DNA methylation status of key cell-cycle regulators such as CDKNA2/p16 and CCNA1 correlates with treatment response to doxorubicin and 5-fluorouracil in locally advanced breast tumors.
To explore alterations in gene promoter methylation as a potential cause of acquired drug resistance to doxorubicin or combined treatment with 5-fluorouracil and mitomycin C in human breast cancers. Paired tumor samples from locally advanced breast cancer patients treated with doxorubicin and 5-fluorouracil-mitomycin C were used in the genome-wide DNA methylation analysis as discovery cohort. An enlarged cohort from the same two prospective studies as those in the discovery cohort was used as a validation set in pyrosequencing analysis. A total of 469 genes were differentially methylated after treatment with doxorubicin and revealed a significant association with canonical pathways enriched for immune cell response and cell-cycle regulating genes including CDKN2A, CCND2, CCNA1, which were also associated to treatment response. Treatment with FUMI resulted in 343 differentially methylated genes representing canonical pathways such as retinoate biosynthesis, gαi signaling, and LXR/RXR activation. Despite the clearly different genes and pathways involved in the metabolism and therapeutic effect of both drugs, 46 genes were differentially methylated before and after treatment with both doxorubicin and FUMI. DNA methylation profiles in genes such as BRCA1, FOXC1, and IGFBP3, and most notably repetitive elements like ALU and LINE1, were associated with TP53 mutations status. We identified and validated key cell-cycle regulators differentially methylated before and after neoadjuvant chemotherapy such as CDKN2A and CCNA1 and reported that methylation patterns of these genes may be potential predictive markers to anthracycline/mitomycine sensitivity.


Neuroleptic malignant syndrome in Parkinson's disease after withdrawal or alteration of dopaminergic therapy.
Neuroleptic malignant syndrome is characterized by altered consciousness, fever, extrapyramidal signs, autonomic instability, elevated creatine kinase level, and leukocytosis. Although originally described in patients receiving neuroleptic drugs, this syndrome may also occur in patients with Parkinson's disease during withdrawal or reduction of levodopa therapy or other dopaminergic drug therapy. We have encountered three cases of neuroleptic malignant syndrome related to withdrawal of levodopa therapy. These cases illustrate the variety of circumstances in which alteration of therapy with dopaminergic drugs can cause this syndrome and the relative unfamiliarity of the neuroleptic malignant syndrome-levodopa relationship among physicians who do not treat large numbers of patients with Parkinson's disease. An understanding of the role of brain dopamine in the pathogenesis of neuroleptic malignant syndrome and an appreciation of the great variety of drugs whose manipulation can result in this potentially fatal syndrome will aid its proper and timely recognition, especially when the offending pharmacologic manipulation does not involve neuroleptic drugs.


Molecular mechanisms for survival regulation of chronic myeloid leukemia stem cells.
Studies on chronic myeloid leukemia (CML) have served as a paradigm for cancer research and therapy. These studies involve the identification of the first cancer-associated chromosomal abnormality and the subsequent development of tyrosine kinase inhibitors (TKIs) that inhibit BCR-ABL kinase activity in CML. It becomes clear that leukemia stem cells (LSCs) in CML which are resistant to TKIs, and eradication of LSCs appears to be extremely difficult. Therefore, one of the major issues in current CML biology is to understand the biology of LSCs and to investigate why LSCs are insensitive to TKI monotherapy for developing curative therapeutic strategies. Studies from our group and others have revealed that CML LSCs form a hierarchy similar to that seen in normal hematopoiesis, in which a rare stem cell population with limitless self-renewal potential gives rise to progenies that lack such potential. LSCs also possess biological features that are different from those of normal hematopoietic stem cells (HSCs) and are critical for their malignant characteristics. In this review, we summarize the latest progress in CML field, and attempt to understand the molecular mechanisms of survival regulation of LSCs.


Glial but not neuronal development in the cochleo-vestibular ganglion requires Sox10.
The cochleo-vestibular ganglion contains neural crest-derived glial cells and sensory neurons that are derived from the neurogenic otic placode. Little is known about the molecular mechanisms that regulate the tightly orchestrated development of this structure. Here, we report that Sox10, a high-mobility group DNA-binding domain transcription factor that is required for the proper development of neural crest cell derivatives, is specifically expressed in post-migratory neural crest cells in the cochleo-vestibular ganglion. Using Sox10-deficient mice, we demonstrate that this transcription factor is essential for the survival, but not the generation, of the post-migratory neural crest cells within the inner ear. In the absence of these neural crest-derived cells, we have investigated the survival of the otocyst-derived auditory neurons. Surprisingly, auditory neuron differentiation, sensory target innervation and survival are conserved despite the absence of glial cells. Moreover, brain-derived neurotrophic factor expression is increased in the hair cells of Sox10-deficient mice, a compensatory mechanism that may prevent spiral ganglion neuronal cell death. Taken together, these data suggest that in the absence of neural crest-derived glial cells, an increase trophic support from hair cells promotes the survival of spiral ganglion neurons in Sox10 mutant mice.


Physiologic estradiol replacement following oophorectomy: failure to maintain precastration gonadotropin levels.
To determine whether regularly menstruating women retain an intact pituitary sensitivity to estrogen negative feedback following bilateral salpingo-oophorectomy, 6 parous women, aged 31 to 47, reporting regular menstrual cycles were studied following total abdominal hysterectomy and bilateral salpingo-oophorectomy for non-endocrine-related indications. During closure of the incision, a 12.5-mg continuous-release crystalline 17 beta-estradiol pellet was implanted in the subcutaneous tissue. Antecubital venous blood was sampled preoperatively and at 1, 4, and 8 weeks postoperatively and stored frozen (-15C) until assayed for follicle-stimulating hormone (FSH), luteinizing hormone (LH), and 17 beta-estradiol by radioimmunoassay. Despite maintenance of serum estradiol levels in the mid-follicular phase range (40 to 80 pg/ml), the serum concentration of both FSH and LH progressively increased. By the fourth postoperative week, both FSH and LH concentrations had increased significantly (P less than .05). This trend continued and, by 8 weeks after surgery, both gonadotropin levels were in the postmenopausal range. The authors conclude that even when replacement begins immediately following castration, physiologic estradiol at concentrations characteristic of the normal midfollicular phase is not sufficient to maintain suppression of gonadotropins. Whether these observations reflect a change in pituitary sensitivity to 17 beta-estradiol feedback, the removal of nonsteroidal inhibitory substances of gonadal origin, or the lack of an appropriate composite steroidal milieu remains unanswered.


Human serum amyloid A (SAA): biosynthesis and postsynthetic processing of preSAA and structural variants defined by complementary DNA.
To study structural variants of human serum amyloid A (SAA), an apoprotein of high-density lipoprotein, complementary DNA clones were isolated from a human liver library with the use of two synthetic oligonucleotide mixtures containing sequences that could code for residues 33-38 and 90-95 of the protein sequence. The SAA-specific cDNA clone (pA1) contains the nucleotide sequence coding for the mature SAA and 10 amino acids of the 18-residue signal peptide. It also includes a 70 nucleotide long 3'-untranslated region and approximately 120 bases of the poly(A) tail. The derived amino acid sequence of pA1 is identical with the alpha form of apoSAA1. A fragment of pA1 containing the conserved (residues 33-38) region of SAA also hybridized with RNA from human acute phase liver and acute phase stimulated, but not unstimulated, mouse and rabbit liver. In contrast, a fragment corresponding to the variable region hybridized to a much greater extent with human than with rabbit or murine RNA. Human acute phase liver SAA mRNA (approximately 600 nucleotides in length) directs synthesis of preSAA (Mr 14 000) in a cell-free translating system. In a Xenopus oocyte translation system preSAA is synthesized and processed to the mature Mr 12 000 product. The complete 18 amino acid signal peptide sequence of preSAA was derived from sequencing cDNA synthesized by "primer extension" from the region of SAA mRNA corresponding to the amino terminus of the mature product. Two other SAA-specific cDNA clones (pA6 and pA10) differed from pA1 in that they lack the internal PstI restriction enzyme site spanning residues 54-56 of pA1.(ABSTRACT TRUNCATED AT 250 WORDS)


Son targeting fertility behavior: some consequences and determinants.
This article draws out some implications of son targeting fertility behavior and studies its determinants. We demonstrate that such behavior has two notable implications at the aggregate level: (a) girls have a larger number of siblings (sibling effect), and (b) girls are born at relatively earlier parities within families (birth-order effect). Empirically testing for these effects, we find that both are present in many countries in South Asia, Southeast Asia, and North Africa but are absent in the countries of sub-Saharan Africa. Using maximum likelihood estimation, we study the effect of covariates on son targeting fertility behavior in India, a country that displays significant sibling and birth-order effects. We find that income and geographic location of families significantly affect son targeting behavior.


[State of the vegetative nervous system and the risk of repeated hospitalization after elimination of hypertonic crisis].
Observation of 58 outpatients with arterial hypertension (AH) revealed a group of 25 subjects who needed repeated hospitalization within 1 year after hypertonic crisis due to unstable conditions (group 1). The two groups were comparable in terms of office AP measurements, but 24 hr AP, systolic AP and its variations were significantly higher while daily index was lower in group 1. Moreover, patients of this group had decreased variability of the cardiac rhythm with increased activity of the suprasegmental level and reduced parasympathetic activity. A rise in BMI in these patients correlated with the state of sympathetic component of the vegetative nervous system. It is concluded that normalization of office AP can not be regarded as evidence of benign course of the disease; evaluation of daily AP characteristics, BMI, and balance of vegetative nervous system is needed to stratify risks for the outpatients with AH followed up after the treatment of hypertonic crisis.


[Aromatic trees and herbs that connect Heaven and earth].
It has been known for a long time that aromatic substances (essential oils) contained in plants often exert psychological effects ranging from sedative to excitatory actions. Medicinal effects have also been confirmed through numerous experiences. In ancient times, aromatic trees and herbs were offered to deities, mostly as incenses that were believed to carry people's wishes, such as requests to cure sick people, to Heaven. In the medieval periods, their deep and subtle aromas elevated aromatics to so-called "treasures of the world," while their various medicinal activities including the psychological effects made them useful as treatment measures. Demands for aromatics in our time as raw materials for cosmetics far outweigh those as medicines. The market for aromatics, however, has become virtually non-existent, as the popularity of synthetic aromatics for cosmetics grew. In West Asia, olibanum and myrrh were highly regarded both as incense and analgesics for tooth pain. In India, sandalwood was prized as incense, and sometimes as an antidote for poisonous snakebites. In China and Japan, agalloch (Kyara is agalloch of the highest quality) was considered the most significant of the aromatics. Agalloch and many other aromatics were in possession of the Emperor's family in 8th century Japan; some of which are kept in Nara to this day. Olfactory sense is ultimately identified in the olfactory area of the frontal lobe of the human brain. When stimuli reach the olfactory area, they also affect other cells such as those around the hypothalamus when they go through it. The hypothalamus is the center of instinctive behaviors with the centers for appetite, sexuality, blood pressure and thirst, and greatly affects the psychological side of the human behavior with its delicate connection to the autonomic nerve system. It therefore may not be surprising that aromatics were often used in medicine, which once had close ties with shamanism, animism and other religious activities. Aromatics smokes that connected people on the earth with deities in Heaven healed people's mind, sometimes curing illness through what is now called aromatherapy. In fact, such use of aromatics is still practiced in China, where aromatics are highly regarded as treatment agents. There have also been reports of aromatics being used for psychological and mental disorders.


Orthodontic mini-implant stability and the ratio of pilot hole implant diameter.
One notable complication of mini-implants that are used to provide anchorage in orthodontic treatment is loosening. The aim of this study was to evaluate the relationship between mini-implant mobility during the healing phase and the prognosis for implant stability. Twenty male Wistar rats (aged 20 weeks) were used. Drills with diameters of 0.8, 0.9, 1.0, and 1.1 mm were used to make pilot holes in the rat tibiae. The inserted mini-implants (diameter 1.4 mm; spearhead 1.2 mm; halfway between maximum and minimum 1.3 mm; length 4.0 mm) were subjected to an experimental traction of force for 3 weeks. Bone-to-implant contact (BIC) was observed histologically. Another 20 male rats (aged 20 weeks) underwent an identical procedure, and the stability of the mini-implants was measured using the Periotest before and after traction. The data were statistically analysed using Scheffé's test. The BIC ratios of the 0.9 and 1.0 mm groups were significantly greater than those of the other groups. The Periotest values measured 3 weeks after implant insertion were significantly lower (P < 0.05) than those measured at insertion, except in the 1.1 mm group. To obtain mini-implant stability, the hole diameter should be between 69 and 77 per cent of the diameter of the mini-implant. A significant decrease in the mobility of the mini-implants 3 weeks post-insertion implies a good prognosis for the subsequent mini-implant stability.


[Treatment of rheumatoid arthritis. Comparative study of the effect of immunoglobulins G eluted from the placenta and of venoglobulins].
A double-blind multicenter study comparing the effect of placenta eluted IgG and venoglobulins in the treatment of rheumatoid arthritis was conducted in 113 hospitalized patients. Rheumatoid arthritis was severe, classical (92 cases) or definite (21 cases), seropositive in 87 cases, with nodules in 32 cases; the mean duration of the disease was 10 years. The majority of patients had previously received numerous slow-acting drugs without result or with side-effects. A statistically significant decrease of all the quantitative indices but one (grip strength) was obtained with both products on the 8th day of treatment; the effect of placenta eluted IgG was statistically superior for the number of swollen joints (P less than 0.025), Ritchie's index (P less than 0.0005) and some extra-articular manifestations. There was no significant decrease in associated treatments and biological parameters (erythrocyte sedimentation rate, rheumatoid factor). Tolerance was excellent; some cases of benign venulitis were observed; treatment was never discontinued on account of side-effects. Further placebo-controlled of each of these immunoglobulins of placental origin are needed for firm conclusions to be drawn.


Effects of antihypertensive agents on sexual function.
Patient compliance with antihypertensive therapy can be improved by minimizing drug-induced sexual dysfunction. Impotence, decreased libido, impaired ejaculation and gynecomastia are potential side effects, depending on the agent prescribed. Centrally acting antihypertensive agents such as methyldopa and clonidine, nonselective beta-adrenergic blockers and potassium-sparing diuretics are the drugs most often associated with sexual dysfunction. Thiazide diuretics cause impotence but may otherwise play a minimal role in sexual dysfunction. Alpha-adrenergic blockers, angiotensin converting enzyme inhibitors and calcium channel blockers have little adverse effect on sexual function. It is important to obtain an adequate history before and after initiating therapy. If sexual dysfunction develops in a patient, a different class of medication can be tried.


Spatially addressable chemoselective C-terminal ligation of an intein fusion protein from a complex mixture to a hydrazine-terminated surface.
Protein immobilization on surfaces is useful in many areas of research, including biological characterization, antibody purification, and clinical diagnostics. A critical limitation in the development of protein microarrays and heterogeneous protein-based assays is the enormous amount of work and associated costs in the purification of proteins prior to their immobilization onto a surface. Methods to address this problem would simplify the development of interfacial diagnostics that use a protein as the recognition element. Herein, we describe an approach for the facile, site-specific immobilization of proteins on a surface without any preprocessing or sample purification steps that ligates an intein fusion protein at its C-terminus by reaction with a hydrazine group presented by a surface. Furthermore, we demonstrate that this methodology can directly immobilize a protein directly from cell lysate onto a protein-resistant surface. This methodology is also compatible with soft lithography and inkjet printing so that one or more proteins can be patterned on a surface without the need for purification.


Pan-phosphatidylinositol 3-kinase inhibition with buparlisib in patients with relapsed or refractory non-Hodgkin lymphoma.
Activation of the phosphatidylinositol 3-kinase/mechanistic target of rapamycin pathway plays a role in the pathogenesis of non-Hodgkin lymphoma. This multicenter, open-label phase 2 study evaluated buparlisib (BKM120), a pan-class I phosphatidylinositol 3-kinase inhibitor, in patients with relapsed or refractory non-Hodgkin lymphoma. Three separate cohorts of patients (with diffuse large B-cell lymphoma, mantle cell lymphoma, or follicular lymphoma) received buparlisib 100 mg once daily until progression, intolerance, or withdrawal of consent. The primary endpoint was overall response rate based on a 6-month best overall response by cohort; secondary endpoints included progression-free survival, duration of response, overall survival, safety, and tolerability. Overall, 72 patients (26 with diffuse large B-cell lymphoma, 22 with mantle cell lymphoma, and 24 with follicular lymphoma) were treated. The overall response rates were 11.5%, 22.7%, and 25.0% in patients with diffuse large B-cell lymphoma, mantle cell lymphoma, and follicular lymphoma, respectively; two patients (one each with diffuse large B-cell lymphoma and mantle cell lymphoma) achieved a complete response. The most frequently reported (>20%) adverse events of any grade in the population in which safety was studied were hyperglycemia, fatigue, and nausea (36.1% each), depression (29.2%), diarrhea (27.8%), and anxiety (25.0%). The most common grade 3/4 adverse events included hyperglycemia (11.1%) and neutropenia (5.6%). Buparlisib showed activity in relapsed or refractory non-Hodgkin lymphoma, with disease stabilization and sustained tumor burden reduction in some patients, and acceptable toxicity. Development of mechanism-based combination regimens with buparlisib is warranted. (This study was funded by Novartis Pharmaceuticals Corporation and registered with ClinicalTrials.gov number, NCT01693614).


New developments in the discovery of agents to treat hepatitis C.
Hepatitis C virus (HCV) has deceived researchers for seventeen years now and although the current therapy regimen has been optimized by the development of pegylated interferon-alpha and the addition of ribavirin, no new agent to treat HCV infected patients has yet reached the market. A new era is approaching the HCV research due to new developments for the propagation of the virus in a cell-based system, which may lead to new drug innovations. Efforts in the search of new treatments for HCV infected patients are either focused on direct antiviral drugs, targeting the structural components or enzymes encoded by the virus, or indirect antiviral drugs, targeting host cell components (immunomodulators etc.). An inspection of the drug pipeline for HCV reveals representatives from both classes and of different mechanisms of action. Among the direct acting antiviral agents, inhibitors of the NS3 protease, the NS5B polymerase, and the viral RNA are the most intensively explored. However, there is also on-going and promising preclinical research, in different stages, on other potential targets as the structural protein E2 (for cell-entry inhibitors), the NS3 helicase, the p7 ion-channel, and the multifunctional NS5A protein. The combat of HCV will certainly require a combination of drugs of different mechanisms in order to reduce the emergence of resistance. The latest developments in the discovery of agents to treat HCV are reviewed, with special focus on direct small-molecule antiviral drugs, from a medicinal chemistry perspective.


Randomized Phase III Trial Evaluating Spartalizumab Plus Dabrafenib and Trametinib for BRAF V600-Mutant Unresectable or Metastatic Melanoma.
Preclinical data suggest the combination of an anti-programmed death receptor 1 antibody plus dabrafenib and trametinib to have superior antitumor activity compared with dabrafenib plus trametinib alone. These observations are supported by translational evidence suggesting that immune checkpoint inhibitors plus targeted therapy may improve treatment outcomes in patients with BRAF V600-mutant metastatic melanoma. COMBI-i is a phase III trial evaluating spartalizumab, an anti-programmed death receptor 1 antibody, in combination with dabrafenib and trametinib (sparta-DabTram), versus placebo plus dabrafenib and trametinib (placebo-DabTram) in patients with BRAF V600-mutant unresectable or metastatic melanoma. Patients received spartalizumab 400 mg intravenously every 4 weeks plus dabrafenib 150 mg orally twice daily and trametinib 2 mg orally once daily or placebo-DabTram. Participants were age ≥ 18 years with unresectable or metastatic BRAF V600-mutant melanoma. The primary end point was investigator-assessed progression-free survival. Overall survival was a key secondary end point (ClinicalTrials.gov identifier: NCT02967692). At data cutoff (July 1, 2020), the median progression-free survival was 16.2 months (95% CI, 12.7 to 23.9 months) in the sparta-DabTram arm versus 12.0 months (95% CI, 10.2 to 15.4 months) in the placebo-DabTram arm (hazard ratio, 0.82 [95% CI, 0.66 to 1.03]; P = .042 [one-sided; nonsignificant]). The objective response rates were 69% (183 of 267 patients) versus 64% (170 of 265 patients), respectively. Grade ≥ 3 treatment-related adverse events occurred in 55% (146 of 267) of patients in the sparta-DabTram arm and 33% (88 of 264) in the placebo-DabTram arm. The study did not meet its primary end point; broad first-line use of sparta-DabTram is not supported by these results. Further biomarker-driven investigation may identify patient subpopulations who could benefit from checkpoint inhibitor plus targeted therapy combinations.


The clinical epidemiology, management, and outcomes of patients diagnosed with encephalitis in North Carolina, 2015-2020.
Despite the relatively high mortality and the difficulty in diagnosis, nearly one-third of patients hospitalized with a documented diagnosis of encephalitis did not undergo a lumbar puncture (LP). When an LP was performed, pathogen-specific testing was greatly underutilized. Infectious etiologies were most common, but over 40% of cases were idiopathic at discharge. These findings suggest that there is a substantial opportunity to improve the quality of care through more accurate and timely diagnosis.


Serum big endothelin-1 levels in female patients with breast cancer.
Endothelin-1[ET-1] acts as a growth factor in various malignancies. Big endothelin-1 (big ET-1) is the precursor of ET-1. The aim of this study was to determine the importance of serum big ET-1 levels as a novel marker of disease in female patients with breast cancer of various clinical stages. The study consisted of 75 female patients with breast cancer who were diagnosed and treated at the Gazi University Department of Medical Oncology and 20 controls. The patients were classified as follows: group A [n=26], patients with newly diagnosed primary breast cancer but without metastasis; group B [n=33], patients with metastatic breast cancer who had undergone treatment for their diseases and in whom metastasis was detected during follow-up; group C [n=16], off-therapy patients whose cancer had been in remission for at least 5 years; and group D [n=20] healthy controls. Serum big ET-1 level were measured with an enzyme immunoassay kit. The median serum big ET-1 levels of the 75 patients with breast cancer [10.96+/-1.36 ng/ml] were statistically significantly higher than those of controls [8.97+/-1.55 ng/ml]. The median serum big ET-1 levels of the patients with primary breast cancer patients [group A] were statistically significantly different from those in the controls, the off-therapy patients and the patients with metastatic disease [11.56+/-0.78 ng/ml, 8.97+/-1.55 ng/ml, 9.76+/-1.52 ng/ml, and 10.83+/-1.18 ng/ml respectively, P=.001]. There was no statistically significant difference in the serum big ET-1 levels of patients in group A in terms of tumor stage, hormone receptor status or lymph node status. Serum big ET-1 levels were statistically significantly higher in patients with metastatic disease than in controls or off-therapy patients (P=.001). The serum big ET-1 levels of off-therapy patients whose disease was in remission were not statistically significantly different from those in controls (P>.05). Serum big ET-1 levels seemed to represent the activation of ET-1 in female patients with breast cancer. Serum big ET- 1 levels can be an indicator of the breast cancer. Further studies are needed to demonstrate the prognostic importance of serum big ET-1 in patients with breast cancer.


Lymphoid hyperplasia, CD45RBhigh to CD45RBlow T-cell imbalance, and suppression of Type I diabetes mellitus result from TNF blockade in NOD-->NOD-scid adoptive T cell transfer.
Sustained antibody-mediated inhibition of tumor necrosis factor (TNF) activity offers protection against Type I (insulin-dependent) diabetes mellitus in non-obese diabetic (NOD) mice. The mechanism of this effect, however, has remained obscure: TNFalpha might be required for the development of specific immune responses to islet antigens or it could directly participate in destruction of beta cells. In this study, autoimmune destruction of beta cells was initiated in NOD-severe combined immunodeficient (scid) mice by transfer of NOD splenic T-cells to induce diabetes. The blockade of TNFalpha activity was achieved during a narrow window of time after transfer. Transient inhibition of TNFalpha greatly reduced the number of islet lymphocytes and the incidence of diabetes in recipients of prediabetic NOD spleen cells. Protection extended beyond the interval of effective TNF blockade. Furthermore, the protective effect was only observed if cells were obtained from 6-week-old donors. The suppression of autoimmunity was reversible in the context of adoptive transfer as indicated by the transfer of splenocytes from the primary recipient to a second NOD-scid host led to a diabetic outcome. The blockade of TNFalpha was accompanied by a considerable increase in spleen size and doubling of the total splenocyte count, suggesting that TNFalpha might normally eliminate a transplanted T-cell subset within the recipients. Further analysis showed an increase in the absolute count of CD4 + T cells and pronounced distortion of the CD45RBhigh to CD45RBlow ratio, with a relative augmentation in the CD45RBlow count in the spleen. TNFalpha appears to regulate the number and subtype distribution of a transplanted T cell population.


The effects of metal plates on post-traumatic remodelling and bone mass.
The long-term effect of stainless steel and titanium alloy plates on structural remodelling and bone mass of osteotomised canine femora was studied and the effects of early and late removal of plates were compared in 27 adult Beagles. Radiological, histological, histomorphometric and tetracycline fluorescence studies led to three conclusions. First, the continuous (60 weeks) presence of plates, irrespective of their composition, delays remodelling and leads to a reduction of bone mass. This loss is significantly greater under stainless steel plates. Secondly, the removal of plates at eight weeks leads during the 52 ensuing weeks to a marked and widespread structural remodelling and to a return to normal bone mass, irrespective of the type of plate used. However, remodelling is more intense after titanium alloy plates have been used; it is not complete 60 weeks after osteotomy. Thirdly, removal of plates at 40 weeks activates remodelling during the ensuing 20 weeks to a lesser degree and to a more limited extent than early plate removal. The clinical significance of this study is that less rigid but stable internal fixation permits the radiological assessment of healing and thus the determination of the optimal moment for removal of the plates. It also reduces the degree of bone loss should the plate be left in situ for any reason.


Cytostatic and apoptotic effects of DNMT and HDAC inhibitors in endometrial cancer cells.
DNA methyltransferase (DNMT) and histone deacetylase are key enzymes mediating the epigenetic regulation of gene expression. DNA hypermethylation and/or histone deacetylation in promoter regions is often associated with downregulation or silencing of transcription. Epigenetic silencing of tumor suppressor genes plays an important role in malignant transformation. DNMT and HDAC inhibitors induce DNA demethylation and histone acetylation, respectively, leading to reactivation of silenced genes, and dramatic morphological and functional changes in cancer cells. In this study, we have conducted a series of experiments to characterize the effects of epigenetic inhibitors in endometrial cancer cells. Using cell lines representing different stages of endometrioid cancers, we examined the impact of DNMT inhibitor, ADC, and HDAC inhibitor, TSA, on cell cycle and apoptosis. We found that while both reagents were capable of inhibiting cell proliferation and inducing cell apoptosis, TSA appeared to be a more potent apoptosis inducer, but with a smaller effect on cell cycle. On the other hand, ADC exhibited strong effects on cell cycle regulation, but had smaller impact on cell apoptosis. We subsequently confirmed the presence of a strong synergism between DNMT and HDAC inhibitors. Thus, ADC and TSA exhibited strong cytostatic and apoptotic effects in endometrial cancer cell lines and the combined application may deliver the highest response in the clinical setting.


Free Energy Diagram for the Heterogeneous Enzymatic Hydrolysis of Glycosidic Bonds in Cellulose.
Kinetic and thermodynamic data have been analyzed according to transition state theory and a simplified reaction scheme for the enzymatic hydrolysis of insoluble cellulose. For the cellobiohydrolase Cel7A from Hypocrea jecorina (Trichoderma reesei), we were able to measure or collect relevant values for all stable and activated complexes defined by the reaction scheme and hence propose a free energy diagram for the full heterogeneous process. For other Cel7A enzymes, including variants with and without carbohydrate binding module (CBM), we obtained activation parameters for the association and dissociation of the enzyme-substrate complex. The results showed that the kinetics of enzyme-substrate association (i.e. formation of the Michaelis complex) was almost entirely entropy-controlled and that the activation entropy corresponded approximately to the loss of translational and rotational degrees of freedom of the dissolved enzyme. This implied that the transition state occurred early in the path where the enzyme has lost these degrees of freedom but not yet established extensive contact interactions in the binding tunnel. For dissociation, a similar analysis suggested that the transition state was late in the path where most enzyme-substrate contacts were broken. Activation enthalpies revealed that the rate of dissociation was far more temperature-sensitive than the rates of both association and the inner catalytic cycle. Comparisons of one- and two-domain variants showed that the CBM had no influence on the transition state for association but increased the free energy barrier for dissociation. Hence, the CBM appeared to promote the stability of the complex by delaying dissociation rather than accelerating association.


The health of the Roma people: a review of the published literature.
The Roma people originated in northern India and have been known in Europe for nearly a thousand years. For much of that time they have been the subjects of discrimination and oppression, culminating in the extermination of half a million Roma in the Nazi death camps. While it is widely believed that the health of Roma people is often poorer than the majority population, these inequalities remain largely unresearched. Published literature on the health of the Roma people was identified using Medline. Opinion pieces were excluded, as were papers relating to anthropometry and to genetic markers. The resultant papers were analysed by country of study and by disease type or care group. Some 70% of papers identified related to just three countries; Spain and the Czech and Slovak Republics. Much literature concentrates upon communicable disease or reproductive health. The limited evidence suggests increased morbidity from non-communicable disease, but there is little published on this topic. Evidence on health care, though fragmentary, suggests poorer access to health services and uptake of preventative care. Published research on the health needs of the Roma population is sparse. The topics that have received attention suggest a focus on concepts of contagion or social Darwinism, indicating a greater concern with the health needs of the majority populations with which they live. There is a need for both further research into the health of Roma people; with particular emphasis on non-communicable disease; and also for interventions that improve Roma health. Such research must, however, be handled with sensitivity, recognising the social and political context of the society concerned.


Inter-rater reliability of streetscape audits using online observations: Microscale Audit of Pedestrian Streetscapes (MAPS) global in Japan.
This study aimed to evaluate the inter-rater reliability of streetscape audits among online observations using the Microscale Audit of Pedestrian Streetscapes-Global version (MAPS-Global) in Japan. MAPS-Global observations were conducted on routes with distances ranging from 400 to 725 m from a residence toward a non-residential destination. Google Street View audits were independently conducted by two trained raters on each route. A tiered scoring system was applied to summarize the items at multiple levels of aggregation. Positive and negative valence scores were created based on the expected association with physical activity. Inter-rater reliability analyses were performed using kappa statistics or intraclass correlation coefficients (ICC). Of the 32 older adults participating in an intervention study in the community-wide physical activity promotion project in Fujisawa City, 19 addresses were used, excluding those with nearby addresses. Results demonstrated "excellent" agreement for most of the summary scores analyzed (kappa or ICC values of 0.75 or higher [80.4 %]), while 6.5 % of items exhibited "good" agreement (ICC = 0.60-0.74). By contrast, only 13.0 % of the scales had ICC values lower than 0.60 ("fair" or "poor" reliability). The results illustrated high reliability for the grand summary scores and composite subscale measures. However, caution should be exercised when interpreting subscale scores for less frequently observed negative attributes and aesthetic/social characteristics. The results presented in this study support the application of online observations using MAPS-Global in urban areas of Japan, which could be implemented to inform decisions related not only to physical activity but also to traffic safety.


Protection of glucagon-like peptide-1 in cisplatin-induced renal injury elucidates gut-kidney connection.
Accumulating evidence of the beyond-glucose lowering effects of a gut-released hormone, glucagon-like peptide-1 (GLP-1), has been reported in the context of remote organ connections of the cardiovascular system. Specifically, GLP-1 appears to prevent apoptosis, and inhibition of dipeptidyl peptidase-4 (DPP-4), which cleaves GLP-1, is renoprotective in rodent ischemia-reperfusion injury models. Whether this renoprotection involves enhanced GLP-1 signaling is unclear, however, because DPP-4 cleaves other molecules as well. Thus, we investigated whether modulation of GLP-1 signaling attenuates cisplatin (CP)-induced AKI. Mice injected with 15 mg/kg CP had increased BUN and serum creatinine and CP caused remarkable pathologic renal injury, including tubular necrosis. Apoptosis was also detected in the tubular epithelial cells of CP-treated mice using immunoassays for single-stranded DNA and activated caspase-3. Treatment with a DPP-4 inhibitor, alogliptin (AG), significantly reduced CP-induced renal injury and reduced the renal mRNA expression ratios of Bax/Bcl-2 and Bim/Bcl-2. AG treatment increased the blood levels of GLP-1, but reversed the CP-induced increase in the levels of other DPP-4 substrates such as stromal cell-derived factor-1 and neuropeptide Y. Furthermore, the GLP-1 receptor agonist exendin-4 reduced CP-induced renal injury and apoptosis, and suppression of renal GLP-1 receptor expression in vivo by small interfering RNA reversed the renoprotective effects of AG. These data suggest that enhancing GLP-1 signaling ameliorates CP-induced AKI via antiapoptotic effects and that this gut-kidney axis could be a new therapeutic target in AKI.


Phase Transitions in Spatial Connectivity during Influenza Pandemics.
We investigated phase transitions in spatial connectivity during influenza pandemics, relating epidemic thresholds to the formation of clusters defined in terms of average infection. We employed a large-scale agent-based model of influenza spread at a national level: the Australian Census-based Epidemic Model (AceMod). In using the AceMod simulation framework, which leverages the 2016 Australian census data and generates a surrogate population of ≈23.4 million agents, we analysed the spread of simulated epidemics across geographical regions defined according to the Australian Statistical Geography Standard. We considered adjacent geographic regions with above average prevalence to be connected, and the resultant spatial connectivity was then analysed at specific time points of the epidemic. Specifically, we focused on the times when the epidemic prevalence peaks, either nationally (first wave) or at a community level (second wave). Using the percolation theory, we quantified the connectivity and identified critical regimes corresponding to abrupt changes in patterns of the spatial distribution of infection. The analysis of criticality is confirmed by computing Fisher Information in a model-independent way. The results suggest that the post-critical phase is characterised by different spatial patterns of infection developed during the first or second waves (distinguishing urban and rural epidemic peaks).


Chronic depolarization enhances the trophic effects of brain-derived neurotrophic factor in rescuing auditory neurons following a sensorineural hearing loss.
The development and maintenance of spiral ganglion neurons (SGNs) appears to be supported by both neural activity and neurotrophins. Removal of this support leads to their gradual degeneration. Here, we examined whether the exogenous delivery of the neurotrophin brain-derived neurotrophic factor (BDNF) in concert with electrical stimulation (ES) provides a greater protective effect than delivery of BDNF alone in vivo. The left cochlea of profoundly deafened guinea pigs was implanted with an electrode array and drug-delivery system. BDNF or artificial perilymph (AP) was delivered continuously for 28 days. ES induced neural activity in two cohorts (BDNF/ES and AP/ES), and control animals received BDNF or AP without ES (BDNF/- and AP/-). The right cochleae of the animals served as deafened untreated controls. Electrically evoked auditory brainstem responses (EABRs) were recorded immediately following surgery and at completion of the drug-delivery period. AP/ES and AP/- cohorts showed an increase in EABR threshold over the implantation period, whereas both BDNF cohorts exhibited a reduction in threshold (P < 0.001, t-test). Changes in neural sensitivity were complemented by significant differences in both SGN survival and soma area. BDNF cohorts demonstrated a significant trophic or survival advantage and larger soma area compared with AP-treated and deafened control cochleae; this advantage was greatest in the base of the cochlea. ES significantly enhanced the survival effects of BDNF throughout the majority of the cochlea (P < 0.05, Bonferroni's t-test), although there was no evidence of trophic support provided by ES alone. Cotreatment of SGNs with BDNF and ES provides a substantial functional and trophic advantage; this treatment may have important implications for neural prostheses.


Endoplasmic reticulum overcrowding as a mechanism of beta-cell dysfunction in diabetes.
This study suggests a molecular mechanism that explains the accumulation of denaturated proinsulin in the endoplasmic reticulum (ER) of beta-cells. Such states were frequently observed in beta-cells experiencing increased demand for insulin production and were shown to lead to secretory dysfunction and diabetes. Here, a self-consistent kinetic model is used to investigate changes in protein translation due to ER overloading. The model is based on a molecular theory that relates the molecular composition and level of molecular crowding in the ER to the kinetic rates of protein folding/misfolding and transit to the Golgi apparatus (GA). This study suggests that molecular crowding forces can increase protein misfolding and impair the transport to the GA, thus overwhelming the quality control mechanism in the ER. A continual accumulation of toxic residues in the ER enhances even further the molecular crowding, accelerating protein denaturation. This article shows that molecular crowding affects differently the transit of various proteins through the ER. Apparently, the molecular crowding level that can inhibit the transport of native proinsulin to the GA influences to a lesser extent the transit of proamylin, a much smaller peptide cosynthesized with proinsulin in the ER. Smaller-volume misfolded proinsulin species may also win the passage competition through the ER and move on the secretory track. However, misfolded proinsulin fails the conversion to active insulin. This study can help us to decipher circumstances leading to the alteration of the secretory function in susceptible beta-cells and the onset of diabetes.


The Earth's Angular Momentum Budget on Subseasonal Time Scales.
Irregular length of day (LOD) fluctuations on time scales of less than a few years are largely produced by atmospheric torques on the underlying planet. Significant coherence is found between the respective time series of LOD and atmospheric angular momentum (AAM) determinations at periods down to 8 days, with lack of coherence at shorter periods caused by the declining signal-to-measurement noise ratios of both data types. Refinements to the currently accepted model of tidal Earth rotation variations are required, incorporating in particular the nonequilibrium effect of the oceans. The remaining discrepancies between LOD and AAM in the 100- to 10-day period range may be due to either a common error in the AAM data sets from different meteorological centers, or another component of the angular momentum budget.


Funicular trajectories of brainstem neurons projecting to the lumbar spinal cord in the monkey (Macaca fascicularis): a retrograde labeling study.
Brainstem nuclei projecting to the lumbar spinal cord in the monkey were identified by using horseradish peroxidase and the fluorescent dye granular blue. These retrogradely transported tracers were used in fluid and/or gel forms to determine the funicular trajectories of the brainstem-spinal projections. The major descending components of the dorsal funiculus arose from the n. gracilis, n. cuneatus, and the n. of the solitary tract. Major components of the dorsolateral funiculus (DLF) came from the raphe complex, medullary and pontine reticular formation, locus coeruleus, Edinger-Westphal n., and red n. Other nuclei giving rise to minor contributions to the DLF included n. gracilis, n. cuneatus, n. of the solitary tract, medial and spinal vestibular n., subcoeruleus, periaqueductal gray, interstitial n. of Cajal, n. of Darkschewitsch, and the anteromedian n. The major components of ventral cord paths (ventrolateral and ventral funiculi) arose from the raphe complex, the medullary and pontine reticular formation, lateral and spinal vestibular n., and the coerulean complex. Minor contributions to the ventral paths descended from the dorsal motor n. of X, n. of the solitary tract, medial vestibular n., paralemniscal reticular formation, dorsal parabrachial n., n. cuneiformis, periaqueductal gray, Kölliker-Fuse n., and red n. The possible functional implications of the funicular distribution of these descending pathways are discussed from the perspective of descending inhibition and pain modulation.


The cost efficiency and clinical quality of institutional long-term care for the elderly.
This study applied the stochastic frontier cost function with inefficiency effects to estimate the association between quality of care and cost efficiency in institutional long-term care wards for the elderly in Finland. We used several clinical quality indicators for indicating adverse care processes and outcomes, based on the Resident Assessment Instrument (RAI)/Minimum Data Set (MDS). Average cost inefficiency among the wards was 22%. We found an association between the clinical quality indicators and cost inefficiency. Higher prevalence of pressure ulcers was associated with higher costs, whereas the higher prevalence of use of depressants and hypnotics increased inefficiency.


X-rays from Sources 3C 273 and M 87.
An x-ray survey of the Virgo region revealed signals from the directions of 3C 273 and M 87. Three other x-ray sources appear in the region scanned, but do not fit any known radio sources. The x-ray flux (1 to 10 angstroms) from the direction of 3C 273 is about 1000 times weaker than from the strongest x-ray source, Sco XR-1. If the source is located at the cosmological distance of 500 megaparsecs, the x-ray luminosity is 7.3 x 10(45) ergs per second. The x-ray luminosity of M87 is 1.5 x 10(43) ergs per second.


Improvement of biochemical parameters in type 1 diabetic rats after the roots aqueous extract of yacon [Smallanthus sonchifolius (Poepp.& Endl.)] treatment.
The aim of this study was to evaluate the effect of yacon (Smallanthus sonchifolius) (Poepp.& Endl.) on clinical parameters under diabetic conditions. The aqueous extract of yacon tuberous roots (YRAE; 0.76 g fructan kg⁻¹ body weight) was prepared at the moment of each administration. Thirty-two male rats were divided into four groups (n=8): control group (C); group that received YRAE (Y); untreated diabetic group (DM1); and diabetic group treated with YRAE (Y-DM1). The diabetes mellitus was induced by streptozotocin (60 mg kg⁻¹ body weight). The animals from Y2 and Y-DM1 received YRAE by gavage, at 7-day intervals, for 30 days. The aqueous extract of yacon roots decreased (p<0.05) the water and food intake in diabetic rats (Y-DM1). YRAE treatment reduced (p<0.05) glycaemia, total cholesterol, VLDL-c, LDL-c and triacylglycerol levels in diabetic rats (YRAE). HDL, urea and creatinine levels did not differ (p>0.05) between the Y and Y-DM1 groups. YRAE normalised alanine aminotransferase (ALT) activity, when comparing DM1 and Y-DM1 rats, but had no effect on lactate dehydrogenase activity (LDH). In conclusion, YRAE was sufficient for controlling water and food consumption, hyperglycaemia and dyslipidaemia, and promote the reduction of the ALT, suggesting a hepatoprotective effect in rats with STZ-induced DM1.


Erythrocyte rheological properties but not whole blood and plasma viscosity are associated with severity of hypertension in older people.
This study was carried out to determine whether changes in hemorheological parameters parallel the severity of essential hypertension. A total of 198 older hypertensive patients were recruited and classified into 3 stages of hypertension according to the grading standard of hypertension. The whole blood viscosity (WBV) at various shear rates, plasma viscosity and erythrocyte rheology (including erythrocyte rigidity index, erythrocyte aggregation index and erythrocyte deformation index) were examined. Erythrocyte rheology paralleled the severity of essential hypertension and was significantly correlated to the average 24 h systolic blood pressure and diastolic blood pressure. Logistic analysis revealed that erythrocyte rigidity and the erythrocyte aggregation index were positively correlated with the severity of hypertension, while the erythrocyte deformation index was negatively correlated. No association was found between WBV, plasma viscosity and the severity of hypertension. The rheological properties of erythrocyte viscosity were correlated with the severity of hypertension in older people but the WBV and plasma viscosity were not.


Analysis of modes and behavior of a multiconjugate adaptive optics system.
We study the so-called three-dimensional mapping of turbulence, a method solving the cone effect (or focus anisoplanatism) by using multiple laser guide stars (LGSs). This method also permits a widening of the corrected field of view much beyond the isoplanatic field. Multiple deformable mirrors, conjugated to planes at chosen altitudes among the turbulent layers, are used to correct in real time the wave fronts measured from the LGSs. We construct an interaction matrix describing the multiconjugate adaptive optics system and analyze the eigenmodes of the system. We show that the global tilt mode is singular because it cannot be localized in altitude, so that it must be corrected only once at any altitude. Furthermore, when the tilt from the LGS cannot be measured, the singularity of the global tilt yields the delocalization of particular forms of defocus and astigmatism. This imposes the use of a single natural guide star located anywhere in the corrected field to measure these modes. We show as an example that the cone effect can be corrected with a Strehl of 0.8 with four LGSs (tilt ignored) on an 8-m telescope in the visible when a single laser star provides a Strehl of 0.1. The maximum field of view of 100 arc sec in diameter can be reconstructed with an on-axis Strehl ratio of 30%. We also show that the measurement of the height of the layers can be done with current techniques and that additional layers, not accounted for, do not significantly degrade the performance in the configuration that we model.


[Effect of the mycotoxin zearalenone on the metabolism of membrane phospholipids of rat lymphocytes].
The data obtained have shown that a single intravenous administration of 1 ml of mycotoxin zearalenon alcohol solution (15 mg/ml) to rats leads to the formation of pronounced abnormalities in lymphocyte membranes phospholipid (PL) metabolism. These changes are conditioned by activation of phospholipase A2, which catalyses the deacylation of PL-glycerides predominantly phosphatidylcholines with the formation of high concentrations of lysophosphatidylcholines. On the other hand, intensification of deacylation processes of PL, which accompanied by the liberation of high quantities of unsaturated fatty acids leads to the active incorporation of its into the processes of lipids free radical peroxidation with the formation of significant quantities of lipid peroxides. Intraperitoneal administration of 1 ml 10% sol of sodium thiosulfate no later then 1-2 h after zearalenon toxic action leads to the normalization of disorders observed.


Improved surface imprinting based on a simplified mass-transfer process for the selective extraction of IgG.
We wished to improve the unsatisfactory adsorption and elution efficiencies in conventional magnetic molecular imprinting technology. In this work, a reliable strategy to prepare magnetic molecularly imprinted nanoparticles (MMINs) with rapid rebinding and elution speed was introduced. To decrease the mass-transfer retention of the templates, glycoprotein immunoglobulin (Ig)G was pre-immobilized to form homogeneous and monostratified three-dimensionally imprinted cavities on the surface of magnetic carriers. To shorten the transfer route of the templates, the polymerizaiton process was controlled precisely to form well-defined molecularly imprinted polymer (MIP) films of thickness 12 nm. In this way, the effectiveness of the mass transfer of the templates was maximized, and the length of the transfer route was minimized. As a result, the prepared MMINs showed improved adsorption and elution efficiencies compared with the conventional magnetic molecularly imprinted polymers (MMIPs), and exhibited great selectivity towards the templates.


Formation of lipid sheaths around nanoparticle-supported lipid bilayers.
High-surface-area nanoparticles often cluster, with unknown effects on their cellular uptake and environmental impact. In the presence of vesicles or cell membranes, lipid adsorption can occur on the nanoparticles, resulting in the formation of supported lipid bilayers (SLBs), which tend to resist cellular uptake. When the amount of lipid available is in excess compared with that required to form a single-SLB, large aggregates of SLBs enclosed by a close-fitting lipid bilayer sheath are shown to form. The proposed mechanism for this process is one where small unilamellar vesicles (SUVs) adsorb to aggregates of SLBs just above the gel-to-liquid phase transition temperature, T(m) , of the lipids (as observed by dynamic light scattering), and then fuse with each other (rather than to the underlying SLBs) upon cooling below T(m) . The sacks of SLB nanoparticles that are formed are encapsulated by the contiguous close-fitting lipid sheath, and precipitate below T(m) , due to reduced hydration repulsion and the absence of undulation/protrusion forces for the lipids attached to the solid support. The single-SLBs can be released above T(m) , where these forces are restored by the free lipid vesicles. This mechanism may be useful for encapsulation/release of drugs/DNA, and has implications for the toxic effects of nanoparticles, which may be mitigated by lipid sequestration.


Pharmacogenetics of the DNA repair pathways in advanced non-small cell lung cancer patients treated with platinum-based chemotherapy.
Genetic variants in DNA repair genes may play a role in the effectiveness of platinum-based chemotherapy in non-small cell lung cancer (NSCLC). We analyzed 17 SNPs in eight genes (ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, XPA, XRCC1 and XRCC2) involved in DNA repair mechanisms and its association with outcome in NSCLC. This prospective study included patients with stages III and IV treated with platinum-based chemotherapy. All patients (n = 161) received cisplatin or carboplatin plus a third-generation drug. Additionally, stage IIIA and IIIB patients (n = 74) received concomitant or sequential radiotherapy. Germline polymorphisms were analyzed using the BioMark system in blood DNA samples. We found that in stage III patients, response was significantly associated with SNPs in ERCC1 and in ERCC3 genes, while radiotherapy-derived toxicity correlated with SNPs in the ERCC2 gene. In stage IV patients, response was associated with a genetic variant in the ERCC4 gene and survival with a SNP in the XRCC1 gene. The complexity of the DNA repair mechanisms along with the heterogeneity in the treatment of lung cancer could explain the role of multiple genes as putative biomarkers of patient outcome.


The contextual interference effect and sport skills.
During the last twenty-five years, the contextual interference effect has been thoroughly studied. This review finds that the effect is relatively robust in basic research, but considerably weaker in applied settings. Motor learning scholars have urged practitioners to develop instructional strategies based upon the inferences of the contextual interference effect. The smaller effects seem to indicate that the concept may have more limited use for the physical educator. It appears that the generalization of procedures from other domains may not adequately accommodate the complexity of motor skills. Manipulating the task difficulty, both nominal and functional, and the contextual continuum may be a promising route for the practitioner.


Cost-effectiveness of angiotensin-converting enzyme inhibitors in nondiabetic advanced renal disease.
National and international clinical guidelines do not consistently recommend treating nondiabetic proteinuric patients with advanced renal disease with an angiotensin-converting enzyme (ACE) inhibitor. To determine the cost-effectiveness of ACE inhibitor therapy in nondiabetic proteinuric patients with advanced renal disease in Germany. Two strategies were compared: treating patients with advanced renal disease with an ACE inhibitor and no ACE inhibitor treatment. A lifetime Markov decision model was developed using published data on costs and health outcomes and simulated the progression of renal disease with costs and benefits discounted at 3%. A statutory health insurance perspective was adopted. In the base-case analysis, ACE inhibitor treatment is associated with lower costs and higher benefit and therefore dominates the no-treatment strategy. A probabilistic sensitivity analysis demonstrates that the probability of savings is 80%. ACE inhibitor treatment for nondiabetic patients with advanced renal disease is highly cost effective.


Phase variation and the Hin protein: in vivo activity measurements, protein overproduction, and purification.
The alternate expression of the Salmonella flagellin genes H1 and H2 is controlled by the orientation of a 995-base-pair invertible segment of DNA located at the 5' end of the H2 gene. The hin gene, which is encoded within the invertible region, is essential for the inversion of this DNA segment. We cloned the hin gene into Escherichia coli and placed it under the control of the PL promoter of bacteriophage lambda. These cells overproduced the Hin protein. In vivo inversion activity was measured by using a recombinant lambda phage which contains the H2 and lacZ genes under the control of the invertible region. Using this phage, we showed that the amount of inversion activity is proportional to the amount of Hin protein in the cell. An inactive form of the protein was purified by using the unusual solubility properties of the overproduced protein. The amino acid composition of the protein agreed with the DNA sequence of the hin gene. Antibodies were made to the isolated protein. These antibodies cross-reacted with two other unidentified E. coli proteins.


(5S,11aS)-5-Hydro-per-oxy-1,5,11,11a-tetra-hydro-[1]benzothieno[3,2-f]indol-izin-3(2H)-one.
The absolute configuration of the title compound, C14H13NO3S, was assigned from the synthesis and confirmed by the structure determination. The central six-membered ring of the indolizine moiety adopts an envelope conformation, with the greatest deviation from the mean plane of the ring being 0.661 (2) Å for the bridgehead C atom. The benzothiene ring attached to the indolizine ring system is planar to within 0.008 (2) Å. In the crystal, mol-ecules form chains parallel to the b axis via O-H⋯O hydrogen bonds.


Genome-wide mapping of Myc binding and gene regulation in serum-stimulated fibroblasts.
The transition from quiescence to proliferation is a key regulatory step that can be induced by serum stimulation in cultured fibroblasts. The transcription factor Myc is directly induced by serum mitogens and drives a secondary gene expression program that remains largely unknown. Using mRNA profiling, we identify close to 300 Myc-dependent serum response (MDSR) genes, which are induced by serum in a Myc-dependent manner in mouse fibroblasts. Mapping of genomic Myc-binding sites by ChIP-seq technology revealed that most MDSR genes were directly targeted by Myc, but represented a minor fraction (5.5%) of all Myc-bound promoters (which were 22.4% of all promoters). Other target loci were either induced by serum in a Myc-independent manner, were not significantly regulated or were negatively regulated. MDSR gene products were involved in a variety of processes, including nucleotide biosynthesis, ribosome biogenesis, DNA replication and RNA control. Of the 29 MDSR genes targeted by RNA interference, three showed a requirement for cell-cycle entry upon serum stimulation and 11 for long-term proliferation and/or survival. Hence, proper coordination of key regulatory and biosynthetic pathways following mitogenic stimulation relies upon the concerted regulation of multiple Myc-dependent genes.


[Staged repair for bilateral ductus arteriosus with pulmonary atresia and non-confluent pulmonary artery--a case report].
Staged operation was successfully performed in an infant with bilateral ductus arteriosus, and absence pulmonary artery. The first stage operation was performed at 2 months old of age. The left pulmonary artery was reconstructed using an equine pericardial roll sized 10 mm in diameter, and a 5 mm Dacron graft was anastomosed between the left subclavian artery and the roll as an aortopulmonary shunt. In the second stage, the same procedure was done on the right side at eight months of age. In the last stage, the patient underwent Rastelli procedure at 2 years old of age. The central pulmonary artery was created with a ring forced EPTFE graft above the ascending aorta, and a Carpentier-Edwards valved conduit (14 mm) was anastomosed between the right ventricle and the EPTFE graft. Post operative course was uneventful. We consider that the staged procedure including the pulmonary artery reconstruction and the aortopulmonary shunt on both sides is recommended in the case of absent central pulmonary artery in infant.


Antioxidants and antioxidant activity of several pigmented rice brans.
This study investigated the antioxidant content and activity of phenolic acids, anthocyanins, α-tocopherol and γ-oryzanol in pigmented rice (black and red rice) brans. After methanolic extraction, the DPPH free radical scavenging activity and antioxidant activity were measured. The pigmented rice bran extract had a greater reducing power than a normal rice bran extract from a long grain white rice. All bran extracts were highly effective in inhibiting linoleic acid peroxidation (60-85%). High-performance liquid chromatography (HPLC) analysis of antioxidants in rice bran found that γ-oryzanol (39-63%) and phenolic acids (33-43%) were the major antioxidants in all bran samples, and black rice bran also contained anthocyanins 18-26%. HPLC analysis of anthocyanins showed that pigmented bran was rich in cyanidin-3-glucoside (58-95%). Ferulic acid was the dominant phenolic acid in the rice bran samples. Black rice bran contained gallic, hydroxybenzoic, and protocatechuic acids in higher contents than red rice bran and normal rice bran. Furthermore, the addition of 5% black rice bran to wheat flour used for making bread produced a marked increase in the free radical scavenging and antioxidant activity compared to a control bread.


Exploratory Graph Analysis for Factor Retention: Simulation Results for Continuous and Binary Data.
Exploratory graph analysis (EGA) is a commonly applied technique intended to help social scientists discover latent variables. Yet, the results can be influenced by the methodological decisions the researcher makes along the way. In this article, we focus on the choice regarding the number of factors to retain: We compare the performance of the recently developed EGA with various traditional factor retention criteria. We use both continuous and binary data, as evidence regarding the accuracy of such criteria in the latter case is scarce. Simulation results, based on scenarios resulting from varying sample size, communalities from major factors, interfactor correlations, skewness, and correlation measure, show that EGA outperforms the traditional factor retention criteria considered in most cases in terms of bias and accuracy. In addition, we show that factor retention decisions for binary data are preferably made using Pearson, instead of tetrachoric, correlations, which is contradictory to popular belief.


Can Emotional and Behavioral Dysregulation in Youth Be Decoded from Functional Neuroimaging?
High comorbidity among pediatric disorders characterized by behavioral and emotional dysregulation poses problems for diagnosis and treatment, and suggests that these disorders may be better conceptualized as dimensions of abnormal behaviors. Furthermore, identifying neuroimaging biomarkers related to dimensional measures of behavior may provide targets to guide individualized treatment. We aimed to use functional neuroimaging and pattern regression techniques to determine whether patterns of brain activity could accurately decode individual-level severity on a dimensional scale measuring behavioural and emotional dysregulation at two different time points. A sample of fifty-seven youth (mean age: 14.5 years; 32 males) was selected from a multi-site study of youth with parent-reported behavioral and emotional dysregulation. Participants performed a block-design reward paradigm during functional Magnetic Resonance Imaging (fMRI). Pattern regression analyses consisted of Relevance Vector Regression (RVR) and two cross-validation strategies implemented in the Pattern Recognition for Neuroimaging toolbox (PRoNTo). Medication was treated as a binary confounding variable. Decoded and actual clinical scores were compared using Pearson's correlation coefficient (r) and mean squared error (MSE) to evaluate the models. Permutation test was applied to estimate significance levels. Relevance Vector Regression identified patterns of neural activity associated with symptoms of behavioral and emotional dysregulation at the initial study screen and close to the fMRI scanning session. The correlation and the mean squared error between actual and decoded symptoms were significant at the initial study screen and close to the fMRI scanning session. However, after controlling for potential medication effects, results remained significant only for decoding symptoms at the initial study screen. Neural regions with the highest contribution to the pattern regression model included cerebellum, sensory-motor and fronto-limbic areas. The combination of pattern regression models and neuroimaging can help to determine the severity of behavioral and emotional dysregulation in youth at different time points.


Grade II astrocytomas are subgrouped by chromosome aberrations.
Grade II astrocytoma is defined as a low-grade tumor, yet patients have a wide range of survival and tumors can quickly progress to high-grade astrocytoma/glioblastoma. Previous studies using comparative genomic hybridization (CGH) failed to demonstrate frequent copy number aberrations (CNA) in these tumors. This may be related to technical difficulties because infiltrating astrocytic tumors are often intermixed with normal brain tissue. We developed methods to exclude most normal tissue and use small amounts of DNA for CGH by microdissecting small regions of tumor from paraffin sections and amplifying extracted DNA using degenerate oligonucleotide-primed polymerase chain reaction (DOP-PCR). Using this method, we examined 30 grade II astrocytoma cases. We found CNA in 25 cases (83%), with a mean of two CNA per case. The most frequent CNA were gains on 7q (12 cases), 5p (5 cases), 9 (5 cases), and 19p (3 cases), and losses on 19q (7 cases), 1p (6 cases), and Xp (3 cases). Gain on 7q and losses on 1p/19q were mutually exclusive. This is the first report on the genetic characterization of low-grade astrocytomas using CGH from microdissected and formalin-fixed tissue. The comparatively large number of cases in this study allows us to suggest that these tumors are genetically subgrouped.


Two-photon excitation fluorescence bioassays.
Application of two-photon excitation of fluorescence in microscopy is one of the major discoveries of the "renaissance" of light microscopy that started in the 1980s. The technique derives its advantages from the biologically "smooth" wavelength of the excitation light and the confinement of the excitation. Difficult, and seemingly nontransparent, samples may be imaged with the technique with good resolution. Although the bioresearch has been concentrating mostly on the positive properties of the technique for imaging, the same properties may be applied successfully to nonimaging bioassays. This article focuses on the development path of two-photon excitation-based assay system.


Subcritical Water Extracts from Agaricus blazei Murrill's Mycelium Inhibit the Expression of Immune Checkpoint Molecules and Axl Receptor.
Agaricus blazei Murrill or Himematsutake is an edible and medicinal mushroom. Agaricus blazei Murrill's fruiting body extracts have anticancer properties, although the mechanism is unknown. Basic or organic solvents, which are hazardous for human health, are generally used to prepare Agaricus blazei Murrill's extracts. The inhibition of immune checkpoint molecules and Axl receptor is an effective therapy in cancer. This study assessed whether subcritical water extracts of the Agaricus blazei Murrill's fruiting body or mycelium affect the expression of Axl and immune checkpoint molecules in lung cancer cells. We used A549 cells and mouse bone marrow-derived dendritic cells in the experiments. We prepared subcritical water extracts from the Agaricus blazei Murrill's fruiting body or mycelium. The subcritical water extracts from the Agaricus blazei Murrill's fruiting body or mycelium significantly inhibited the expression of immune checkpoint molecules and Axl compared to saline-treated cells. Additionally, the hot water extract, subcritical water extract, and the hot water extraction residue subcritical water extract from the Agaricus blazei Murrill's mycelium significantly enhanced the expression of maturation markers in dendritic cells. These observations suggest that the subcritical water extract from Agaricus blazei Murrill's mycelium is a promising therapeutic tool for stimulating the immune response in cancer.


PI3K activation is associated with intracellular sodium/iodide symporter protein expression in breast cancer.
The sodium/iodide symporter (NIS) is a membrane glycoprotein mediating active iodide uptake in the thyroid gland and is the molecular basis for radioiodide imaging and therapeutic ablation of thyroid carcinomas. NIS is expressed in the lactating mammary gland and in many human breast tumors, raising interest in similar use for diagnosis and treatment. However, few human breast tumors have clinically evident iodide uptake ability. We previously identified PI3K signaling as important in NIS upregulation in transgenic mouse models of breast cancer, and the PI3K pathway is commonly activated in human breast cancer. NIS expression, subcellular localization, and function were analyzed in MCF-7 human breast cancer cells and MCF-7 cells stably or transiently expressing PI3K p110alpha subunit using Western blot of whole cell lysate, cell surface biotinylation Western blot and immunofluorescence, and radioiodide uptake assay, respectively. NIS localization was determined in a human breast cancer tissue microarray using immunohistochemical staining (IHC) and was correlated with pre-existing pAkt IHC data. Statistical analysis consisted of Student's t-test (in vitro studies) or Fisher's Exact Test (in vivo correlational studies). In this study, we demonstrate that PI3K activation in MCF-7 human mammary carcinoma cells leads to expression of underglycosylated NIS lacking cell surface trafficking necessary for iodide uptake ability. PI3K activation also appears to interfere with cell surface trafficking of exogenous NIS as well as all-trans retinoic acid-induced endogenous NIS. A correlation between NIS expression and upregulation of PI3K signaling was found in a human breast cancer tissue microarray. Thus, the PI3K pathway likely plays a major role in the discordance between NIS expression and iodide uptake in breast cancer patients. Further study is warranted to realize the application of NIS-mediated radioiodide ablation in breast cancer.


Investigation of the redox behavior of ferroquine, a new antimalarial.
Ferroquine (FQ or SR97193) is a unique ferrocene antimalarial drug candidate which just entered phase IIb clinical trials in autumn 2007. FQ is able to overcome the chloroquine (CQ) resistance problem, an important limit to the control of Plasmodium falciparum, the principal causative agent of malaria. However, as for other therapeutic agents such as chloroquine (CQ) and artemisin, its mechanism of action remains partially unknown. Most investigations have so far focused on comparing the activity of FQ to that of CQ in order to understand how the ferrocene core contributes to a stronger antiplasmodial activity. Studies have already shown that the ferrocene altered the shape, volume, lipophilicity, basicity and also electronic profile of the parent molecule and, hence, its pharmacodynamic behavior. However, few investigations have been undertaken to probe the real contribution of redox properties of the ferrocene (iron(II))/ferricinium (iron(III)) system in FQ as reported in this article. In our experimental and theoretical approach, we considered the redox profile of the ferrocene core of FQ in the specific conditions (acidic and oxidizing) of the parasitic digestive vacuole as a possible discriminating property from CQ in the antimalarial activity.


The incidence of low back problems among nursing students in Hong Kong.
To determine the cumulative incidence (CI) of and risk factors for musculoskeletal problems among nursing students in Hong Kong. Although low back problems have been identified internationally as one of the major work-related hazards among nursing personnel, only a few studies have examined the problem among nursing students. Two-year prospective cohort study; data collected at baseline and 2 (T1), 12 (T2) and 26 (T3) months after baseline. Three cohorts [i.e. two full-time (FT) and one part-time (PT) cohorts] of nursing students were recruited from one of the universities in Hong Kong. They were invited to complete a baseline and three follow-up questionnaires. CIs of low back problems among the three cohorts were calculated and tested for their association. The multivariate logistic regression was also used to identify the risk factors for low back problems. Initially, the seven-day, 30-day and 12-month prevalence in baseline as well as the T1 (64%) and T2 (94%) CIs of low back problems for the PT cohort were significantly higher than those of the two FT cohorts (their CIs ranged from 45-67%). However, the CIs for the FT cohorts were increased from 45% at T1-83% at T3, while the CIs for the PT cohort was only increased from 64-80%, respectively. At T3, the CIs for both FT cohorts caught up with the CI for the PT cohort (chi(2) = 0.068, p = 0.07). As expected, the risk factors for low back problems were multifactorial, i.e. personal, psychosocial and physical. Nursing students had similar CI of low back problems as registered nurses 26 months after baseline, i.e. during their nursing training and before becoming a registered nurse. The results of this study, for the first time, identified that low back problems were developed during the period of nursing school training rather than after nurses enter the workforce. These findings have crucial implications for reducing low back problems among nursing personnel. There is a need to evaluate nursing students' experience in their nursing study and provide appropriate support to them to reduce their personal, physical and psychosocial stress. The ability of nursing students to deliver high quality patient care depends in part on their ability to conserve their own health and well-being.


Disruption of the cytoskeleton during Semaphorin 3A induced growth cone collapse correlates with differences in actin organization and associated binding proteins.
Repulsive guidance cues induce growth cone collapse or collapse and retraction. Collapse results from disruption and loss of the actin cytoskeleton. Actin-rich regions of growth cones contain binding proteins that influence filament organization, such as Arp2/3, cortactin, and fascin, but little is known about the role that these proteins play in collapse. Here, we show that Semaphorin 3A (Sema 3A), which is repulsive to mouse dorsal root ganglion neurons, has unequal effects on actin binding proteins and their associated filaments. The immunofluorescence staining intensity of Arp-2 and cortactin decreases relative to total protein; whereas in unextracted growth cones fascin increases. Fascin and myosin IIB staining redistribute and show increased overlap. The degree of actin filament loss during collapse correlates with filament superstructures detected by rotary shadow electron microscopy. Collapse results in the loss of branched f-actin meshworks, while actin bundles are partially retained to varying degrees. Taken together with the known affects of Sema 3A on actin, this suggests a model for collapse that follows a sequence; depolymerization of actin meshworks followed by partial depolymerization of fascin associated actin bundles and their movement to the neurite to complete collapse. The relocated fascin associated actin bundles may provide the substrate for actomyosin contractions that produce retraction.


Modelling the fear effect in predator-prey interactions.
A recent field manipulation on a terrestrial vertebrate showed that the fear of predators alone altered anti-predator defences to such an extent that it greatly reduced the reproduction of prey. Because fear can evidently affect the populations of terrestrial vertebrates, we proposed a predator-prey model incorporating the cost of fear into prey reproduction. Our mathematical analyses show that high levels of fear (or equivalently strong anti-predator responses) can stabilize the predator-prey system by excluding the existence of periodic solutions. However, relatively low levels of fear can induce multiple limit cycles via subcritical Hopf bifurcations, leading to a bi-stability phenomenon. Compared to classic predator-prey models which ignore the cost of fear where Hopf bifurcations are typically supercritical, Hopf bifurcations in our model can be both supercritical and subcritical by choosing different sets of parameters. We conducted numerical simulations to explore the relationships between fear effects and other biologically related parameters (e.g. birth/death rate of adult prey), which further demonstrate the impact that fear can have in predator-prey interactions. For example, we found that under the conditions of a Hopf bifurcation, an increase in the level of fear may alter the direction of Hopf bifurcation from supercritical to subcritical when the birth rate of prey increases accordingly. Our simulations also show that the prey is less sensitive in perceiving predation risk with increasing birth rate of prey or increasing death rate of predators, but demonstrate that animals will mount stronger anti-predator defences as the attack rate of predators increases.


Comparative in vitro activity of piperacillin/tazobactam against gram-negative bacilli.
To describe the in vitro activity of piperacillin/tazobactam against clinical isolates of Gram-negative bacteria, compared with other antibacterial agents. Survey of susceptibility of clinical isolates of Gram-negative bacilli. Academic hospitals of the University isolates of the Witwatersrand teaching complex. BACTERIAL STRAINS: 180 selected clinical isolates of Gram-negative bacilli. Minimum inhibitory concentrations (MICs) determined by agar dilution using techniques according to the recommendations of the National Committee for Clinical Laboratory Standards. Ciprofloxacin, biapenerm, imipenem, cefepime and cefpirome were all highly active against most of the Enterobacteriaceae. All the ampicillin-resistant strains of Enterobacteriaceae were susceptible to piperacillin/tazobactam, MIC90 values being 4/4 mg/l for Klebsiella and Proteus/Providencia spp., 8/4 mg/l for Citrobacter and Serratia spp., and 16/4 mg/l for Escherichia coli. All the agents, with the exception of ampicillin (MIC90 4 mg/l) and chloramphenicol (MIC90 4 mg/l), were highly active against the Haemophilus influenzae isolates tested. All Bacteroides fragilis strains were susceptible to piperacillin/tazobactam (MIC90 8/4 mg/l), as well as to co-amoxiclav (MIC90 4/2 mg/l), biapenem and imipenem (MIC90s 0.5 mg/l). The Pseudomonas spp. tested included strains resistant to piperacillin/tazobactam, ceftazidime, biapenem, gentamicin, tobramycin and ciprofloxacin. Cefepime was the most active agent against Pseudomonas isolates, with 90% of the strains being susceptible to this agent, while biapenem was the most active agent against the Acinetobacter isolates investigated. The in vitro spectrum of activity of piperacillin/tazobactam against the majority of isolates was comparable to those of the other new agents tested.


High-Throughput Synthesis and Structure of Zeolite ZSM-43 with Two-Directional 8-Ring Channels.
The aluminosilicate zeolite ZSM-43 (where ZSM = Zeolite Socony Mobil) was first synthesized more than 3 decades ago, but its chemical structure remained unsolved because of its poor crystallinity and small crystal size. Here we present optimization of the ZSM-43 synthesis using a high-throughput approach and subsequent structure determination by the combination of electron crystallographic methods and powder X-ray diffraction. The synthesis required the use of a combination of both inorganic (Cs+ and K+) and organic (choline) structure-directing agents. High-throughput synthesis enabled a screening of the synthesis conditions, which made it possible to optimize the synthesis, despite its complexity, in order to obtain a material with significantly improved crystallinity. When both rotation electron diffraction and high-resolution transmission electron microscopy imaging techniques are applied, the structure of ZSM-43 could be determined. The structure of ZSM-43 is a new zeolite framework type and possesses a unique two-dimensional channel system limited by 8-ring channels. ZSM-43 is stable upon calcination, and sorption measurements show that the material is suitable for adsorption of carbon dioxide as well as methane.


Long-term renal function in patients with irradiated bilateral Wilms tumor. National Wilms' Tumor Study Group.
The treatment of bilateral Wilms tumor (BWT) involves a multidisciplinary approach including surgery, chemotherapy, and radiation therapy. The long-term renal function in patients receiving all three treatment modalities has not been evaluated. Long-term renal function was evaluated in 81 children with synchronous BWT who received radiation therapy as part of their treatment. Renal function was assessed by measuring blood urea nitrogen (BUN) and serum creatinine (Cr). The normal range for the BUN was defined as 10-24 mg/dl, and the Cr was considered normal at levels of <1.5 mg/dl. Moderate elevations were defined as a BUN of 25-50 mg/dl and/or a Cr of 1.6-2.5 mg/dl and marked elevations as a BUN of >50 mg/dl and/or a Cr of >2.5 mg/dl. BUN and Cr levels were measured prior to treatment and at the following intervals: 6 months after treatment, 1 year after treatment, 2 years after treatment, and at last follow-up. Any elevation during the posttreatment follow-up period was considered abnormal. A total of 28 children (34.6%) had elevated BUN and/or Cr levels, and 18 had moderate and 10 had marked renal insufficiency. No dose-response relationship was established when comparing the radiation doses of those with elevated values to those with normal values. The renal complication rate was moderate, and other factors including surgery, extent and nature of chemotherapy, and recurrent tumor must also be taken into account. The elevations present in several children could be attributed to tumor recurrence and in one case to gentamicin toxicity. The management of children with BWT should consider all of these risks, and attempts to preserve renal parenchyma are warranted.


Sprinting performance and resistance-based training interventions: a systematic review.
The purpose of this systematic review was to search the scientific literature for original research, addressing the effects different forms of resistance-based training have on sprinting performance in competitive sprinters. Specific key words (Sprinters OR Sprint) NOT (Rugby, Soccer, Cycling, Swimming, Paralympic, and Nutrition) were used to search relevant databases through November 2013 for related literature. Original research was reviewed using the Physiotherapy Evidence Database scale. Five studies met the inclusion criteria: actively competitive adult male sprinters who participated in a resistance-based intervention (>4 weeks), with outcome measures in the form of 10- to 100-m sprint times. Exclusion criteria included acute studies (<4 weeks), nonsprinting populations, and studies with no performance outcome measures (10- to 100-m sprint times). Three of the 5 studies used both locomotor resistance and fixed plane resistance, whereas the remaining 2 studies used more fixed plane resistance, for example, squat and leg extension. Three of the studies showed a statistical improvement in sprinting performance measures, for example, a decrease in 30-m sprint time (p = 0.044), whereas 1 study showed a decrease in sprinting performance. The analysis concluded that resistance-based training has a positive effect on sprinting performance. Varied input of locomotor resistance and fixed plane resistance has resulted in similar percentage change for sprinting performance. This review adds to the body of knowledge by strongly highlighting the dearth of literature exploring the effects of resistance-based training on sprinting performance in competitive sprinters. The short duration and wide range of exercises implemented in studies to date are of concern, but coaches should not hesitate to implement well-planned resistance programs for their sprint athletes.


Testosterone, androgen receptor gene CAG repeat length, mood and behaviour in adolescent males.
Androgen activity has been implicated in a range of traits and behaviours that have well-documented sex differences. However, the results of the studies on the relationship between testosterone and these traits and behaviours are inconsistent. This study has analyzed i) whether CAG repeat length, a presumed modulator of androgen receptor sensitivity, is associated with sex-dimorphic traits and behaviours (aggressive and non-aggressive risk-taking (ART and NART), dominance, depressive symptoms and self-esteem), and ii) whether CAG repeat length interacts with free testosterone (FT) with respect to these traits and behaviours. Data obtained from a group of adolescent boys (n=301; mean age: 14.4 years) were analyzed using multivariate general linear modelling (SPSS, Chicago, IL, USA 15.0). We found no direct correlation between CAG repeat length and dependent variables. We found significant interactions between CAG repeat length and testosterone, indicating that FT was more positively related to ART and NART with a shorter repeat length, and that an inverse association of FT with depressive symptoms and a positive association with self-esteem were stronger in boys with a longer CAG repeat length. Our findings indicate the importance of studying FT and CAG repeat length simultaneously with respect to sex-dimorphic traits, taking into account the possible interactions between the two.


Carbon monoxide exposures reported to the UK National Poisons Information Service: a 4-year study.
Unintentional carbon monoxide (CO) poisoning poses a public health challenge. The UK National Poisons Information Service (NPIS) provides advice to healthcare professionals via the online database, TOXBASE®, and a 24-hour telephone line. Our aim was to analyse all CO-related enquiries to the NPIS. We analysed enquiries regarding unintentional CO exposure (1st July 2015-30th June 2019). Information on patient demographics, CO source and location, clinical features and poisoning severity was collected from telephone enquiries and TOXBASE accesses. 2970 unintentional non-fire-related CO exposures were reported. Exposures occurred commonly in the home (60%) with faulty boilers frequently implicated (27.4%). Although five fatalities were reported, 68.7% of patients experienced no or minor symptoms only (headache most frequently reported). Despite being the gold standard measurement, blood carboxyhaemoglobin concentration was only recorded in 25.6% patients, with no statistically significant correlation with severity. Unintentional CO exposures in the UK commonly occur in domestic settings and although are generally of low severity, fatalities continue to occur. Carboxyhaemoglobin measurement is important to confirm exposure but further work is required to assess its validity as a prognostic indicator in CO exposure. Public health policy should continue to focus on raising awareness of the dangers of CO.


Thyrotropin-releasing hormone stimulation of adrenocorticotropin production by mouse pituitary tumor cells in culture: possible model for anomalous release of adrenocorticotropin by thyrotropin-releasing hormone in some patients with Cushing's disease and Nelson's syndrome.
ACTH-producing mouse pituitary tumor cells in culture (AtT-20/NYU-1 cells) were found to have binding sites for thyrotropin-releasing hormone (TRH). These putative receptors bound TRH with high affinity; the apparent equilibrium dissociation constant was 3.7 nM. The affinity of the receptors for a series of TRH analogues was similar to those previously reported for TRH-receptor interactions on thyrotropic and mammotropic cells in culture. Like some human pituitary tumors in situ, AtT-20/NYU-1 cells were found to produce the alpha subunit of the glycoprotein hormones (alpha). Alpha accumulation in the medium was constant (3.1 ng/mg cell protein per h) and was not affected by TRH. In contrast, TRH increased the amount of ACTH accumulated in the medium from AtT-20/NYU-1 cells to 190 and 420% of control at 1 and 24 h, respectively. TRH induced a dose-dependent increase in ACTH release during a 30-min incubation; half-maximal stimulation occurred at approximately 0.1 nM. TRH had no effect on ACTH release in vitro from anterior pituitary cells derived from normal rats. Because TRH stimulates release of ACTH in some untreated patients with Cushing's disease and Nelson's syndrome as well as pathological states associated with pituitary tumors (but not in normal subjects), AtT-20/NYU-1 cells may serve as an important in vitro model for human pituitary ACTH-secreting adenomas. Moreover, these findings suggest that the primary abnormality in Cushing's disease and Nelson's syndrome, allowing TRH stimulation of ACTH release, may be intrinsic to neoplastic adrenocorticotrophs rather than in neuroregulation of ACTH release.


Cardiorenal Interactions Revisited: How to Improve Heart Failure Outcomes in Patients With Chronic Kidney Disease.
To summarize current advances in the understanding and management of heart failure (HF) in patients with advanced chronic kidney disease (CKD). Diagnosis of HF and treatment of congestion are crucial in the management of patients with advanced CKD to reduce symptoms, preserve organ function, and improve outcomes. Echocardiography and cardiovascular biomarkers may help to differentiate cardiac from non-cardiac components of overhydration. Renal replacement therapy or ultrafiltration may be required to treat congestion. Furthermore, patients with advanced CKD are frequently undertreated with disease-modifying HF therapies, but the use of beta-blockers and ACEi should be considered under close monitoring of kidney function and serum potassium. The use of the new oral potassium binders may translate into improved outcomes. The treatment of HF in patients with advanced CKD requires a multi-disciplinary approach. New diagnostic and therapeutic strategies are under evaluation and may contribute to improved outcomes.


Temperature course and distribution during plasma heating with a microwave device.
In spite of the much shorter thawing times, the use of microwave devices for heating units of fresh frozen plasma is still being discussed. Concerns about general and localised overheating are the main arguments against the use of microwave devices. We evaluated the warming of fresh frozen plasma using the recently introduced Transfusio-therm 2000(R) microwave blood warmer. Units of fresh frozen plasma were weighed and the heating times were recorded. The surface temperature of the fresh frozen plasma bags during heating was recorded every 10 s. Temperature variation on the surface was examined by measuring the difference between peripheral and centrally placed temperature sensors. After heating, plasma temperature was determined using a calibrated thermometer. There were no signs of overheating during the heating process. The surface temperature of three units of fresh frozen plasma heated simultaneously (n = 45) was 34.0 degrees C (SD, 1.5 degrees C) after a mean heating time of 23.2 min (SD, 1.1 min). The mean (SD) temperature difference was -0.6 (0.5) degrees C and the mean (SD) plasma temperature was 33.6 (0.8) degrees C. Heating one fresh frozen plasma unit at a time (n = 20), the mean (SD) heating time was 6.3 (0.4) min. The surface temperature after heating was 34.3 (0.2) degrees C, the mean (SD) temperature difference was -0.6 (0.4) degrees C and the mean (SD) plasma temperature after heating 33.1 (0.6) degrees C. We conclude that no general or localised overheating of fresh frozen plasma occurs during or after heating with the microwave blood warmer.


The application of a violence risk assessment tool among Chinese psychiatric service users: a preliminary study.
The Violence Risk Screening-10 (V-RISK-10) is one of the few instruments available for evaluating violence risk among general psychiatric service users. This naturalistic prospective study involved 376 inpatients in a general psychiatric hospital in Beijing and intended to determine whether this brief instrument could be applied to a sample of Chinese consumers and whether its predictive properties could be retained. Risk assessment at admission was compared to the record of aggression and violence during the first month of hospitalization. During the research period, 108 of the 376 consumers caused 265 incidences of aggression. Receiver operating characteristics for the V-RISK-10 Chinese version yielded an area under the curve of 0.63. Its sensitivity/specificity was 0.80/0.38 and the corresponding positive/negative predictive value was 0.34/0.82. Intraclass correlation coefficient for the whole instrument was 0.89. Compared to the results of the original V-RISK-10, its predictive accuracy was lower. However, with some modification, the V-RISK-10 still shows promise as an instrument for use in daily practice in Chinese clinical settings.