The impact of a decade long opisthorchiasis control program in northeastern Thailand.
Based on the figures obtained from a regional survey in 1981, the overall prevalence of opisthorchiasis in northeastern Thailand was as high as 34.6%. Traditional consumption of improperly cooked fish dishes and unhygienic defecating habits among rural inhabitants have been recognized as significant factors determining such high prevalence of this liver fluke in that area. Following experience of Mahidol University's Faculty of Tropical Medicine in Thailand of treating liver fluke infected individuals with praziquantel, the Ministry of Public Health started a liver fluke control program in the northeast as special service units in 1984 in 4 provinces. In 1988, the program was expanded to cover all 19 northeastern provinces, services being rendered at a community level covering stool examination and treatment of positive cases. Intensive health education was integrated as one element of liver fluke control program. During the early phase of operation (attack phase) a mobile stool examination team was the crucial strategy for active service. Following the attack phase, passive service was operated at each health service facility provided that results of population based program evaluation in each area showed a low prevalence according to the set target. Regionwide assessments in 1991 and 1992 indicated a declining trend of prevalence from 34.6% to 30.19% and 24.01%, respectively. In 1994, a population-based sampling survey was carried out to measure the effect of the liver fluke control program over 10 years operation (1984-1994) on both behavioral outcomes and prevalence impact. Sample for the assessment of behavior were 1,268 individuals, while another 1,912 samples were used for determining disease prevalence. Health related behaviors regarding frequent consumption of uncooked fish dishes decreased from 14% in 1990 to 7% in 1994 while occasional consumption remains as high as 42%. The prevalence of opisthorchiasis is 18.5% with a large variation in infection rate (5.20-56.25%).


How bacteria choose phosphate.
Discriminating against arsenate: Determination of the structure of periplasmic phosphate binding proteins at very high resolution provides the basis for understanding the high discrimination of bacteria against arsenate. The results complete our insight into earlier erroneous conclusions on the ability of certain bacteria to use arsenate instead of phosphate.


Clinical, electrodiagnostic, and sonographic studies in ulnar neuropathy at the elbow.
The aim of this study was to determine possible correlations between the clinical characteristics, electrophysiological features, and sonographic ulnar-nerve diameter in patients with ulnar neuropathy at the elbow (UNE). We prospectively performed clinical, electrodiagnostic, and sonographic studies in 102 patients having either purely sensory signs (35%) or sensorimotor signs (65%) of UNE. Nerve conduction studies had a sensitivity of 78%, and the addition of sonography increased this to 98%. The diagnostic value of both tests was not different among cases with and without motor deficit. Motor studies with recording from the abductor digiti minimi and first dorsal interosseous muscles were equally sensitive for the detection of conduction block or velocity slowing across the elbow, but the combination yielded more positive cases than when only one study was performed. There were modest negative correlations between the electrodiagnostic parameters and the sonographic ulnar-nerve diameter. Electrodiagnostically and sonographically, there were no significant differences between clinically pure sensory and mixed sensorimotor cases of UNE, except for electrodiagnostic findings suggesting loss of motor axons in cases with motor signs. Almost half the patients with only sensory signs had electromyographic evidence of motor axonal loss. We conclude that, although UNE is clinically heterogeneous, the electrophysiological and sonographic findings are fairly consistent despite the clinical manifestations.


Face-to-face or not-to-face: A technology preference for communication.
This study employed the Model of Technology Preference (MTP) to explain the relationship of the variables as the antecedents of behavioral intention to adopt a social networking site (SNS) for communication. Self-administered questionnaires were distributed to SNS account users using paper-based and web-based surveys that led to 514 valid responses. The data were analyzed using structural equation modeling (SEM). The results show that two out of three attributes of the attribute-based preference (ATRP) affect attitude-based preference (ATTP). The data support the hypotheses that perceived enjoyment and social presence are predictors of ATTP. In this study, the findings further indicated that ATTP has no relationship with the behavioral intention of using SNS, but it has a relationship with the attitude of using SNS. SNS development should provide features that ensure enjoyment and social presence for users to communicate instead of using the traditional face-to-face method of communication.


Target-specific differences in somatodendritic morphology of layer V pyramidal neurons in rat motor cortex.
Dendritic geometry has been shown to be a critical determinant of information processing and neuronal computation. However, it is not known whether cortical projection neurons that target different subcortical nuclei have distinct dendritic morphologies. In this study, fast blue retrograde tracing in combination with intracellular Lucifer yellow injection and diaminobenzidine (DAB) photoconversion in fixed slices was used to study the morphological features of corticospinal, corticostriatal, and corticothalamic neurons in layer V of rat motor cortex. Marked differences in the distribution of soma, somal size, and dendritic profiles were found among the three groups of pyramidal neurons. Corticospinal neurons were large, were located in deep layer V, and had the most expansive dendritic fields. The apical dendrites of corticospinal pyramidal neurons were thick, spiny, and branched. In contrast, nearly all corticostriatal neurons were small cells located in superficial layer V. Their apical dendritic shafts were significantly more slender, though spiny like those of corticospinal neurons. Corticothalamic neurons, which were located in superficial layer V and in layer VI, had small or medium-sized soma, slender apical dendritic shafts, and dendrites that were largely spine free. This study indicates that, in layer V of rat motor cortex, each population of projection neurons has a unique somatodendritic morphology and suggests that distinct modes of cortical information processing are operative in corticospinal, corticostriatal, and corticothalamic neurons.


Pancreatic islet cell therapy for type I diabetes: understanding the effects of glucose stimulation on islets in order to produce better islets for transplantation.
While insulin replacement remains the cornerstone treatment for type I diabetes mellitus (T1DM), the transplantation of pancreatic islets of Langerhans has the potential to become an important alternative. And yet, islet transplant therapy is limited by several factors, including far too few donor pancreases. Attempts to expand mature islets or to produce islets from stem cells are far from clinical application. The production and expansion of the insulin-producing cells within the islet (so called beta cells), or even creating cells that secrete insulin under appropriate physiological control, has proven difficult. The difficulty is explained, in part, because insulin synthesis and release is complex, unique, and not entirely characterized. Understanding beta-cell function at the molecular level will likely facilitate the development of techniques to manufacture beta-cells from stem cells. We will review islet transplantation, as well as the mechanisms underlying insulin transcription, translation and glucose stimulated insulin release.


Serious infections caused by multiply-resistant Enterococcus faecium.
Three liver transplant patients developed serious intraabdominal infections and recurrent bacteremias due to strains of Enterococcus faecium with high-level resistance to vancomycin. The enterococci were also resistant to all other antibacterials except pristinamycin, which, given orally, proved ineffective. One strain was sensitive to tetracycline. Increasingly, clinicians are likely to encounter infections caused by multiply-resistant enterococci, and these cases illustrate the seriousness of such infections in compromised patients.


A journey to uncharted territory: new technical frontiers in studying tumor-stromal cell interactions.
The crosstalk between tumor cells and cells of the tumor stroma dictate malignant progression and represent an intriguing and viable anticancer therapeutic target. The successful development of therapeutics targeting tumor-stroma interactions is tied to the insight provided by basic research on such crosstalk. Tumor-stroma interactions can be transient and dynamic, and they occur within defined spatiotemporal contexts among genetically and compositionally heterogeneous populations of cells, yet methods currently applied to study the said crosstalk do not sufficiently address these features. Emerging imaging and genetic methods, however, can overcome limitations of traditional approaches and provide unprecedented insight into tumor-stroma crosstalk with unparalleled accuracy. The comprehensive data obtained by applying emerging methods will require processing and analysis by multidisciplinary teams, but the efforts will ultimately rejuvenate hope in developing novel therapies against pro-tumorigenic tumor-stroma crosstalk.


An ester bond linking a fragment of a serine proteinase to its serpin inhibitor.
Most known members of the serpin superfamily are serine proteinase inhibitors. Serpins are therefore important regulators of blood coagulation, complement activation, fibrinolysis, and turnover of extracellular matrix. Serpins form SDS-resistant complexes of 1:1 stoichiometry with their target proteinases by reaction of their P1-P1' peptide bond with the active site of the proteinases. The nature of the interactions responsible for the high stability of the complexes is a controversial issue. We subjected the complex between the serine proteinase urokinase-type plasminogen activator (uPA) and the serpin plasminogen activator inhibitor-1 (PAI-1) to proteolytic digestion under nondenaturing conditions. The complex could be degraded to a fragment containing two disulfide-linked peptides from uPA, one of which included the active site Ser, while PAI-1 was left undegraded. By further proteolytic digestion after denaturation and reduction, it was also possible to degrade the PAI-1 moiety, and we isolated a fragment containing 10 amino acids from uPA, encompassing the active site Ser, and 6 amino acids from PAI-1, including the P1 Arg. Characterization of the fragment gave results fully in agreement with the hypothesis that it contained an ester bond between the hydroxyl group of the active site Ser and the carboxyl group of the P1 Arg. These data for the first time provide direct evidence that serine proteinases are entrapped at an acyl intermediate stage in serine proteinase-serpin complexes.


Pulmonary embolism: diagnosis, incidence and implications.
The purpose of this study was to determine the prevalence of pulmonary embolism at an academic tertiary care center, to identify the methods of diagnosis, and to characterize the outcomes for this population. A retrospective analysis of multiple data sources including records from the Medical Information System, and the Departments of Pathology, Radiology, Nuclear Medicine and Pharmacy were reviewed for all patients with positive reports of pulmonary embolism. These were verified by the medical records and a listing of all positive cases was developed. A total of 320 patients developed pulmonary embolism during the study period and 121 died before discharge. The prevalence was 3.5 cases per 1000 admissions, with a mortality of 1 per 1000 cases. Significant misclassification of patients and errors in rate estimation would have occurred if multiple sources of information were not used. Definitive diagnosis and appropriate treatment with a Greenfield filter was associated with improved early survival. By relying on ICD-9 coding, 80% of fatalities and 13% of patients with positive angiograms would have been missed.


Escort cells generate a dynamic compartment for germline stem cell differentiation via combined Stat and Erk signalling.
Two different compartments support germline stem cell (GSC) self-renewal and their timely differentiation: the classical niche provides maintenance cues, while a differentiation compartment, formed by somatic escort cells (ECs), is required for proper GSC differentiation. ECs extend long protrusions that invade between tightly packed germ cells, and alternate between encapsulating and releasing them. How ECs achieve this dynamic balance has not been resolved. By combining live imaging and genetic analyses in Drosophila, we have characterised EC shapes and their dynamic changes. We show that germ cell encapsulation by ECs is a communal phenomenon, whereby EC-EC contacts stabilise an extensive meshwork of protrusions. We further show that Signal Transducer and Activator of Transcription (Stat) and Epidermal Growth Factor Receptor (Egfr) signalling sustain EC protrusiveness and flexibility by combinatorially affecting the activity of different RhoGTPases. Our results reveal how a complex signalling network can determine the shape of a cell and its dynamic behaviour. It also explains how the differentiation compartment can establish extensive contacts with germ cells, while allowing a continual posterior movement of differentiating GSC daughters.


Analysis of single nucleotide polymorphisms in the NOS2A gene and interaction with smoking in age-related macular degeneration.
Age-related macular degeneration (AMD) is a complex degenerative retinal disease influenced by both genetic and environmental risk factors. We assessed whether single nucleotide polymorphisms (SNPs) in the NOS2A gene increase risk and modulate the effect of smoking in AMD. 998 Caucasian subjects (712 AMD cases and 286 controls) were genotyped for 17 SNPs in NOS2A. Multivariable logistic regression models containing SNP genotypes, age, sex, smoking status and genotype/smoking interaction were constructed. SNP rs8072199 was significantly associated with AMD (OR = 1.3; 95% CI : 1.02, 1.65; P = 0.035). A significant interaction with smoking was detected at rs2248814 (P = 0.037). Stratified data by genotypes demonstrated that the association between AMD and smoking was stronger in carriers of AA genotypes (OR = 35.98; 95% CI: 3.19, 405.98) than in carriers of the AG genotype (OR = 3.05; 95% CI: 1.36, 6.74) or GG genotype (OR = 2.1; 95% CI: 0.91, 4.84). The results suggest a possible synergistic interaction of AA genotype with smoking, although the result bears replication in larger samples. Our data suggests that SNPs in the NOS2A gene are associated with increased risk for AMD and might modulate the effect of smoking on AMD.


Identification of essential regulatory elements responsible for the explicit expression of IL-28Rα and their effect on critical SNPs using in-Silico methods.
IL-28Rα and IL10Rβ collectively construct a fully functional hetero-dimeric receptor for type III interferons (IFNs). IL-28Rα is the private chain for type III IFNs since their involvement in any other pathway has not been reported yet and they are highly expressed in response to certain viral attack or cancers. IL-28Rα is specific in their expression pattern and it expresses within few cell types only. The regulatory mechanisms governing the expression of IL-28Rα at the molecular level are not completely known yet and need to be scrutinized at primary levels. In the present study, various in-silico techniques were applied and it was observed that AP1-2, STAT 1-6, P-53, LyF-1 (lymphoid transcription factor), c-Jun, PU.1, CREB (cAMP response element-binding), PLAG (pleotropic adenoma gene), MYOD (myoblast determination protein 1), NOFL and KLFS as transcription factors that are selected with preference. Interestingly AP-2, c-Jun, LyF-1, STAT, NF-Y and P53 have also been reported in literature recently as some of the key regulatory elements as well. Based on the fact that interlinking between different interferon stimulation genes (ISGs) is also not very clear and induction of one type of interferon can affect the efficacy of the other, we found that IFN-λ4 induction can increase the expression of IL-28Rα, similar to IFN-λ3 but contrary to type I IFNs, which has either no effect on the expression of IL-28Rα or can down regulate its expression at higher concentrations (data not published).


Mono- and Disamarium Azacryptand Complexes: A Platform for Cooperative Rare-Earth Metal Chemistry.
Mono- (H3LSm) and disamarium complexes (LSm2) were prepared by reaction of the azacryptand N[(CH2)2NHCH2-p-C6H4CH2NH(CH2)2]3N (H6L) with 1 or 2 equiv of Sm[N(SiMe3)2]3, respectively. The disamarium complex features free coordination sites on both metal centers available for bridging ligands shielded by phenylenes from tetrahydrofuran (THF) coordination. The reaction of LSm2 with KCN and 18-crown-6 yielded the adduct [LSm2-μ-η1:η1-CN][K(18-crown-6)(THF)2] featuring a bridging cyanide. The complexes were characterized by crystallography, electrochemical analysis, NMR, and optical spectroscopy, and the effective magnetic moments were determined via the Evans method.


Mechanistic investigation of drug release from asymmetric membrane tablets: effect of media gradients (osmotic pressure and concentration), and potential coating failures on in vitro release.
An asymmetric membrane (AM) tablet was developed for a soluble model compound to study the in vitro drug release mechanisms in challenge conditions, including osmotic gradients, concentration gradients, and under potential coating failure modes. Porous, semipermable membrane integrity may be compromised by a high fat meal or by the presence of a defect in the coating that could cause a safety concern about dose-dumping. The osmotic and diffusional release mechanisms of the AM tablet were independently shut down such that their individual contribution to the overall drug release was measured. Shut off of osmotic and diffusional release was accomplished by performing dissolution studies into receptor solutions with osmotic pressure above the internal core osmotic pressure and into receptor solutions saturated with drug, respectively. The effect of coating failure modes on in vitro drug release from the AM tablet was assessed through a simulated high-fat meal and by intentionally compromising the coating integrity. The predominant drug release mechanism for the AM tablet was osmotic and accounted for approximately 90-95% of the total release. Osmotic release was shutoff when the receptor media osmotic pressure exceeded 76 atm. Diffusional release of the soluble drug amounted to 5-10% of the total release mechanism. The observed negative in vitro food effect was attributed to the increased osmotic pressure from the high fat meal when compared to the predicted release rates in sucrose media with the same osmotic pressure. This suppression in drug release rate due to a high fat meal is not anticipated to affect in vivo performance of the dosage form, as the rise in pressure is short-lived. Drug release from the AM system studied was determined to be robust to varying and extreme challenge conditions. The conditions investigated included varying pH, agitation rate, media osmotic pressure, media saturated with drug to eliminate the concentration gradient, simulated high fat meal, and intentionally placed film coating defects. Osmotic and diffusional shut off experiments suggest that the mechanism governing drug release is a combination of osmotic and diffusional at approximately 90-95% and 5-10%, respectively. In addition, the coating failure mode studies revealed this formulation and design is not significantly affected by a high fat meal or by an intentionally placed defect in the film coating, and more specifically, did not result in a burst of drug release.


Skating mechanics of change-of-direction manoeuvres in ice hockey players.
Ice hockey requires rapid transitions between skating trajectories to effectively navigate about the ice surface. Player performance relates in large part to effective change-of-direction manoeuvres, but little is known about how those skills are performed mechanically and the effect of equipment design on them. The purpose of this study was to observe the kinetics involved in those manoeuvres as well as to compare whether kinetic differences may result between two skate models of varying ankle mobility. Eight subjects with competitive ice hockey playing experience performed rapid lateral (90°) left and right change-of-direction manoeuvres. Kinetic data were collected using force strain gauge transducers on the blade holders of the skates. Significantly greater forces were applied by the outside skate (50-70% body weight, %BW) in comparison to the inside skate (12-24%BW, p < 0.05). Skate model and turn direction had no main effect, though significant mixed interactions between leg side (inside/outside) with skate model or turn direction (p < 0.05) were observed, with a trend for left-turn dominance. This study demonstrates the asymmetric dynamic behaviour inherent in skating change-of-direction tasks.


Hypomagnesemia following posterior spinal fusion in adolescent idiopathic scoliosis.
Adolescent idiopathic scoliosis (AIS) patients undergoing posterior spinal fusion (PSF) usually require surveillance in the pediatric ICU (PICU). Some reports have documented evidence of hypomagnesemia following PSF at PICU. Little has been studied about relationship between AIS and postoperative serum magnesium (Mg+2) levels. The aim of this study is to determine the prevalence and risk factors of hypomagnesemia in AIS patients admitted to PICU after PSF. IRB approved the cross-sectional study of AIS patients admitted to PICU after PSF from January 2016 to May 2017. Serum electrolyte levels of phosphorous, calcium, sodium, potassium and hemoglobin were taken preoperative and 24 h postoperative and compared with postoperative magnesium levels. Blood volume reinfused from cell saver return (CSR), estimated blood loss (EBL), volume of fluids intraoperative and average of vertebra levels operated were charted and compared with postoperative magnesium levels. A total of 46 AIS patients undergoing PSF met inclusion criteria, with an average age of 15 years (78% female). Postoperatively, hypomagnesemia was reported in 24/46 patients (53%). No association was found between hypomagnesemia and serum electrolyte (phosphorous, calcium, sodium and potassium) or hemoglobin levels. In addition, no statistical association was found with age, operative time, vertebrae level fused, CSR, EBL and volume of fluids intraoperatively. Fifty-three percent of pediatric patients developed hypomagnesemia after surgical correction for AIS. Further investigation of this electrolyte disturbance will likely result in a useful clinical tool for physician in the management of AIS.


Role of Genetic Polymorphism of Angiotensin-Converting Enzyme, Plasminogen Activator Inhibitor-1 and Endothelial Nitric Oxide Synthase in the Prognosis of Coronary Artery Disease.
This study was to investigate the effects of multiple genetic polymorphisms and conventional risk factors in the prognosis of coronary artery disease (CAD). One hundred and fifty five patients with CAD were prospectively recruited, they were subgrouped as single vessel disease (SVD) and multiple vessel disease (MVD). All patients were detected I/D polymorphism of angiotensin-converting enzyme (ACE) gene, 4G/5G polymorphism of plasminogen activator inhibitor-1 (PAI-1) gene, and G894→T mutation of endothelial nitric oxide synthase (eNOS) gene. The patients were followed up for 10-65 months, mean 35 months. End points were major adverse cardiovascular events (MACE), including angina, myocardial infarction, and cardiac sudden death. During the follow-up period, MACE developed in 81 patients, 73 patients with angina, seven with myocardial infarction, and one with cardiac sudden death. CAD patients with MVD were more probable of developing MACE during follow-up. Distribution of PAI-1 gene polymorphism was significantly different between SVD and MVD patients, p < 0.001. The frequency of DD genotype of ACE and 4G/4G genotype of PAI-1 in patients with MACE were significantly higher than those in patients without MACE, p < 0.001 and p = 0.002, respectively. Incidence of diabetes mellitus was significantly higher in patients with MACE than in patients without MACE, P = 0.03. Cox regression analysis showed that diabetes mellitus (HR 2.36, 95% CI 1.33-4.46, p = 0.003), 4G/4G polymorphism of PAI-1 gene (HR 3.45, 95% CI 1.71-6.56, p = 0.009), and D/D polymorphism of ACE gene (HR 2.99, 95% CI 1.84-5.76, p = 0.005), were independent predictors of the MACE. Our results showed that the conventional risk factors and genetic polymorphisms have significant influence on prognosis of CAD patients. CAD patients with diabetes mellitus, DD genotype of ACE, and 4G/4G genotype of PAI-1 suggested poor prognosis.


Acyclovir-induced thrombotic microangiopathy.
Acyclovir is a commonly used antiviral drug. Acute kidney injury (AKI) due to intratubular crystal precipitation and interstitial nephritis is well known. Here we present a case of acyclovir induced AKI in a 61 year old male with herpes zoster, which presented like thrombotic microangiopathy with acute interstitial nephritis. This is the first case report on acyclovir causing thrombotic microaniopathy with partial improvement in renal function after plasmapharesis.


Functional interaction between human herpesvirus 6 immediate-early 2 protein and ubiquitin-conjugating enzyme 9 in the absence of sumoylation.
The immediate-early 2 (IE2) protein of human herpesvirus 6 is a potent transactivator of cellular and viral promoters. To better understand the biology of IE2, we generated a LexA-IE2 fusion protein and screened, using the yeast two-hybrid system, a Jurkat T-cell cDNA library for proteins that could interact with IE2. The most frequently isolated IE2-interacting protein was the human ubiquitin-conjugating enzyme 9 (Ubc9), a protein involved in the small ubiquitin-like modifier (SUMO) conjugation pathway. Using deletion mutants of IE2, we mapped the IE2-Ubc9-interacting region to residues 989 to 1037 of IE2. The interaction was found to be of functional significance to IE2, as Ubc9 overexpression significantly repressed promoter activation by IE2. The C93S Ubc9 mutant exhibited a similar effect on IE2, indicating that the E2 SUMO-conjugating function of Ubc9 is not required for its repressive action on IE2. No consensus sumoylation sites or evidence of IE2 conjugation to SUMO could be demonstrated under in vivo or in vitro conditions. Moreover, expression levels and nuclear localization of IE2 were not altered by Ubc9 overexpression, suggesting that Ubc9's repressive function likely occurs at the transcriptional complex level. Overall, our results indicate that Ubc9 influences IE2's function and provide new information on the complex interactions that occur between herpesviruses and the sumoylation pathway.


Physical enrichment of transposon mutants from saturation mutant libraries using the TraDISort approach.
Transposon-insertion sequencing methods are finding their way into the molecular toolbox of many fields of microbiology. These methods can identify the genomic locations and density of transposon insertions in saturated transposon mutant libraries and can be used to make inferences on gene function. For example, where no insertions or very few insertions are identified within a gene in a mutant library grown under permissive conditions, the gene may be essential. Furthermore, where mutations are enriched or lost in a gene after passaging the library through a selective process, the gene is likely to be involved in phenotypes linked to the process. Typically, a fitness based selection such as a stress condition is used in these experiments and the processed sequencing data are used to identify genes required for fitness under the selection. Our research team recently expanded the utility of the transposon directed insertion sequencing (TraDIS) method by applying a physical separation of a transposon mutant library mediated by fluorescence activated cell sorting, rather than a fitness-based selection. This approach, which we have named "TraDISort" is significant because it allows the study of phenotypes that are not linked to cell survival. The TraDISort approach has a broad range of future applications, in drug development, metabolic engineering and in studies of basic bacterial cell physiology.


Use of the "crash room" in a rural hospital: case review of 100 cases.
There is little published literature about the characteristics of patients with high triage levels seen in the emergency departments of rural hospitals. We sought to determine the demographics of patients brought into the "crash room" of a rural hospital, to assess the pathologies that brought them to the hospital and to study their final disposition. We conducted a retrospective chart review of visits to the crash room of our rural hospital. We used the hospital's crash room register to compile a list of the last 100 consecutive visits to the crash room as of July 20, 2011. We extracted initial data from the register and additional data by chart review. Patients with triage levels 1 to 3 were brought to the crash room at a rate of 0.36 cases/wk/1000 population. Although circulatory disease, respiratory disease and "chest pain" accounted for 44.6% of final diagnoses, a wide range of pathology was seen in the crash room. Trauma and poisonings, and mental disorders accounted for 21.0% and 9.0% of diagnoses, respectively. The final diagnosis was nonspecific, vague or "unknown" in 20% of the visits. Of the crash room cases, 17% required transfer to a secondary care hospital. Crash room visits in this rural hospital occurred at a rate of 0.48 cases/wk/1000 population. Most patients seen in the crash room were not given the traditional triage levels 1 or 2 that are usually associated with crash room care. The final diagnosis was nonspecific in 17.0% of cases, and mental disorders accounted for 9.0% of crash room visits.


Treatment of Hypovitaminosis D in an Orthopaedic Trauma Population.
To determine the incidence of hypovitaminosis D and to evaluate a supplementation intervention. We hypothesized that patients would exhibit high adherence with a free sample, and levels would become sufficient. Prospective observational study. Level 1 trauma center. One hundred forty-four consecutive, skeletally mature patients treated for acute fractures. All were provided 600 mg calcium and 800 IU vitamin D3 capsules twice daily. Serum 25(OH) D levels were obtained on presentation and after supplementation. Patient surveys determined adherence, vitamin D intake, and sun exposure. Ninety-one men and 53 women, mean age 45 years, mean body mass index 28.1, were studied. Mean baseline 25(OH) D level was 20.2 ng/mL, including 9 patients taking vitamin D supplements before injury. All others (mean baseline 16.9 ng/mL) were prescribed calcium and vitamin D and were offered free supplements when discharged. Seventy-seven patients completed surveys, and mean 25(OH) D level was 36.7 ng/mL after a mean of 7.0 weeks of supplementation (P < 0.0001). Seventy-nine percent reported adherence to supplement recommendations. All adherent patients achieved normal levels. Sixteen patients were nonadherent, with 10 who forgot to take the supplement, 4 choosing not to use it, 1 choosing to sell the sample, and 1 losing the sample. Hypovitaminosis D was present in 97% of orthopaedic trauma patients who were not already taking supplements. The intervention was effective in reducing hypovitaminosis D within several weeks, with all supplemented patients achieving normal levels. Seventy-nine percent of patients adhered to recommendations. Further study to determine the long-term cost-effectiveness of this strategy seems warranted. Therapeutic, Level II. See Instructions for Authors for a complete description of levels of evidence.


Design, synthesis, biological evaluation, and in silico studies of quinoxaline derivatives as potent p38α MAPK inhibitors.
A new series of quinoxaline derivatives possessing the hydrazone moiety were designed, synthesized, and screened for in-vitro anti-inflammatory activity by the bovine serum albumin (BSA) denaturation technique, and for antioxidant activity, by the (2,2'-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay. The synthesized compounds were also tested for p38α mitogen-activated protein (MAP) kinase inhibition. The in-vivo anti-inflammatory activity was assessed by the carrageenan-induced rat paw edema inhibition method. All the compounds (4a-n) exhibited moderate to high in-vitro anti-inflammatory activity. Compound 4a displayed the highest inhibitory activity in the BSA assay (83.42%) in comparison to the standard drug diclofenac sodium (82.90%), while 4d exhibited comparable activity (81.87%). The DPPH assay revealed that compounds 4a and 4d have free radical scavenging potential (74.70% and 74.34%, respectively) comparable to the standard butylated hydroxyanisole (74.09%). Furthermore, the p38α MAP kinase inhibition assay demonstrated that compound 4a is highly selective against p38α MAP kinase (IC50 = 0.042) in comparison to the standard SB203580 (IC50 = 0.044). The five most active compounds (4a-4d and 4f) with good in-vitro profiles were selected for in-vivo anti-inflammatory studies. Compounds 4a and 4d were found to display the highest activity (83.61% and 82.92% inhibition, respectively) in comparison to the standard drug diclofenac sodium (82.65% inhibition). These compounds (4a and 4d) also exhibited better ulcerogenic and lipid peroxidation profiles than diclofenac sodium. The molecular docking and molecular dynamics simulation studies were also performed and found to be in agreement with the p38α MAP kinase inhibitory activity.


The special needs of children.
British literature related to the care of children in hospital states that they have 'special needs'. This concept is not defined; neither are different writers in total agreement about what these needs may be. This paper attempts to define needs, concluding that they are 'requirements that should be met'. Children are seen as dynamic beings because they are in a state of constant development, both physically and psychosocially. It is this state of development that makes their needs special to them. They have special requirements, which should be met in specific ways. Through the presentation of indicators of behaviours which would enable such needs to be met, it can be demonstrated that children should be cared for by people with the appropriate knowledge and understanding. When children are admitted to hospital there may be a number of different people involved in determining how a need should be met. An important part of this process should be nurses who have been specially educated for work with this age group.


Using the early postoperative intraocular pressure to predict pressure control after a trabeculectomy.
The goal of this study was to identify the early postoperative intraocular pressure (IOP) that predicts low pressure control after a trabeculectomy with mitomycin C. This study retrospectively analyzed the medical records of the initial trabeculectomy with mitomycin C in patients with primary open-angle glaucoma. We established 2 target postoperative IOPs, ≤11 and ≤15 mm Hg. The preoperative and early postoperative factors contributing to the success and failure of postoperative IOP control were studied by multiple regression analyses. These factors included the sex and age of patients, record of cataract surgery, number of preoperative medications, preoperative IOP, IOP recorded 2 weeks after surgery, laser suture lysis after surgery, and the presence of a shallow anterior chamber and choroidal detachment during the first month after surgery. The optimal IOP levels 2 weeks after surgery for long-term IOP control were examined using the Kaplan-Meier survival analyses. Sixty-six patients (66 eyes) with open-angle glaucoma participated in the study. The age and IOP 2 weeks after surgery were selected as the confounding factors affecting the probability of successfully satisfying both target IOPs;≤11 and≤15 mmHg postoperatively. An IOP under 8 mm Hg at 2 weeks after surgery was found to be associated with maintaining the postoperative IOP at either ≤11 and ≤15 mm Hg for an extended period. An IOP of 8 mm Hg was associated with successful outcomes in patients undergoing trabeculectomy. Also, younger age was found to be a risk factor for surgical failure.


Low-dose prophylaxis protocol for heterotopic ossification after hip preservation surgery in a sport participants cohort.
Heterotopic ossification (HO) is a well-known complication of arthroscopic and open surgical treatment of femoroacetabular impingement (FAI). Incidence of heterotopic ossification has been reported in the literature between 0% and 44% after hip arthroscopy and between 18.2% and 25% after anterior mini-open surgery. Currently, pharmacological prophylaxis with NSAIDs and selective COX-2 inhibitors are commonly used and their effectiveness is well documented in literature. We hypothesized that the low-dose prophylaxis protocol with selective cox-2 inhibitors decreases the risk of heterotopic ossification in open or arthroscopic hip preservation surgery in athletes. This study is an analysis of prospectively gathered data on 98 sport participant patients who underwent arthroscopic or anterior mini-open treatment for FAI between April 2008 and April 2018. All the patients received postoperative oral prophylaxis with 60 mg etoricoxib once daily for two weeks. Post-operative X-rays were performed at 1, 3, and 12 months after surgery and reviewed by two orthopedic surgeons blinded to the type and side of surgery. HO were graded according to the Brooker classification. Descriptive statistics was used to analyze demographic data. Bivariate analysis was performed to analyze the association of HO with each of the following variables: type of surgery, physical activity, time of evolution of symptoms, age at surgery, and sex. Finally, a regression model analysis was performed to determine the presence of confounding effects between variables. The study cohort was composed of 54 patients in the arthroscopic treatment group and 44 patients in the anterior mini-open group. HO was identified in 6 (13.6%) patients in the mini-open group. No HO was identified in the arthroscopic group. In the bivariate analysis, "type of surgery" was the only variable that showed a statistically significant association with HO (p = 0.007). Results of this study suggest that anterior mini-open treatment was characterized by a higher risk of HO development compared to hip arthroscopy for femoroacetabular impingement treatment regardless of pharmacological prophylaxis. The treatment regimen of 60 mg etoricoxib daily for two weeks was an effective prophylaxis for HO formation in sport participant patients compared with data available in the literature.


Health Economic Evaluations of Cancer in Brazil: A Systematic Review.
Background: A large number of health economic evaluation (HEE) studies have been published in developed countries. However, Brazilian HEE literature in oncology has not been studied. To investigate whether the scientific literature has provided a set of HEE in oncology capable of supporting decision making in the Brazilian context. Methods: A systematic review was conducted to identify and characterize studies in this field. We searched multiple databases selecting partial and full HEE studies in oncology (1998-2013). Results: Fifty-five articles were reviewed, of these, 33 (60%) were full health economic evaluations. Type of cancers most frequently studied were: breast (38.2%), cervical (14.6%), lung (10.9%) and colorectal (9.1%). Procedures (47.3%) were the technologies most frequently evaluated. In terms of the intended purposes of the technologies, most (63.6%) were treatments. The majority of the incremental cost-effectiveness ratios (ICERs) reported have been below the cost-effectiveness threshold suggested by the World Health Organization (WHO). Conclusions: There has been an increase in the number of HEEs related to cancer in Brazil. These studies may support decision-making processes regarding the coverage of and reimbursement of healthcare technologies for cancer treatment in Brazil.


Tetrahedraphene: A Csp3 -centered 3D Molecular Nanographene Showing Aggregation-Induced Emission.
The bottom-up synthesis of 3D tetrakis(hexa-peri-hexabenzocoronenyl)methane, "tetrahedraphene", is reported. This molecular nanographene constituted by four hexa-peri-hexabenzocoronene (HBC) units attached to a central sp3 carbon atom, shows a highly symmetric arrangement of the HBC units disposed in the apex of a tetrahedron. The X-ray crystal structure reveals a tetrahedral symmetry of the molecule and the packing in the crystal is achieved mostly by CH⋅⋅⋅π interactions since the interstitial solvent molecules prevent the π⋅⋅⋅π interactions. In solution, tetrahedraphene shows the same electrochemical and photophysical properties as the hexa-t Bu-substituted HBC (t Bu-HBC) molecule. However, upon water addition, it undergoes a fluorescence change in solution and in the precipitated solid, showing an aggregation induced emission (AIE) process, probably derived from the restriction in the rotation and/or vibration of the HBCs. Time-Dependent Density Functional Theory (TDDFT) calculations reveal that upon aggregation, the high energy region of the emission band decreases in intensity, whereas the intensity of the red edge emission signal increases and presents a smoother decay, compared to the non-aggregated molecule. All in all, the excellent correlation between our simulations and the experimental findings allows explaining the colour change observed in the different solutions upon increasing the water fraction.


Transcutaneous implantation of valproic acid-encapsulated dissolving microneedles induces hair regrowth.
The interest in alternative material systems and delivery methods for treatment of androgenetic alopecia has been increasing in the recent decades. Topical application of valproic acid (VPA), an FDA-approved anticonvulsant drug, has been shown to effectively stimulate hair follicle (HF) regrowth by upregulating Wnt/β-catenin, a key pathway involved in initiation of HF development. Moreover, a majority of studies have suggested that cutaneous wound re-epithelialization is capable of inducing HF through Wnt/β-catenin pathway. Here, we report fabrication and evaluation of a novel VPA-encapsulating dissolving microneedle (DMN-VPA) that creates minimally invasive dermal micro-wounds upon application, significantly improving the VPA delivery efficiency. DMN-VPA not only delivers encapsulated VPA with higher accuracy than topical application, it also stimulates wound re-epithelialization signals involved in HF regrowth. Through a series of in vivo studies, we show that micro-wounding-mediated implantation of DMN-VPA upregulates expression of Wnt/β-catenin pathway, alkaline phosphatase, proliferating cell nuclear antigen, loricrin and HF stem cell markers, including keratin 15, and CD34 more effectively than topical application.


Epigallocatechin gallate delays the onset of type 1 diabetes in spontaneous non-obese diabetic mice.
Type 1 diabetes (T1D) results from the autoimmune-mediated destruction of pancreatic β-cells, leading to deficiency of insulin production. Successful islet transplantation can normalise hyperglycaemia in T1D patients; however, the limited availability of the islets, loss of islet cell mass through apoptosis after islet isolation and potential autoimmune destruction of the transplanted islets prevent the widespread use of this procedure. Therefore, the search for novel and cost-effective agents that can prevent or treat T1D is extremely important to decrease the burden of morbidity from this disease. In the present study, we discovered that ( - )-epigallocatechin gallate (EGCG, 0·05 % in drinking-water), the primary polyphenolic component in green tea, effectively delayed the onset of T1D in non-obese diabetic (NOD) mice. At 32 weeks of age, eight (66·7 %) out of twelve mice in the control group developed diabetes, whereas only three (25 %) out of twelve mice in the EGCG-treated group became diabetic (P < 0·05). Consistently, mice supplemented with EGCG had significantly higher plasma insulin levels and survival rate but lower glycosylated Hb concentrations compared with the control animals. EGCG had no significant effects on food or water intake and body weight in mice, suggesting that the glucose-lowering effect was not due to an alteration in these parameters. While EGCG did not modulate insulitis, it elevated the circulating anti-inflammatory cytokine IL-10 level in NOD mice. These findings demonstrate that EGCG may be a novel, plant-derived compound capable of reducing the risk of T1D.


The global failure of facing the pandemic.
The COVID-19 pandemic outbreak in late 2019 has had social, political, and economic consequences worldwide. However, its emergence was not a surprise. In 2015, a Panel organised by the World Health Organization highlighted the importance of learning about the crisis caused by the Ebola epidemic. In 1992, the Committee on Emerging Microbial Threats to Health of the US Institute of Medicine warned of the possibility of an emerging global microbial threat. In this text, we point out five arguments that reveal the global failure in facing the pandemic: (1) deficiency in the global alert system and the fragility of the International Health Regulations (IHR-2005), (2) problems of the international response to the pandemic, related to global health governance, (3) the dispersed global adoption of the elimination strategy (zero Covid) widely seen as a policy of restriction of freedom instead as a strategy of inequities reduction, (4) fragile control of the disease with a narrow reading of the associated problems, and (5) global setbacks in achieving the Sustainable Development Goals in the context of ongoing neoliberal national policies. Finally, we argue that overcoming the weaknesses discussed requires strengthening health systems in all their components and expanding social welfare policies.[Figure: see text].


Non-invasive measurement techniques for quantitative assessment of optic nerve head blood flow.
Diseases of the optic nerve head involving changes in blood flow are common. However, the pathophysiology is not always fully understood. Several non-invasive methods for measuring optic nerve head blood flow are available, but currently no gold standard has been established. Methods for measuring blood flow in optic neuropathies including colour Doppler imaging, retinal function imager, optical coherence tomography angiography and laser speckle flowgraphy are reviewed. Ultrasound colour Doppler imaging is a fast measurement technique where several different parameters, especially the blood flow velocity, can be calculated. Though used for many years in ophthalmology, its use is not standardized and it requires significant observer skills. The retinal function imager is a direct method where the haemoglobin in erythrocytes is visualized and blood flow velocities in retinal vessels are calculated from a series of photos. The technique is not suitable for direct measurement of blood flow within the optic nerve head. Laser speckle flowgraphy uses a laser light which creates a light scatter pattern in the tissue. Particles moving in the area causes changes in the speckle pattern from which a relative blood flow can be estimated. It is, however, not known whether optic nerve head microcirculation is measurable with the technique. Optical coherence tomography angiography uses multiple scans to evaluate blood flow with good reproducibility but often problems with artefacts. The technique is continuously being refined and increasingly used in research as a tool for the study of blood flow in retinopathies and optic neuropathies. Most of the conducted studies are based on small sample sizes, but some of the methods show promising results in an optic nerve head blood flow research setting. Further and larger studies are required to provide standardized and comparable measurements before one or more of the methods can be considered clinical helpful in daily practice.


Squaring the Circle and Cubing the Sphere: Circular and Spherical Copulas.
Do there exist circular and spherical copulas in [Formula: see text]? That is, do there exist circularly symmetric distributions on the unit disk in [Formula: see text] and spherically symmetric distributions on the unit ball in [Formula: see text], d ≥ 3, whose one-dimensional marginal distributions are uniform? The answer is yes for d = 2 and 3, where the circular and spherical copulas are unique and can be determined explicitly, but no for d ≥ 4. A one-parameter family of elliptical bivariate copulas is obtained from the unique circular copula in [Formula: see text] by oblique coordinate transformations. Copulas obtained by a non-linear transformation of a uniform distribution on the unit ball in [Formula: see text] are also described, and determined explicitly for d = 2.


Hepatorenal syndrome: Update on diagnosis and therapy.
Hepatorenal syndrome (HRS) is a manifestation of extreme circulatory dysfunction and entails high morbidity and mortality. A new definition has been recently recommended by the International Club of Ascites, according to which HRS diagnosis relies in serum creatinine changes instead that on a fixed high value. Moreover, new data on urinary biomarkers has been recently published. In this sense, the use of urinary neutrophil gelatinase-associated lipocalin seems useful to identify patients with acute tubular necrosis and should be employed in the diagnostic algorithm. Treatment with terlipressin and albumin is the current standard of care. Recent data show that terlipressin in intravenous continuous infusion is better tolerated than intravenous boluses and has the same efficacy. Terlipressin is effective in reversing HRS in only 40%-50% of patients. Serum bilirubin and creatinine levels along with the increase in blood pressure and the presence of systemic inflammatory response syndrome have been identified as predictors of response. Clearly, there is a need for further research in novel treatments. Other treatments have been assessed such as noradrenaline, dopamine, transjugular intrahepatic portosystemic shunt, renal and liver replacement therapy, etc. Among all of them, liver transplant is the only curative option and should be considered in all patients. HRS can be prevented with volume expansion with albumin during spontaneous bacterial peritonitis and after post large volume paracentesis, and with antibiotic prophylaxis in patients with advanced cirrhosis and low proteins in the ascitic fluid. This manuscript reviews the recent advances in the diagnosis and management of this life-threatening condition.


Human herpesvirus-6 and epstein-barr virus infections at different histopathological grades of oral squamous cell carcinomas.
The aim of this study was to determine the prevalence and viral load of Epstein-Barr virus (EBV) and Human herpesvirus-6 (HHV-6) in different histopathologic grades of oral squamous cell carcinoma (OSCC). Forty-five formalin-fixed paraffin-embedded tissue section of OSCC patients were analyzed by quantitative real-time polymerase chain reaction for detection of EBV and HHV-6. The mean age of the patients was 58.6 years, 69% of whom were female, and 31% were male. Overall, the positive rate for EBV and HHV-6 were 16.7% and 27.1%, respectively; and the mean viral load EBV was 27.9 × 10(3) and 38.5 × 10(3) for HHV-6. No correlation was demonstrated between the viral load of EBV DNA (P = 0.35) and HHV-6 (P = 0.38) at the different OSCC histopathologic grades. These findings neither lend support to the hypothesis that EBV and HHV-6 are directly involved in OSCC nor rule out the possibility that these viruses play an indirect role in carcinogenesis in this area.


Prevalence of Giardia infection in households of Giardia cases and risk factors for household transmission.
Giardia is a leading but neglected cause of infectious gastroenteritis worldwide and is treatable. There is a substantial burden of undetected Giardia in the UK and for every one case of Giardia reported to national surveillance there are 14 cases in the community. We aimed to ascertain the prevalence of, and risk factors associated with secondary household Giardia infections to assess the burden of infection and inform control measures. We identified all giardiasis cases notified in nine local authorities in Lancashire between June 2014 and June 2015, and invited their household contacts to submit faecal specimens for Giardia testing and complete a risk factor questionnaire. We estimated the proportion of households with additional Giardia infection. We compared household risk factors between households with and without additional Giardia using Fisher's exact test. We used multivariable logistic regression to identify independent risk factors for additional Giardia infections. We identified additional Giardia infections in 30% (27/91) of included households. A total of 41 infections were found from 212 household members, of which 37 were asymptomatic. The majority of infections were assemblage B (57%) but there were also a high number of mixed infections (20%). Risk factors significantly associated with additional household infections were; having children under 5 years in the household (odds ratio 42; 95% confidence intervals 10-178) and the presence of gastrointestinal illness in the household before the onset of the index case (odds ratio 9; 95% confidence intervals 1.5-48). Our finding of a high household prevalence of asymptomatic infection has raised the public health question of whether treatment of asymptomatic household contacts may be justified in preventing Giardia re-infection of the index case or in preventing secondary cases and household clusters. We recommend the communication of this risk in household contacts of Giardia and reinforcement of standard hygiene controls.


Ineffective Communication: The Uninformed Injured Worker.
Effective communication has been demonstrated to impact patient health outcomes, specifically in improving symptom resolution, safety, function, and emotional well-being, and to lower malpractice claims. I hypothesized that the communication process with patients with Workers' Compensation is inadequate. Prospectively, claimants presenting for an independent medical evaluation or an impairment rating were assessed concerning the education that they received with regard to their claim. Basic principles were based on the Utah Labor Commission Employee's Guide to Workers' Compensation and an employee information sheet. There were 556 consecutive claimants assessed. None of the participants expressed any familiarity with the employee information sheet. Although there was a mean of 12 months since the date of claim to the evaluation, 536 participants (96.4%) were effectively unaware of the principles surrounding their claim; of these participants, 6 had attorneys and 23 had prior industrial claims. Of the 3.6% of participants who had received the State Employee Guide, 5 had a prior evaluation with the medical director of the Labor Commission, 6 had located the information online, and 9 had been provided information by their nurse-case manager. Even with this information, the context or importance of the information was not well understood. There were 16.4% of participants who were aware of the mileage compensation. Two claimants were aware that the insurer, not the employer, was responsible for managing the claim, 2 claimants were aware that their claim was open for life, and 1 claimant was aware that claimants could change physicians. Workers' Compensation programs were designed to expedite care and treatment while decreasing the adversarial environment for workplace injuries. Yet delays and confrontational events continue to be experienced by the injured worker. This often results in the impression that workplace injuries have worse outcomes for the same diagnosis. The lack of effective education with regard to the rights and responsibilities of the claimant may also lead to this poorer outcome. Given studies showing the benefits of patient education in preventing malpractice claims and improving health-care outcomes, it is suggested that improved patient education for the injured worker is warranted and may lead to improved outcomes with diminished adversarial events.


The inter-relational effect of metabolic syndrome and sexual dysfunction on hypogonadism in type II diabetic men.
We sought to establish the interplay of metabolic syndrome (MetS) and/or sexual dysfunction (SD) on hypogonadism. Sexual functioning was assessed using Golombok Rust Inventory of Sexual Satisfaction in 274 consecutive diabetic men visiting the diabetic clinic of the Tema General Hospital between November 2010 and March 2011. MetS was assessed employing the criteria of World Health Organization, International Diabetic Federation and the National Cholesterol Education Program Adult Treatment Panel III while testosterone levels were estimated. The mean ages and duration of diabetes from this study were 59.9±11.3 and 6.8±5.9 years, respectively. The prevalence of hypogonadism was 7.3%, with the -SD/+MetS subjects showing the highest prevalence of hypogonadism, irrespective of the criteria used. Additionally, subjects with MetS and its components had a significantly lower level of testosterone compared with those without MetS and its components. Using standard nine-point scale, it was observed that subjects who avoided sexual act had significantly (P=0.0410) lower testosterone values (5.8±2.3 ng ml-1) than subjects who did not avoid sexual act (6.4±2.6 ng ml-1). MetS alone impacted more on hypogonadism than SD alone or both conditions altogether.


Molecular targeting of inosine-5'-monophosphate dehydrogenase by FF-10501 promotes erythropoiesis via ROS/MAPK pathway.
One of the major symptoms of myelodysplastic syndromes (MDS) is severe cytopenia. Despite cytokine therapies, such as erythropoiesis-stimulating agents, many patients still require blood transfusions, and the development of new therapeutic approaches is needed. In this work, we studied the effects of the inosine-5'-monophosphate (IMP) dehydrogenase (IMPDH) inhibitor FF-10501 on erythropoiesis of human hematopoietic cells. Differentiation of K562 chronic myeloid leukemia cells to an erythroid lineage was promoted by FF-10501 in a dose-dependent manner. Interestingly, we found that metabolic conversion of IMP to hypoxanthine leads to elevation of reactive oxygen species (ROS). The differentiative effects of FF-10501 were abolished by the ROS scavenger dimethylthiourea or the p38 MAPK inhibitor SB203580. Furthermore, FF-10501 promoted erythropoiesis from CD34+ hematopoietic stem/progenitor cells, accompanied with ROS accumulation, while high-dose FF-10501 mainly showed cytotoxic effects. These findings denote the potential of IMPDH inhibition therapy with FF-10501 in amelioration of anemia in MDS patients.


Effect of smoking cessation on sexual functions in men aged 30 to 60 years.
We aimed to evaluate the effects of smoking cessation on the sexual functions in men aged 30 to 60 years. Male patients aged 30 to 60 years that presented to the smoking cessation polyclinic between July 2017 and December 2018 were prospectively included in the study. The amount of exposure to tobacco was evaluated in packyear. The patients filled the International Index of Erectile Function (IIEF) form before the cessation and six months after cessation of smoking. Patients were subgrouped according to age, education level and packs/year of smoking and this groups were compared in terms of IIEF total and all of the IIEF domains. The evaluations performed by grouping the patients according to age (30-39, 40-49 and 50-60 years) and education level (primary-middle school and high schooluniversity) revealed that the total IIEF scores obtained after smoking cessation were significantly higher compared to the baseline scores in all groups (p=0.007 for the 30-39 years group and p < 0.001 for the remaining groups). According to grouping by exposure to smoking (≤25, 26-50, 51-75, 76-100 and 101≥ packs/year), the total IIEF scores significantly increased after smoking cessation in all groups except 101≥ packs/year (p=0.051 for the 101≥ group and p < 0.001 for the remaining groups). Erectile function is directly proportional to the degree of exposure to smoking, and quitting smoking improves male sexual function in all age groups between 30-60 years of age regardless of pack-year and education level.


Molecular dynamics simulation of self- and mutual diffusion coefficients for confined mixtures.
The self- and mutual diffusion coefficients for binary mixtures of Ar-Kr both in the bulk and in the nanopores were studied by molecular dynamics simulations. The composition dependences and the relationships between the self- and the mutual diffusion coefficients both in the bulk and in the nanopores were further discussed. It was found that the simulation results (D(c.m.)) are close to the calculated ones (D(s)) for the Ar-Kr system. Both self- and mutual diffusion coefficients in nanopores are much lower than that of the bulk, and they ever decrease as the pore width decreases. Nevertheless, the self- and mutual diffusion coefficients increase as the mole fraction of Ar increases, and as expected, increase as the temperature increases. The self-diffusion coefficients of mixtures both in the bulk and in the nanopores are predicted by the Carman model and by the molecular cluster model.


An empiric antibiotic protocol using risk stratification improves antibiotic selection and timing in critically ill children.
Timely and appropriate empiric antibiotics can improve outcomes in critically ill patients with infection. Evidence and guidelines to guide empiric antibiotic decisions are lacking for critically ill children. To evaluate the impact of an empiric antibiotic protocol on appropriateness of initial antibiotics and time to appropriate antibiotics in critically ill children with suspected infection. A computer order entry-based, pediatric intensive care unit-specific, empiric antibiotic protocol including risk stratification for healthcare-associated infections was implemented in a tertiary pediatric intensive care unit. Antibiotic and culture data were evaluated for a total of 556 infectious episodes in 491 patients from 2004 (preprotocol, n = 252) and 2007 (protocol, n = 304) with suspected infection. Antibiotics appropriateness based on risk factors and culture results was assessed, as was time from initial culture to appropriate antibiotics. Patients treated using the protocols were more likely to receive appropriate empiric antibiotics based on risk factors (76 vs. 15%; P < 0.0001) and culture results (89 vs. 64%; P < 0.0001). Patients treated after protocol implementation had a shorter time to appropriate antibiotics (median, 5.9 vs. 9.6 h; P < 0.0001), particularly in those who grew healthcare-associated pathogens (5.8 vs. 24 h; P = 0.0001). No significant baseline characteristic differences were seen. An empiric antibiotic protocol in the pediatric intensive care unit incorporating risk stratification for healthcare-associated infections resulted in increased appropriateness of empiric antibiotics and in decreased time to appropriate antibiotics in critically ill children with infection.


[Evaluation of an attenuation correction method in brain perfusion single photon emission computed tomography using magnetic resonance imaging].
Generally, the Chang method depends on counts for the attenuation correction (AC) method in brain perfusion single-photon emission computed tomography (SPECT), because the head outlined for a uniform attenuation coefficient map is set to the sinogram of the projection data by the threshold (Sinogram Threshold Chang method). Magnetic resonance imaging (MRI) is a routine examination in our hospital. Patients who underwent N-isopropyl-p-[(123)I] iodoamphetamine ((123)I-IMP) SPECT are undergoing MRI. Therefore, we thought it help AC accuracy to set an accurate head outline by using the image. We jointly made "Software for an attenuation coefficient map using MRI" for trial purposes. This paper investigated whether the AC method using MRI promotes the accuracy of brain perfusion SPECT in some clinical samples. With AC methods using gamma ray transmission computed tomography (TCT) or X-ray CT (CT) also being taken into account, the AC method using MRI was compared with the Sinogram Threshold Chang method. As a result, count dependency was excluded by an accurate head outline setting that used MRI, and the AC method using MRI approached the effect of the AC method using TCT and CT more than the Sinogram Threshold Chang method. Therefore, it is suggested that the AC method using MRI is useful for the accuracy of brain perfusion SPECT.


[Zollinger-Ellison syndrome].
After an exposition of the modern trends on the definition, ethiopathogenesis, symptomatology and therapy of the Zollinger-Ellison Syndrome, the authors presents a case of Z.-E. Syndrome, which occurred to their observation.


Assay of hepatic microsomal testosterone hydroxylases by high-performance liquid chromatography.
A high-performance liquid chromatographic (HPLC) method for the assay of the hepatic microsomal polysubstrate monooxygenase catalyzed hydroxylation of testosterone is described. The metabolites are extracted from the incubation mixture with dichloromethane and the extract is washed with dilute alkali and water, dried over anhydrous sodium sulfate, and evaporated to dryness. The residue is dissolved in methanol and an aliquot analyzed. The products are separated by reverse-phase chromatography with a methanol/water/tetrahydrofuran gradient and quantitated at 240 nm by the internal standard technique. The assay does not use radioactively labeled testosterone and can measure hydroxylase activity in microsomal samples containing less than 1.0 mg protein. At least seven products, 2 alpha-, 2 beta-, 6 beta-, 7 alpha-, 16 alpha-, and 16 beta-hydroxytestosterone and androstenedione, are resolved by HPLC. The major products formed by microsomes from untreated adult male rats are 2 alpha- (not 2 beta-) and 16 alpha-hydroxytestosterone and androstenedione which constituted 60% of the total products, followed by 6 beta-, 7 alpha-, and smaller quantities of 2 beta- and 16 beta-hydroxytestosterone. The carrier of the substrate in the incubation mixture was found to affect significantly the metabolite pattern and total activity, and of the several solvents studied methanol yielded the highest total activity. Since the 6 beta-, 7 alpha-, and 16 alpha-hydroxylation of testosterone is catalyzed by distinct forms of cytochrome P-450, this assay which measures seven products may serve as a useful qualitative probe of the cytochrome P-450 population of the monooxygenase.


The utility of a 3-O-allyl group as a protective group for ring-opening polymerization of alpha-D-glucopyranose 1,2,4-orthopivalate derivatives.
To clarify the utility as a protective group of 3-O-allyl group on ring-opening polymerization of alpha-D-glucopyranose 1,2,4-orthopivalate derivatives, four orthopivalate derivatives, 3-O-allyl-6-O-pivaloyl- (1), 3-O-allyl-6-O-benzyl- (2), 3,6-di-O-allyl- (3), and 3-O-allyl-6-O-methyl-alpha-D-glucopyranose 1,2,4-orthopivalates (4), were selected as starting monomers and were polymerized under -30 degrees C in CH2Cl2 using BF3.Et2O as a catalyst. All the orthopivalate derivatives 1-4 were found to give stereoregular polysaccharides, (1-->4)-beta-D-glucopyranans. Thus, it was concluded that the allyl group as a protective group at 3-O position of glucose othropivalate is acceptable to yield stereoregular (1-->4)-beta-D-glucopyranans, cellulose derivatives.


Time-series analysis of hepatitis A, B, C and E infections in a large Chinese city: application to prediction analysis.
Viral hepatitis is recognized as one of the most frequently reported diseases, and especially in China, acute and chronic liver disease due to viral hepatitis has been a major public health problem. The present study aimed to analyse and predict surveillance data of infections of hepatitis A, B, C and E in Wuhan, China, by the method of time-series analysis (MemCalc, Suwa-Trast, Japan). On the basis of spectral analysis, fundamental modes explaining the underlying variation of the data for the years 2004-2008 were assigned. The model was calculated using the fundamental modes and the underlying variation of the data reproduced well. An extension of the model to the year 2009 could predict the data quantitatively. Our study suggests that the present method will allow us to model the temporal pattern of epidemics of viral hepatitis much more effectively than using the artificial neural network, which has been used previously.


Clinical evaluation of endralazine (BO22708), a new vasodilator, in essential hypertension.
In the treatment of severe hypertension the choice of vasodilator is limited by side-effects, of which the lupus erythematosus syndrome induced by hydralazine is potentially the most serious, particularly in patients with the slow acetylator phenotype. This study describes the clinical evaluation of a new vasodilator, endralazine, which is related to hydralazine but which is not metabolised to any great extent by acetylation. In 6 essential hypertensives not adequately controlled by combined beta-blocker and diuretic therapy the additional administration of the first dose of 10 mg endralazine resulted in a significant reduction in blood pressure, without orthostatic symptoms, but associated with significant increases in heart rate and plasma noradrenaline concentration. These 6 patients and a further 9 similar hypertensive patients were then prescribed twice daily endralazine for 4 weeks with significant improvement in blood pressure control. During this short period of maintenance treatment with endralazine the single dose observations were repeated and no significant changes in heart rate or plasma noradrenaline concentration were observed. In summary, endralazine is an effective vasodilator/antihypertensive which was well tolerated in a triple therapy regimen in this study.


Reactions of Mg and Mg2 with SO2 in low-temperature matrices: association or insertion?
Laser-ablated magnesium species were codeposited with SO2 in excess argon or neon on the substrate at 4 K. The reactions mainly produced Mg(η(2)-O2S), Mg(η(2)-O2S)2, Mg2(η(2)-O2S), OMg2(η(2)-SO), and Mg(η(2)-SO) complexes, which were identified by isotopic substitutions and density functional frequency calculations (B3LYP and BPW91). In addition, the collected infrared spectra suggest that the single Mg atoms could react with SO2 to form the Mg(η(2)-O2S) complex on annealing, which further reacts with SO2 to produce the Mg(η(2)-O2S)2 complex on irradiation. In contrast, the reactions of magnesium dimers lead to cleavage of the S═O bond in SO2 on irradiating. Structural and bonding characteristics of these generated complexes, which shed light on the different performances of single Mg atom and its dimer in their reactions with small molecules, are discussed.


5,17-Dibromo-26,28-dihy-droxy-25,27-diprop-oxy-2,8,14,20-tetra-thia-calix[4]arene.
In the title compound, C(30)H(26)Br(2)O(4)S(4), the thia-calix[4]arene unit adopts a pinched cone conformation, with one of the ether-substituted rings bent towards the calix cavity and the two phenolic rings bent outwards. The phenyl rings make dihedral angles of 27.12 (9), 36.71 (10), 75.04 (8), and 76.01 (7)° with the virtual plane defined by the four bridging S atoms. The two opposite ether-substituted rings are almost parallel to each other, with an inter-planar anagle of 2.99 (12)°, while the two phenolic rings are nearly perpendicular to each other, making a dihedral angle of 74.52 (11)° and a Br⋯Br distance of 13.17 (2) Å. Two intra-molecular O-H⋯O hydrogen bonds between the OH groups and the same ether O atom stabilize the cone conformation. In the crystal, two different chains of mol-ecules, one with alternating and the other with tail-to-tail orientations, are formed by inter-molecular offset-face-to-face π-π stacking inter-actions with distances of 3.606 (3) to 4.488 (4) Å between the centroids of the aromatic rings.


[Chronic respiratory insufficiency and pulmonary heart disease--therapeutic aspects].
The term chronic respiratory insufficiency embraces always the involvement of the heart under the picture of pulmonary heart disease. The pathogenetic peculiarities of the impairment of the heart function and of the development of oedemas must be considered in the treatment. At present, treatment can only be symptomatic, and its long-term efficiency must be critically estimated. The importance of long-term oxygen therapy at home is explained.


Comparing the efficacy of pain managements after total hip arthroplasty: A network meta-analysis.
The aim of our current study is to compare efficiency of various interventions implemented for pain management after total hip arthroplasty (THA). PubMed and EMBASE were searched for randomized clinical trials (RCTs) reporting the pain scales for evaluate the efficacy of pain control after THA including at least one pair of direct control groups. Pain scale values and the associated 95% credible interval (CrI) were used to describe efficacy. Surface under the cumulative ranking curve (SUCRA) of each means of pain control was calculated to compare the relative ranking of different interventions. Thirty-five eligible literatures were involved in data analysis. The interventions for postoperative pain management we examined were psoas compartment block (PCB), posterior nerve block (PNB), fascia iliaca block (FIB), periarticular injection (PAI), femoral nerve block (FNB), lumbar plexus block (LPB), spinal anesthesia (SA), epidural analgesia (EPI), intrathecal morphine (IA), intravenous patient-controlled analgesia (IV-PCA), patient-controlled analgesia (PCA), onsteroidal anti-inflammatory drug (NSAID), local infiltration analgaesia (LIA), and reverse LIA (rLIA). In 0 to 6 hours analysis, patients under SA were found to have significantly lower pain score and SA was ranked the best. In 6 to 12 hours analysis, SA was found to be significantly more effective than other interventions and its SUCRA was the highest. No intervention showed a significant effect on reducing pain score for 12 to 24 hours and 24 to 48 hours after THA. SA is the best intervention to reduce THA postoperative pain in the first 24 hours. LPB is a better choice to reduce pain 12 to 48 hours after THA.


Clinicopathologic and Racial/Ethnic Differences of Colorectal Cancer Among Adolescents and Young Adults.
Despite overall reductions in colorectal cancer burden, incidence rates continue to rise among younger patients, and causes remain unknown. We examined differences in clinicopathologic and racial/ethnic characteristics within the adolescent and young adult (AYA) population diagnosed with colorectal cancer in the United States. Using the National Cancer Institute's Surveillance, Epidemiology, and End Results program data, we identified individuals diagnosed with first primary colorectal cancer between ages 15 and 39 years from 2010 to 2015. Adjusted multivariable logistic regression models were used to quantify clinicopathologic and racial/ethnic differences across age at onset subgroups (15-19, 20-24, 25-29, 30-34, and 35-39 years). We identified 5,350 AYA patients diagnosed with colorectal cancer. Of note, 28.6% of AYA cases were diagnosed with right-sided tumors (cecum to transverse colon). The proportion of right-sided colorectal cancers differed significantly by age group at diagnosis (38.3% vs 27.3% of AYAs aged 15-19 vs 35-39 years, respectively; P trend = 0.01). Proportions of cases with mucinous adenocarcinoma and signet ring cell carcinoma histopathologic subtypes significantly increased with younger age at onset (P trends = 0.01 and 0.03, respectively). Differences in clinical stage were observed across AYA age groups, with stage II disease increasing with younger age (P trend = 0.01). The proportion of Hispanic AYAs was higher within younger patients, accounting for 21.0% of the AYA population aged 35-39 years up to 28.3% of 15-19-year-old individuals (P trend = 0.003). Within the AYA population, colorectal cancers differ by clinicopathologic and racial/ethnic characteristics. Further investigation of the clinical and biologic diversity of colorectal cancers that partially underlie age- and race-related differences in cancer susceptibility and outcomes is warranted.


Probing atomic scale transformation of fossil dental enamel using Fourier transform infrared and nuclear magnetic resonance spectroscopy: a case study from the Tugen Hills (Rift Gregory, Kenya).
A series of fossil tooth enamel samples was investigated by Fourier transform infrared (FTIR) spectroscopy, (13)C and (19)F magic-angle spinning nuclear magnetic resonance (MAS NMR) and scanning electron microscopy (SEM). Tooth remains were collected in Mio-Pliocene deposits of the Tugen Hills in Kenya. Significant transformations were observed in fossil enamel as a function of increasing fluorine content (up to 2.8wt.%). FTIR spectroscopy revealed a shift of the ν1 PO4 stretching band to higher frequency. The ν2 CO3 vibrational band showed a decrease in the intensity of the primary B-type carbonate signal, which was replaced by a specific band at 864cm(-1). This last band was ascribed to a specific carbonate environment in which the carbonate group is closely associated to a fluoride ion. The occurrence of this carbonate defect was consistently attested by the observation of two different fluoride signals in the (19)F NMR spectra. One main signal, at ∼-100ppm, is related to structural F ions in the apatite channel and the other, at -88ppm, corresponds to the composite defect. These spectroscopic observations can be understood as resulting from the mixture of two phases: biogenic hydroxylapatite (bioapatite) and secondary fluorapatite. SEM observations of the most altered sample confirmed the extensive replacement of the bioapatite by fluorapatite, resulting from the dissolution of the primary bioapatite followed by the precipitation of carbonate-fluorapatite. The ν2 CO3 IR bands can be efficiently used to monitor the extent of this type of bioapatite transformation during fossilization.


Subcortical evidence for a contribution of arousal to fMRI studies of brain activity.
Cortical activity during periods of rest is punctuated by widespread, synchronous events in both electrophysiological and hemodynamic signals, but their behavioral relevance remains unclear. Here we report that these events correspond to momentary drops in cortical arousal and are associated with activity changes in the basal forebrain and thalamus. Combining fMRI and electrophysiology in macaques, we first establish that fMRI transients co-occur with spectral shifts in local field potentials (LFPs) toward low frequencies. Applying this knowledge to fMRI data from the human connectome project, we find that the fMRI transients are strongest in sensory cortices. Surprisingly, the positive cortical transients occur together with negative transients in focal subcortical areas known to be involved with arousal regulation, most notably the basal forebrain. This subcortical involvement, combined with the prototypical pattern of LFP spectral shifts, suggests that commonly observed widespread variations in fMRI cortical activity are associated with momentary drops in arousal.


Causes, implications, and treatment of systolic hypertension.
Mild hypertension is currently defined as systolic blood pressure between 140 and 160 mm Hg. The prevalence of systolic hypertension (including this mild category) in individuals 65 and older is 21% for men and 23% for women. Risk factors include obesity, excessive sodium and alcohol consumption, and possibly calcium and bone metabolism. Determinants of arterial wall rigidity and subsequent increase in pulse-wave velocity are also clearly factors. Much of the associated disease occurs in individuals with systolic pressures between 140 and 159 mm Hg. A particularly high-risk group appears to be those with an elevated systolic blood pressure and a low diastolic blood pressure. Systolic hypertension has now been found to be related to the progression of peripheral atherosclerosis, with lower progression rates among treated individuals. In addition, the beneficial effects of antihypertensive therapy have been found to be strongest among individuals with evidence of subclinical peripheral atherosclerosis. The high prevalence of mild systolic hypertension and its clear association with atherosclerotic disease suggests that older individuals with early systolic hypertension should be identified and treated. Clinical trials to test the efficacy of such treatment should be a high priority, perhaps in subgroups with early subclinical disease.


Transradial Szabo technique for intervention of ostial lesions.
The aim of our study is to assess the feasibility and safety of transradial intervention (TRI) of coronary ostial lesions using the Szabo technique. When performing TRI of coronary ostial lesions, precise stent positioning is of paramount importance. TRI has experienced increasing popularity in the U.S.; however, utilization of the Szabo technique has not been systematically evaluated in this setting. We report the results of ostial stent deployment using the Szabo technique for 2 experienced TRI operators and centers. This was a retrospective analysis of 40 consecutive patients who underwent PCI from April 2009 to September 2011. All patients who underwent PCI via the transradial route with the Szabo technique for ostial lesions performed by experienced transradial operators (>200 cases/yr) were included. In our study of 40 patients with 41 coronary ostial lesions, overall procedural success rate was 100%. Stent dislodgement was seen in 1 patient. Clinical follow up was 100%, with a mean duration of 292.7±200 days. Target lesion revascularization (TLR) was seen in 2 patients (5%). One patient had an episode of transient ischemic attack (TIA) at 33 days after PCI; another experienced subacute stent thrombosis at 81 days while on dual antiplatelet therapy. MACE was 7.5% overall. In our study, treatment of coronary ostial lesions with the Szabo technique via TRI is associated with a high procedural success rate and a low MACE of 7.5%.


The uptake of HIV post-exposure prophylaxis within a sexual assault setting in Sydney, Australia.
Our aim was to compare the assault characteristics of victims presenting to a sexual assault service who were prescribed HIV post-exposure prophylaxis (HIV PEP) with those not prescribed HIV PEP. A retrospective review was carried out of the medical records of victims who were seen over a 12-month period in 1999/2000.HIV PEP may have been potentially appropriate for 117 victims, of whom nine (7.7%) were prescribed PEP (eight women, one man). There was a trend for prescription of PEP to depend on the type of assault, with those suffering anal penetration most likely to be prescribed PEP, followed by those with vaginal, and then oral penetration (P = 0.08). Those who gave a history of oral or vaginal mucosal contact with ejaculate were more likely to receive PEP compared with those in whom ejaculation occurred at a non-mucosal site (P = 0.03). Most prescribed PEP regimens involved three antiretroviral drugs. In this study, HIV PEP, when prescribed, was in accord with existing guidelines. Future studies should aim to better document HIV seroconversions in victims of sexual assault and HIV seroprevalence in assailants.


Utility of Immunophenotypic Measurable Residual Disease in Adult Acute Myeloid Leukemia-Real-World Context.
Introduction: One of the mainstays of chemotherapy in acute myeloid leukemia (AML) is induction with a goal to achieve morphological complete remission (CR). However, not all patients by this remission criterion achieve long-term remission and a subset relapse. This relapse is explained by the presence of measurable residual disease (MRD). Methods: We accrued 451 consecutive patients of adult AML (from March 2012 to December 2017) after informed consent. All patients received standard chemotherapy. MRD testing was done at post-induction and, if feasible, post-consolidation using 8- and later 10-color FCM. Analysis of MRD was done using a combination of difference from normal and leukemia-associated immunophenotype approaches. Conventional karyotyping and FISH were done as per standard recommendations, and patients were classified into favorable, intermediate, and poor cytogenetic risk groups. The presence of FLT3-ITD, NPM1, and CEBPA mutations was detected by a fragment length analysis-based assay. Results: As compared to Western data, our cohort of patients was younger with a median age of 35 years. There were 62 induction deaths in this cohort (13.7%), and 77 patients (17.1%) were not in morphological remission. The median follow-up was 26.0 months. Poor-risk cytogenetics and the presence of FLT3-ITD were significantly associated with inferior outcome. The presence of post-induction MRD assessment was significantly associated with adverse outcome with respect to OS (p = 0.01) as well as RFS (p = 0.004). Among established genetic subgroups, detection of MRD in intermediate cytogenetic and NPM1 mutated groups was also highly predictive of inferior outcome. On multivariate analysis, immunophenotypic MRD at the end of induction and FLT3-ITD emerged as independent prognostic factors predictive for outcome. Conclusion: This is the first data from a resource-constrained real-world setting demonstrating the utility of AML MRD as well as long-term outcome of AML. Our data is in agreement with other studies that determination of MRD is extremely important in predicting outcome. AML MRD is a very useful guide for guiding post-remission strategies in AML and should be incorporated into routine treatment algorithms.


Morbidity patterns among the underweight, overweight and obese between 2 and 18 years: population-based cross-sectional analyses.
No study has documented how symptomatic morbidity varies across the body mass index (BMI) spectrum (underweight, normal weight, overweight and obese) or across the entire child and adolescent age range. To (1) quantify physical and psychosocial morbidities experienced by 2-18-year-olds according to BMI status and (2) explore morbidity patterns by age. Cross-sectional data from two Australian population studies (the Longitudinal Study of Australian Children and the Health of Young Victorians Study) were collected during 2000-2006. Participants were grouped into five age bands: 2-3 (n=4606), 4-5 (n=4983), 6-7 (n=4464), 8-12 (n=1541) and 13-18 (n=928) years. Outcomes-Parent- and self-reported global health; physical, psychosocial and mental health; special health-care needs; wheeze; asthma and sleep problems. Exposure-measured BMI (kg m(-2)) categorised using standard international cutpoints. The variation in comorbidities across BMI categories within and between age bands was examined using linear and logistic regression models. Comorbidities varied with BMI category for all except sleep problems, generally showing the highest levels for the obese category. However, patterns differed markedly between age groups. In particular, poorer global health and special health-care needs were associated with underweight in young children, but obesity in older children. Prevalence of poorer physical health varied little by BMI in 2-5-year-olds, but from 6 to 7 years was increasingly associated with obesity. Normal-weight children tended to experience the best psychosocial and mental health, with little evidence that the U-shaped associations of these variables with BMI status varied by age. Wheeze and asthma increased slightly with BMI at all ages. Deviation from normal weight is associated with health differences in children and adolescents that vary by morbidity and age. As well as lowering risks for later disease, promoting normal body weight appears central to improving the health and well-being of the young.


Microwave-assisted, one-pot reaction of 7-azaindoles and aldehydes: a facile route to novel di-7-azaindolylmethanes.
A novel and highly efficient synthetic method leveraging microwave-assisted organic synthesis (MAOS) to yield di-7-azaindolylmethanes (DAIMs) is reported. Under MAOS conditions, reaction of 7-azaindole with aldehydes resulted predominantly in DAIMs, as opposed to the expected 7-azaindole addition products that form at ambient temperature. Based upon studies of different indoles and azaindoles with various aromatic and aliphatic aldehydes, we herein propose a mechanism where rapid and efficient microwave heating promotes nucleophilicity of 7-azaindoles towards the corresponding alkylidene-azaindolene intermediate to form the DAIM. This sequence provides a versatile approach to efficiently synthesize novel DAIMs that may be useful pharmaceuticals.


Natural-product diversity of the New Caledonian marine ecosystem compared to other ecosystems: a pharmacologically oriented view.
In comparison with other ecosystems, biodiversity and natural-product diversity of the New Caledonian marine ecosystem, comprising lagoons, barrier reefs, and deep waters in seamount regions, are described here phylogenetically with the aid of molecular drawings and tabulation of data. Admittedly, since the inception of these studies in 1977, the comparison is biased by selection of New Caledonian organisms on the basis of positive pharmacologically oriented bioassays. However, we show that these and other distortions must be accepted to draw any comparison on a regional basis, which, nonetheless, turn out to be useful for the progress of knowledge, particularly in directing future explorations of biodiversity in the search for new pharmacologically active metabolites.


[Vascular dementia--a concise concept?].
Although cerebrovascular disease are the most common causes of dementia after Alzheimer's disease, vascular dementia (VD) has remained so far an ill-defined term. The main problems in the definition of VD arise from finding criteria for both terms "vascular" and "dementia". The detailed criteria for the diagnosis of VD proposed by several groups or institutions (ADDTC, DSM-IV, ICD-10, NINDS-ARIEN) are critically reviewed. The diagnostic value of some clinical findings, especially the very frequent white matter luciencies in CT (leuko-araiosis), are discussed. The available studies suggest a differentiation of VD into some subtypes (listed according to the frequency): subcortical VD, VD with acute onset, multi-infarct-dementia, mixed types, and specific forms. Nevertheless, these subtypes give only little information about the etiology of the underlying vascular process and, therefore, no clear indication for specific therapeutic strategies.


Expression of alpha-methylacyl-coenzyme A racemase in dysplastic Barrett's epithelium.
Although identification of epithelial dysplasia in Barrett's esophagus (BE) is critically important because of a significant risk of progression to invasive adenocarcinoma, the diagnosis of dysplasia may be challenging. Among confounding factors are interobserver variability, tangential sectioning, and severe mucosal inflammation leading to architectural and cytologic atypia similar to that of dysplasia. alpha-methylacyl-coenzyme A racemase (AMACR) is an enzyme involved in beta-oxidation of branched fatty acids and an established marker of prostate cancer. It is expressed in colon adenomas and adenocarcinomas but not in normal colonic epithelium suggesting a role in development of gastrointestinal malignancies. We investigated whether expression of AMACR can be used to identify dysplasia of BE and to distinguish it from reactive atypia. Ninety-six routinely processed biopsy and/or resection specimens (23 negative for dysplasia; 19, low-grade dysplasia; 22, high-grade dysplasia; 16, reactive atypia; and 16, esophageal adenocarcinoma) were immunostained using a monoclonal anti-AMACR antibody p504S. AMACR staining was uniformly negative in the groups negative for dysplasia and with reactive atypia. Only 2 (11%) of 19 specimens with low-grade dysplasia showed positive immunostaning, compared with 14 (64%) of 22 in high-grade dysplasia group. Of 16 specimens, 12 (75%) showed positive staining for AMACR in the adenocarcinoma group. Our data suggest that AMACR immunoreactivity is moderately sensitive in identification of high-grade dysplasia in BE and is highly specific in distinguishing high-grade dysplasia from reactive atypia. Further validation and prospective studies are warranted.


Effects of increasing heart rate induced by efferent sympathetic neuronal stimulation, isoproterenol or cardiac pacing on myocardial function and oxygen utilization.
The effects of increasing heart rate by six different methods on cardiac function were investigated in 17 open-chest anesthetized dogs. Heart rate was increased approximately 30% by (1) right interganglionic nerve stimulation, (2) atrial pacing, (3) ventricular pacing, (4) atrioventricular sequential pacing, (5) right stellate ganglion stimulation, and (6) isoproterenol administration. During heart rate increases induced by atrial pacing left ventricular intramyocardial pressure, coronary blood flow, oxygen delivery per unit of myocardial oxygen consumption, and myocardial efficiency were unchanged. Ventricular pacing reduced left ventricular cavity and septal intramyocardial pressure, while circumflex coronary flow increased, resulting in reduced oxygen delivery relative to myocardial oxygen consumption. Similarly, atrioventricular sequential pacing increased circumflex coronary artery flow and myocardial oxygen consumption, and decreased septal intramyocardial pressure and oxygen delivery per unit of myocardial oxygen consumption. Right stellate ganglion stimulation and isoproterenol increased left anterior descending and circumflex coronary artery blood flow, intramyocardial pressure, and myocardial oxygen consumption. Estimated myocardial efficiency (left ventricle) was decreased by ventricular pacing and isoproterenol, and was unchanged by atrial pacing and right interganglionic nerve stimulation. Increases in heart rate induced by right interganglionic nerve stimulation did not alter myocardial oxygen consumption, or the index of cardiac efficiency. It is concluded that augmentation of heart rate by either ventricular or atrioventricular pacing impairs myocardial function so that there is a decrease of left ventricular efficiency and isoproterenol augments chronotropism and myocardial force relative to cardiac external work so there is a reduction in cardiac efficiency. In contrast, atrial pacing or right interganglionic nerve stimulation augments chronotropism such that myocardial oxygen consumption and efficiency are unchanged.


Myrtus communis Liquor Byproduct as a Source of Bioactive Compounds.
The fatty acid (FA), polyphenol content and evaluation of the antioxidant capacity of exhausted Myrtus communis berries (EMB) resulting from the production of myrtle liqueur were assessed. All parts of the exhausted berries exhibited high concentrations of carbohydrates, proteins, lipids and phenolic compounds. The lipid fraction contained a high amount of poly unsaturated fatty acids (PUFA), mainly represented by linoleic acid (>70%). Of the phenolic acids evaluated by liquid chromatography/mass spectrometry, ellagic acid was the most predominant (>50%), followed by gallic and quinic acids. Quercetin and quercetin3-O-rhamnoside were the most abundant flavonoids. The seed extracts showed a higher antioxidant potential than the pericarp extracts; the same trend was observed for total phenolic compounds evaluated by spectrophotometric assay. The overall high content of bioactive compounds and the high antioxidant potential of this byproduct sustain its suitability for a number of industrial applications, such as a food ingredient in novel foods, an additive in cosmetic formulations or a component of animal feed formulations.