinal epithelial cells, alter specialized intestinal epithelial cell functions, including electrogenic ion secretion and possibly epithelial cell adhesion and migration.


Subunit selectivity and epitope characterization of mAbs directed against the GABAA/benzodiazepine receptor.
mAbs bd 17, bd 24, and bd 28 raised against bovine cerebral gamma-aminobutyric acid (GABAA)/benzodiazepine receptors were analyzed for their ability to detect each of 12 GABAA receptor subunits expressed in cultured mammalian cells. Results showed that mAb bd 17 recognizes epitopes on both beta 2 and beta 3 subunits while mAb bd 24 is selective for the alpha 1 subunit of human and bovine, but not of rat origin. The latter antibody reacts with the rat alpha 1 subunit carrying an engineered Leu at position four, documenting the first epitope mapping of a GABAA receptor subunit-specific mAb. In contrast to mAbs bd 17 and bd 24, mAb bd 28 reacts with all GABAA receptor subunits tested but not with a glycine receptor subunit, suggesting the presence of shared epitopes on subunits of GABA-gated chloride channels.


Alcohol consumption in relation to plasma sex hormones, prolactin, and sex hormone-binding globulin in premenopausal women.
Alcohol consumption is a consistent risk factor for breast cancer, and evidence suggests premenopausal plasma hormones are associated with breast cancer. Plasma concentrations of estradiol, estrone, estrone sulfate, testosterone, androstenedione, progesterone, prolactin, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), and sex hormone-binding globulin (SHBG) were measured in samples collected in 1996-99. Average alcohol intake was calculated from semiquantitative food frequency questionnaires collected in 1995 and 1999. We used generalized linear models to calculate geometric mean hormone concentrations across alcohol categories and the percentage difference for the highest versus lowest category. Comparing women who consumed >20 g/d with nondrinkers, levels were 25.7% higher for luteal estrone (geometric mean, 106 vs. 84.5 pg/mL; Ptrend = 0.001), 27.2% higher for luteal estradiol (182 vs. 143 pg/mL; Ptrend = 0.006), and 16.8% higher for SHBG (85.6 vs. 73.3 nmol/L; Ptrend = 0.03); concentrations of free testosterone were 17.9% lower (0.16 vs. 0.20 ng/dL; Ptrend = 0.002). Women consuming >10 g/d compared with nondrinkers had 26.5% higher concentrations of follicular estrone sulfate (950 vs. 751 pg/mL; Ptrend = 0.04). We did not observe significant associations between alcohol and the other sex hormones evaluated. Significant positive associations were observed with beer intake, but not other alcohol types, for DHEA (Pinteraction = 0.003) and androstenedione (Pinteraction = 0.006). Alcohol consumption was significantly positively associated with plasma luteal estrogen concentrations, but not with androgen levels, nor estrone or estradiol measured in the follicular phase. Differences in premenopausal estrogen levels may contribute to the association between alcohol and breast cancer.


Adenovirus infection of the renal allograft with sparing of pancreas graft function in the recipient of a combined kidney-pancreas transplant.
We report a case of adenovirus infection of the renal allograft in a combined kidney/pancreas transplant recipient. The clinical presentation was renal allograft failure, which eventually reversed. The pancreatic graft function remained stable. A renal biopsy showed massive tubular necrosis associated with a prominent granulomatous reaction. The process had a striking regional distribution within the kidney with the injury and inflammation limited to the outer medulla. Adenovirus type 11 was isolated from renal tissue by culture, and adenovirus was demonstrated by immunofluorescence and electron microscopy in the kidney biopsy. Immunosuppression may result in unusual patterns of response to infectious agents. This case demonstrated tropism of the adenovirus to only selected tubules within the kidney, with sparing of other organ function including, specifically, the pancreas allograft. The differential diagnosis of a granulomatous reaction in the transplant kidney must be expanded to include viral infection, in particular, adenovirus.


Discussing wisdom teeth with patients: a critique of information materials.
To assess the quality of information leaflets about third molar extraction. Quality assessment of information leaflets about third molar extraction. We focused particularly on the extent to which they reflect current research evidence. All fifteen oral and maxillofacial surgery departments in Scotland were asked to provide copies of existing patient information materials on third molar surgery. Six different leaflets were assessed. Most were apparently intended for people who were about to undergo and/or had just undergone the procedure rather than for people facing decisions about extraction. The leaflets appeared to reflect varying policies about third molar extraction and some of the information provided did not reflect current research evidence. There is currently a lack of good quality information materials available to people who are considering third molar extraction. It is likely that there are also problems with the quality of other patient information leaflets. Health care professionals need to review the quality of patient information leaflets to ensure that the information provided reflects current research evidence.


[A case of atraumatic hematomyelia extending from the C1 to T11 segments of the spinal cord].
Intramedullary spinal cord hemorrhage (hematomyelia) is rare and usually related to trauma. Spinal vascular malformations such as intramedullary cavernomas and intradural arteriovenous malformations are the most common cause of atraumatic hematomyelia. Other considerations include warfarin or heparin anticoagulation, bleeding disorders, spinal cord tumors, and delayed complication of spinal radiation. We report the case of 48-year-old man receiving warfarin and aspirin therapy, who showed upper limb pain and dysesthesia from left axilla to left femur. Paraplegia, sensory disturbance, bladder and rectal disturbance developed gradually over two weeks, accompanied by severe back and neck pain. MRI showed hematomyelia extending from the C1 to T11 segments of the spinal cord. The hemorrhage was located mainly in the left side of the posterior column. Few cases of hematomyelia extending over 18 segments of the spinal cord have been reported. Past literature reports of hematomyelia tend to extend longitudinally above and below the area of initial hemorrhage. We thought that the shape of this hematomyelia extending longitudinally over several segments was formed by a similar pathogenesis to pencil-shaped softening of the spinal cord.


Changes in nucleoli and nucleolar fibrillar centres of chromaffin cells in rat adrenal medulla over a 24-hour period: an ultrastructural and stereological analysis.
A stereological and ultrastructural study was performed on the nucleoli of the adrenal medulla chromaffin cells of rats exposed to a standardized 12 h light/12 h dark cycle with free access to food and water. The animals were killed three at a time, every 4 h during the 24-h span and fixed by intracardiac perfusion. In these reticulated nucleoli, the stereological analysis over a 24-h period showed a variation dependent on the time of killing for the two parameters investigated, the mean nucleolar volume, Vnu, and the mean volume of the fibrillar centres, Vfc(nu). The minimal value occurred at 0300 h (dark span) and the maximal one at 0700 h (at the onset of the light span). Between these two extreme values, Vnu increased 1.8-fold and Vfc(nu) 5.3-fold. These data are compared with a previous description from our laboratory of circadian rhythm in nucleoli of sympathetic neurons of superior cervical ganglion in the same animals. Analogies and differences are pointed out, but apart from these considerations the present study provides a new example of temporal organization at the cellular level in the organelle involved in ribosomal RNA synthesis and ribosome assembly.


Smith predictor-based robot control for ultrasound-guided teleoperated beating-heart surgery.
Performing surgery on fast-moving heart structures while the heart is freely beating is next to impossible. Nevertheless, the ability to do this would greatly benefit patients. By controlling a teleoperated robot to continuously follow the heart's motion, the heart can be made to appear stationary. The surgeon will then be able to operate on a seemingly stationary heart when in reality it is freely beating. The heart's motion is measured from ultrasound images and thus involves a non-negligible delay due to image acquisition and processing, estimated to be 150 ms that, if not compensated for, can cause the teleoperated robot's end-effector (i.e., the surgical tool) to collide with and puncture the heart. This research proposes the use of a Smith predictor to compensate for this time delay in calculating the reference position for the teleoperated robot. The results suggest that heart motion tracking is improved as the introduction of the Smith predictor significantly decreases the mean absolute error, which is the error in making the distance between the robot's end-effector and the heart follow the surgeon's motion, and the mean integrated square error.


Sweet and Blind Spots in E3 Ligase Ligand Space Revealed by a Thermophoresis-Based Assay.
Repurposing E3 ubiquitin ligases for targeted protein degradation via customized molecular glues or proteolysis-targeting chimeras (PROTACs) is an increasingly important therapeutic modality. Currently, a major limitation in the design of suitable molecular glues and PROTACs is our fragmentary understanding of E3 ligases and their ligand space. We here describe a quantitative assay for the discovery and characterization of E3 ligase ligands that is based on the thermophoretic behavior of a custom reporter ligand. Thereby, it is orthogonal to commonly employed fluorescence-based assays and less affected by the optical properties of test compounds. It can be employed for the high-throughput screening of compound libraries for a given ligase but also for hit validation, which we demonstrate with the identification of unexpected well-binders and non-binders, yielding new insights into the ligand space of cereblon (CRBN).


Loss of DNA ligase IV prevents recognition of DNA by double-strand break repair proteins XRCC4 and XLF.
The repair of DNA double-strand breaks by nonhomologous end-joining (NHEJ) is essential for maintenance of genomic integrity and cell viability. Central to the molecular mechanism of NHEJ is DNA ligase IV/XRCC4/XLF complex, which rejoins the DNA. During adenovirus (Ad5) infection, ligase IV is targeted for degradation in a process that requires expression of the viral E1B 55k and E4 34k proteins while XRCC4 and XLF protein levels remain unchanged. We show that in Ad5-infected cells, loss of ligase IV is accompanied by loss of DNA binding by XRCC4. Expression of E1B 55k and E4 34k was sufficient to cause loss of ligase IV and loss of XRCC4 DNA binding. Using ligase IV mutant human cell lines, we determined that the absence of ligase IV, and not expression of viral proteins, coincided with inhibition of DNA binding by XRCC4. In ligase IV mutant human cell lines, DNA binding by XLF was also inhibited. Expression of both wild-type and adenylation-mutant ligase IV in ligase IV-deficient cells restored DNA binding by XRCC4. These data suggest that the intrinsic DNA-binding activities of XRCC4 and XLF may be subject to regulation and are down regulated in human cells that lack ligase IV.


Haemophagocytic lymphohistiocytosis in pregnancy and the postpartum period: A retrospective case series analysis.
Haemophagocytic lymphohistiocytosis (HLH) is an extremely rare condition characterised by excessive immune activation leading to haemophagocytic activity and has seldom been reported in pregnancy. HLH manifests as relapsing fevers with features of multi- organ failure and has a high mortality. A retrospective case series analysis using national data from MBRRACE-UK maternal death reports (n=5) and case notes from patients diagnosed with HLH during pregnancy at New Cross Hospital, Wolverhampton (n=2) between 2012 and 2021. A total of seven cases were included. Cases uniformly presented with fever and experienced prodromal illnesses consisting of lymphadenopathy, fevers, and malaise. Gestation at presentation ranged from 9/40 to 11 months postpartum. All patients had multiple cytopaenias. Other common features included elevated liver enzymes (n=5), hyperferritinaemia (n=5), splenomegaly (n=4), hypofibrinogenemia (n=4) and elevated soluble interleukin-2 receptor α (CD25) levels (n=3). Underlying causes were identified in four cases. Median time from presentation to diagnosis was 35 days. Bone marrow biopsy was diagnostic in a majority of cases. Corticosteroids and ciclosporin were the most frequently used treatments. In some cases early delivery by caesarean section or termination of pregnancy was necessary to permit maternal treatment. Progression to multi-organ failure resulting in maternal death occurred in five cases: two cases survived. Pregnancy outcomes were: livebirth at term (n=2), preterm livebirth (n=3), termination of pregnancy (n=1), and miscarriage (n=1). Of the surviving infants, one had bone marrow suppression with anaemia at birth and sensorineural deafness. Due to the rarity of the condition, diagnosis is often delayed. In view of the high mortality, clinicians should consider HLH early when reviewing pregnant patients with unexplained pyrexia and multi-organ dysfunction. Early involvement of haematology should be sought, as prompt diagnosis is crucial for meaningful attempts at curative therapy. Important treatment considerations include fetal viability, maternal condition and treatment toxicity.


Erection Hardness Score in Masturbation Can Serve as a Preliminary Screening Tool for Organic Erectile Dysfunction.
To explore the efficacy, in terms of sensitivity and specificity, of Erection Hardness Score (EHS) applied to masturbation in diagnosing predominantly organic erectile dysfunction (ED), compared to the actual standard, which is nocturnal penile tumescence and rigidity (NPTR). A total of 189 consecutive patients who came to our outpatient clinic from October 2019 to October 2020, reporting ED and an abridged International Index of Erectile Function (IIEF-6) score <26 were enrolled. Patients filled out two psychometric questionnaires: the IIEF-6 applied to partnered intercourse and the EHS applied to masturbation, then they underwent the NPTR test with Rigiscan for 2 consecutive nights in good sleep condition. Sensitivity, specificity, positive predictive value, and negative predictive value of EHS and IIEF-6 scales with NPTR as the standard, as well as the correlation between EHS, IIEF-6, and NPTR results were calculated. Results show that the sensitivity of the EHS scale for the diagnosis of ED was 60.0%, the specificity was 95.7%, the positive predictive value was 83.3%, the negative predictive value was 86.9%, and the coincidence rate was 86.2%. The correlation coefficient was 0.572 and the area under the ROC curve was 0.78, which means the strength of erection in masturbation as evaluated by the EHS can effectively help in discriminating between predominantly organic and apparently nonorganic ED. An EHS score of 3-4, meaning good-optimal erectile function during masturbation, decreases the likelihood of predominantly organic ED and reduces the need for further NPTR testing.


A Comprehensive Comparison of Six Publicly Available Algorithms for Localization of QRS Complex on Electrocardiograph.
The QRS complex is the most prominent feature of the electrocardiogram (ECG) that is used as a marker to identify the cardiac cycles. Identification of QRS complex locations enables arrhythmia detection and heart rate variability estimation. Therefore, accurate and consistent localization of the QRS complex is an important component of automated ECG analysis which is necessary for the early detection of cardiovascular diseases. This study evaluates the performance of six popular publicly available QRS complex detection methods on a large dataset of over half a million ECGs in a diverse population of patients. We found that a deep-learning method that won first place in the 2019 Chinese physiological challenge (CPSC-1) outperforms the remaining five QRS complex detection methods with an F1 score of 98.8% and an absolute sdRR error of 5.5 ms. We also examined the stratified performance of the studied methods on various cardiac conditions. All six methods had a lower performance in the detection of QRS complexes in ECG signals of patients with pacemakers, complete atrioventricular block, or indeterminate cardiac axis. We also concluded that, in the presence of different cardiac conditions, CPSC-1 is more robust than Pan-Tompkins which is the most popular model for QRS complex detection. We expect that this study can potentially serve as a guide for researchers on the appropriate QRS detection method for their target applications.Clinical Relevance-This study highlights the overall performance of publicly available QRS detection algorithms in a large dataset of diverse patients. We showed that there are specific cardiac conditions that are associated with the poor performance of QRS detection algorithms and may adversely influence the performance of algorithms that rely on accurate and reliable QRS detection.


Photoreactivatiion, excision, and strand-rejoining repair in R factor-containing minicells of Escherichia coli K-12.
Chromosomeless "minicells" are formed by misplaced cell fissions near the polar extremities of an Escherichia coli K-12 mutant strain. Resistance (R)-factor deoxyribonucleic acid (DNA) can be introduced into minicells by segregation from an R(+) (R64-11) derivative of the original mutant. We have assessed the ability of R(+) minicells to correct defects produced in their plasmid DNA by ultraviolet (UV) and gamma radiations. Minicells harboring plasmid DNA, in comparison with their repair-proficient minicell-producing parents, possess (i) an equal competence to rejoin single-strand breaks induced in DNA by gamma rays, (ii) a reduced capacity for the photoenzymatic repair of UV-induced pyrimidine dimers, and (iii) a total inability to excise dimers, apparently owing to a deficiency in UV-specific endonuclease activity responsible for mediating the initial incision step in excision repair. Assuming that the DNA repair properties of R(+) minicells reflect the concentration of repair enzymes located in the plasmid-containing polar caps of entire cells, these findings suggest that: (i) the enzymes responsible for rejoining single-strand breaks are distributed throughout the cell; (ii) photoreactivating enzyme molecules tend to be concentrated near bacterial DNA and to a lesser extent near plasmid DNA; and (iii) UV-specific endonuclease molecules are primarily confined to the central region of the E. coli cell and, thus, seldom segregate with R-factor DNA into minicells.


Multiplex diagnosis of viral infectious diseases (AIDS, hepatitis C, and hepatitis A) based on point of care lateral flow assay using engineered proteinticles.
Lateral flow assay (LFA) is an attractive method for rapid, simple, and cost-effective point of care diagnosis. For LFA-based multiplex diagnosis of three viral intractable diseases (acquired immune deficiency syndrome and hepatitis C and A), here we developed proteinticle-based 7 different 3D probes that display different viral antigens on their surface, which were synthesized in Escherichia coli by self-assembly of human ferritin heavy chain that was already engineered by genetically linking viral antigens to its C-terminus. Each of the three test lines on LFA strip contains the proteinticle probes to detect disease-specific anti-viral antibodies. Compared to peptide probes, the proteinticle probes were evidently more sensitive, and the proteinticle probe-based LFA successfully diagnosed all the 20 patient sera per each disease without a false negative signal, whereas the diagnostic sensitivities in the peptide probe-based LFAs were 65-90%. Duplex and triplex assays performed with randomly mixed patient sera gave only true positive signals for all the 20 serum mixtures without any false positive signals, indicating 100% sensitivity and 100% specificity. It seems that on the proteinticle surface the antigenic peptides have homogeneous orientation and conformation without inter-peptide clustering and hence lead to the enhanced diagnostic performance with solving the problems of traditional diagnostic probes. Although the multiplex diagnosis of three viral diseases above was demonstrated as proof-of-concept here, the proposed LFA system can be applied to multiplex point of care diagnosis of other intractable diseases.


Functionalized truxenes: adsorption and diffusion of single molecules on the KBr(001) surface.
In this work, we have studied the adsorption and diffusion of large functionalized organic molecules on an insulating ionic surface at room temperature using a noncontact atomic force microscope (NC-AFM) and theoretical modeling. Custom designed syn-5,10,15-tris(4-cyanophenylmethyl)truxene molecules are adsorbed onto the nanoscale structured KBr(001) surface at low coverages and imaged with atomic and molecular resolution with the NC-AFM. The molecules are observed rapidly diffusing along the perfect monolayer step edges and immobilized at monolayer kink sites. Extensive atomistic simulations elucidate the mechanisms of adsorption and diffusion of the molecule on the different surface features. The results of this study suggest methods of controlling the diffusion of adsorbates on insulating and nanostructured surfaces.


Nuclear factor-kappaB in development, prevention, and therapy of cancer.
Nuclear factor-kappaB (NF-kappaB) is a signal transcription factor that has emerged as an important modulator of altered gene programs and malignant phenotype in development of cancer. Major carcinogens and oncogenic viruses induce NF-kappaB activation, and a variety of subsequent oncogenic events contribute to a progressive increase in constitutive NF-kappaB activation as an important common pathway in most forms of cancer. NF-kappaB target genes promote tumor cell proliferation, survival, migration, inflammation, and angiogenesis. Inhibition of NF-kappaB has been found to be an important mechanism of action of steroids, nonsteroidal anti-inflammatory drugs, and natural and synthetic compounds that show therapeutic and preventive activity. Newer agents targeting the proteasome, inhibitor-kappaB kinase, and other upstream kinases involved in NF-kappaB activation have shown anticancer activity in clinical or preclinical studies.


Magnetic resonance imaging evaluation of the labrum to predict acetabular development in developmental dysplasia of the hip: A STROBE compliant study.
Recently, more attention has been paid to the role of the acetabular labrum. Therefore, we designed a retrospective cohort study of patients with residual hip dysplasia (RHD) who underwent magnetic resonance imaging (MRI). The objective of this study was to investigate an association between the MRI appearance of the labrum before school age and the natural history of RHD.We retrospectively investigated 45 hips of 40 patients who underwent MRI at about 3 and 4 years of age for RHD and were conservatively followed up with until 6 years of age or older. We evaluated the extent of eversion with a new method that measures the β angle (MRI β angle) using landmarks of the Graf method on MRI T2*-weighted images. The outcome measure was the Severin classification at the final follow-up. We compared the radiographic and MRI parameters at approximately 3 and 4 years of age between the good and poor outcome groups. The Student t test or one-way analysis of variance was used to compare the quantitative variables between groups. The Chi-square test was used to perform a ratio comparison.Although there was a significant difference in the center-edge (CE) angle, there was no significant difference in the acetabular index and the ratio of the presence of femoral head necrosis and the break in Shenton line between the good and poor groups. The MRI β angle was significantly greater in the poor outcome group than in the normal and good outcome groups. The cut-off value of the MRI β angle to differentiate the good and poor outcome groups was 65°, and its specificity and sensitivity were 92% and 53%, respectively.There was labral eversion on MRI scans in patients with RHD. Acetabular development before adolescence was poorer with greater labral eversion on MRI scans. The specificity for poor acetabular development was high when the MRI β angle was 65° or more. The MRI β angle has the potential to predict acetabular development.


Aldosterone-receptor antagonism in hypertension.
The role of the renin-angiotensin-aldosterone system (RAAS) in hypertension has since long been recognized and aldosterone has been acknowledged as one of the key hormones in the pathophysiology, not only in primary aldosteronism but also in essential hypertension and drug-resistant hypertension. Aldosterone-receptor antagonists (ARAs) are increasingly used in patients with resistant hypertension, often with impressive results. However, definitive evidence for the benefit of ARAs in these patients from randomized, controlled trials is lacking. This review gives an overview of the current data on this topic. Future studies should focus on the identification of factors that are able to predict the response to treatment, as to select patients who will benefit most from treatment with ARAs. On the basis of the current knowledge, we recommend prescription of ARAs to patients with primary aldosteronism, resistant hypertension and patients with hypertension and hypokalemia.


Direct C(sp3)-H Cross Coupling Enabled by Catalytic Generation of Chlorine Radicals.
Here we report the development of a C(sp3)-H cross-coupling platform enabled by the catalytic generation of chlorine radicals by nickel and photoredox catalysis. Aryl chlorides serve as both cross-coupling partners and the chlorine radical source for the α-oxy C(sp3)-H arylation of cyclic and acyclic ethers. Mechanistic studies suggest that photolysis of a Ni(III) aryl chloride intermediate, generated by photoredox-mediated single-electron oxidation, leads to elimination of a chlorine radical in what amounts to the sequential capture of two photons. Arylations of a benzylic C(sp3)-H bond of toluene and a completely unactivated C(sp3)-H bond of cyclohexane demonstrate the broad implications of this manifold for accomplishing numerous C(sp3)-H bond functionalizations under exceptionally mild conditions.


Reactivation of a cell-free model from Physarum polycephalum: studies on cryosections indicate an inhibitory effect of Ca++ on cytoplasmic actomyosin contraction.
Cell-free models should offer "in situ conditions" to study the physiology of cytoplasmic actomyosin in its natural environment, while, if possible, still associated with its regulatory control proteins and other cytoplasmic components. Detergents and glycerol as the usual media to permeabilize the plasmalemma and to extract a portion of the cytoplasmic components, are accompanied by several disadvantages. We investigated a cell-free model consisting of cryosections of plasmodial strands that were previously enriched with "stress fibrils" and fluorescently labelled with phallotoxins and that contain the non-denatured structures that are to be reactivated in situ. The contraction reaction can be directly observed in the fluorescence microscope. This procedure allows the study of contraction conditions in the natural environment of the fibrils. The aim of these reactivation experiments was to identify the role of calcium ions. According to our results, a reactivation of cryosections is not Ca++ dependent but is partly inhibited at concentrations of 10(-4) to 5 X 10(-2)M Ca++. Complete inhibition occurs at 10 to 20 mM Ca++. Electron microscopical investigations revealed that the fluorescently labelled contracting structures were identical to actomyosin fibrils.