Tumor suppressor CEBPA interacts with and inhibits DNMT3A activity.
DNA methyltransferases (DNMTs) catalyze DNA methylation, and their functions in mammalian embryonic development and diseases including cancer have been extensively studied. However, regulation of DNMTs remains under study. Here, we show that CCAAT/enhancer binding protein α (CEBPA) interacts with the long splice isoform DNMT3A, but not the short isoform DNMT3A2. CEBPA, by interacting with DNMT3A N-terminus, blocks DNMT3A from accessing DNA substrate and thereby inhibits its activity. Recurrent tumor-associated CEBPA mutations, such as preleukemic CEBPAN321D mutation, which is particularly potent in causing AML with high mortality, disrupt DNMT3A association and cause aberrant DNA methylation, notably hypermethylation of PRC2 target genes. Consequently, leukemia cells with the CEBPAN321D mutation are hypersensitive to hypomethylation agents. Our results provide insights into the functional difference between DNMT3A isoforms and the regulation of de novo DNA methylation at specific loci in the genome. Our study also suggests a therapeutic strategy for the treatment of CEBPA-mutated leukemia with DNA-hypomethylating agents.


The Effect of Fluoride Varnish on Enamel Shear Bond Strength of Pit and Fissure Sealants.
The purpose of this study was to determine the effects of fluoride varnish on the enamel shear bond strength of pit and fissure sealants. Ninety-six teeth were divided into three duplicated test groups: sealant (S)/sealant thermocycle (ST) received Clinpro Sealant only; varnish sealant (VS)/varnish sealant thermocycle (VST) received five percent sodium fluoride (NaF) varnish plus sealant (VPS); and VPS/VPS thermocycle (VPST) received NaF, polish with Clinpro Prophy Paste, plus sealant. One set of each group (ST, VST, VPST) was thermocycled to represent aging, and one set (S, VS, PVS) was not. The shear bond strengths for the thermocycled groups and nonthermocycled groups were determined, and two-way analysis of variance tested the effects of thermocycling and varnish. Thermocycling did not have a significant effect on the peak stresses of the groups (P=0.0552), so sets were combined. The peak stress for S/ST was significantly higher than for VS/VST (P<0.0001). The peak stress for VPS/VPST was significantly higher than for VS/VST (P<0.0001). The peak stress for S/ST was significantly higher than VPS/VPST (P=0.025). Fluoride varnish applied immediately before pit and fissure sealant placement negatively affected the shear bond strength of the sealant. Mechanically cleaning a fluoride varnish-coated tooth with prophy paste did not provide pit and fissure sealant enamel shear bond strengths comparable to those of untreated enamel.


Depletion of microRNA-451 in response to allergen exposure accentuates asthmatic inflammation by regulating Sirtuin2.
The incidence of asthma has increased from 5.5% to near 8% of the population, which is a major health concern. The hallmarks of asthma include eosinophilic airway inflammation that is associated with chronic airway remodeling. Allergic airway inflammation is characterized by a complex interplay of resident and inflammatory cells. MicroRNAs (miRNAs) are small noncoding RNAs that function as posttranscriptional modulators of gene expression. However, the role of miRNAs, specifically miR-451, in the regulation of allergic airway inflammation is unexplored. Our previous findings showed that oxidant stress regulates miR-451 gene expression in macrophages during an inflammatory process. In this paper, we examined the role of miR-451 in regulating macrophage phenotype using an experimental poly-allergenic murine model of allergic airway inflammation. We found that miR-451 contributes to the allergic induction of CCL17 in the lung and plays a key role in proasthmatic macrophage activation. Remarkably, administration of a Sirtuin 2 (Sirt2) inhibitor diminished alternate macrophage activation and markedly abrogated triple-allergen [dust mite, ragweed, Aspergillus fumigatus (DRA)]-induced lung inflammation. These data demonstrate a role for miR-451 in modulating allergic inflammation by influencing allergen-mediated macrophages phenotype.


Clinical comparison between glucose and sucrose additions to a basic electrolyte mixture in the outpatient management of acute gastroenteritis in children.
In a double-blind trial in 94 children attending outpatients the value of glucose or a sucrose addition to a basic electrolyte mixture for the management of acute gastroenteritis was compared. Of the children treated with added sucrose 10% failed to respond compared with 27% of those treated with added glucose. This difference was significant (P=0-05), but the time to recovery in those in the two groups who responded to treatment was not significantly different. Thus, despite theoretical advantages, there was no practical advantage in using glucose rather than sucrose. A 5% sucrose electrolyte solution with its relatively low osmolality, ready availability, and ease of preparation is recommended as the treatment of choice in the outpatient management of acute gastroenteritis in infancy.


Universal newborn hearing screening in Singapore: the need, implementation and challenges.
With about 1 in 1000 born with severe to profound hearing loss and about 5 in 1000 with lesser degrees of loss, congenital deafness is the commonest major birth defect. It is the recommended standard that hearing loss in newborns be detected by 3 months of age and intervention implemented by 6 months of age. Delayed detection and intervention may affect speech, language and psychosocial development, resulting in poor academic achievements. Universal newborn hearing screening (UNHS) is the only effective way of detecting all babies with hearing loss, within the recommended time frame. A survey in Singapore revealed that traditional childhood hearing screening programmes resulted in late detection (mean age, 20.8 months; range, 0 to 86 months) and late intervention (mean age, 42.4 months; range, 1 to 120 months). Increasingly, UNHS is becoming standard medical care in developed countries. In Singapore, UNHS has been implemented in all hospitals with obstetric services. Although a screening rate of more than 99% has been achieved in public hospitals, private hospitals have a screening rate of only about 77%. Parents' awareness and acceptance of early detection is still lacking, and this needs to be addressed by appropriate public education. Support from obstetricians and paediatricians will significantly contribute towards this objective. Effective programme management is essential; this includes the use of data management systems, the maintenance of a team of experienced screeners, and efficient coordination between screening and diagnostic services. Early detection of childhood deafness, together with early and effective intervention, maximises the chances of successful integration into mainstream education and society.


Evaluation in swine of a subunit vaccine against pseudorabies.
A subunit vaccine against pseudorabies virus (PRV) was prepared by treating a mixture of pelleted virions and infected cells with the nonionic detergent Nonidet P-40 and emulsifying the extracted proteins incomplete Freund's adjuvant. Three 7-week-old pigs without antibodies against PRV were given 2 IM doses of this vaccine 3 weeks apart. Thirty days after the 2nd vaccination, 10(6) median tissue culture infective doses (TCID50) of a virulent strain of PRV were administered intranasally. Tonsillar and nasal swabs were collected daily between 2 and 10 days after challenge exposure. The pigs vaccinated with the subunit vaccine were not found to shed virulent PRV. Two groups of five 7-week-old pigs vaccinated with commercially available vaccines, either live-modified or inactivated virus, and subsequently exposed to 10(6) TCID50 of virulent PRV, shed virulent virus for up to 8 days. The subunit vaccine induced significantly higher virus-neutralizing antibody titers than either the live-modified or inactivated virus vaccine.


Genetic risk scores associated with baseline lipoprotein subfraction concentrations do not associate with their responses to fenofibrate.
Lipoprotein subclass concentrations are modifiable markers of cardiovascular disease risk. Fenofibrate is known to show beneficial effects on lipoprotein subclasses, but little is known about the role of genetics in mediating the responses of lipoprotein subclasses to fenofibrate. A recent genomewide association study (GWAS) associated several single nucleotide polymorphisms (SNPs) with lipoprotein measures, and validated these associations in two independent populations. We used this information to construct genetic risk scores (GRSs) for fasting lipoprotein measures at baseline (pre-fenofibrate), and aimed to examine whether these GRSs also associated with the responses of lipoproteins to fenofibrate. Fourteen lipoprotein subclass measures were assayed in 817 men and women before and after a three week fenofibrate trial. We set significance at a Bonferroni corrected alpha <0.05 (p < 0.004). Twelve subclass measures changed with fenofibrate administration (each p = 0.003 to <0.0001). Mixed linear models which controlled for age, sex, body mass index (BMI), smoking status, pedigree and study-center, revealed that GRSs were associated with eight baseline lipoprotein measures (p < 0.004), however no GRS was associated with fenofibrate response. These results suggest that the mechanisms for changes in lipoprotein subclass concentrations with fenofibrate treatment are not mediated by the genetic risk for fasting levels.


Differences in in vitro proliferative responsiveness to granulocyte colony-stimulating factor and interleukin 2 of bone marrow cells from mice treated with chemotherapeutic drugs.
The toxicity effects of several anticancer drugs on normal mouse bone marrow (BM) were estimated using the in vitro proliferative responsiveness [( 3H]thymidine incorporation) of the treated BM cells to recombinant human granulocyte colony-stimulating factor (G-CSF) and recombinant human interleukin 2 (IL-2). From the response pattern of the treated BM cells to G-CSF and IL-2, the anticancer drugs were classified into three groups: (a) BM cells from cyclophosphamide- or nimustine hydrochloride-treated mice showed an increased responsiveness to G-CSF but a decreased responsiveness to IL-2; (b) BM cells from vindesine- or peplomycin-treated mice showed an increased responsiveness to both G-CSF and IL-2; and (c) BM cells from mitomycin C-treated mice showed a decreased responsiveness to both G-CSF and IL-2. These different response patterns may reflect qualitative differences in the myelotoxicity effects of these anticancer drugs.


RAB7A phosphorylation by TBK1 promotes mitophagy via the PINK-PARKIN pathway.
Removal of damaged mitochondria is orchestrated by a pathway involving the PINK1 kinase and the PARKIN ubiquitin ligase. Ubiquitin chains assembled by PARKIN on the mitochondrial outer membrane recruit autophagy cargo receptors in complexes with TBK1 protein kinase. While TBK1 is known to phosphorylate cargo receptors to promote ubiquitin binding, it is unknown whether TBK1 phosphorylates other proteins to promote mitophagy. Using global quantitative proteomics, we identified S72 in RAB7A, a RAB previously linked with mitophagy, as a dynamic target of TBK1 upon mitochondrial depolarization. TBK1 directly phosphorylates RAB7AS72, but not several other RABs known to be phosphorylated on the homologous residue by LRRK2, in vitro, and this modification requires PARKIN activity in vivo. Interaction proteomics using nonphosphorylatable and phosphomimetic RAB7A mutants revealed loss of association of RAB7AS72E with RAB GDP dissociation inhibitor and increased association with the DENN domain-containing heterodimer FLCN-FNIP1. FLCN-FNIP1 is recruited to damaged mitochondria, and this process is inhibited in cells expressing RAB7AS72A. Moreover, nonphosphorylatable RAB7A failed to support efficient mitophagy, as well as recruitment of ATG9A-positive vesicles to damaged mitochondria. These data reveal a novel function for TBK1 in mitophagy, which parallels that of LRRK2-mediated phosphorylation of the homologous site in distinct RABs to control membrane trafficking.


Rehabilitation Research in Denmark Between 2001 and 2020: A Scoping Review.
The demand for rehabilitation has increased, and evidence is rapidly growing; however, a rehabilitative health strategy receives less attention than treatment. Knowledge of what is being researched, who are the target groups and who contributes to rehabilitation research is deficient. We did not find any reviews mapping rehabilitation research regarding the research questions. The objective was to identify and synthesize existing scientific evidence on rehabilitation research published by Danish institutions between 2001 and 2021. The research questions to be explored were: Among which study groups has rehabilitation research been published?. Which types of studies on rehabilitation have been published?. Which institutions have been involved in rehabilitation research? The process was guided according to the Joanna Briggs Institute's (JBI's) scoping review methodology. Four databases were searched. All types of peer-reviewed studies on any target group and rehabilitation setting, with any affiliation to a Danish institution, were eligible to be included. Studies referring to population and the type of design were categorized. Institutions were counted as Danish first authorship. The search revealed 3,100 studies, and following screening 1,779 were included. A total of 24 broad study groups were identified, mostly diagnosis-based health conditions. Musculoskeletal, cancer, and cardiac had 342, 228, and 174 studies, respectively. A total of 1,545 had a Danish first authorship, most of the Danish publications came from hospitals (56.6%) and universities (28.4%). The publication trend showed an almost linear development, with a 10-15% increase during the period. Following screening 1,779 studies were included involving 24 broad study groups. Most categories were diagnosis-based; musculoskeletal, cancer, and cardiac health conditions encompassed most studies. All study designs were represented, and 1/10 were secondary studies. The majority (87%) of studies had a Danish first authorship. The majority of first affiliations were among hospitals followed by universities. A few municipalities were presented although they are yet to have research responsibility. Publication trends showed an increase primarily from 2013. https://osf.io/, identifier [10.17605/OSF.IO/2AENX].


Saikosaponin A inhibits the activation of pancreatic stellate cells by suppressing autophagy and the NLRP3 inflammasome via the AMPK/mTOR pathway.
Pancreatic stellate cells (PSCs) are the main effector cells in the development of pancreatic fibrosis. Finding substances that inhibit PSC activation is an important approach to inhibiting pancreatic fibrosis. Saikosaponin A (SSa) has numerous pharmacological activities, but its effect on PSCs remains unknown. This study was conducted to explore the effects of SSa on PSC activation in cultured rat PSCs. Cell viability, proliferation, migration and apoptosis were evaluated by MTT assays, the iCELLigence System, Transwell assays and flow cytometry. Markers of PSC activation, autophagy and the NLRP3 inflammasome were measured by real-time PCR, immunofluorescence and western blotting. Rapamycin and phenformin hydrochloride were used to determine the effect of SSa via the AMPK/mTOR pathway. The results showed that SSa suppressed PSC viability, proliferation, and migration and promoted apoptosis. SSa inhibited PSC activation, restrained PSC autophagy and suppressed the NLRP3 inflammasome. In addition, there was interaction between autophagy and the NLRP3 inflammasome during SSa inhibition of PSCs. Moreover, promotion of p-AMPK increased autophagy and the NLRP3 inflammasome. Inhibition of p-mTOR increased autophagy and decreased the NLRP3 inflammasome. Our results indicated that SSa inhibited PSC activation by inhibiting PSC autophagy and the NLRP3 inflammasome via the AMPK/mTOR pathway. These findings provide a theoretical basis for the use of SSa to treat pancreatic fibrosis and further suggest that targeting autophagy and the NLRP3 inflammasome may provide new strategies for the treatment of pancreatic fibrosis.


IL-6, a risk factor for hepatocellular carcinoma: FLLL32 inhibits IL-6-induced STAT3 phosphorylation in human hepatocellular cancer cells.
Hepatocellular carcinoma (HCC) is one of the most common human cancers and the patients' five-year survival rate is very low. Growing evidence indicates that interleukin-6 (IL-6) is a risk factor for HCC. High serum IL-6 may promote HCC development in hepatitis B patients. Therefore, IL-6 could be considered a HCC biomarker and blockade of IL-6 pathway may be a promising therapeutic alternative for HCC. STAT3 is major pathway to mediate signal from IL-6 to the nucleus, where different genes associated with proliferation and apoptosis are regulated. We previous reported that IL-6 induces cell survival upon drug treatment in HCC cells and inhibition of IL-6/STAT3 pathway using anti-IL-6 antibody or STAT3 small-molecule inhibitor LLL12 reduces this effect. Here we summarized the recent studies of IL-6 in HCC and showed another STAT3 small-molecule inhibitor FLLL32 also blocked IL-6-induced STAT3 activation in HCC cells. FLLL32 is a novel curcumin analogue, which has been described to suppress the constitutive activation of STAT3 in pancreatic and breast cancer cells in vitro and vivo. We demonstrated that FLLL32 blocked IL-6-induced STAT3 phosphorylation and nuclear translocation.


Training surgically competent doctors for South African rural settings.
The training of surgically competent doctors for South African rural settings is governed by several factors and determinants which include population demographics, distribution of doctors, infrastructural development and socio-economic conditions of the communities. Demands will be influenced by the disease profile, available facilities and academic support. Training options will include community-oriented/based (undergraduate) curriculum and restructured internship training period and acquisition of skills. Postgraduate diplomas and fellowships and continuing medical education and academic support will form an integral part of the training.


Erythropoietin suppresses the formation of macrophage foam cells: role of liver X receptor alpha.
In addition to the hematopoietic effect of erythropoietin, increasing evidence suggests that erythropoietin also exerts protective effects for cardiovascular diseases. However, the role of erythropoietin and its underlying mechanism in macrophage foam cell formation are poorly understood. Compared with wild-type specimens, erythropoietin was increased in atherosclerotic aortas of apolipoprotein E-deficient (apoE(-/-)) mice, mainly in the macrophage foam cells of the lesions. Erythropoietin levels in culture medium and macrophages were significantly elevated in response to oxidized low-density lipoprotein in a dose-dependent manner. Furthermore, erythropoietin markedly attenuated lipid accumulation in oxidized low-density lipoprotein-treated macrophages, a result that was due to an increase in cholesterol efflux. Erythropoietin treatment significantly increased ATP-binding cassette transporters (ABC) A1 and ABCG1 mRNA and protein levels without affecting protein expression of scavenger receptors, including scavenger receptor-A, CD36, and scavenger receptor-BI. The upregulation of ABCA1 and ABCG1 by erythropoietin resulted from liver X receptor alpha activation, which was confirmed by its prevention on expression of ABCA1 and ABCG1 after pharmacological or small interfering RNA inhibition of liver X receptor alpha. Moreover, the erythropoietin-mediated attenuation on lipid accumulation was abolished by such inhibition. Finally, reduced lipid accumulation and marked increase in ABCA1 and ABCG1 were demonstrated in erythropoietin-overexpressed macrophages. Our data suggest that erythropoietin suppresses foam cell formation via the liver X receptor alpha-dependent upregulation of ABCA1 and ABCG1.


Effect of colonic perfusion with sulfated and nonsulfated bile acids on mucosal structure and function in the rat.
A single-pass perfusion system was used in conscious restrained rats to measure changes in water and electrolyte transport and in protein and deoxyribonucleic acid output after perfusing 5-15-mM solutions of sulfated or nonsulfated bile acids through the colon. Perfusion with 5 mM nonsulfated deoxycholic acid or chenodeoxycholic acid changed net water and sodium absorption to net secretion, provoked marked increases in protein and DNA output into the perfusion effluent, and caused microscopic mucosal damage. In contrast, perfusion with 5 and 15 mM sulfated deoxycholic acid or with 5 mM sulfated chenodeoxycholic acid had no effect on water and electrolyte transport and caused only modest changes in protein and DNA output. To see whether or not sulfated bile acid could prevent the effect of its nonsulfated parent compound on colonic structure and function, perfusion with a mixture of 5 mM nonsulfated and 10 mM sulfated deoxycholic acid was performed. This produced net secretion of water and sodium together with less marked increases of protein and deoxyribonucleic acid output and less pronounced microscopic mucosal damage than was seen after 5 mM nonsulfated deoxycholic acid alone. Finally, 5 mM nonsulfated cholic acid had no effect on water or sodium transport, but 5 mM sulfated cholic acid, with one alpha-hydroxyl group masked and two alpha-hydroxyl groups "exposed," reduced water transport. These results suggest that sulfation prevents the cathartic effect of alpha-dihydroxyl bile acids in the colon.


Effects of Cold Water Immersion on Muscle Oxygenation During Repeated Bouts of Fatiguing Exercise: A Randomized Controlled Study.
Postexercise cold water immersion has been advocated to athletes as a means of accelerating recovery and improving performance. Given the effects of cold water immersion on blood flow, evaluating in vivo changes in tissue oxygenation during cold water immersion may help further our understanding of this recovery modality. This study aimed to investigate the effects of cold water immersion on muscle oxygenation and performance during repeated bouts of fatiguing exercise in a group of healthy young adults. Twenty healthy subjects performed 2 fatiguing bouts of maximal dynamic knee extension and flexion contractions both concentrically on an isokinetic dynamometer with a 10-min recovery period in between. Subjects were randomly assigned to either a cold water immersion (treatment) or passive recovery (control) group. Changes in muscle oxygenation were monitored continuously using near-infrared spectroscopy. Muscle performance was measured with isokinetic dynamometry during each fatiguing bout. Skin temperature, heart rate, blood pressure, and muscle soreness ratings were also assessed. Repeated measures ANOVA analysis was used to evaluate treatment effects. The treatment group had a significantly lower mean heart rate and lower skin temperature compared to the control group (P < 0.05). Cold water immersion attenuated a reduction in tissue oxygenation in the second fatiguing bout by 4% when compared with control. Muscle soreness was rated lower 1 day post-testing (P < 0.05). However, cold water immersion had no significant effect on muscle performance in subsequent exercise. As the results show that cold water immersion attenuated decreased tissue oxygenation in subsequent exercise performance, the metabolic response to exercise after cold water immersion is worthy of further exploration.


Triadic male-infant-male interaction serves in bond maintenance in male Assamese macaques.
While the ultimate consequences of social bonds start to be better understood, the proximate behavioural mechanisms underlying the formation and maintenance of these close affiliative relationships have received less attention. We investigated the possible function of male-infant-male interactions (MIMIs) in male-male social bonding processes by analysing about 9000h of focal animal observations collected on two groups of wild Assamese macaques. In support of an agonistic buffering function of MIMIs, after engaging in a MIMI upon approach, subordinates stayed longer in close proximity of a dominant male. Overall, the frequency of MIMIs increased the stronger the affiliative relationship between two males, suggesting that MIMIs like grooming function in relationship maintenance. We did not find support for a role of MIMIs in bond formation as the frequency of MIMIs did not affect the time a male dyad spent in proximity in the consecutive year. Our results contribute to the general debate on behaviours influencing social dynamics in group living mammals.


Identification and validation of telomerase related lncRNAs signature to predict prognosis and tumor immunotherapy response in bladder cancer.
Telomerase allows eukaryotic cells to proliferate indefinitely, an important characteristic of tumor cells. Telomerase-related long no coding RNAs (TERLs) are involved in prognosis and drug sensitivity prediction; however, their association with bladder cancer (BLCA) is still unreported. The objective of this research is to determine a predictive prognostic TERL signature for OS and to provide an efficient treatment option for BLCA. The RNA sequence, clinical information, and mutational data of BLCA patients were acquired from The Cancer Genome Atlas (TCGA) database. With the help of the data from least absolute shrinkage and selection operator (LASSO) regression and Cox regression, a prognostic signature was established including 14 TERLs, which could divide BLCA patients into low-risk (L-R) and high-risk (H-R) cohorts. The time-dependent receiver operating characteristic (ROC) curve demonstrated the greater predictive power of the model. By combing the TERLs-based signature and clinical risk factors (age, sex, grade, and stage), a prognostic nomogram was constructed to forecast the survival rates of patients with BLCA at 1-, 3-, and 5-years, which was well matched by calibration plots C-index and Decision curve analysis (DCA). Furthermore, the L-R cohort showed higher tumor mutation burden (TMB) and lower tumor immune dysfunction and exclusion (TIDE) than the H-R cohort, as well as substantial variability in immune cell infiltration and immune function between the two cohorts was elucidated. As for external validation, LINC01711 and RAP2C-AS1 were identified as poor prognostic factors by survival analysis from the Kaplan-Meier Plotter database, which were validated in BLCA cell lines (EJ, 253J, T24, and 5637) and SV-HUC-1 cells as the control group using qRT-PCR. In addition, interference with the expression of RAP2C-AS1 suppresses the proliferation and migration of BLCA cells, and RAP2C-AS1 could affect the expression of CD274 and CTLA4, which could serve as prognostic markers and characterize the tumor microenvironment in BLCA. Overall, the model based on the 14-TERLs signature can efficiently predict the prognosis and drug treatment response in individuals with bladder cancer.


Understanding the Barriers and Opportunities for Effective Management of Shared Sanitation in Low-Income Settlements-The Case of Kumasi, Ghana.
Improved sanitation for all is a daunting task for low-income countries, and shared toilets often provide an alternative to private household sanitation for most urban residents. This study sought to provide better understanding of the existing barriers and opportunities for improved management of shared sanitation. The study used focus group discussions and in-depth interviews with 70 users (landlords and tenants) of shared sanitation in Kumasi, Ghana to assess barriers and opportunities of "high-quality" shared sanitation. The commonly used toilet facilities were dry toilets-Kumasi Ventilated Improved Pit latrine and Ventilated Improved Pit latrines; and flush systems-water closet and pour flush connected to septic tanks. Between 2 and 21 households, or 4 and 84 people, shared one facility. Participants' description of "high-quality" (Ideal) shared sanitation was centred on cleanliness, user behaviour, smell, and user crowding. They also identified challenges of shared sanitation as overcrowded users, poor user behaviours, conflicts among users, and high cost associated with frequent desludging. However, opportunities for improvement included users' preference for shared toilets due to enjoyed benefits, existing facility management practices, and mutual understanding among users (tenants and landlords). Interventions and policy guidelines to influence behaviour change of shared sanitation users are proposed and are intended to be delivered by local government and users.


Examining antecedents of clean indoor air policy support: implications for campaigns promoting clean indoor air.
This investigation sought to examine the association between knowledge of the risks associated with environmental tobacco smoke and voter support for clean indoor air policies. In doing so, 2 antecedents were employed to enhance understanding of this relationship: attitudes and subjective norms. In addition, differences between nonsmokers and smokers were assessed across the aforementioned variables. The study sampled participants (N = 550) living in the Appalachian foothills as a means of conducting formative research prior to developing messages promoting clean indoor air policies. The study controlled for tobacco usage, age, biological sex, and income. Results revealed that awareness of risk is a good predictor of attitudes and social norms, and in return, attitudes and social norms are good predictors of support for clean indoor air policies. In addition, results reveal that nonsmokers maintain a significantly stronger belief in the dangers associated with environmental tobacco smoke, as well as more favorable attitudes, subjective norms, and support for clean indoor air policies when compared with smokers. These findings are discussed with a focus on message design strategies for practitioners and academics with interests in promoting clean indoor air policies.


Pancreatic blood flow in the rat during enlargement, involution, and cholecystokinin treatment.
We studied the effect of raw soya flour (RSF) given as a single gavage or for long-term periods on pancreatic blood flow. These effects were compared with the response to treatment with cholecystokinin (CCK) since it has been suggested that RSF feeding releases CCK. In acute experiments total pancreatic blood flow was significantly increased after infusion of CCK (60 Ivy dog units X kg-1 X h-1) and after gavage with preparations of RSF or heated soya flour (HSF). When expressed as flow per 100 g pancreatic weight, the greatest increase was seen after gavage with RSF. In separate chronic studies, total pancreatic blood flow was significantly increased in rats fed RSF for 4 wk compared with rats fed HSF, but because of pancreatic enlargement in rats fed RSF flow per 100 g pancreatic weight was similar in the two groups. When rats fed RSF for 4 wk were changed to standard rat cubes for 48 h before study, pancreatic blood flow (ml/min and ml X min-1 X 100 g pancreas-1) and total pancreatic DNA decreased significantly compared with rats fed RSF continuously. However, when CCK was infused intravenously during the 48-h period on cubes, pancreatic blood flow and DNA remained significantly increased and were not significantly different from values in rats fed RSF continuously. These results show that the effects of RSF feeding and CCK treatment on pancreatic growth and blood flow are similar and are consistent with the postulated role of CCK as the trophic hormone released by RSF feeding.


Recent trends in diagnoses of HIV and other sexually transmitted infections in England and Wales among men who have sex with men.
To examine trends in rates of diagnoses of HIV and other sexually transmitted infections (STIs) in men who have sex with men (MSM) in England and Wales between 1997 and 2002. Estimates of the MSM population living in England and Wales, London and the rest of England and Wales were applied to surveillance data, providing rates of diagnoses of HIV and STIs and age group specific rates for HIV and uncomplicated gonorrhoea. Between 1997 and 2002, rates of diagnoses of HIV and acute STIs in MSM increased substantially. Rates in London were higher than elsewhere. Rises in acute STIs were similar throughout England and Wales, except for uncomplicated gonorrhoea and infectious syphilis, with greater increases outside London. Rates of gonorrhoea diagnoses doubled between 1999 and 2001 (661/100,000, 1271/100,000, p<0.001) in England and Wales followed by a slight decline to 1210/100,000 (p=0.03) in 2002-primarily the result of a decline in diagnoses among men aged 25-34 (1340/100,000, 1128/100,000, p<0.001) and 35-44 (924/100,000, 863/100,000, p=0.03) in London. HIV was the third most common STI diagnosed in MSM in England and Wales and the second in London, with the highest rate (1286/100,000) found among men aged 35-44 in London in 2002. Rates of diagnosis of HIV and other STIs have increased substantially among MSM in England and Wales. Increases show heterogeneity by infection, geography, and age over time. Rates in London were twice those seen elsewhere, with greatest changes over time. The observed changes reflect concomitant increases in high risk behaviour documented in behavioural surveillance survey programmes.


[Short dual antiplatelet therapy: how, when and why].
Dual antiplatelet therapy (DAPT) is a cornerstone of antithrombotic treatment in patients undergoing percutaneous coronary intervention. The optimal duration of DAPT, i.e. the minimal period needed to ensure the best safety and efficacy, to prevent ischemic complications, including stent thrombosis, has been extensively explored in multiple randomized controlled trials over the last years. Accumulating evidence is supporting a clinical approach where there is a prevailing role of the risk of bleeding: in patients at high bleeding risk (HBR) it is generally advisable to reduce the duration of DAPT irrespective of their risk of thrombosis. In addition, among HBR patients, (i) new recommendations prefer direct oral anticoagulants (DOAC) over vitamin K antagonists in DOAC-eligible patients with atrial fibrillation and coronary artery disease; (ii) measures to minimize bleedings while on DAPT should be pursued, including de-escalation of P2Y12 receptor inhibitor therapy; and (iii) new studies are testing reversal strategies for short DAPT regimens, with early discontinuation of aspirin. In the present review, we discuss the rationale and decision-making considerations to reduce safely DAPT duration in HBR patients.


Online Versus Telephone Methods to Recruit and Interview Older Gay and Bisexual Men Treated for Prostate Cancer: Findings from the Restore Study.
Recently, researchers have faced the challenge of conflicting recommendations for online versus traditional methods to recruit and interview older, sexual minority men. Older populations represent the cohort least likely to be online, necessitating the use of traditional research methods, such as telephone or in-person interviews. By contrast, gay and bisexual men represent a population of early adopters of new technology, both in general and for medical research. In a study of older gay and bisexual men with prostate cancer, we asked whether respondents preferred online versus offline methods for data collection. Given the paucity of research on how to recruit older gay and bisexual men in general, and older gay and bisexual men with prostate cancer in particular, we conducted an observational study to identify participant preferences when participating in research studies. To test online versus offline recruitment demographic data collection, and interview preferences of older gay and bisexual men with prostate cancer. Email blasts were sent from a website providing support services for gay and bisexual men with prostate cancer, supplemented with an email invitation from the web-host. All invitations provided information via the study website address and a toll-free telephone number. Study tasks included respondents being screened, giving informed consent, completing a short survey collecting demographic data, and a 60-75 minute telephone or Internet chat interview. All materials stressed that enrollees could participate in each task using either online methods or by telephone, whichever they preferred. A total of 74 men were screened into the study, and 30 were interviewed. The average age of the participants was 63 years (standard deviation 6.9, range 48-75 years), with most residing in 14 American states, and one temporarily located overseas. For screening, consent, and the collection of demographic data, 97% (29/30) of the participants completed these tasks using online methods. For the interview, 97% (29/30) chose to be interviewed by telephone, rather than Internet chat. Older gay and bisexual men, when given choices, appear to prefer a mixed methods approach to qualitative investigations. For most aspects of the study, the older men chose online methods; the exception was the interview, in which case almost all preferred telephone. We speculate that a combination of the deeply personal nature of the topic (sexual effects of prostate cancer treatment), unfamiliarity with online chat, and possibly the subject burden involved in extensive typing contributed to the preference of telephone versus online chat. Recruitment of older men into this study showed good geographic diversity. We recommend that other qualitative researchers consider a mixed methods approach when recruiting older populations online.


Native topology or specific interactions: what is more important for protein folding?
Fifty-five molecular dynamics runs of two three-stranded antiparallel beta-sheet peptides were performed to investigate the relative importance of amino acid sequence and native topology. The two peptides consist of 20 residues each and have a sequence identity of 15 %. One peptide has Gly-Ser (GS) at both turns, while the other has d-Pro-Gly ((D)PG). The simulations successfully reproduce the NMR solution conformations, irrespective of the starting structure. The large number of folding events sampled along the trajectories at 360 K (total simulation time of about 5 micros) yield a projection of the free-energy landscape onto two significant progress variables. The two peptides have compact denatured states, similar free-energy surfaces, and folding pathways that involve the formation of a beta-hairpin followed by consolidation of the unstructured strand. For the GS peptide, there are 33 folding events that start by the formation of the 2-3 beta-hairpin and 17 with first the 1-2 beta-hairpin. For the (D)PG peptide, the statistical predominance is opposite, 16 and 47 folding events start from the 2-3 beta-hairpin and the 1-2 beta-hairpin, respectively. These simulation results indicate that the overall shape of the free-energy surface is defined primarily by the native-state topology, in agreement with an ever-increasing amount of experimental and theoretical evidence, while the amino acid sequence determines the statistically predominant order of the events.


Activity and follow-up 1978.
The total number of kidney grafts performed in Scandiatransplant is 3,915 of which 514 are from 1978. The waiting list seems to be stable at approx. 600 patients. The correlation of HLA-A, B matching and graft survival is highly significant. 3rd and 4th grafts have a much lower survival than 1st and 2nd. Overall results have decreased somewhat during the years.


Circular permutation of E. coli EPSP synthase: increased inhibitor resistance, improved catalytic activity, and an indicator for protein fragment complementation.
We performed the first circular permutation analysis for E. coli 5-enolpyruvylshikimate-3-phosphate synthase, and identified one circular permutant with notably increased resistance to its specific inhibitor and several others with moderately improved catalytic activity. Valid circular permutation sites can be used as effective split sites of protein fragment complementation.


Drosophila Rae1 controls the abundance of the ubiquitin ligase Highwire in post-mitotic neurons.
The evolutionarily conserved Highwire (Hiw)/Drosophila Fsn E3 ubiquitin ligase complex is required for normal synaptic morphology during development and axonal regeneration after injury. However, little is known about the molecular mechanisms that regulate the Hiw E3 ligase complex. Using tandem affinity purification techniques, we identified Drosophila Rae1 as a previously unknown component of the Hiw/Fsn complex. Loss of Rae1 function in neurons results in morphological defects at the neuromuscular junction that are similar to those seen in hiw mutants. We found that Rae1 physically and genetically interacts with Hiw and restrains synaptic terminal growth by regulating the MAP kinase kinase kinase Wallenda. Moreover, we found that the Rae1 is both necessary and sufficient to promote Hiw protein abundance, and it does so by binding to Hiw and protecting Hiw from autophagy-mediated degradation. These results describe a previously unknown mechanism that selectively controls Hiw protein abundance during synaptic development.


Development of a sea anemone toxin as an immunomodulator for therapy of autoimmune diseases.
Electrophysiological and pharmacological studies coupled with molecular identification have revealed a unique network of ion channels--Kv1.3, KCa3.1, CRAC (Orai1 + Stim1), TRPM7, Cl(swell)--in lymphocytes that initiates and maintains the calcium signaling cascade required for activation. The expression pattern of these channels changes during lymphocyte activation and differentiation, allowing the functional network to adapt during an immune response. The Kv1.3 channel is of interest because it plays a critical role in subsets of T and B lymphocytes implicated in autoimmune disorders. The ShK toxin from the sea anemone Stichodactyla helianthus is a potent blocker of Kv1.3. ShK-186, a synthetic analog of ShK, is being developed as a therapeutic for autoimmune diseases, and is scheduled to begin first-in-man phase-1 trials in 2011. This review describes the journey that has led to the development of ShK-186.


Monocarboxylate transporters in temporal lobe epilepsy: roles of lactate and ketogenic diet.
Epilepsy is a serious neurological disorder that affects approximately 1 % of the general population, making it one of the most common disorders of the central nervous system. Furthermore, up to 40 % of all patients with epilepsy cannot control their seizures with current medications. More efficacious treatments for medication refractory epilepsy are therefore needed. A better understanding of the mechanisms that cause this disorder is likely to facilitate the discovery of such treatments. Impairment in cerebral energy metabolism has been proposed as a possible causative factor in the pathogenesis of temporal lobe epilepsy (TLE), which is one of the most common types of medication-refractory epilepsies in adults. In this review, we will discuss some of the current hypotheses regarding the possible causal relationship between brain energy metabolism and TLE. Emphasis will be placed on the role of energy substrates (lactate and ketone bodies) and their transporter molecules, particularly monocarboxylate transporters 1 and 2 (MCT1 and MCT2). We recently reported that the cellular distribution of MCT1 and MCT2 is perturbed in the hippocampus in patients with TLE. The changes may be an adaptive response aimed at keeping high levels of lactate in the epileptic tissue, which may serve to counteract epileptic activity by downregulating cAMP levels through the lactate receptor GPR81, newly discovered in hippocampus. We propose that the perturbation of MCTs may be further involved in the pathophysiology of TLE by influencing brain energy homeostasis, mitochondrial function, GABA-ergic and glutamatergic neurotransmission, and flux of lactate through the brain.


Chronic typhlitis in baboons fed a semisynthetic low-fibre diet.
Baboons were fed a low-fibre, semisynthetic diet for 20 months. After this period, 19 of 20 animals were found to have chronic typhlitis at postmortem examination. In contrast, baboons that had been fed a similar diet for approximately 3 months, did not show this inflammatory change of the caecum. One baboon that was sacrificed after 10 months on the diet also did not have typhlitis. As no indications of an infectious or other cause could be found, it was ocncluded that the low fibre content of the diet might have been a causative factor of the typhlitis observed.


Polymyxin B suppresses the endotoxin inhibition of concanavalin a-mediated erythrocyte agglutination.
The lectin agglutinability of human erythrocytes has been utilized to examine interactions of gram-negative endotoxin with mammalian cell plasma membranes. Erythrocytes treated in buffer with Escherichia coli 0127:B8 lipopolysaccharide (LPS) or Salmonella minnesota Re595 glycolipid for 1 h became resistant to agglutination by the lectin concanavalin A (ConA) in buffer free of LPS or glycolipid. Polymyxin B, a cationic cyclic lipopeptide which specifically binds to the lipid A toxophore, was tested for possible effects on the LPS and glycolipid inhibition of Con A erythrocyte agglutination. The presence of polymyxin B during the initial 1-h treatment with LPS or glycolipid blocked the ability of the endotoxins to render erythrocytes refractory to agglutination by ConA. Inhibition by polymyxin B was stoichiometric, and in repeated experiments, LPS was completely suppressed in the hemagglutination assay at a polymyxin B:LPS weight ratio of 1:4.1 (increasing polymyxin concentration, constant LPS concentration) and 1:5.1 (constant polymyxin concentration, increasing LPS concentration). These stoichiometry values are similar to values obtained for inhibition by polymyxin B of LPS lymphoid cell activation. It was concluded, therefore, that endotoxin inhibition of ConA erythrocyte agglutination reflects interactions of erythrocyte membranes with the lipid A region of endotoxin. In addition, the stoichiometry of polymyxin B inhibition suggests a similar extent of lipid A-dependent LPS interaction with erythrocytes and lymphoid cells.


Simultaneous weekly supplementation of iron and zinc is associated with lower morbidity due to diarrhea and acute lower respiratory infection in Bangladeshi infants.
Given the high prevalence of micronutrient deficiencies and infectious diseases in infants in developing countries, an evaluation of the efficacy of different micronutrient formulations on infant morbidity is a priority. The efficacy of weekly supplementation of four different micronutrient formulations on diarrhea and acute lower respiratory infection (ALRI) morbidity was evaluated in Bangladeshi infants. In a double-blind, randomized, controlled community trial, 799 infants aged 6 mo were randomly assigned to one of the following 5 groups: 1) 20 mg elemental iron with 1 mg riboflavin, 2) 20 mg elemental zinc with 1 mg riboflavin, 3) 20 mg iron and 20 mg zinc with 1 mg riboflavin, 4) a micronutrient mix (MM) containing 20 mg iron, 20 mg zinc, 1 mg riboflavin along with other minerals and vitamins and 5) a control treatment, 1 mg riboflavin only. Health workers visited each infant weekly until age 12 mo to feed the supplement and to collect data on diarrhea and ALRI morbidity. Hemoglobin, serum ferritin and serum zinc levels of a sample of infants were measured at 6 and 12 mo. Compared with the control group, at 12 mo, serum ferritin levels were higher in the iron + zinc group, and serum zinc levels were higher in the zinc and iron + zinc groups. Simultaneous supplementation with iron + zinc was associated with lower risk of severe diarrhea, 19% lower in all infants and 30% lower in less well-nourished infants with weight-for-age Z-score below -1. Iron + zinc supplementation was also associated with 40% lower risk of severe ALRI in less well-nourished infants. MM supplementation was associated with a 15% higher risk of diarrhea in all infants and 22% higher risk in less well-nourished infants. Intermittent simultaneous supplementation with iron + zinc seems promising; it will be useful to determine whether higher doses would provide greater benefits.


Adult male circumcision: reflections on successes and challenges.
Voluntary medical male circumcision (VMMC) is a cost-effective HIV-prevention intervention that reduces the risk of HIV acquisition in men by 60%. Although some countries are successfully scaling up VMMC, not all are doing this. When VMMC scale-up experiences are viewed in the context of models for the diffusion of innovation, some important themes emerge. Successful VMMC programs have in common locally led campaigns, a cultural tolerance of VMMC, strong political leadership and coordination, and adequate human and material resources. Challenges with VMMC scale-up have been marked by less flexible implementation models that seek a full integration of VMMC services at public medical facilities and by struggles to achieve geographic parity in access to care. Innovation diffusion models, especially the endogenous technology model, and multiple levels of influence on diffusion--individual males and their sex partners, communities, and health systems--remind us that the adoption of a prevention intervention, such as VMMC, is expected to start out slowly and, as information spreads, gradually speed up. In addition, the diffusion models suggest that customizing approaches to different populations is likely to accelerate VMMC scale-up and help achieve a long-term, sustainable impact on the HIV epidemic.


The ZupT transporter plays an important role in zinc homeostasis and contributes to Salmonella enterica virulence.
Zinc is an essential metal for cellular homeostasis and function in both eukaryotes and prokaryotes. To acquire this essential nutrient, bacteria employ transporters characterized by different affinity for the metal. Several studies have investigated the role of the high affinity transporter ZnuABC in the bacterial response to zinc shortage, showing that this transporter has a key role in adapting bacteria to zinc starvation. In contrast, the role of the low affinity zinc importer ZupT has been the subject of limited investigations. Here we show that a Salmonella strain lacking ZupT is impaired in its ability to grow in metal devoid environments and that a znuABC zupT strain exhibits a severe growth defect in zinc devoid media, is hypersensitive to oxidative stress and contains reduced levels of intracellular free zinc. Moreover, we show that ZupT also plays a role in the ability of S. Typhimurium to colonize the host tissues. During systemic infections, the single zupT mutant strain was attenuated only in Nramp1(+/+) mice, but competition experiments between znuABC and znuABC zupT mutants revealed that ZupT contributes to metal uptake in vivo independently of the presence of a functional Nramp1 transporter. Altogether, the here reported results show that ZupT plays an important role in Salmonella zinc homeostasis, being involved in metal import both in vitro and in infected animals.


Evolution and Structural Characteristics of Plant Voltage-Gated K+ Channels.
Plant voltage-gated K+ channels have been referred to as "plant Shakers" in reference to animal Shaker channels, the first K+ channels identified. Recent advances in our knowledge of K+ channel evolution and structure have significantly deepened the divide between these plant and animal K+ channels, suggesting that it is time to completely retire the "plant Shaker" designation. Evolutionary genomics reveals that plant voltage-gated K+ channels and metazoan Shakers derive from distinct prokaryotic ancestors. The plant channels belong to a lineage that includes cyclic nucleotide-gated channels and metazoan ether-à-go-go and hyperpolarization-activated, cyclic nucleotide-gated channels. We refer to this lineage as the CNBD channel superfamily, because all these channels share a cytoplasmic gating domain homologous to cyclic nucleotide binding domains. The first structures of CNBD superfamily channels reveal marked differences in coupling between the voltage sensor and ion-conducting pore relative to metazoan Shaker channels. Viewing plant voltage-gated K+ channel function through the lens of CNBD superfamily structures should lead to insights into how these channels are regulated.


Long-term follow-up after uveal melanoma charged particle therapy.
To examine the results of helium ion irradiation in 218 uveal melanoma patients treated more than 10 years ago. Retrospective review of 218 eyes treated with helium ion radiation for uveal melanoma between 1978 and 1984. Several parametric and non-parametric statistical analysis techniques were used. In 218 eyes treated with helium ion radiation for uveal melanoma, the mean dimension for largest basal diameter was 11.9 mm (range 5 mm to 24 mm). The mean tumor thickness was 6.7 mm (range 1.3 mm to 14.2 mm). Following helium ion radiation 208 (95.4%) of 218 eyes had local tumor control. At 10 years after radiation 46 (22.4%) of 218 eyes were enucleated; the majority (37 of 46) of enucleations were due to anterior ocular segment complications. At 10 years after radiation 102 (46.8%) of the 218 patients were dead; half had non-tumor related deaths and 51 died from metastatic melanoma. Best corrected visual acuity after radiation was > or = 20/40 in 21 of 93 eyes of patients that were alive and retained their eyes 10 or more years after treatment. In patients with tumors that were less than 6 mm in height and more than 3 mm away from the nerve or the fovea, 13 of 18 (72%) retained > or = 20/40. In contrast, only 11% of the patients with either thicker tumors or those close to the nerve or fovea retained that level of acuity. The actuarial enucleation rate at 5 years was 17.2% (2.7% S.E.) and at 10 years this was 22.4% (3.1% S.E). The recurrence tumor control rate at both 5 and 10 years was 5.3% (S.E 1.7%). Helium ion radiation of uveal melanoma is associated with good local tumor control and reasonable retention of the treated eye 10 years after treatment. In tumors that are less than 6 mm in thickness and greater than 3 mm from the optic nerve and fovea, many retain excellent vision. Approximately one-half of the deaths 10 years after treatment were due to non-tumor-related causes.


Predicting hospitalization for heat-related illness at the census-tract level: accuracy of a generic heat vulnerability index in Phoenix, Arizona (USA).
Vulnerability mapping based on vulnerability indices is a pragmatic approach for highlighting the areas in a city where people are at the greatest risk of harm from heat, but the manner in which vulnerability is conceptualized influences the results. We tested a generic national heat-vulnerability index, based on a 10-variable indicator framework, using data on heat-related hospitalizations in Phoenix, Arizona. We also identified potential local risk factors not included in the generic indicators. To evaluate the accuracy of the generic index in a city-specific context, we used factor scores, derived from a factor analysis using census tract-level characteristics, as independent variables, and heat hospitalizations (with census tracts categorized as zero-, moderate-, or high-incidence) as dependent variables in a multinomial logistic regression model. We also compared the geographical differences between a vulnerability map derived from the generic index and one derived from actual heat-related hospitalizations at the census-tract scale. We found that the national-indicator framework correctly classified just over half (54%) of census tracts in Phoenix. Compared with all census tracts, high-vulnerability tracts that were misclassified by the index as zero-vulnerability tracts had higher average income and higher proportions of residents with a duration of residency < 5 years. The generic indicators of vulnerability are useful, but they are sensitive to scale, measurement, and context. Decision makers need to consider the characteristics of their cities to determine how closely vulnerability maps based on generic indicators reflect actual risk of harm.


Outer membrane protein composition in disease isolates of Haemophilus influenzae: pathogenic and epidemiological implications.
The outer membrane protein composition of 50 disease isolates of Haemophilus influenzae has been determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. All strains, including 28 strains of serotype b, one strain each of serotypes a, c, d, e, and f, and 17 untypable strains, had an outer membrane protein composition typical of gram-negative bacteria, i.e., these membranes contained two to three dozen proteins with four to six proteins accounting for most of their protein content. Variation in the mobility of these major outer membrane proteins from strain to strain was common but not universal; the observed patterns provided useful data and new insight into the epidemiology of type b disease. The basic findings can be summarized as follows: (i) All 50 strains possessed three proteins (one minor and two major) each having identical mobilities. The other proteins, both major and minor, varied in mobility. (ii) All type b strains possessed a fourth (major) protein of identical mobility. (iii) The 28 type b strains, on the basis of the mobility of the six major outer membrane proteins, could be divided into eight subtypes. Of all the other strains examined, both typable and untypable, only the serotype a strain belonged to one of these subtypes. (iv) The untypable strains showed considerable variation in the mobilities of their major outer membrane proteins. Of these 17 strains, 13 had an additional major outer membrane protein not present in encapsulated strains. (v) The outer membrane protein composition of a single strain remained unchanged after many passages on solid media, but varied with the growth phase. (vi) The outer membrane protein composition of isolates obtained from nine patients during an epidemic of type b meningitis varied, indicating that a single strain was not responsible for the epidemic. At least five different strains were responsible for these nine cases. (vii) Identical outer membrane protein compositions were observed in the following: in a type b strain and a mutant of this strain deficient in capsule production, indicating that the level of capsule synthesis is not obviously related to outer membrane protein composition; in type b strains isolated from different anatomic sites of patients acutely ill with meningitis, indicating that the strain associated with bacteremia is the same as that isolated from the cerebrospinal fluid; in type b strains isolated from siblings who contracted meningitis at about the same time, indicating infection with the same strain; and in type b strains isolated from the initial and repeat infection of a single patient, suggesting that reinfection was due to the same strain.


The Role of PYY in Pancreatic Islet Physiology and Surgical Control of Diabetes.
Bariatric surgery in obese individuals leads to rapid and lasting remission of type 2 diabetes (T2D). This phenomenon occurs independently of weight loss possibly via a combination of factors. The incretin hormone GLP-1 has so far been recognised as a critical factor. However, recent data have indicated that elevation in another gut hormone, peptide tyrosine tyrosine (PYY), may drive the beneficial effects of surgery. Here we discuss recent findings on PYY-mediated control of glucose homeostasis and its role in diabetes, in the context of what is known for GLP-1. Identification of factors that increase the expression of PYY following bariatric surgery and elucidation of its role in diabetes reversal may have clinical relevance as a nonsurgical therapy for T2D.


Pituitary incidentaloma diagnosed as acromegaly triggered by trauma: A case report.
Pituitary incidentaloma (PI) is a generic term for pituitary tumors that are identified on images acquired for non-malignant conditions. Acromegaly is an extremely rare form of PI. Occasionally, a functional pituitary adenoma (PA) may be misdiagnosed as PI, which may result in a poor clinical outcome. Here we report the first case, to the best of our knowledge, of PI diagnosed as trauma-triggered acromegaly. A 42-year-old man with a chief complaint of head trauma was referred to our hospital after computed tomography (CT) revealed a pituitary tumor. His appearance was suggestive of acromegaly. Mild hypertrophy of the extremities was also observed. Preoperative blood tests, magnetic resonance imaging (MRI), and endocrine tolerance test findings indicated acromegaly. Accordingly, we suspected a growth hormone (GH)-producing PA, and we performed endoscopic transsphenoidal surgery (eTSS). Histopathology showed a densely granulated GH-producing PA, which was also confirmed via immunohistochemistry. Two months after surgery, blood tests showed decreased levels of GH and insulin-like growth factor-1. In addition, a postoperative endocrine tolerance test revealed no abnormalities. There was no recurrence at 24 months after surgery. The findings from this case suggest that PIs can also present as functional adenomas, which can be diagnosed using initial hormone examinations and endocrine tolerance tests. Therefore, thorough endocrine examination is necessary for early diagnosis and treatment and improved patient outcomes.


Surface Microstructure Engineering in MAPbBr3 Microsheets for Performance-Enhanced Photodetectors.
Metal halide-perovskite-based photodetectors have recently emerged as a class of promising optoelectronic devices in various fields. Meanwhile, nano/microstructuring perovskite-based photodetectors are a facile integration with complementary metal-oxide semiconductors for miniaturized imaging systems. However, there are still challenges to be overcome in reducing the losses caused by light reflection on the surface of microstructural perovskites. In this work, surface microstructure engineering is employed in MAPbBr3 microsheets for reducing light reflection and improving light absorption, resulting in high-performance perovskite photodetectors. MAPbBr3 microsheets, which possess different surface morphologies of flat, upright hemisphere arrays and inverted hemisphere arrays (IHAs), are fabricated by a simple microstructure template-assisted space confinement process. The light absorption capacity of IHA MAPbBr3 is significantly higher than that of the other two structures. Hence, IHA photodetectors with excellent figures of merit, including low dark current, decent responsivity, and fast speed, are achieved. Furthermore, the noise of the IHA photodetectors is only ∼10-13 A/Hz, which results in the superior sensitivity for weak light detection with a specific detectivity up to 1011 Jones. Our results demonstrate that surface engineering is a simple, low-cost, yet effective approach to improve the performance of nano-/micro-optoelectronic devices.


[Effect of vitamin C on the condition of NO-synthase system in experimental stomach ulcer].
We investigated the effect of Vitamin C (Vit C) on the changes of activity of the enzymes of NO-synthase system, nitric oxide content, lipoperoxidation processes, activity of SOD and catalase in gastric mucosa (GM), and concentrations of L-arginine, Vit C and Vit E in the blood of rats under conditions of experimental ulcer of the stomach caused by adrenaline injection. Vit C displayed a pronounced antioxidant action, reduced the degree of destructive affections, diminished the activity of iNOS and lipoperoxidation processes, decreased the NO content and SOD activity. Furthermore, the concentration of L-arginine and Vit C in the blood was increased. Combined action of Vit C with L-arginine reduced the degree of GM lesions, activity of eNOS and the content of NO in GM whereas the concentration of L-arginine in blood was increased. Under conditions of Vit C action and iNOS and COX-2 blockage, the activity of NO-synthases and lipoperoxidation processes were slightly decreased, indicating on dominant action of Vit C.


[The effect of small doses of ionizing radiation on the development of vascular brain diseases].
Overall 1,104 persons exposed to industrial radiation were examined for the effect of minor doses of ionizing radiation on the development of the initial forms of cerebrovascular diseases (CVD). Use was made of an original method of five-factorial screening prediction of the development of CVD. As a result of the examination, 603 persons (54.6%) made up a group at greater risk for cerebrovascular insufficiency. Arterial hypertension was found to be the leading risk factor while the age 45-49 years turned out most dangerous from the standpoint of the onset of the diseases under consideration. No relationship was established between the total dose of external radiation and the risk of the development of cerebrovascular disorders. 96 persons at greater risk for CVD were subjected to a thorough clinical and instrumental examination. Of these, 79.2% appeared to have initial manifestations of brain circulatory insufficiency and stage I dyscirculatory encephalopathy.


Adenovirus protein maturation at 42 degrees C.
Incubation of adenovirus type 2 infected cells at 42 degrees C resulted in an inhibition of assembly of virus particles although all the major viral structural polypeptides and virus-induced cellular polypeptides so far identified were detected by electrophoretic analysis. Selective high salt-acid-urea extraction of low mol. wt. polypeptides revealed the absence of protein VII at 42 degrees C whereas precursor polypeptide P-VII and core protein V were found. Pulse-chase and temperature shift experiments indicated that cleavage of P-VII into VII was a reversible thermosensitive process, requiring de novo protein synthesis after shift-down to 37 degrees C. Virus particles assembled at 37 degrees C after transfer from 42 to 37 degrees C contained both viral DNA and polypeptides pre-labelled during the eclipse phase at 42 degrees C, including core protein VII.


Postoperative nausea and vomiting in korle bu teaching hospital.
Postoperative nausea and vomiting (PONV) is one of the most distressing morbidities associated with surgery. Even though the incidence can be as high as 30% elsewhere no work has been done to assess the incidence in any health facility in Ghana. This study was carried out to find out the incidence, risk factors and the management of PONV in a tertiary healthcare facility. This was a prospective study. The study was carried out in Korle Bu Teaching Hospital (KBTH). All patients above the age of 18 years who had surgery including general surgery were included in the study. Information obtained using a questionnaire included demographic data, the type of anaesthesia, the incidence of PONV and its management. Three hundred and six (306) completed forms out of 322 questionnaires were analyzed. One hundred and six patients (34%) had episodes of PONV of whom 82 (77.4%) had intra-operative opioids. Of the other factors only age was found to be a risk factor with patients in the 20-49 age group constituting 71.8% (p=0.007). Eleven out of 93 patients who reported the episode to a health worker received medication for their PONV. Drugs used included promethazine and anti-malaria. Thirty-four percent of patients in the study had PONV indicating that the problem is not uncommon among post-surgical patients in KBTH. Awareness of the problem should be highlighted and adequate management should be given to all patients. Patients at risk should be identified and appropriate management instituted.


Separate O-grouping schemes for serotyping clinical isolates of Proteus vulgaris and Proteus mirabilis.
Antisera were prepared against type strains of the original scheme of B. Perch (Acta Pathol. Microbiol. Scand. 25:703-714, 1948) and against newly defined types to produce separate schemes for O-grouping Proteus vulgaris and Proteus mirabilis. In assessing the schemes for their effectiveness it was found that 82% of 208 P. vulgaris isolates and 88% of 194 P. mirabilis isolates from two hospitals were typable. Only 3.4% of the P. vulgaris isolates agglutinated in P. mirabilis antisera, and 1.5% of the P. mirabilis agglutinated in P. vulgaris antisera, indicating that separation of the schemes would be more advantageous in routine typing. P. mirabilis of groups O3, O6, O10, O29, and O30 were most frequently isolated. Of the P. vulgaris isolates, 25% belonged to newly defined O-groups, and one of these was the largest with 14% of all isolates of this species. The application of serotyping using separate schemes for each species was advocated in epidemiological studies.


Nomograms Predict Survival Outcome of Primary Intramedullary Spinal Cord Lymphoma Patients.
BACKGROUND Primary intramedullary spinal cord lymphoma (PISCL) is a rare cause of myelopathies. Considering its poor prognosis, it is essential to determine the appropriate treatment strategies and to develop nomograms to predict survival outcome for PISCL patients. MATERIAL AND METHODS Data were collected from the Surveillance, Epidemiology and End Results (SEER) database. We used 364 patients to investigate overall survival (OS) and 289 patients for cancer-specific survival (CSS). Kaplan-Meier method was to evaluate correlations of survival with different treatment strategies and clinicopathologic factors. Univariate and multivariable analyses were conducted to assess OS and CSS based on different variables. Risk factors were integrated to build nomograms. RESULTS Most of the 414 PISCL patients diagnosed with positive histology had diffuse B cell lymphoma, were under 60 years old, were male, were of white race, had 1 primary tumor, were married, were low stage, and had previously undergone chemotherapy. We found that radiation therapy had no effect on patient OS and CSS, and patients receiving chemotherapy alone tended to have better OS and CSS in comparison with other groups. In addition, we showed that clinicopathologic factors, including histologic type, age, stage, and marital status, could serve as independent prognostic factors for PISCL patient OS and CSS. These factors were utilized to construct nomograms. The calibration curves demonstrated good agreement. The concordance indexes for OS and CSS were 0.672 (P=0.024) and 0.683 (P=0.029), respectively. CONCLUSIONS Practical nomograms were established for patients' OS and CSS. Besides, this study can guild clinician to make the right decision for appropriate treatment of PISCL patients.


Ultrasound Arthroscopy of Hip in Treatment of Osteochondritis Dissecans.
An ultrasound arthroscopy (UA) technique is a promising tool for the evaluation of the articular cartilage during arthroscopic examination. However, the applicability of UA for the evaluation of the hip joint is unknown. We describe a UA assessment of a patient with osteochondritis dissecans at the femoral head. An ultrasound catheter designed for intravascular imaging was inserted into the hip joint by use of conventional arthroscopic portals, and the cartilage surfaces of the femoral head and acetabulum were investigated with ultrasound. UA provided essential quantitative information on the integrity of the articular cartilage and the condition of the subchondral plate not assessable with conventional arthroscopy. Furthermore, the UA technique provided the possibility to monitor arthroscopy-assisted retrograde drilling and bone transplantation in the hip joint.


Mass spectrometry imaging of plant metabolites--principles and possibilities.
Covering: up to the end of 2013 New mass spectrometry imaging (MSI) techniques are gaining importance in the analysis of plant metabolite distributions, and significant technological improvements have been introduced in the past decade. This review provides an introduction to the different MSI techniques and their applications in plant science. The most common methods for sample preparation are described, and the review also features a comprehensive table of published studies in MSI of plant material. A number of significant works are highlighted for their contributions to advance the understanding of plant biology through applications of plant metabolite imaging. Particular attention is given to the possibility for imaging of surface metabolites since this is highly dependent on the methods and techniques which are applied in imaging studies.


Comparative and transcriptional analysis of the predicted secretome in the lignocellulose-degrading basidiomycete fungus Pleurotus ostreatus.
Fungi interact with their environment by secreting proteins to obtain nutrients, elicit responses and modify their surroundings. Because the set of proteins secreted by a fungus is related to its lifestyle, it should be possible to use it as a tool to predict fungal lifestyle. To test this hypothesis, we bioinformatically identified 538 and 554 secretable proteins in the monokaryotic strains PC9 and PC15 of the white rot basidiomycete Pleurotus ostreatus. Functional annotation revealed unknown functions (37.2%), glycosyl hydrolases (26.5%) and redox enzymes (11.5%) as the main groups in the two strains. When these results were combined with RNA-seq analyses, we found that the relative importance of each group was different in different strains and culture conditions and the relevance of the unknown function proteins was enhanced. Only a few genes were actively expressed in a given culture condition in expanded multigene families, suggesting that family expansi on could increase adaptive opportunities rather than activity under a specific culture condition. Finally, we used the set of P. ostreatus secreted proteins as a query to search their counterparts in other fungal genomes and found that the secretome profiles cluster the tested basidiomycetes into lifestyle rather than phylogenetic groups.


Carotid atherosclerotic alterations in systemic lupus erythematosus patients treated at a Brazilian university setting.
To determine the frequency of carotid plaque and intima-media thickness (IMT) in patients with systemic lupus erythematosus (SLE) and their association with risk factors in a Brazilian university setting. Carotid plaque and IMT were identified and measured by ultrasonography. Traditional risk factors and lupus-related factors were analysed. One hundred and seventy-two patients (women = 96%, age = 38 +/- 11 years) were evaluated. The frequency of carotid plaque was 9.3%. The median (IR) IMT was 0.60 mm (0.54-0.71 mm). Age, family history (FH) of premature coronary disease, low-density cholesterol (LDL-c) >100 mg/dL, hypertriglyceridemia, diabetes, hypertension, smoking, postmenopause, number of risk factors, Framingham risk score, age at diagnosis, duration of lupus, mucocutaneous manifestations and duration of prednisone use were associated with plaque (P < 0.05), univariate analysis. Nephritis, immunosuppressive therapy, intravenous methylprednisolone and a higher average daily dose of prednisone were associated with the absence of plaque. Independent predictors of plaque were smoking (P = 0.004), LDL-c >100 mg/dL (P = 0.044), Framingham score (P = 0.006) and absence of immunosuppressive therapy (P = 0.032). There was an independent correlation between IMT and age (P < 0.001) and duration of prednisone use (P = 0.020). Subclinical atherosclerosis was associated with traditional risk and SLE-related factors, especially the absence of immunosuppressive therapy. The present study suggests that the levels of LDL-c should be kept under 100mg/dL in lupus.


Arthrodesis as an early alternative to nonoperative management of charcot arthropathy of the diabetic foot.
This study was performed to evaluate the use of arthrodesis of the tarsal-metatarsal area for the treatment of Eichenholtz stage-I Charcot arthropathy in patients with diabetes. Currently, the standard treatment of stage-I Charcot arthropathy is the application of a non-weight-bearing total-contact cast. Although this treatment can be effective for allowing a patient to walk without undergoing an operation, a nonunion or malunion may still result. The subsequent deformities may lead to complications, including ulceration of the foot and the need for operative intervention. Recently, a group of patients who had had early operative intervention for a variety of reasons provided us with the opportunity to objectively evaluate the effects of such treatment. This analysis provided valuable information about whether this treatment is a reasonable alternative to current nonoperative approaches. Between January 1991 and December 1996, fourteen patients had an operation because of Eichenholtz stage-I diabetic neuropathy. The classification of the disease as Eichenholtz stage I (the developmental stage) was based on radiographic evidence of varying degrees of articular-surface and subchondral-bone resorption and fragmentation as well as joint subluxation or dislocation without evidence of coalescence or callus formation. The operative procedure consisted of extensive debridement, open reduction, and internal fixation of the tarsal-metatarsal region with autologous bone graft. Postoperative treatment consisted of immobilization of the limb in a non-weight-bearing cast for a minimum of six weeks. All of the patients returned for a final follow-up visit at a mean of forty-one months (range, 25.3 to 77.3 months) postoperatively, at which time clinical and radiographic evaluations as well as gait analysis (with measurement of plantar pressures) were performed. The gait-analysis data was compared with similar data from a group of fourteen patients with diabetic neuropathy who had had a below-the-knee amputation and with that from a group of fourteen patients with diabetic neuropathy who had no history of plantar ulceration. All of the arthrodesis procedures were successful. Clinically, none of the patients had immediate or long-term complications postoperatively. No patient reported ulceration after the operation. The mean time to assisted weight-bearing was 10 +/- 3.3 weeks (range, six to fifteen weeks), the mean time to unassisted weight-bearing was 15 +/- 8.8 weeks (range, eight to thirty-four weeks), and the mean time to return to the use of regular shoes was 27 +/- 14.4 weeks (range, twelve to sixty weeks). All of the patients regained the level of walking ability that they had had prior to the arthropathy. The calculated confidence intervals revealed no differences between the arthrodesis group and either of the two comparison groups with regard to the time-distance gait parameters of velocity, cadence, and stride length or with regard to the minimum, maximum, and total range of motion of each of the joints. In contrast to able-bodied subjects, all three groups showed a reduction in sagittal-plane ankle motion that was primarily related to loss of plantar flexion. The first metatarsal, great toe, and heel showed the highest peak plantar pressures, with little difference among the groups. To our knowledge, the present study is the first to demonstrate the potential for early operative treatment to restore anatomical alignment and improve function of diabetic patients with stage-I Charcot arthropathy.


A Phytochrome-Derived Photoswitch for Intracellular Transport.
Cells depend on the proper positioning of their organelles, suggesting that active manipulation of organelle positions can be used to explore spatial cell biology and to restore cellular defects caused by organelle misplacement. Recently, blue-light dependent recruitment of specific motors to selected organelles has been shown to alter organelle motility and positioning, but these approaches lack rapid and active reversibility. The light-dependent interaction of phytochrome B with its interacting factors has been shown to function as a photoswitch, dimerizing under red light and dissociating under far-red light. Here we engineer phytochrome domains into photoswitches for intracellular transport that enable the reversible interaction between organelles and motor proteins. Using patterned illumination and live-cell imaging, we demonstrate that this system provides unprecedented spatiotemporal control. We also demonstrate that it can be used in combination with a blue-light dependent system to independently control the positioning of two different organelles. Precise optogenetic control of organelle motility and positioning will provide a better understanding of and control over the spatial biology of cells.


Iron and proteins for iron storage and detoxification.
Iron is required by most organisms, but is potentially toxic due to the low solubility of the stable oxidation state, Fe(III), and to the tendency to potentiate the production of reactive oxygen species, ROS. The reactivity of iron is counteracted by bacteria with the same strategies employed by the host, namely by sequestering the metal into ferritin, the ubiquitous iron storage protein. Ferritins are highly conserved, hollow spheres constructed from 24 subunits that are endowed with ferroxidase activity and can harbour up to 4500 iron atoms as oxy-hydroxide micelles. The release of the metal upon reduction can alter the microorganism-host iron balance and hence permit bacteria to overcome iron limitation. In bacteria, the relevance of the Dps (DNA-binding proteins from starved cells) family in iron storage-detoxification has been recognized recently. The seminal studies on the protein from Listeria innocua demonstrated that Dps proteins have ferritin-like activity and most importantly have the capacity to attenuate the production of ROS. This latter function allows bacterial pathogens that lack catalase, e.g. Porphyromonas gingivalis, to survive in an aerobic environment and resist to peroxide stress.


Encephalitozoon hellem in two eclectus parrots (Eclectus roratus): identification from archival tissues.
Members of the phylum Microspora are obligate, intracellular, single-celled parasites identified in a wide range of vertebrate and invertebrate hosts. Only a few cases of microsporidial infections have been documented in psittacine birds including peach-faced, masked, and Fischer's lovebirds (Agapornis roseicollis, A. personata, and A. fischeri, respectively), budgerigars (Melopsittacus undulatus), and a double yellow-headed Amazon parrot (Amazona ochrocephala). Parasite identification has typically been limited to phylum or genus, and no avian species of microsporidia has clearly been described. In this report, microsporidia were identified in the kidney and intestine of a new host, the eclectus parrot (Eclectus roratus). Parasites were identified as Encephalitozoon hellem using morphologic, ultrastructural, and small subunit ribosomal RNA gene sequence data obtained from archived tissues. This parasite species was first identified in immunocompromised humans and may be a potential zoonotic pathogen. The epidemiology and prevalence of this parasite in humans and birds should be further explored.


Inelastic Mach-Zehnder Interferometry with Free Electrons.
We use a novel scanning electron Mach-Zehnder interferometer constructed in a conventional transmission electron microscope to perform inelastic interferometric imaging with free electrons. An electron wave function is prepared in two paths that pass on opposite sides of a gold nanoparticle, where plasmons are excited before the paths are recombined to produce electron interference. We show that the measured spectra are consistent with theoretical predictions, specifically that the interference signal formed by inelastically scattered electrons is π out of phase with respect to that formed by elastically scattered electrons. This technique is sensitive to the phase of localized optical modes, because the interference signal amounts to a substantial fraction of the transmitted electrons. Thus, we argue that inelastic interferometric imaging with our scanning electron Mach-Zehnder interferometer provides a new platform for controlling the transverse momentum of free electrons and studying coherent electron-matter interactions at the nanoscale.


A Chichibabin's Hydrocarbon-Based Molecular Cage: The Impact of Structural Rigidity on Dynamics, Stability, and Electronic Properties.
A three-dimensional π-conjugated polyradicaloid molecular cage c-Ph14, consisting of three Chichibabin's hydrocarbon motifs connected by two benzene-1,3,5-triyl bridgeheads, was synthesized. Compared with its linear model compound l-Ph4, the prism-like c-Ph14 has a more rigid structure, which shows significant impact on the molecular dynamics, stability, and electronic properties. A higher rotation energy barrier for the quinoidal biphenyl units was determined in c-Ph14 (15.64 kcal/mol) than that of l-Ph4 (11.40 kcal/mol) according to variable-temperature NMR measurements, leading to improved stability, a smaller diradical character, and an increased singlet-triplet energy gap. The pressure-dependent Raman spectroscopic studies on the rigid cage c-Ph14 revealed a quinoidal-to-aromatic transformation along the biphenyl bridges. In addition, the ellipsoidal cavity in the cage allowed selective encapsulation of fullerene C70 over C60, with an associate constant of about 1.43 × 104 M-1. Moreover, c-Ph14 and l-Ph4 exhibited similar redox behavior and their cationic species (c-Ph146+ and l-Ph42+) were obtained by chemical oxidation, and the structures were identified by X-ray crystallographic analysis. The biphenyl unit showed a twisted conformation in l-Ph42+ and remained coplanarity in c-Ph146+. Notably, molecules of c-Ph146+ form a one-dimensional columnar structure via close π-π stacking between the bridgeheads.


Laparoscopic fundoplication for dysphagia and peptic esophageal stricture.
Peptic esophageal stricture with dysphagia is a late manifestation of severe gastroesophageal reflux disease (GERD). Although laparoscopic fundoplication is an effective antireflux operation, its efficacy for persons with peptic esophageal stricture and dysphagia has not been well defined. The aim of this study was to evaluate outcomes after fundoplication in this subgroup of GERD patients. Forty GERD patients with moderate, severe, or incapacitating dysphagia and peptic esophageal stricture were compared to a control group of 121 GERD patients without significant dysphagia or stricture. Reflux symptom severity was scored by each patient preoperatively and at most recent follow-up postoperatively (mean 1.5 years) using a scale ranging from 0 to 4 (0 = symptoms absent; 4 = symptoms incapacitating). Symptom scores were compared by the Wilcoxon rank-sum test. Postoperative redilation and fundoplication failure rates were also determined. At a mean follow-up of 1.5 years after fundoplication, the median dysphagia score had improved from 3 to 0 (P <0.001) in stricture patients and remained low (score 0) in the control group. The median heartburn score also improved from 3 to 0 (P <0.001) in stricture patients, with an identical response in the control group (P <0.001). Among dysphagia/stricture patients, 35 (87.5%) reported overall satisfaction and have not required secondary medical treatment or esophageal dilation. Four patients (10%) have required endoscopic redilation for residual dysphagia and one (2.5%) had reoperation for fundoplication herniation shortly after operation. Laparoscopic fundoplication is an effective therapy for patients with dysphagia and peptic esophageal stricture.


The natural history of preventive medicine, or breaking the chains of causation.
In the past the natural history of disease has shown chains of causation. With the acute diseases, these chains have usually been quite short and easily broken. With the chronic diseases of today, they are far longer and more complicated. Often they involve patterns of behaviour extending over half a lifetime. These patterns are, in turn, determined partly by genetic make-up, partly by family and social environment. The study of these chains necessitated both observation and social survey methods. The breaking of the chains entails the use of propaganda or mass education. By far the most effective educational agent is the spoken word, coming from someone held in respect. The most effective persuader is fear. In social medicine we can seldom plan large-scale experiments. We have to seize such opportunities as life presents. One such opportunity was the creation of the new towns after the war. It was found that good social planning yielded good results in terms of social satisfaction, and infant-mortality and psychosis rates. The prevention of neurosis is a more difficult matter. In administration and in politics resistance to learning from the experience of others is strong. The preventive medicine of the future will necessitate the teaching of common sense applied to human behaviour to extremely resistant audiences.


Prevention of endothelial cell injury by activated protein C: the molecular mechanism(s) and therapeutic implications.
Activated protein C (APC), a natural anticoagulant, is formed from protein C by the action of thrombin bound to thrombomodulin on the endothelial cell surface. APC regulates the coagulation system by inactivating the activated form of factors V and VIII in the presence of protein S. Tumor necrosis factor-alpha (TNF-alpha) plays critical roles in the development of disseminated intravascular coagulation, acute respiratory distress syndrome and shock in sepsis by inducing endothelial cell damage through activation of neutrophils. APC reduces the pulmonary endothelial cell injury and hypotension in rats administered endotoxin (ET) by inhibiting TNF-alpha production through inhibition of its transcription. Furthermore, APC reduces the ischemia/reperfusion-induced renal injury and the stress-induced gastric mucosal injury in rats. Inhibition by APC of the endothelial cell damage inhibited the decrease in the endothelial production of prostacyclin in vivo. These therapeutic effects could not be attributed to its anticoagulant effects, but to inhibition of TNF-alpha production. APC inhibits ET-induced TNF-alpha production in vitro in human monocytes by inhibiting activation of NFkappaB and AP-1 by inhibiting degradation of IkappaB and mitogen-activated protein kinase pathways, respectively. Recombinant APC was reported to reduce the mortality of patients with severe sepsis. These observations strongly suggest that APC might be involved not only in regulation of the coagulation system, but in regulation of inflammatory responses by preventing endothelial cell injury. Furthermore, APC reduced the spinal cord injury induced by compression-trauma or ischemia/reperfusion by inhibiting TNF-alpha production in rats, suggesting that APC may be a potential therapeutic agent for spinal cord injury in which only limited therapeutic measures are currently available.


Genome-wide gene expression profiling of human narcolepsy.
The objective of this study was to perform global gene expression profiling of patients affected by narcolepsy with cataplexy (NRLCP). This enabled identifying new potential biomarkers and relevant molecules possibly involved in the disease pathogenesis. In this study 10 NRLCP patients and 10 healthy controls were compared. Total RNA isolated from blood specimens was analyzed using microarray technology followed by statistical data analysis to detect genome-wide differential gene expression between patients and controls. Functional analysis of the gene list was performed in order to interpret the biological significance of the data. One hundred and seventy-three genes showed significant (p < 0.01) differential expression between the two tested conditions. The biological interpretation allowed categorizing differentially expressed genes involved in neurite outgrowth/extension and brain development, which could be possibly regarded as peripheral markers of the disease. Moreover, the NRLCP-related gene expression profiles indicated a dysregulation of metabolic and immune-related mechanisms. In conclusion, the gene expression profile associated to NRLCP suggested that molecular markers of neurological impairment, dysmetabolic and immune-related mechanisms, can be detected in blood of NRLCP patients.


Structure of a dinucleotide: thymidylyl-(5'-3')-thymidylate-5' (pTpT).
The crystal and molecular structure of the naturally occurring deoxyribose dinucleotide sodium thymidylyl-(5'-->3')-thymidylate-5' has been determined by x-ray diffraction. There are four molecules of dinucleotide and 52 water molecules in an orthorhombic unit cell of dimensions (in angstroms) a = 16.06, b = 15.13, c = 15.65, space group P2(1)2(1)2. There is a very high degree of conformational consistency between the two halves of the molecule when the dinucleotide is viewed as the combination of two 5'-mononucleotides. The planes of the two thymines are not parallel, but are tilted 38 degrees with respect to each other. An extensive system of hydrogen bonding exists involving the bases, waters, phosphates, and sodiums; no base-base hydrogen bonding occurs. The dinucleotide structural parameters should be of assistance in interpreting DNA fiber diagrams in terms of possible structures.


Methodological approaches to analyzing IVF data with multiple cycles.
Which methodological approaches are most appropriate for analyzing IVF data with multiple cycles in the context of a binary outcome? Both mixed effect models and generalized estimating equation (GEE) modeling approaches can account for multiple IVF cycles and may reduce bias over first-cycle only approaches, but CIs were narrowest with cluster-weighted generalized estimating equation models (CWGEE). There is a lack of consensus among investigators regarding how to best incorporate data from multiple cycles and whether to present odds or risks in the analysis of IVF data. Failure to account for correlated outcomes within individuals and informative cluster size may lead to invalid CIs and biased estimates. The Environment and Reproductive Health (EARTH) Study is an ongoing prospective cohort study of subfertile couples conducted at an academic medical center. This cohort was established in 2004 and follows couples seeking treatment for infertility throughout the course of their treatment and pregnancy. Women aged 18-46 years enrolled in the EARTH Study from 2004 to 2017 who initiated at least one IVF cycle were eligible. Cycle initiation was defined as beginning ovulation induction with the intent to progress through an IVF or ICSI cycle. This analysis included 442 women undergoing 642 cycles who met the study inclusion criteria. We compared the results and interpretations of log-binomial and logistic models restricting to the first cycle, as well as mixed effects models, unweighted GEE models, and CWGEE models including all cycles. This analysis was conducted for two distinct exposures: maternal age at cycle initiation, and maternal preconception urinary concentrations of di(2-ethylhexyl) phthalate (DEHP) metabolites (previously reported to be associated with a decreased probability of live birth). In general, the CIs were widest for mixed effects models and narrowest for CWGEE models. Further, in models evaluating the sum of urinary concentrations of DEHP metabolites (∑DEHP, available for 91% of women), the point estimates were surprisingly different between the first-cycle and multiple-cycle models. We observed significant associations between maternal age and live birth in all models. However, we observed no associations between ∑DEHP and live birth. This analysis was limited to an example dataset in which the true effect of any exposure is unknown. While this allows us to observe model performance in the context of real data, future analyses should be conducted within simulated datasets under various assumptions to further evaluate the appropriateness of each approach. In addition, we did not address differential loss to follow-up in our statistical approaches. The use of CWGEE models should be more widely considered in the analysis of IVF data with multiple cycles per woman. The CWGEE approach is computationally simple, addresses non-ignorable (informative) cluster size, and is robust against mis-specification of the underlying covariance structure. Among the methods compared in this analysis, CWGEE models generally yielded the narrowest CIs, possibly indicating the most precise estimates. We also stress the importance of estimating risks rather than odds in the analysis of IVF data. The project was funded by Grants (R01ES022955, R01ES009718, and P30ES000002) from the National Institutes of Health. None of the authors has any conflicts of interest to declare.


Deep learning approach for hyperspectral image demosaicking, spectral correction and high-resolution RGB reconstruction.
Hyperspectral imaging is one of the most promising techniques for intraoperative tissue characterisation. Snapshot mosaic cameras, which can capture hyperspectral data in a single exposure, have the potential to make a real-time hyperspectral imaging system for surgical decision-making possible. However, optimal exploitation of the captured data requires solving an ill-posed demosaicking problem and applying additional spectral corrections. In this work, we propose a supervised learning-based image demosaicking algorithm for snapshot hyperspectral images. Due to the lack of publicly available medical images acquired with snapshot mosaic cameras, a synthetic image generation approach is proposed to simulate snapshot images from existing medical image datasets captured by high-resolution, but slow, hyperspectral imaging devices. Image reconstruction is achieved using convolutional neural networks for hyperspectral image super-resolution, followed by spectral correction using a sensor-specific calibration matrix. The results are evaluated both quantitatively and qualitatively, showing clear improvements in image quality compared to a baseline demosaicking method using linear interpolation. Moreover, the fast processing time of 45 ms of our algorithm to obtain super-resolved RGB or oxygenation saturation maps per image for a state-of-the-art snapshot mosaic camera demonstrates the potential for its seamless integration into real-time surgical hyperspectral imaging applications.


Evidence-based medicine in pediatric rheumatology.
Evidence-based medicine (EBM) has increasingly gained importance over the past two decades. This review defines and discusses EBM in the light of specific issues relating to pediatrics and pediatric rheumatology. The efforts of pediatric rheumatologists to practice and promote EBM are summarized.