Diabetes in Western Australian children: descriptive epidemiology.
The prevalence and incidence of diabetes mellitus in the age group zero to 14 years in Western Australia were determined from a survey by means of Schools Health Services. Additional information from the State's computer-linked hospital records system, the State's only children's hospital, diabetic clinics and physicians enabled virtually complete ascertainment of cases of childhood diabetes. Only 60% of school-age diabetic children were known to school nurses before the survey, but the nurses were able to identify two-thirds of the remainder during the survey. Among non-Aboriginal children, the prevalence of diabetes in the age group zero to 14 years was 0.59 per 1000 children and the incidence was 12.3 per 100,000 children per year. These rates are somewhat lower than those that have been reported from the United Kingdom and North America, and substantially lower than the rates that were reported from Scandinavia. All but one of the diabetic children who were identified required insulin and were assumed to be insulin-dependent. An excess of boys was found. None of 8715 Aboriginal or part-Aboriginal children had insulin-dependent diabetes mellitus, which indicates that this racial group has a low prevalence of this condition. In case--control studies, which used questionnaires for parents, no significant trends were found in relation to the history of immunizations or of specific viral illnesses except for a past history of varicella which was less frequent in diabetic children. A past history of established breast-feeding (of more than one week) was less frequent in diabetic children, as was the ingestion of vitamin C supplements before the onset of diabetes. Some evidence for a seasonality of onset was obtained. The diabetic children were absent from school for more days and had more admissions to hospital than did non-diabetic children. The majority of diabetic children were prescribed insulin twice a day or more often (84%); performed home blood-glucose monitoring (74%); and attended hospital diabetic clinics (91%).


Os odontoideum in identical twins: perspectives on etiology.
Most authorities favor the hypothesis of an acquired etiology of os odontoideum. We present the cases of identical twin sisters with os odontoideum in association with a congenital partial fusion of the posterior elements of the second and third cervical vertebrae, and discuss the implications. We believe that this is the first report of familial os odontoideum in a context which suggests a genetic etiology.


International agreement to join forces in synthesizing evidence on new methods for cervical cancer prevention.
Recently published baseline results of randomised controlled trials, comparing cytology with HPV-based cervical cancer screening, consistently show increased detection of high-grade cervical intraepithelial neoplasia (CIN) in the HPV-arm. These results are in line with the pooled estimates of the relative sensitivity derived from cross-sectional studies. From two randomised trials, also the longitudinal outcomes observed at the second screening round were reported. HPV-negative women, had a relative risk of developing CIN3 in the next 3 to 5 years, compared to cytology-negative women, of 0.53 (95% CI: 0.29-0.92) and 0.45 (95% CI: 0.28-0.67), respectively in the Swedish and Dutch trial. Consensus was reached at the Cochrane Workshop on Cervical Cancer Prevention, organized at the occasion of the 24th Conference of the International Papillomavirus Society, to join forces to conduct future meta-analyses of the HPV screening trials and to synthesize evidence on new methods for cervical cancer prevention.


(-)-Dihydromylione A, a novel tetracyclic sesquiterpene ketone containing two conjugated cyclopropane rings, from Mylia taylorii (liverwort).
A novel tetracyclic sesquiterpene ketone named (-)-dihydromylione A (III) was isolated from the liverwort, and the structure was determined together with the absolute configuration to be ent-5, 10-cyclo-aromadendr-3-one by connecting the compound with co-occurring (-)-myliol (II).


Cigarette smoking and associated risk of multiple sclerosis in the Iranian population.
Exposure to cigarette smoke is emerging as an environmental risk factor for multiple sclerosis (MS). We investigated the possible association between environmental tobacco smoke, its cumulative exposure, and MS risk. We used data from the Iranian Multiple Sclerosis Registry to identify a case-control of 662 patients who had MS and a comparison group of 394 patients. Information regarding current smoking status, including the number of cigarettes smoked per day, duration, and smoking pack-years indicative of cumulative dose of tobacco smoked was obtained. We analyzed the incidence of MS among ever-smokers who had been smokers during their disease course and prior to disease onset in comparison with never-smokers who had never been exposed by calculating the odds ratio (OR) with a 95% confidence interval (CI) employing logistic regression. Of the 662 MS patients, there were 523 women (79.0%) and 139 men (21.0%), with a mean age of 31 ± 10.0 years at disease onset. The risk for MS was increased among ever-smokers (OR = 1.78, 95% CI = 1.22-2.59, p = 0.03) compared to never-smokers. As compared with never smokers, the OR for patients with 6-10 pack years was 2.91 for men (95% CI = 1.11-9.47, p = 0.03) and 1.69 for women (95% CI = 1.02-6.45, p = 0.04). Our results demonstrate that cigarette smoking is significantly associated with an increased risk for MS. The risk effects of smoking were more noticeable in male patients and at higher tobacco doses.


Soluble RAGEs - Prospects for treating & tracking metabolic and inflammatory disease.
Emerging evidence links the receptor for advanced glycation endproducts (RAGE) to the pathogenesis of tissue damage in chronic metabolic and inflammatory diseases. In human subjects, multiple reports suggest that in the plasma/serum, circulating levels of distinct forms of soluble RAGEs may be biomarkers of the presence or absence, and the extent of chronic disease. These considerations prompt us to consider in this review, what are soluble RAGEs; how are they formed; what might be their natural functions; and may they serve as biomarkers of inflammatory and metabolic disease activity? In this brief review, we seek to address what is known and suggest new areas for scientific investigation to uncover the biology of soluble RAGEs.


Ubiquitin carboxyl-terminal hydrolase L1 promotes hypoxia-inducible factor 1-dependent tumor cell malignancy in spheroid models.
Hypoxia-inducible factor 1 (HIF-1) is a critical heterodimeric transcription factor for tumor malignancy. Recently, ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) has been reported to function as a deubiquitinating enzyme for the stabilization of its α subunit (HIF-1α). In the present study, we showed that UCHL1 inhibition can be an effective therapeutic strategy against HIF-1-dependent tumor malignancy. In 2D monolayer culture, a UCHL1 inhibitor suppressed HIF activity and decreased the transcription of HIF downstream genes by inhibiting the UCHL1-mediated accumulation of HIF-1α. Phenotypically, UCHL1 inhibition remarkably blocked cell migration. In 3D spheroid culture models, ectopic expression of UCHL1 significantly upregulated malignancy-related factors such as solidity, volume, as well as viable cell number in an HIF-1α-dependent manner. Conversely, inhibition of the UCHL1-HIF-1 pathway downregulated these malignancy-related factors and also abolished UCHL1-mediated cell proliferation and invasiveness. Finally, inhibition of UCHL1 promoted HIF-1α degradation and lowered the expression of HIF-1 target genes in the 3D model, as also observed in 2D monolayer culture. Our research indicates that the UCHL1-HIF-1 pathway plays a crucial role in tumor malignancy, making it a promising therapeutic target for cancer chemotherapy.


[Incidence of antibodies inhibiting hemagglutination by influenza virus A/New Jersey/8/76 (Hws1N1) in sera of swine and the population of Umbria].
The authors studied the seroepidemiology of influenza virus A/New Jersey/8/76 (Hsw1N1) in Umbria, in animals and human populations. Human samples demonstrated seropositive evidence only in those subjects with an age above 50 years. The results from swine samples instead proves the circulation of virus in pigs.


Endomorphin-1 and endomorphin-2 activate mu-opioid receptors in myenteric neurons of the guinea-pig small intestine.
The novel opioid tetrapeptides, endomorphin-1 and endomorphin-2, recently isolated from bovine and human brain bind with high affinity and selectivity to central mu-opioid receptors. In the digestive tract, a comprehensive pharmacological analysis of the receptors involved in endomorphin action has not been reported. In this study, we analyzed the effects of endomorphin-1 and endomorphin-2 on longitudinal muscle-myenteric plexus preparations (LMMPs) from the guinea-pig ileum. Both peptides (30 pM - 1 microM) inhibited (-log EC50 values: 8.61 and 8.59, respectively) the amplitude of electrically-induced twitch contractions in a concentration-dependent fashion, up to its abolition. Conversely, in unstimulated LMMPs, they failed to affect contractions to applied acetylcholine (100 nM). In stimulated LMMPs, the highly selective mu-opioid receptor antagonist, D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP), caused a concentration-dependent (30 nM-1 microM), parallel rightward shift of endomorphin-1 and endomorphin-2 inhibitory curves, without depression of their maximum. Following Schild analysis, calculated pA2 values were 7.81 and 7.85, respectively, with slopes not different from unity. Concentration-response curves to both peptides were not affected by 30 nM naltrindole (a selective delta-receptor antagonist) or 30 nM nor-binaltorphimine (a selective kappa-receptor antagonist). These results demonstrate that endomorphins selectively activate mu-opioid receptors located on excitatory myenteric plexus neurons, and that they act as full agonists.


Synthesis and characterization of chitosan-g-N-methyl piperazinium chloride: A hybrid flocculant.
Flocculation is one of the most widely applied techniques for water treatment. Flocculants based on natural polymer has received more attention due to their eco-friendliness in recent years. New water soluble N-methyl piperazinium chloride grafted chitosan flocculant (chitosan-g-N-MPC) was successfully synthesized and thoroughly characterized using FTIR, NMR and powder X-ray diffraction analytical techniques. Incorporation of N-MPC enhanced the ionic character of the chitosan backbone and improved its water solubility. The flocculation performance of chitosan-g-N-MPC was tested against bentonite suspension. The flocculation performance of chitosan-g-N-MPC was investigated under various pH conditions. Turbidity and zeta potential measurements were employed to investigate the flocculation behavior of the chitosan-g-N-MPC. The characteristics of the industrial wastewater before and after flocculation were analyzed. The morphology of the polymer and flocs were studied by TEM analysis.


Tumor Necrosis Factor-alpha (TNF-α) Enhances miR-155-Mediated Endothelial Senescence by Targeting Sirtuin1 (SIRT1).
BACKGROUND Sirtuin1 (SIRT1) participates in a wide variety of cellular processes, but the molecular mechanism remains largely unknown. miR-155 is an element of the inflammatory signaling pathway in atherosclerosis. Therefore, we tested the hypothesis that TNF-alpha stimulates miR-155 to target SIRT1 and thereby regulates endothelial senescence, and we also explored the function of miR-155 as a regulator of cardiovascular diseases. MATERIAL AND METHODS TNF-alpha was used to stimulate human umbilical vein endothelial cells (HUVECs), after which protein and gene expression were assessed via Western blotting and RT-qPCR. miR-155 targeting of SIRT1 was confirmed via luciferase reporter assays, while MTT and senescence-associated ß-galactosidase (SA-ß-gal) assays were used for quantifying cellular proliferation and senescence. RESULTS We found that miR-155 was upregulated in response to TNF-alpha treatment, in addition to inducing marked changes in SIRT1/FoxO-1/p21 pathway protein level. When we overexpressed miR-155 mimics, SIRT1 was markedly reduced, whereas miR-155 inhibition had the opposite effect in TNF-alpha-treated cells. We additionally confirmed that miR-155 was able to directly bind to SIRT1 3'-UTR, and that inhibition of miR-155 reduced the ability of TNF-alpha to induce senescence in HUVECs, thereby leading to their enhanced proliferation. Simvastatin was associated with suppression of miR-155 expression in HUVECs following TNF-alpha treatment, and with a corresponding reduction in TNF-alpha-induced senescence, whereas miR-155 overexpression had the opposite effect. CONCLUSIONS Our findings suggest that TNF-alpha upregulates miR-155, which then targets SIRT1, suppressing its expression and driving HUVEC apoptosis. Simvastatin disrupted this senescence mechanism via the miR-155/SIRT1/FoxO-1/p21 pathway signaling. Hence, miR-155 is a possible therapeutic approach to endothelial senescence in the development of cardiovascular diseases.


HDL inflammatory index correlates with and predicts severity of organ failure in patients with sepsis and septic shock.
High density lipoprotein (HDL) is important for defense against sepsis but becomes dysfunctional (Dys-HDL) during inflammation. We hypothesize that Dys-HDL correlates with organ dysfunction (sequential organ failure assessment (SOFA) score) early sepsis. A prospective cohort study of adult ED sepsis patients enrolled within 24 hours. Eighty eight patients were analyzed. Dys-HDL (expressed as HDL inflammatory index (HII)) correlated with SOFA at enrollment (r = 0.23, p = 0.024) and at 48 hours (r = 0.24, p = 0.026) but HII change over the first 48 hours did not correlate with change in SOFA (r = 0.06, p = 0.56). Enrollment HII was significantly different in patients with most severe organ failure (2.31, IQR 1.33-5.2) compared to less severe organ failure (1.81, IQR 1.23-2.64, p = 0.043). Change in HII over 48 hours was significantly different for in-hospital non-survivors (-0.45, IQR-2.6, -0.14 p = 0.015) and for 28-day non-survivors (-1.12, IQR -1.52, 0.12, p = 0.044). In a multivariable linear regression equation (R2 = 0.13), for each unit HII increase, 48-hour SOFA increased by 0.72 (p = 0.009). HII correlated with SOFA and predicted 48-hour SOFA score in early sepsis. Future studies are needed to delineate potential mechanisms. NCT02370186. Registered February 24, 2015.


Performance management of Clostridium difficile infection in hospitals - The carrot or stick approach?
Public and political pressure for healthcare quality indicator monitoring, specifically healthcare-associated infection (HAI) has intensified the debate regarding the merits of public reporting and target setting as policy approaches. This paper reviews the evidence for these approaches with a focus on HAI, including Clostridium difficile infection (CDI). Healthcare key performance indicators (KPIs) and associated targets have been used widely with little evaluation. While targets are associated with some HAI reductions including CDI, as their control is multi-factorial, it is likely that reductions are due to numerous, concurrent control measures. Targets may help tackle organizational-wide issues that require high level management engagement and have contributed to the increased access and influence of infection control teams. HAI public reporting has also gained traction and is mandatory in many countries despite little scientific evaluation. CDI is one of the KPIs used but there is little consensus as to the best KPI for public reporting. Countries without public reporting have also seen improvements. Using indicator-based strategies rather than evidence-based ones risk improving the KPI but not necessarily quality of care. 'Bottom-up' approaches focussing on quality improvement and innovation generated by front line staff are seen as a lever for sustainable change. Positive deviance, where the resourcefulness and problem solving abilities of staff is harnessed, enables 'bottom-up' changes with process and outcome improvements. As implementation of best practice in healthcare is dependent on behavioural and cultural change, it is most likely that a combination of 'top-down' and 'bottom-up' approaches are required for sustainable improvement. This combined approach was used to improve staff influenza vaccination rates. Regulation may initially direct the spot-light onto infection control needs but true sustainable HAI reduction will only be fostered with concurrent cultural and behavioural shifts in practice and ownership of the HAI burden across clinical, policy and management domains. It will be interesting if this approach will be increasingly used by policy makers, however, irrespective it is clear that there is a need for rigorous evaluation of our HAI policy approaches from this point forward.


Does serotonin influence aggression? comparing regional activity before and during social interaction.
Serotonin is widely believed to exert inhibitory control over aggressive behavior and intent. In addition, a number of studies of fish, reptiles, and mammals, including the lizard Anolis carolinensis, have demonstrated that serotonergic activity is stimulated by aggressive social interaction in both dominant and subordinate males. As serotonergic activity does not appear to inhibit agonistic behavior during combative social interaction, we investigated the possibility that the negative correlation between serotonergic activity and aggression exists before aggressive behavior begins. To do this, putatively dominant and more aggressive males were determined by their speed overcoming stress (latency to feeding after capture) and their celerity to court females. Serotonergic activities before aggression are differentiated by social rank in a region-specific manner. Among aggressive males baseline serotonergic activity is lower in the septum, nucleus accumbens, striatum, medial amygdala, anterior hypothalamus, raphe, and locus ceruleus but not in the hippocampus, lateral amygdala, preoptic area, substantia nigra, or ventral tegmental area. However, in regions such as the nucleus accumbens, where low serotonergic activity may help promote aggression, agonistic behavior also stimulates the greatest rise in serotonergic activity among the most aggressive males, most likely as a result of the stress associated with social interaction.


Periapical lesions decrease insulin signal and cause insulin resistance.
Inflammatory cytokines are associated with decreased insulin signal transduction. Moreover, local oral inflammation, such as that accompanying periodontal disease, is associated with insulin resistance and type 2 diabetes mellitus. The aim of this study was to evaluate the effect of periapical lesions (PLs) on insulin signaling and insulin sensitivity in rats. We hypothesized that PLs alter systemic insulin signaling and insulin sensitivity via elevated plasmatic tumor necrosis factor α (TNF-α). Wistar rats were divided into control (CN) and PL groups. PLs were induced by exposing pulpal tissue to the oral environment. After 30 days, insulin sensitivity was measured using the insulin tolerance test. After euthanization, maxillae were processed for histopathology. Plasmatic concentrations of tumor necrosis factor α (TNF-α) were determined via the enzyme-linked immunosorbent assay. Insulin signal transduction was evaluated using insulin receptor substrate tyrosine phosphorylation status and serine phosphorylation status in periepididymal white adipose tissue via Western blotting. For insulin signaling and insulin tolerance tests, the analyses performed were analysis of variance followed by the Tukey post hoc test. For TNF-α analysis, the Student's t test was used. In all tests, P < .05 was considered significant. The rats with PLs showed higher plasmatic TNF-α, lower constant rate for glucose disappearance values, and reduced pp185 tyrosine phosphorylation status but no change in serine phosphorylation status in white adipose tissue after insulin stimulation. PLs can cause alterations to both insulin signaling and insulin sensitivity, probably because of elevation of plasmatic TNF-α. The results from this study emphasize the importance of the prevention of local inflammatory diseases, such as PLs, with regard to the prevention of insulin resistance.


Mechanisms of histone lysine-modifying enzymes: A computational perspective on the role of the protein environment.
Epigenetic pathways are involved in a wide range of diseases, including cancer and neurological disorders. Specifically, histone modifying and reading processes are the most broadly studied and are targeted by several licensed drugs. Although there have been significant advances in understanding the mechanistic aspects underlying epigenetic regulation, the development of selective small-molecule inhibitors remains a challenge. Experimentally, it is generally difficult to elucidate the atomistic basis for substrate recognition, as well as the sequence of events involved in binding and the subsequent chemical processes. In this regard, computational modelling is particularly valuable, since it can provide structural features (including transition state structures along with kinetic and thermodynamic parameters) that enable both qualitative and quantitative evaluation of the mechanistic details involved. Here, we summarize knowledge gained from computational modelling studies elucidating the role of the protein environment in histone-lysine modifying and reading mechanisms. We give a perspective on the importance of calculations to aid and advance the understanding of these processes and for the future development of selective inhibitors for epigenetic regulators.


Onset and duration of action of single doses of formoterol inhaled via Turbuhaler.
The aim of the study was to investigate the time of onset and the duration of the bronchodilating effect of different doses of formoterol administered via Turbuhaler in patients with moderate asthma. Thirty-one patients (five women) with a mean forced expiratory volume in 1 s (FEV1) of 1.97 +/- 0.54 1 and a mean reversibility of 31 +/- 14% of baseline were included in this double-blind, randomized, placebo-controlled and cross-over study. The patients inhaled single doses of placebo, i.e. 6, 12, 24, or 48 micrograms formoterol fumarate, on 5 separate days. Serial measurements of specific airways conductance (SGAW) and FEV1 were performed at regular time intervals for 12 h. The majority of the patients had at least a 50% increase in SGAW within 1-4 min after administration of all active treatments. The maximum increase in FEV1 over placebo was dose-dependent: 12% (6 micrograms), 18% (12 micrograms), 19% (24 micrograms), and 26% (48 micrograms) (P < 0.001). Twelve hours after administration of 6, 12, 24, and 48 micrograms formoterol, the mean increase in FEV1 was still 7%, 15%, 18%, and 27%, respectively, above the value following placebo. Headache was the most frequently reported adverse event in all treatments including placebo. After inhalation of 48 micrograms, three patients experienced mild tremor lasting for less than 1 h; likewise, one patient experienced the same event for 3 h after placebo. Formoterol administered via Turbuhaler10 gave a rapid and dose-related bronchodilating effect lasting for 12 h and was well tolerated.


Malignant hyperthermia susceptibility in patients with exertional rhabdomyolysis: a retrospective cohort study and updated systematic review.
Two potentially fatal syndromes, malignant hyperthermia (MH), an adverse reaction to general anesthesia, and exertional rhabdomyolysis (ER) share some clinical features, including hyperthermia, muscle rigidity, tachycardia, and elevated serum creatine kinase. Some patients with ER have experienced an MH event and/or have been diagnosed as MH susceptible (MHS). In order to assess the relationship between ER and MH further, we conducted a retrospective cohort study summarizing clinical and genetic information on Canadian patients with ER who were diagnosed as MHS. In addition, a systematic literature review was performed to compile further evidence on MH susceptibility and RYR1 and CACNA1S variants associated with rhabdomyolysis. Demographic, clinical, and genetic information was collected on Canadian MHS patients who presented with rhabdomyolysis. In addition, we performed a systematic review of the literature published during 1995-2016 on genetic screening of the RYR1 and CACNA1S genes in patients with ER. Retrospective data on Canadian MHS patients with ER showed that ten out of 17 patients carried RYR1 or CACNA1S variants that were either known MH-causative mutations or potentially pathogenic variants. The systematic review revealed 39 different rare RYR1 variants, including 13 MH-causative/associated mutations and five rare potentially deleterious CACNA1S variants in 78% of patients with ER. Findings from the Canadian patient cohort and the systematic review all signal a potential association between MH susceptibility and ER. The presence of MH-causative mutations and putative deleterious RYR1 variants in ER patients without a history of adverse anesthetic reactions suggests their possible increased risk for MH.


Impact of the invasion of the imported fire ant.
The impact of the imported fire ant (IFA) is complex, in large part, because several very different species of "Fire Ants" have invaded and one of these has two forms, all of which are hard to separate by the public, as well as, some investigators not focused on the ant. Each of these different "IFA" species and forms differ in their impact. Further, these ants impact a number of "things" ranging from the environment and wildlife (plants and animals) as well as people, their environment and infrastructure. In addition, they can not only lead to death of living things (including people), but they can destroy many aspects of our environment and infrastructure at the cost of millions of dollars. But there are some beneficial aspects and some people can make many thousands of dollars due to their presence. This is an attempt to look at these issues.


Neutron diffraction study of the non-Fermi liquid compound CeNiGa₂: magnetic behaviour as a function of pressure and temperature.
The magnetic symmetry and structure of the non-Fermi liquid heavy fermion compound CeNiGa2 has been determined by neutron powder diffraction. The orthorhombic CeNiGa2 compound orders antiferromagnetically below 4.4(2) K at ambient pressure with a magnetic moment magnitude of μCe = 0.80(4) μB for moments aligned along the c-axis. The magnetic (Shubnikov) space group is C2cm'm'm. The nature of the magnetic order of CeNiGa2 is further elucidated by neutron diffraction at elevated pressures up to 4.5 kbar, allowing for the confirmation of a critical pressure PC of about 4.2(2) kbar above which the magnetic moment ordering is suppressed.


Promoting conversations between physicians and families about childhood obesity: evaluation of physician communication training within a clinical practice improvement initiative.
Childhood obesity rates have incrementally increased since the 1980s, sparking calls for initiatives focused on addressing this public health concern. In response, the family medicine residency clinic profiled in this research designed, executed, and evaluated a practice improvement initiative focused on physician communication behaviors and clinic processes that impact the management of unhealthy pediatric weight. The results of the evaluation effort demonstrated increased physician knowledge of communication principles, improvements in weight management counseling rates, and opportunities for health delivery system changes to promote the effective clinical management of unhealthy pediatric weight.


The accuracy of body mass index and calf circumference values when assessing sarcopenia in a multi-ethnic cohort of middle-aged and older adults: West China health and aging trend study results.
This analysis was designed to explore the utility of body mass index (BMI) and calf circumference (CC) values in the diagnosis of sarcopenia. A cross-sectional analysis of community-dwelling adults ≥50 years old was conducted. An InBody 770 bioimpedance analysis (BIA) device was used for measuring muscle mass, a grip-strength dynamometer was used to assess muscle strength, and a 4 m gait speed (GS) analysis was used to gauge physical function. The Asian Working Group for Sarcopenia (AWGS) 2019 criteria were used to define sarcopenia. The cut-off values for BMI and CC were based on the computed Younden's index values and AWGS 2019 criteria, respectively. The area under the ROC curves (AUC), specificity, sensitivity, and positive and negative predictive values (PPV and NPV) were calculated to establish the value of BMI and CC for the diagnosis of sarcopenia. In total, the data of 4177 participants ≥50 years of age were analyzed. These included 2668 (63.9%) females and 1509 (36.1%) males. Of these participants, 946 (22.6%) met the criteria for sarcopenia, including 408 (27%) males and 538 (20.2%) females. The sensitivity, specificity, and NPVs obtained when using BMI and CC values to predict sarcopenia were as follows: 84.03%/65.51%/0.90 and 74.76%/83.51%/0.87, respectively, in males; 87.36%/64.12%/0.94 and 78.25%/82.09%/0.93, in females. The respective AUC values for BMI and CC in males were 0.83 (0.80-0.85) and 0.85 (0.83-0.88), while in females they were 0.85 (0.83-0.87) and 0.88 (0.87-0.90). These data suggest that BMI and CC can both serve as accurate predictors of sarcopenic incidence in a multi-ethnic population ≥50 years of age. The specificity values for BMI were relatively low in both males and females, however, underscoring the relative advantages of measuring CC when assessing individual sarcopenia risk.


Characterization of an interaction between protein C and ceruloplasmin.
Coagulation factors V and VIII are substrates for activated protein C. Binding sites for the protease have been localized to homologous sequences within the terminal A domains of these proteins. Since ceruloplasmin contains significant sequence homology to these domains, a study was undertaken to determine whether ceruloplasmin was an activated protein C-binding protein. Ceruloplasmin was observed to inhibit the activated protein C-catalyzed inactivation of both factor Va and factor VIII. Searches of the ceruloplasmin sequence revealed a decapeptide sequence, HAGMETTYTV (residues 1028-1037) that shares 60 and 40% sequence identity with the activated protein C binding sequence in factors VIII and V, respectively. This peptide also inhibited factor Va inactivation and in addition was observed to enhance the amidolytic activity of activated protein C. The ferrous oxidase activity of ceruloplasmin was stimulated 5-fold by activated protein C, and this effect was negated by the peptide HAGMETTYTV. These results indicate that these conserved sequences of ceruloplasmin and factors V and VIII interact with activated protein C and suggest that this region may be important in the regulation of this anticoagulant protein.


Antimicrobial resistance: Concerns of healthcare providers and people with CF.
Chronic lung infections and their treatment pose risks for the development of antimicrobial resistance (AMR) in people with cystic fibrosis (PWCF). In this study, we evaluated the attitudes of healthcare providers' (HCP) and PWCF or their parents' toward AMR within the international CF community. HCP and PWCF identified through listservs and CF-related organizations were asked to complete an AMR centered survey, with additional questions on antimicrobial stewardship (AMS) for HCP. Descriptive analyses are reported. The responding 443 HCP and 464 PWCF/Parents were from 30 and 25 countries, respectively. Sixty-two percent of HCP and 56% of PWCF stated they were "very concerned" about AMR, with Pseudomonas spp. and Burkholderia spp. considered the most concerning organisms for both HCP and PWCF/Parents. Non-tuberculous mycobacteria were of greater concern to HCP compared to PWCF/Parents. There was a discrepancy regarding AMR education to PWCF, with 80% of HCP stating having discussed this with PWCF/Parents, but only 50% of PWCF recalling such discussions. These results highlight that AMR is relevant to CF HCP and PWCF internationally, indicating that educational tools and research are warranted.


Olefination with Sulfonyl Halides and Esters: Synthesis of Unsaturated Sulfonyl Fluorides.
Methanedisulfonyl fluoride, CH2(SO2F)2, transforms aromatic aldehydes into β-arylethenesulfonyl fluorides, useful substrates for the SuFEx "click"-type transformations. The reaction mimics mechanism of the Horner-Wadsworth-Emmons olefination, which runs via addition of the carbanion, followed by cyclization-fragmentation of the four-membered ring intermediate. In the absence of base, electron-rich aldehydes follow an alternative pathway of the Knoevenagel condensation to provide unsaturated 1,1-disulfonyl fluorides. We demonstrate also trapping of elusive ethene-1,1-disulfonyl fluoride, CH2═C(SO2F)2, with 4-(dimethylamino)pyridine (DMAP) that forms zwitterionic adduct, characterized with X-ray studies.


Infant maltreatment: caretaker-infant interaction and developmental consequences at different levels of parenting failure.
A total of 53 mother-infant dyads, divided into five diagnostic groups (nonaccidental trauma combined with failure-to-thrive, nonaccidental trauma combined with iron-deficiency anemia, nonaccidental trauma only, neglect only, and normal control subjects) were observed during a feeding session. Qualitative differences were found in the relational characteristics of dyads in which multiple forms of maltreatment existed. Developmental examinations revealed that infants subjected to severe abuse and neglect were significantly retarded in their mental and motor development compared with the remaining index and control groups. The results were interpreted to suggest that relational disturbances are at the core of the problem of infant maltreatment and that on the basis of interactional symptomatology, two broadly different clinical conditions have been identified.


Association of Pseudohypoparathyroidism and Autoimmune Polyglandular Syndrome: Causal or Coincidental?
Pseudohypoparathyroidism (PHP) is a state of parathyroid hormone resistance and is characterised by low serum calcium, and elevated serum phosphate and parathyroid hormone level. Association of PHP with autoimmune disorders is rare and seldom reported in the literature. Here we describe a case of PHP who subsequently developed multiple autoimmune disorders (type 3 polyglandular autoimmune syndrome), which has not been reported so far.


Adjuvant therapy for high-grade, uterus-limited leiomyosarcoma: results of a phase 2 trial (SARC 005).
Between 30% and 50% of women who have high-grade uterine leiomyosarcoma (uLMS) limited to the uterus at diagnosis remain progression-free at 2 years. Adjuvant pelvic radiation does not improve outcome. The objective of the current study was to determine the 2-year and 3-year progression-free survival (PFS) among a prospective cohort of women who received adjuvant gemcitabine plus docetaxel followed by doxorubicin. Women with uterus-limited, high-grade uLMS and adequate organ function were eligible. Within 12 weeks of complete resection and after confirmation that they had no evidence of disease on computed tomography (CT) images, the patients received 4 cycles of fixed-dose-rate gemcitabine plus docetaxel. Those who were confirmed disease-free on CT scans after cycle 4 received 4 cycles of doxorubicin. CT imaging for recurrence was performed every 3 months for 2 years, then every 6 months for 3 years. In total, 47 women were enrolled (46 evaluable) in 3 years. Characteristics included a median age of 53 years; 1988 International Federation of Gynecology and Obstetrics stage I disease in 81% of patients, stage II disease in 15%, and serosa-only stage IIIA disease in 4%; American Joint Committee on Cancer stage II disease in 13% of patients and stage III disease in 87%; a median tumor size of 8 cm (range, 2.5-30 cm); and a median mitotic rate of 18 mitoses per 10 high-power fields (range, 5-83 mitoses per 10 high-power fields). At a median follow-up of 39.8 months, 21 of 46 patients developed recurrent disease (45.7%). The median time to recurrence was 27.4 months (range, 3-40 months). Seventy-eight percent of patients (95% confidence interval, 67%-91%) were progression-free at 2 years, and 57% (95% confidence interval, 44%-74%) were progression-free at 3 years. The median PFS was not reached and exceeded 36 months. Among women with high-grade, uterus-limited uLMS who received treatment with adjuvant gemcitabine plus docetaxel followed by doxorubicin, 78% remained progression-free at 2 years, and 57% remained progression-free at 3 years. A randomized trial of adjuvant chemotherapy versus observation to determine whether adjuvant chemotherapy can improve survival in women with uterus-limited uLMS is underway.


Characterization of an irritant 4-deoxyphorbol diester from Euphorbia tirucalli.
Latex of Euphorbia tirucalli, collected in Colombia, yielded 12-O-2Z-4E-octadienoyl-4-deoxyphorbol-13-acetate (1), which exhibited an irritant potency equivalent to that of the standard irritant, phorbol-12-tetradecanoate-13-acetate, in a mouse ear test system. The unsaturated 4-deoxyphorbol diesters recently reported in E. tirucalli grown in South Africa were not observed in the present study.


Ultrastructural localization of radiolabelled L-dopa in the endocrine hypothalamus of the rat.
Light and electron microscopic autoradiography has been employed to define the neuroanatomical patterns of uptake and binding of radiolabelled L-dopa in the endocrine hypothalamus of the rat. A dorsomedial continuum of arcuate and periventricular neurons selectively sequester 3HL-dopa 20 min following its intraventricular infusion. By 40 and 60 min following the infusion labelling of neurons is minimal and supports the notion of rapid degradation. Other cell compartments such as tanycytes demonstrate uptake of 3H L-dopa. The ultrastructural localization and distribution of radiolabelled L-dopa (or its metabolites) in the rodent hypothalamus is discussed with respect to mechanisms and cell compartments involved in neuroendocrine regulatory processes.


Taurine regulates mitochondrial calcium homeostasis.
We have investigated the protective role of taurine in glutamate-mediated cell death and the involvement of mitochondria in this process. In cultured cerebellar granule cells, glutamate induces a rapid and sustained elevation in cytoplasmic free calcium ([Ca2+]i), causing the collapse of the mitochondrial electrochemical gradient (MtECG) and subsequent cell death. We found that pre-treatment with taurine, did not affect the level of calcium uptake with glutamate but rather reduced its duration; the calcium increase was transient and returned to basal levels about 10 min after adding glutamate. Furthermore, taurine reduced mitochondrial calcium concentration under non-depolarizing conditions. Treatment of cerebellar granule cells with taurine enhanced mitochondrial activity as measured by rhodamine uptake, both in the presence or absence of glutamate. We conclude that taurine prevents or reduces glutamate excitotoxicity through both the enhancement of mitochondrial function and the regulation of intracellular (cytoplasmic and mitochondrial) calcium homeostasis.


The heat shock protein gp96 induces maturation of dendritic cells and down-regulation of its receptor.
Peptides associated with the heat shock protein gp96 induce a specific T cell response against cells from which gp96 is isolated. Recently, we have shown that gp96 binds to a yet unknown receptor present on dendritic cells (DC) and that receptor-mediated uptake is required for cross-presentation of gp96-associated peptides by DC. We now describe that gp96 mediates maturation of DC as determined by up-regulation of MHC class II and CD86 molecules, secretion of the cytokines IL-12 and TNF-alpha and enhanced T cell stimulatory capacity. Heat-denatured gp96 is not able to induce DC maturation and cytokine secretion. Furthermore, we show that mature DC are no longer able to bind gp96 molecules. Hence, the gp96 receptor is down-regulated on mature DC, suggesting that this receptor behaves similar to other receptors involved in antigen uptake like the scavenger receptor CD36, the mannose receptor or the integrins alpha(v)beta(3) and alpha(v)beta(5). Together, our findings provide an additional explanation for the remarkable immunogenicity of gp96 as a cross-priming antigen carrier and direct activator of DC.


Meeting report: myelodysplastic syndromes at ASH 2007.
Myelodysplastic syndromes (MDS) remain challenging to both clinicians and biologists. This year's edition of the Annual Meeting of the American Society of Hematology has provided several breakthroughs in the biology and therapeutics of MDS, such as uncovering of the molecular genetics of the 5q- syndrome and clear evidence of a survival advantage with a hypomethylating agent in high-risk MDS. We summarize those advances and delineate some perspectives for these diseases.


The impact of pension insurance types on the health of older adults in China: a study based on the 2018 CHARLS data.
Pension insurance is an essential safeguard for the quality of life and health of older adults because it provides a stable and dependable source of income after retirement. China has constructed a multi-level social security system to accommodate the diverse needs of older adults, and offers various levels of pension insurance to maximize their interests. This study uses propensity score matching and ordinary least squares techniques to analyze 7,359 data from the 2018 China Health and Retirement Longitudinal Study (CHARLS) in order to explore the relationship between different pension insurance categories and the health of older individuals. The research findings reveal that advanced insurances greatly benefit the health of older adults more than basic pension insurances, and the findings pass the robustness test. In addition, the effect was found to be heterogeneous, depending on the location of retirement and the marital status of older adults.Our findings suggest that both material and non-material consumption may be potential mechanisms by which pension insurance affects the health of older adults, providing new evidence for the causal mechanism between pension insurance and the health of older adults. This study expands the scope of research on the health effects of pension insurance by covering a large representative sample across the country. The results show the important impact of the level of pension insurance on the health of older adults and can contribute to the development of social policies to promote the physical and mental health of older adults.


Clinical Utility of Implementing a Frontline NGS-Based DNA and RNA Fusion Panel Test for Patients with Suspected Myeloid Malignancies.
The use of molecular genetic biomarkers is rapidly advancing to aid diagnosis, prognosis, and clinical management of hematological disorders. We have implemented a next-generation sequencing (NGS) assay for detection of genetic variants and fusions as a frontline test for patients suspected with myeloid malignancy. In this study, we summarize the findings and assess the clinical impact in the first 1613 patients tested. All patients were assessed using NGS based Oncomine Myeloid Research Assay (ThermoFisher) including 40 genes (17 full genes and 23 genes with clinically relevant "hotspot" regions), along with a panel of 29 fusion driver genes (including over fusion 600 partners). Among 1613 patients with suspected myeloid malignancy, 43% patients harbored at least one clinically relevant variant: 91% (90/100) in acute myeloid leukemia patients, 71.7% (160/223) in myelodysplastic syndrome (MDS), 77.5% (308/397) in myeloproliferative neoplasm (MPN), 83% (34/41) in MPN/MDS, and 100% (40/40) in chronic myeloid leukemia patients. Comparison of NGS and cytogenetics results revealed a high degree of concordance in gene fusion detection. Our findings demonstrate clinical utility and feasibility of integrating a NGS-based gene mutation and fusion testing assay as a frontline diagnostic test in a large reported cohort of patients with suspected myeloid malignancy, in a clinical laboratory setting. Overlap with cytogenetic test results provides opportunity for testing reduction and streamlining.


Invertebrate neurobiology: short-term memories for limb targeting.
Scanning movements made by stick insects' forelimbs are modified for several seconds after a brief contact with an object, suggesting that the neural networks controlling local limb movements in insects can form short-term positional memories.


Skilled Nursing Facilities After Total Knee Arthroplasty: The Time for Selective Partnerships Is Now!
Bundled payment initiatives for total knee arthroplasty (TKA) patients are dramatically impacted by discharges to skilled nursing facilities (SNFs), making target prices set by the Center for Medicare and Medicaid Services difficult to achieve. However, we hypothesized that a granular examination of SNF discharges would reveal that some may disproportionately increase costs compared to others. The institutional database was retrospectively queried for primary TKA patients under bundled payment initiatives. The 4 most common SNFs utilized by our patient population (A, B, C, and D) were investigated for length of stay, cost of care, and whether the overall target price for the episode of care (EOC) was reached. In total, 1223 TKA patients were analyzed, with 378 (30.9%) discharged to an SNF and 246 patients selecting one of the 4 most common SNFs (A: 198, B: 21, C: 15, D: 12). Each SNF represented a significant fiscal portion of the total EOC; however, SNF D had significantly longer length of stay (21 vs 13 days, P < .001) and cost of care ($11,805 vs $6015, P < .001) relative to the others, resulting in no EOC under the target price. SNF costs >24.6% of the total EOC were predictive of exceeding the target price. Bundled payment models are significantly impacted by SNF disposition; however, select facilities disproportionately impact this system. In order to maintain free patient selection for disposition, post-acute care facilities must be held accountable for controlling cost, or a separate bundled payment provided.


Knockdown of HSP110 attenuates hypoxia-induced pulmonary hypertension in mice through suppression of YAP/TAZ-TEAD4 pathway.
Pulmonary hypertension (PH) is a progressive and fatal cardiopulmonary disease characterized by pulmonary vascular remodeling and increased pulmonary vascular resistance and artery pressure. Vascular remodeling is associated with the excessive cell proliferation and migration of pulmonary artery smooth muscle cells (PASMCs). In this paper, the effects of heat shock protein-110 (HSP110) on PH were investigated. The C57BL/6 mice and human PASMCs (HPASMCs) were respectively exposed to hypoxia to establish and simulate PH model in vivo and cell experiment in vitro. To HSP110 knockdown, the hypoxia mice and HPASMCs were infected with adeno-associated virus or adenovirus carring the shRNAs (short hairpin RNAs) for HSP110 (shHSP110). For HSP110 and yes-associated protein (YAP) overexpression, HPASMCs were infected with adenovirus vector carring the cDNA of HSP110 or YAP. The effects of HSP110 on PH development in mice and cell proliferation, migration and autophagy of PASMCs under hypoxia were assessed. Moreover, the regulatory mechanisms among HSP110, YAP and TEA domain transcription factor 4 (TEAD4) were investigated. We demonstrated that expression of HSP110 was significantly increased in the pulmonary arteries of mice and HPASMCs under hypoxia. Moreover, knockdown of HSP110 alleviated hypoxia-induced right ventricle systolic pressure, vascular wall thickening, right ventricular hypertrophy, autophagy and proliferation of PASMCs in mice. In addition, knockdown of HSP110 inhibited the increases of proliferation, migration and autophagy of HPASMCs that induced by hypoxia in vitro. Mechanistically, HSP110 knockdown inhibited YAP and transcriptional co-activator with PDZ-binding motif (TAZ) activity and TEAD4 nuclear expression under hypoxia. However, overexpression of HSP110 exhibited the opposite results in HPASMCs. Additionally, overexpression of YAP partially restored the effects of shHSP110 on HPASMCs. The interaction of HSP110 and YAP was verified. Moreover, TEAD4 could promote the transcriptional activity of HSP110 by binding to the HSP110 promoter under hypoxia. Our findings suggest that HSP110 might contribute to the development of PH by regulating the proliferation, migration and autophagy of PASMCs through YAP/TAZ-TEAD4 pathway, which may help to understand deeper the pathogenic mechanism in PH development.


Gene expression responses to Zika virus infection in peripheral blood mononuclear cells from pregnant and non-pregnant women.
Congenital Zika syndrome is caused by mother-to-fetus transmission of the Zika virus (ZIKV). Peripheral blood mononuclear cells (PBMCs) are permissive to ZIKV infection and may carry ZIKV to the placenta. To identify pregnancy-related differences in PBMC responses against ZIKV infection, we compared gene expression profiles of ZIKV-infected and non-infected PBMCs cultured from pregnant and non-pregnant women. ZIKV-infected pregnant conditions generally overexpressed M1-shifted pro-inflammatory responses and underexpressed M2-shifted anti-inflammatory responses. Additionally, transcripts involved in osteoclast differentiation and cardiac myopathies were upregulated following ZIKV infection. Our results suggest potential roles of pregnancy-induced immune dysregulation in shaping neonatal pathology associated with ZIKV infection.


Targeted therapy for medullary and extramedullary relapse of FLT3-ITD acute myeloid leukemia following allogeneic hematopoietic stem cell transplantation.
We report a case with extramedullary tumors affecting the supraclavicular region that presented as a relapse of acute myeloid leukemia (AML) with FLT3-ITD mutation after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Treatment with gilteritinib resulted in remarkable response with disappearance of both the medullary and extramedullary tumors. Subsequently, a 2nd allo-HSCT was performed in an attempt to cure his AML and complete molecular response has been sustained with gilteritinib resumption without worsening GVHD. Targeted therapy with gilteritinib for medullary and extramedullary relapse of FLT3-ITD AML could be effective and suitable as a bridging therapy for allo-HSCT.


Structure, expression, and evolution of the 5-enolpyruvylshikimate-3-phosphate synthase genes of petunia and tomato.
5-Enolpyruvylshikimate-3-phosphate (EPSP) synthase is an enzyme of the shikimate pathway which is located in the chloroplasts in higher plants. This enzyme is the target of the nonselective herbicide glyphosate. We have isolated and sequenced cDNA clones encoding EPSP synthase from petunia and tomato. The deduced amino acid sequences of the two enzyme precursors show 93% identity in the mature protein regions and 58% identity in the transit peptides. The sequences of the plant enzymes show significantly greater similarity to bacterial EPSP synthases than to fungal EPSP synthases. A genomic clone containing an EPSP synthase gene was isolated from a library of petunia DNA and was shown to contain seven intervening sequences. This gene is expressed approximately 25-fold higher in flower petals than in other organs of petunia. Transcription of this gene is initiated at multiple sites in petunia leaves and in a glyphosate-tolerant petunia cell line overproducing EPSP synthase mRNA. In petals, however, transcription of this gene is initiated almost entirely from only one of these sites. In contrast to petunia, the levels of EPSP synthase mRNA in different organs of tomato do not differ significantly.


Differential effects of mixtures of cholesterol oxidation products on bovine aortic endothelial cells and human monocytic U937 cells.
Cholesterol oxidation products or oxysterols are of interest due to their hypothesized role in the development of atherosclerosis. The objective of the present study was to assess the cytotoxic effects of mixtures of oxysterols: 25-hydroxycholesterol (25-OHC), 7beta-hydroxycholesterol (7beta -OHC), and cholesterol-5beta,6beta -epoxide (beta -epox) on two cell types associated with the atherosclerotic process, bovine aortic endothelial (BAE) cells and human monocytic U937 cells. Cells were exposed to 25-OHC, 7beta -OHC, or beta -epox, or equimolar mixtures (30 mu M) of 25-OHC and 7beta -OHC, 25-OHC and beta-epox, or 7beta-OHC and beta -epox for 48 h. Cell viability was assessed using the fluorescein diacetate/ethidium bromide (FDA/ EtBr) assay and nuclear morphology following staining with Hoechst 33342. 25-OHC was the least toxic of the oxysterols and did not induce apoptosis in either cell line. Both 7beta-OHC and beta -epox treatments were cytotoxic and induced apoptosis in the cells. Cotreatment with 25-OHC did not alter the toxicity of 7beta -OHC and beta -epox in U937 cells but did decrease the percentage apoptotic cell death. In contrast, in the BAE cells cotreatment with 25-OHC had a slight protective effect on 7beta -OHC and beta-epox-induced toxicities and a marked decrease in apoptotic cell death. The 7beta -OHC and beta -epox mixture induced a significant increase in apoptotic cell death in U937 cells but decreased this mode of cell death in the BAE cells. The effects of oxysterols on glutathione levels also differed between the cells with changes noted in U937 and not in BAE cells. Results demonstrate interactive effects when oxysterols are studied as mixtures rather than single compounds in vitro.


Anticoagulant Effects of Heparin Complexes with Prolyl-Glycine Peptide and Glycine and Proline Amino Acids.
The study demonstrates the formation of heparin complexes with prolyl-glycine peptide and proline and glycine amino acids. The method was developed for in vitro production of these complexes at 1:1 dipeptide to heparin molar ratio and 2:1 amino acid to heparin molar ratio. These complexes, unlike the constituents, proline and glycine, exhibited significant anticoagulant, antiplatelet, and fibrin-depolymerization activities of varying degree in vitro and in vivo. The heparin-dipeptide complex produced maximum effect. The dipeptide by itself also showed anticoagulant properties, but less pronounced than in the complex with heparin.


Does green finance promote green innovation? Evidence from China.
The green finance sector is key to accelerating the green transformation of economic structures and promoting green economic growth. However, understanding how to effectively combine green finance and green innovation is still in the exploratory stage. Using the implementation of the Green Credit Guidelines (hereinafter Guidelines) in 2012 as a quasi-natural experiment, we examine the causal relationship between green finance and green innovation. According to our findings, the green innovation performance of green credit-restricted industries improved significantly after the implementation of the Guidelines, although quality improvements of green innovation were not evident. This was a result of improved management efficiency and investment efficiency. Additionally, the Guidelines appear to have a more positive impact on green innovation for firms with lower levels of managerial short-termism or firms in regions with stronger environmental law enforcement. Green innovation can significantly enhance the environmental and social performance of a company.


Effects of polar carotenoids on dimyristoylphosphatidylcholine membranes: a spin-label study.
Spin labeling methods were used to study the structure and dynamic properties of dimyristoylphosphatidylcholine (DMPC) membranes as a function of temperature and the mole fraction of polar carotenoids. The results in fluid phase membranes are as follows: (1) Dihydroxycarotenoids, zeaxanthin and violaxanthin, increase order, decrease motional freedom and decrease the flexibility gradient of alkyl chains of lipids, as was shown with stearic acid spin labels. The activation energy of rotational diffusion of the 16-doxylstearic acid spin label is about 35% less in the presence of 10 mol% of zeaxanthin. (2) Carotenoids increase the mobility of the polar headgroups of DMPC and increase water accessibility in that region of membrane, as was shown with tempocholine phosphatidic acid ester. (3) Rigid and highly anisotropic molecules dissolved in the DMPC membrane exhibit a bigger order of motion in the presence of polar carotenoids as was shown with cholestane spin label (CSL) and androstane spin label (ASL). Carotenoids decrease the rate of reorientational motion of CSL and do not influence the rate of ASL, probably due to the lack of the isooctyl side chain. The abrupt changes of spin label motion observed at the main phase transition of the DMPC bilayer are broadened and disappear at the presence of 10 mol% of carotenoids. In gel phase membranes, polar carotenoids increase motional freedom of most of the spin labels employed showing a regulatory effect of carotenoids on membrane fluidity. Our results support the hypothesis of Rohmer, M., Bouvier, P. and Ourisson, G. (1979) Proc. Natl. Acad. Sci. USA 76, 847-851, that carotenoids regulate the membrane fluidity in Procaryota as cholesterol does in Eucaryota. A model is proposed to explain these results in which intercalation of the rigid rod-like polar carotenoid molecules into the membrane enhances extended trans-conformation of the alkyl chains, decreases free space in the bilayer center, separate the phosphatidylcholine headgroups and decreases interaction between them.


Miliary pulmonary nodules due to Mycobacterium xenopi in a steroid-induced immunocompromised patient successfully treated with chemotherapy: a case report.
Mycobacterium xenopi-infected patients have a high prevalence of pulmonary cavities and nodules. However, the clinical course for patients with miliary nodules due to M. xenopi has not yet been reported. We encountered a case of miliary nodules with gradually worsening coughing and sputum production in a 44-year-old male who had renal dysfunction due to glomerulosclerosis with a decade-long history of steroid therapy. Although we started anti-tuberculosis treatment on clinical suspicion of miliary tuberculosis, cultures of sputum and bronchial lavage were both positive for M. xenopi. The patient was successfully treated with rifampin, ethambutol and clarithromycin, without fibrosis. It was unclear whether the miliary pattern was induced by hematogenous or endobronchial spread of the M. xenopi infection. Even when clinical and radiological disease manifestations are similar to those of miliary tuberculosis, M. xenopi infection should be considered in the differential diagnosis of miliary nodules.


Respiratory function in the elderly.
Aging reduces the reserve capacity of virtually all pulmonary functions. Age-related alterations in the respiratory system are based on structural changes that lead to functional impairment of gas exchange. Pulmonary complications during anesthesia and the postoperative period are significantly increased in elderly patients with pre-existing diseases. The physiologic changes in the aged respiratory system and their anesthetic implications are reviewed in this article.


Management of tracheomalacia in association with congenital tracheo-oesophageal fistula.
Tracheomalacia is commonly associated with oesophageal atresia and tracheo-oesophageal fistula. Severe cases may present with life threatening cyanotic and apnoeic attacks following surgical repair of the oesophageal atresia. The anaesthetic, and surgical management (by tracheopexy), of such a case are described.


Type of hematological malignancy is crucial for the return to work prognosis: a register-based cohort study.
The aims of this study were to determine the proportion of return to work (RTW) among sick-listed patients diagnosed with one of eight subtypes of hematological malignancies; to evaluate the influence of type of hematological malignancy, comorbidity, use of anxiolytics and antidepressants, socioeconomic and demographic factors on RTW; and to investigate if these associations differ between genders. We combined data from national registers on all Danish patients diagnosed with hematological malignancies between 2000 and 2007. A total of 1,741 patients on long-term sick leave were followed until RTW, emigration, permanent withdrawal from the labor market, death, or February 2012, whichever came first. A total of 1,140 (65 %) patients returned to work. A strong association was found between type of diagnosis and RTW (p < 0.001), and the proportion of RTW was lowest for patients with multiple myeloma or acute leukemia compared to patients with Hodgkin lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, chronic myeloid leukemia, and chronic lymphoid leukemia. Use of antidepressants or anxiolytics after diagnosis, gender, age, and educational level were also associated with RTW. Surprisingly, comorbidity was not associated with RTW (p = 0.94); gender only modified the association between age and RTW. Two thirds of patients with hematological malignancies on sick leave RTW. A number of factors seem to lead to a poor prognosis, the hematological diagnosis being the most important, and these should be taken into account when performing studies on work outcome for patients with hematological malignancies. Knowledge in this area should assist in identification of hematological cancer patients at risk of not returning to work so that early targeted rehabilitation interventions can be initiated.


Shared neuroendocrine patterns of post-traumatic stress disorder and alexithymia.
High norepinephrine/cortisol ratios have been shown to be useful indicators of post-traumatic stress disorder (PTSD). Alexithymia can result from overwhelming stress; thus, we hypothesized that sympathetic-adrenal medullary/hypothalamic-pituitary adrenal ratios would be positively associated with alexithymia severity. In the present study, we correlated 3-methoxy-4-hydroxyphenylethylene glycol (MHPG)/adrenocorticotropic hormone (ACTH) and MHPG/cortisol ratios with self-report Toronto Alexithymia Scale (TAS) scores in a group (n = 17) of nondepressed, formerly alcohol-dependent men. The correlations between the respective ratios and TAS scores were 0.515 (p = 0.034) and 0.561 (p = 0.019). We suggest that increasing degrees of alexithymia are accompanied by an increasing separation of these two endocrine systems and then speculate that this dissociation has an anatomical basis in the lateralization of emotions.


Uptake and intracellular distribution of collagen-functionalized single-walled carbon nanotubes.
Carbon nanotubes (CNTs) have shown great potential for biological and medical applications because of their intrinsic unique properties. However, applications of CNTs have been severely restricted by their super-hydrophobicity and easy aggregation in aqueous medium, which are related to cytotoxicity and other negative cellular effects. In this study, single-walled carbon nanotubes (SWCNTs) were functionalized with collagen (collagen-SWCNTs). The collagen-SWCNTs retained the inherent properties of SWCNTs and the suspension solution was stable for months. The cellular effects, uptake and intracellular distribution of the collagen-SWCNTs were investigated by using them for culture of bovine articular chondrocytes (BACs). The collagen-SWCNTs showed no obvious negative cellular effects and high amount of SWCNTs were internalized by cells. The internalized collagen-SWCNTs were distributed in the perinuclear region and retained in the cells for more than one week. Adsorption of SWCNTs by extracellular matrix (ECM) was shown to be an important step for cellular uptake of SWCNTs. The high stability, easy cellular uptake and long retention in cells of the collagen-SWCNTs will facilitate the biomedical and biotechnological applications of SWCNTs.


Long-term efficacy of mexiletine alone and in combination with class Ia antiarrhythmic drugs for refractory ventricular arrhythmias.
The efficacy of mexiletine used alone, and in combination with a class Ia antiarrhythmic drug, was assessed in 159 previously drug-refractory patients with ventricular tachycardia (VT) during serial electrophysiologic studies and during long-term (5-year) clinical follow-up. Electrically-inducible ventricular tachycardia was suppressed by mexiletine alone in 23% of patients tested, and a combined antiarrhythmic drug regimen was effective in 29% of the trials performed. Mexiletine was much more likely to be effective in patients presenting with nonsustained VT or ventricular fibrillation than in patients with sustained VT (p less than 0.005). After 1 and 4 years of treatment, 18% and 42% of the patients treated with mexiletine alone had died suddenly or suffered recurrent symptomatic VT, compared to 11% and 25% of patients treated with the combined antiarrhythmic drug regimens (p = NS). Mexiletine therapy was associated with frequent, though readily reversible, adverse reactions. However, mexiletine treatment had to be discontinued permanently in 8 of 92 patients (9%) because of intolerable side effects. We conclude that the added efficacy and possible improved arrhythmia-free survival associated with combining mexiletine with a class Ia agent should be further investigated.


The Perceptual Basis of Vast Space.
"Vast" is a word often applied to environmental terrain that is perceived to have large spatial extent. This judgment is made even at viewing distances where traditional metric depth cues are not useful. This paper explores the perceptual basis of vast experience, including reliability and visual precursors. Experiment 1 demonstrated strong agreement in ratings of the spatial extent of two-dimensional (2D) scene images by participants in two countries under very different viewing conditions. Image categories labeled "vast" often exemplified scene attributes of ruggedness and openness (Oliva & Torralba, 2001). Experiment 2 quantitatively assessed whether these properties predict vastness. High vastness ratings were associated with highly open, or moderately open but rugged, scenes. Experiment 3 provided evidence, consistent with theory, that metric distance perception does not directly mediate the observed vastness ratings. The question remains as to how people perceive vast space when information about environmental scale is unavailable from metric depth cues or associated scene properties. We consider possible answers, including contribution from strong cues to relative depth.


Laser resonance ionization mass spectrometry measurements of cesium in nuclear burn-up and sediment samples.
Isotopic ratio measurements of 135Cs to 137Cs were performed using both resonance ionization mass spectrometry (RIMS) and thermal ionization mass spectrometry (TIMS) to determine the chronological age of nuclear fuel burn-up samples. Initial measurements on a lake sediment sample are being performed at NIST for determination of cesium content in the sample. Atomization behavior of the graphite furnace source, the overall efficiency and selectivity were measured for different sample preparations. Single-resonance excitation 6s 2S1/2 (F=4) --> 6p 2P3/2 (F' = 5) with an extended cavity diode laser followed by photoionization with the 488nm line of an argon ion laser yielded optical selectivity for 135Cs and 137Cs of more than two orders of magnitude against stable 133Cs and overall selectivity of 10(8). An overall efficiency of 5 x 10(-7) was measured for standard 133Cs solutions and for the nuclear fuel burn-up samples.


Oxysterols, but not cholesterol, inhibit human immunodeficiency virus replication in vitro.
Oxysterols, oxygenated derivatives of cholesterol selected for their cytostatic activity and their inhibitory effect on cholesterol synthesis, have been investigated for their anti-human immunodeficiency virus (HIV) activity in vitro. The three oxysterols tested, 7 beta-hydroxycholesterol (7 beta-OHC), 25-hydroxycholesterol (25-OHC) and 7 beta, 25-dihydroxycholesterol (7,25-OHC), inhibit viral replication at micromolar concentrations. The selectivity indexes for 7 beta-OHC and 25-OHC are quite modest (2 to 8) but reproducible; the dihydroxycholesterol 7,25-OHC exhibited antiviral properties at concentrations 13- to 25-fold lower than the highest concentration tested at which no toxicity was measurable. Oxysterols are naturally occurring compounds, and we speculate on their physiological relevance in HIV-infected individuals.


Assembly of Multigene Constructs Using the Modular Cloning System MoClo.
Modular cloning systems that rely on type IIS enzymes for DNA assembly have many advantages for complex pathway engineering. These systems are simple to use, efficient, and allow users to assemble multigene constructs by performing a series of one-pot assembly steps, starting from libraries of cloned and sequenced parts. The efficiency of these systems also facilitates the generation of libraries of construct variants. We describe here a protocol for assembly of multigene constructs using the Modular Cloning system MoClo. Making constructs using the MoClo system requires users to first define the structure of the final construct to identify all basic parts and vectors required for the construction strategy. The assembly strategy is then defined following a set of standard rules. Multigene constructs are then assembled using a series of one-pot assembly steps with the set of identified parts and vectors.


Microwave-assisted solubilization and solution properties of hyperbranched polysaccharide.
A water-insoluble hyperbranched beta-d-glucan (TM3a), extracted from sclerotia of Pleurotus tuber-regium, was treated by microwave exposure to improve its solubility in water. This method led to complete dissolution of the TM3a polysaccharide in 0.02 wt% aqueous NaN(3). Various treatment periods were tested, and optimal conditions corresponded to 35s at 765W. The solution properties of TM3a in water were studied systematically by using size-exclusion chromatography combined with laser light scattering, viscometry, and dynamic light scattering at 25 degrees C. The dependences of intrinsic viscosity ([eta]), radius of gyration (S(2)(z)(1/2)), and hydrodynamic radius (R(h)) on weight average molecular weight (M(w)) for TM3a in 0.02 wt% aqueous NaN(3) at 25 degrees C were found to be [eta]=3.02x10(-2)M(w)(0.44+/-0.1)(cm(3)g(-1)), S(2)(z)(1/2)=8.32x10(-2)M(w)(0.38+/-0.2)(nm), and R(h)=4.37x10(-2)M(w)(0.46+/-0.08)(nm) in the M(w) range from 8.20x10(5) to 4.88x10(6). The fractal dimension, ratio of rho=S(2)(z)(1/2)R(h), and the <r(2)>(o)/M(w) value of TM3a were calculated and discussed. The results indicated that TM3a existed in a sphere-like conformation in 0.02wt% aqueous NaN(3). Furthermore, by using transmission electron microscopy, we observed directly the spherical molecules of TM3a. This work gave valuable information on improvement of solubility and chain conformation characterization of the water-insoluble polysaccharide in water.


Photic responses of suprachiasmatic area neurons in diurnal degus (Octodon degus) and nocturnal rats (Rattus norvegicus).
Photic sensitivity of cells in the suprachiasmatic nuclei (SCN), the principal pacemaker of the mammalian circadian system, has been documented in several species. In nocturnal rodents, the majority of photically responsive SCN cells are activated by retinal illumination. One report identified mostly photic suppressions among SCN cells in a diurnal rodent, studied under somewhat different conditions. We examined photic sensitivity of SCN cells in a predominantly diurnal rodent, the degu, studied in vivo under identical conditions to rats, and found that a large majority of photic SCN cells were suppressed by light. In both rats and degus, SCN cells were more responsive to light during the subjective night than during the subjective day. Light-responsive cells did not show a daily rhythm in baseline firing rates in either species, but rat SCN cells that did not respond to light were more active spontaneously during the subjective day. Light-unresponsive SCN cells in degus did not show a similar pattern. There are substantial differences in the neurophysiological activity and photic responsiveness of SCN cells in diurnal degus and nocturnal rats.


Dicaesium tetra-magnesium penta-kis-(carbonate) deca-hydrate, Cs2Mg4(CO3)5·10H2O.
The title carbonate hydrate, Cs2Mg4(CO3)5·10H2O, was crystallized at room temperature out of aqueous solutions containing caesium bicarbonate and magnesium nitrate. Its monoclinic crystal structure (P21/n) consists of double chains of composition 1 ∞[Mg(H2O)2/1(CO3)3/3], isolated [Mg(H2O)(CO3)2]2- units, two crystallographically distinct Cs+ ions and a free water mol-ecule. The crystal under investigation was twinned by reticular pseudomerohedry.


Effect of cycloheximide on glucagon-induced autophagy. Quantitative examinations on hepatocytes in the rat.
By means of fine structural evaluation, a highly significant inhibitory effect of cycloheximide (20 mg/kg) on glucagon-induced autophagy is demonstrated in rat hepatocytes, which also presumably affects physiologic autophagic activities. Contrary to other investigators, we think in vivo global inhibition experiments using cycloheximide as an inhibitor of protein synthesis do not provide substantial information on the origin of the segregating membranes.


Chitosan polyplex nanoparticle vector for miR-145 expression in MCF-7: Optimization by design of experiment.
miR-145, a tumor suppressor micro RNA (miRNA), is down regulated in cancer and can be introduced as a therapeutic agent in various cancers including breast cancer. In this study, miR-145 plasmid was transfected to MCF-7 cells using chitosan polyplex nanoparticles. The vector was prepared according to an optimized fabricating method determined by response surface analysis and D-optimal design. Effects of chitosan molecular weight (Mw) and polymer amine to DNA phosphate ratio (N/P) as the variables were investigated on size, zeta potential, stability, and transfection efficiency of the polyplex nanoparticles. The results indicated that there is an interaction between effects of Mw and N/P ratio on the size of nanoparticles. Gel retardation assay demonstrated that the stability of the complexes in serum and preparation medium during storage time depends on the formulation variables. Statistical analysis affirmed that in spite of particle size, the variables of N/P ratio, time of incubation, and zeta potential affect the gene transfection. In conclusion, by selecting the perfect formulation prepared through an optimized method, it is possible to achieve a high transfection efficacy for miR-145 as an anticancer biological macromolecule.


Nanomedicines for Endothelial Disorders.
The endothelium lines the internal surfaces of blood and lymphatic vessels and has a critical role in maintaining homeostasis. Endothelial dysfunction is involved in the pathology of many diseases and conditions, including disorders such as diabetes, cardiovascular diseases, and cancer. Given this common etiology in a range of diseases, medicines targeting an impaired endothelium can strengthen the arsenal of therapeutics. Nanomedicine - the application of nanotechnology to healthcare - presents novel opportunities and potential for the treatment of diseases associated with an impaired endothelium. This review discusses therapies currently available for the treatment of these disorders and highlights the application of nanomedicine for the therapy of these major disease complications.


Bacterial expression of the capsid antigen domain and identification of native gag proteins in spumavirus-infected cells.
A bacterial expression plasmid containing the central part of the gag gene of the human spumaretrovirus (HSRV) was constructed and expressed in E. coli. The expected protein product consisting of the complete region of the HSRV capsid antigen and part of the matrix protein was expressed in relatively large amounts. Polyclonal antisera raised against this recombinant protein were used to identify authentic gag precursors of 78 and 74 kDa and processed gag proteins of 60, 58, and 33 kDa in HSRV-infected human embryonal fibroblast cells by radioimmunoprecipitation. The recombinant antigen will be useful for the detection of antibodies against HSRV gag proteins in human sera.


Dopamine Enhances the Resistance of Apple to Valsa mali Infection.
Apple Valsa canker is considered one of the most serious apple diseases. Dopamine is a catecholamine with key physiological functions in plants. Tyrosine decarboxylase (TYDC) is not only involved in the synthesis of dopamine in plants but may also play an important role in the resistance of plants to pathogen infection. In this study, we show that 100-μM exogenous dopamine application and Malus domestica TYDC (MdTYDC) overexpression (or overexpressing, OE) enhances the resistance of apple to Valsa mali infection, likely because the increased dopamine content reduces the accumulation of H2O2 and increases the accumulation of phenolic compounds and salicylic acid (SA) in dopamine-treated and OE apple plants. The activity of chitinase and β-1, 3-glucanase and the expression of SA-related genes were induced more strongly by V. mali in dopamine-treated and OE apples. The dopamine content was significantly higher in dopamine-treated and OE apples than in their respective controls under both normal and inoculated conditions (P < 0.05). Overall, these findings indicate that the application of exogenous dopamine and the OE of MdTYDC may enhance the resistance of apples to V. mali infection by altering the dopamine content, which improves antioxidant capacity, promotes the accumulation of phenolic compounds and SA, and enhances the activity of disease resistance-related proteins.


Tumor-associated lymphoid cells: analysis of host cells that bind to syngeneic and allogeneic tumor cells shortly after tumor administration.
A single intraperitoneal injection of irradiated EL-4 leukemia into syngeneic hosts induced in vivo immunity and in vitro cell-mediated response against EL-4. A nonadherent, theta-positive, peritoneal exudate lymphocyte fraction that bound to and lysed EL-4 in vitro was isolated from the tumor site. This system allowed the study of immune processes involving host lymphocytes as early as 3 days after tumor inoculation.


Glycogen accumulation in normal and irradiated minced muscle autografts on frog gastrocnemius.
Alterations induced in glycogen content and phosphorylase activity have been studied in normal and irradiated minced muscle autografts on frog gastrocnemius at days 1, 3, 5, 7, 10, 15 and 30 postgrafting. The changes observed in the glycogen content and phosphorylase activity conform to the degeneration and regeneration phases of muscle repair. An attempt has been made to explain the altered glycogen utilizing capacities of the frog skeletal muscle during its repair and regeneration.


Distraction and driving: results from a case-control responsibility study of traffic crash injured drivers interviewed at the emergency room.
Use of cellular phones has been shown to be associated with crashes but many external distractions remain to be studied. To assess the risk associated with diversion of attention due to unexpected events or secondary tasks at the wheel. Responsibility case-control study. Adult emergency department of the Bordeaux University Hospital (France) from April 2010 to August 2011. 955 injured drivers presenting as a result of motor vehicle crash. The main outcome variable was responsibility for the crash. Exposures were external distraction, alcohol use, psychotropic medicine use, and sleep deprivation. Potential confounders were sociodemographic and crash characteristics. Beyond classical risk factor found to be associated with responsibility, results showed that distracting events inside the vehicle (picking up an object), distraction due to driver activity (smoking) and distracting events occurring outside were associated with an increased probability of being at fault. These distraction-related factors accounted for 8% of injurious road crashes. Retrospective responsibility self-assessment. Diverted attention may carry more risk than expected. Our results are supporting recent research efforts to detect periods of driving vulnerability related to inattention.


"Yoga resets my inner peace barometer": A qualitative study illuminating the pathways of how yoga impacts one's relationship to oneself and to others.
The purpose of this qualitative study was twofold: (1) to better understand how yoga practitioners perceive intra- and interpersonal outcomes of their yoga practice, and (2) to develop a conceptual model of yoga effects on intra- and interpersonal outcomes that may underlie the "relational" influences of yoga. As part of a larger study, 107 community-dwelling yoga practitioners (age M=41.2±15.9years) completed open-ended questions which asked questions focusing on whether yoga influences one's relationship to oneself and to others. A subsample (n=12) completed in-depth interviews. The open-ended responses were analyzed using content analysis, and verbatim interview transcripts were analyzed for emergent themes using a constant comparison approach. Four emerging themes were identified such that practitioners talked about the ability of yoga to generate calm states, mindfulness, (self-)compassion, and a sense of connectedness. Throughout the themes, a common pattern emerged such that yoga practice first led to positive intrapersonal changes, which then influenced one's interpersonal relationships. Based on these results, a conceptual model was developed depicting potential pathways of how yoga works to enhance relational outcomes. Findings demonstrate the promise yoga holds to improve one's relationship to oneself (intrapersonal) through mindfulness and self-compassion, and to others (interpersonal), through the enhancement of compassion and social connectedness, which may potentially lead to enhanced health and wellbeing outcomes. Further empirical testing of the model is warranted.


Differential gene expression in peripheral blood T cells from patients with psoriasis, lichen planus, and atopic dermatitis.
Psoriasis, lichen planus (LP), and atopic dermatitis (AD) are common chronic inflammatory skin diseases mediated by immune responses. We used RNA sequencing to investigate messenger RNA expression patterns in peripheral T cells of Chinese patients with psoriasis, LP, or AD and of healthy individuals. After peripheral T-cell proliferation, messenger RNA expression patterns were investigated by RNA sequencing, and 6 randomly selected genes were verified by real-time reverse transcriptase polymerase chain reaction. Six genes were down-regulated and 33 were up-regulated in these diseases. Gene ontology analysis revealed enrichment of genes involved in positive regulation of T-cell activation. Regulation of nuclear premessenger RNA domain containing 1B (RPRD1B) expression was enhanced in psoriasis. The role of hereditary factors in RPRD1B expression in T cells was not considered. Immunomodulators (thymopeptide, levamisole, BCG polysaccharide, nucleic acid injection, and transfer factor) were previously given to patients with psoriasis and LP, but not to patients with AD; the effects of these immunomodulators on gene expression is uncertain. RPRD1B may be involved in T-cell activation in our Chinese psoriatic cohort, and may play a role in stimulating epidermal hyperproliferation.


Nobiletin alleviates myocardial ischemia-reperfusion injury via ferroptosis in rats with type-2 diabetes mellitus.
Susceptibility to myocardial ischemia-reperfusion (IR) injury in type-2 diabetes (T2DM) remains disputed, although studies have reported that ferroptosis is associated with myocardial IR injury. Nobiletin, a flavonoid isolated from citrus peels, is an antioxidant that possesses anti-inflammatory and anti-diabetic activities. However, it remains unknown whether nobiletin has any protective effects on susceptibility to myocardial IR injury during T2DM in rats via ferroptosis. To investigate the effects and underlying mechanisms of nobiletin on myocardial IR injury during T2DM, we induced myocardial IR model in rats at T2DM onset vs mature disease. We also established a high-fat high-glucose (HFHG) and hypoxia-reoxygenation (H/R) model in H9c2 cells to imitate abnormal glycolipid metabolism during T2DM. Myocardial injury, oxidative stress and ferroptosis towards myocardial IR in rats with mature T2DM but not at T2DM onset were increased. These changes were restored under treatment with ferrostain-1 or nobiletin. Both ferrostain-1 and nobiletin decreased the expression of ferroptosis-related proteins including Acyl-CoA synthetase long chain family member 4 (ACSL4) and nuclear receptor coactivator 4 (NCOA4) but not glutathione peroxidase 4 (GPX4) in rats with mature T2DM and cells with HFHG and H/R injury. Nobiletin strengthened the effect of si-ACSL4 on inhibiting ACSL4 expression, and also inhibited the effect of Erastin or oe-ACSL4 on increasing ACSL4 expression. Taken together, our data indicates that ferroptosis involves in susceptibility to myocardial IR injury in rats during T2DM. Nobiletin has therapeutic potential for alleviating myocardial IR injury associated with ACSL4- and NCOA4-related ferroptosis.


Altered ribostasis: RNA-protein granules in degenerative disorders.
The molecular processes that contribute to degenerative diseases are not well understood. Recent observations suggest that some degenerative diseases are promoted by the accumulation of nuclear or cytoplasmic RNA-protein (RNP) aggregates, which can be related to endogenous RNP granules. RNP aggregates arise commonly in degenerative diseases because RNA-binding proteins commonly self-assemble, in part through prion-like domains, which can form self-propagating amyloids. RNP aggregates may be toxic due to multiple perturbations of posttranscriptional control, thereby disrupting the normal "ribostasis" of the cell. This suggests that understanding and modulating RNP assembly or clearance may be effective approaches to developing therapies for these diseases.


Preliminary evaluation of two-row versus three-row circular staplers for colorectal anastomosis after rectal resection: a single-center retrospective analysis.
Circular staplers for colorectal anastomoses significantly ameliorated post-operative outcomes after rectal resection. The more recent three-row technology was conceived to improve anastomotic resistance and, thus, lower the incidence of anastomotic complications. The aim of this study was to evaluate potential advantages of three-row circular staplers (Three-CS) on anastomotic leakage (AL), stenosis (AS), and hemorrhage (AH) rates after rectal resection as compared to two-row circular staplers (Two-CS). All rectal resections for rectal cancer between 2016 and 2021 were retrospectively included. Patients were classified according to the circular stapler employed in Two-CS and Three-CS cohorts. AL, AS, and AH rates were compared between the two populations. Additionally, the prognostic role of the type of circular stapler on AL onset was evaluated. Three-hundred and seventy-five patients underwent a rectal resection with an end-to-end anastomosis during the study period: 197 constituted the Two-CS group and 178 the Three-CS cohort. AL rate was 6.7%, significantly higher in the Two-CS group (19-9.6%) as compared to the Three-CS cohort (6-3.4%) (p = 0.01). No difference was noted in terms of AL severity. Although not statistically significant, a lower incidence rate of AL was evidenced even in the subset of patients with low rectal cancers (4.5% vs 12.5% in the two-row cohort; p = 0.33). At the multivariate analysis, Two-CS was a negative prognostic factor for AL onset (OR: 2.63; p = 0.03). No difference was noted between the two groups in terms of AS and AH. Three-row CSs significantly decrease the rate of AL after rectal resection. Further multicenter controlled trials are still needed to confirm the advantages of three-row CSs on anastomotic complications.


Potential toxicity and affinity of triphenylmethane dye malachite green to lysozyme.
Malachite green is a triphenylmethane dye that is used extensively in many industrial and aquacultural processes, generating environmental concerns and health problems to human being. In this contribution, the complexation between lysozyme and malachite green was verified by means of computer-aided molecular modeling, steady state and time-resolved fluorescence, and circular dichroism (CD) approaches. The precise binding patch of malachite green in lysozyme has been identified from molecular modeling and ANS displacement, Trp-62, Trp-63, and Trp-108 residues of lysozyme were earmarked to possess high-affinity for this dye, the principal forces in the lysozyme-malachite green adduct are hydrophobic and π-π interactions. Steady state fluorescence proclaimed the complex of malachite green with lysozyme yields quenching through static type, which substantiates time-resolved fluorescence measurements that lysozyme-malachite green conjugation formation has an affinity of 10(3)M(-1). Moreover, via molecular modeling and also CD data, we can safely arrive at a conclusion that the polypeptide chain of lysozyme partially destabilized upon complexation with malachite green. The data emerged here will help to further understand the toxicological action of malachite green in human body.


Glucocorticoid regulation of mouse mammary tumor virus gene expression.
Glucocorticoid hormones act rapidly and specifically to stimulate the synthesis of mouse mammary tumor virus RNA in a variety of mouse mammary tumor cells and infected heterologous cells. The increase in viral RNA production appears to be mediated by receptor proteins and requires the presence of basal levels of viral RNA. Infection of heterologous cells with MMTV may alter host cell responses to glucocorticoids; in addition, production of unintegrated viral DNA in these cells has provided reagents required for studying the structure and function of the viral DNA itself. The advent of new techniques for genetic manipulation of eukaryotic cells and for isolation of large amounts of specific DNA sequences should now permit detailed analyses of steroid hormone action in this system.


Stability of latanoprost in an ophthalmic lipid emulsion using polyvinyl alcohol.
Latanoprost in water is not stable against heat stress due to hydrolysis of the isopropyl ester in the latanoprost molecule. Therefore, the storage condition of latanoprost ophthalmic solution, Xalatan brand, was in a low temperature (2-8 degrees C). We formulated a favorable ophthalmic lipid emulsion of latanoprost using polyvinyl alcohol as emulsifier which showed a good heat stability. The assays of the latanoprost ophthalmic lipid emulsions adjusted to pH 5.0, 6.0 and 7.0 were 100.4%, 100.7% and 99.2% after storage for 4 weeks at 60 degrees C, respectively. The possibility of room temperature storage for the latanoprost ophthalmic lipid emulsion was demonstrated.


Circulating insulin-like growth factor-I levels are correlated with the atherosclerotic profile in healthy subjects independently of age.
To investigate the relationships between the GH-IGF-I axis and the atherosclerotic profile, we designed this open, observational, prospective study. Peak GH after GHRH+arginine (ARG) test, serum IGF-I and IGF binding protein-3 (IGFBP-3), lipid profile, homeostasis model assessment (HOMA) index and intima-media thickness (IMT) at common carotid arteries were measured in 174 healthy individuals (92 women, 82 men, aged 18-80 yr). Exclusion criteria for this study were: 1) body mass index (BMI) > or = 30 kg/m2; 2) personal history of cardiovascular diseases; 3) previous or current treatments of diabetes or hypertension; 4) previous corticosteroids treatment for longer than 2 weeks or estrogens for longer than 3 months; 5) smoking of more than 15 cigarettes/day and alcohol abuse. Subjects were divided according to age in decade groups from < 20 to > 70 yr. BMI increased with age, as did systolic and diastolic blood pressures, although they remained in the normal range. The GH peak after GHRH+ARG test was significantly higher in the subjects aged < 20 yr than in all the other groups (p < 0.01), but was similar in the remaining groups. An inverse correlation was found between the IGF-I z-score and total/HDL-cholesterol ratio (p = 0.02) and mean IMT (p = 0.0009); IGFBP-3 z-score and mean IMT (p = 0.043); IGF: IGFBP-3 molar ratio and total/HDL-cholesterol ratio (p < 0.0001) and mean IMT (p < 0.0001). Atherosclerotic plaques were found in 7 out of 12 subjects (53.8%) with a z-IGF-I score from < or = -2 to -1, in 4 out of 63 (6.3%) with a z-IGF-I score from -0.99 to 0.1 out of 66 (1.5%) with a z-IGF-I score from 0.1 to 1 and none of the 33 subjects with an IGF-I z-score >1 (p = 0.006). At multi-step regression analysis, age was the best predictor of HDL-cholesterol levels and mean IMT, IGF-I level was the best predictor of total cholesterol and total/HDL-cholesterol ratio, the IGF-I/IGFBP-3 molar ratio was the best predictor of triglycerides levels. The z-scores of IGF-I and IGFBP-3 were the second best predictors of mean IMT after age. In conclusion, IGF-I and IGFBP-3 were negatively correlated with common cardiovascular risk factors, studied as total/HDL-cholesterol ratio, and/or early atherosclerosis, studied as IMT at common carotid arteries. The prevalence of atherosclerotic plaques, though not hemodinamically significant, was higher in the subjects having a z-score of IGF-I of < or = -2 to -1. Our results support a role of the IGF/IGFBP-3 axis in the pathogenesis of atherosclerosis.


Fibrillatory excitation in the pulmonary vein is associated with the presence of dissociated pulmonary vein activity after isolation.
Circumferential pulmonary vein (PV) isolation has been widely accepted for catheter ablation in patients with atrial fibrillation (AF). Dissociated PV activity might appear after PV isolation (PVI). However, little is known of dissociated PV activity. This study aimed to reveal the electrophysiological properties and clinical implications of dissociated PV activity. The study subjects were 52 patients (62 ± 7 years, 38 men) who underwent PVI for AF. Electrophysiological properties of the left atrium (LA) and PVs during and after PVI were investigated. Out of 181 targeted PVs, 177 with successful isolation were analyzed. Dissociated PV activity appeared in 14 PVs (8 %) in 12 patients (23 %) after PVI; from the left superior PV in eight, right superior PV in five, and left inferior PV in one. The mean cycle length of dissociated PV activity was 4277 ± 2565 ms. The presence of AF prior to achieving PVI was significantly higher in PV without dissociated PV activity (105 out of 163, 64 %) than in PV with dissociated PV activity (five out of 14, 36 %, P = 0.03). The observed dissociated PV activity was enhanced (new appearance or reduced cycle length) by isoproterenol and suppressed by pacing within the isolated PV. Dissociated PV activity, although influenced by uncertain factors such as overdrive suppression and autonomic situations, would be an indicator of LA-PV bidirectional block and might not be the target of additional ablation after PVI.


The significance of elevated early follicular-phase follicle stimulating hormone (FSH) levels: observations in unstimulated in vitro fertilization cycles.
Our objective was to determine the effect of elevated early follicular-phase serum follicle stimulating hormone (FSH) levels on follicle growth and oocyte maturity in unstimulated in vitro fertilization (IVF) cycles. We compared cycles with elevated day 3 FSH levels (> 20 mIU/ml) to subsequent cycles in the same patients when day 3 FSH returned to normal and to cycles among women with normal day 3 FSH levels. Seven cycles in seven patients had an elevated day 3 FSH (high-FSH group). These were compared to 11 subsequent cycles in which there was a return to a normal baseline FSH and to 13 cycles in 13 patients that entered the unstimulated protocol with a normal baseline day 3 FSH. The day of human chorionic gonadotropin (hCG) administration was similar in all groups as were the serum estradiol (E2) levels. Although the high-FSH group tended to have smaller maximum follicular diameters, the difference was not statistically significant. The highest FSH level on cycle day 3 in a completed cycle was 56.2 mIU/ml. The total number of oocytes aspirated and the number of embryos obtained was similar in all groups. Whereas there were no pregnancies in the high-FSH group, 2 of the subsequent 11 normal day 3 FSH cycles resulted in clinical pregnancies. Two of the 13 patients in the normal day 3 FSH values also achieved pregnancies. We conclude that cycle day 3 serum FSH levels as high as 56.2 mIU/ml may be associated with apparently normal follicular growth, oocyte fertilization, and embryo cleavage in unstimulated cycles. However, pregnancies are not observed. In addition, FSH levels vary widely from cycle to cycle and elevated levels in one cycle do not necessarily imply that pregnancy may not occur in a subsequent cycle when FSH levels return to normal.


The efficacy of chemotherapeutic agents against murine bladder metastasis.
Three chemotherapeutic agents, methotrexate, cyclophosphamide and cis-diamminedichloro-platinum (cis-platinum), were examined for their effectiveness against metastases in a murine transitional cell carcinoma model. Systemic treatment of the drugs was applied against a MBT-2 derived subline which generates 100% incidence of lung metastases in C3H mice by five weeks. The drugs were examined for their effect against the number of metastases, incidence of metastasis and size of the subcutaneously implanted primary tumor. All three compounds significantly reduced both the number of lung metastases and the incidence when compared to untreated animals. None of the agents proved 100% effective against metastatic tumors. These results suggest the existence of a chemotherapeutic resistant population of metastatic cells. Administration of methotrexate and cis-platinum effectively reduced the size of the primary tumor as compared to untreated animals. Cyclophosphamide did not significantly affect primary tumor size. The response of the antineoplastic agents against the metastatic tumor cells indicates that the L3F2 metastatic cell line is an effective model to study agents against metastatic bladder cancer.