Substance P in the ascending cholinergic reticular system.
The neocortex receives a major cholinergic innervation from magnocellular neurones in the basal forebrain. However, an ascending cholinergic reticular system has also been postulated to arise from acetylcholinesterase (AChE)-containing neurones in the midbrain and pontine tegmentum. Lesions of this region decrease both AChE and choline acetyltransferase (ChAT) in various forebrain areas, and recent immunohistochemical studies have identified a group of ChAT-containing cell bodies in the midbrain reticular formation and dorsolateral pontine tegmentum. Here we have combined retrograde tracing with ChAT immunohistochemistry to demonstrate that this tegmental cholinergic cell group also directly innervates the cerebral cortex. Other immunohistochemical studies have indicated that the neuropeptide substance P is also present in certain cells in the laterodorsal tegmentum, and these too appear to project to the forebrain. We have therefore performed immunohistochemistry for both ChAT and substance P and have discovered that a subpopulation of the ascending cholinergic reticular neurones contains substance P. Thus, peptide-cholinergic coexistence, previously noted in peripheral neurones, also occurs in the brain.


Original flow chart for the management of hydroureteronephrosis caused by pessary placement.
The use of a pessary to treat a pelvic organ prolapse (POP) is a valid non-invasive option. Severe complications are usually associated with neglected, oversized, or misplaced pessaries. Major complications include fistulas, bowel or bladder erosion, and hydroureteronephrosis (HUN). We reviewed the literature and our experience in the management of HUN in the last decade, as a consequence of pessary placement. We used flow charts to take an accurate medical history of each patient. Blood and urine analyses were taken at admission to assess the potential presence of sepsis, renal failure, and urinary tract infection. Physical examination included vaginal examination. In cases of pessary presence with a concomitant increase of serum creatinine value, a possible ureteral obstruction is suspected. In order to assess the presence of HUN and its underlying causes, a computed tomography (CT) scan should be performed to assess the mechanism of urinary tract obstruction. However, in case of renal insufficiency, abdominal ultrasonography (US) could be sufficient. If HUN is detected in a patient with no signs of urosepsis, we suggest a conservative management by the removal of the pessary and catheter placement. When urosepsis is suspected, it is mandatory to administer antibiotic therapy and evaluate the HUN drainage by nephrostomy. There is no uniform management of women with HUN and a concomitant pessary. For this reason, and based on the literature and our experience, we propose an original management flowchart.


Simultaneous determination of protein aggregation, degradation, and absolute molecular weight by size exclusion chromatography-multiangle laser light scattering.
The feasibility of size exclusion chromotography (SEC)-multiangle laser-light scattering as a technique to investigate aggregation and degradation of glycosylated and nonglycosylated proteins, and antibodies under various conditions such as addition of detergent, changes in pH, and variation of protein concentration and heat stress temperature was examined. Separation of proteins and their aggregates was performed using SEC-high-performance liquid chromatography. Detection of analytes was carried out with on-line UV, refractive index, and multiangle laser light-scattering detectors. Quantification and molecular weight determination were performed using commercial software. Aggregation and degradation were examined under various conditions and quantitative results are presented for bovine serum albumin, choriogonadotropin, glyceraldehyde-3-phosphate dehydrogenase, Herceptin, and ReoPro. This method can simultaneously determine both the quantities and the molecular weights of macromolecules from a single injection. The determination of molecular weight is absolute which avoids misleading results caused by molecular shape or interactions with the column matrix. This technique is valuable not only for assessing the extent of aggregation but also for effectively monitoring molecule degradation as evidenced by molecular weight reduction and change in monomer amount.


Elicitation of T-cell-derived IFN-γ-dependent immunity by highly conserved Plasmodium ovale curtisi Duffy binding protein domain region II (PocDBP-RII).
Infections with Plasmodium ovale are widely distributed but rarely investigated, and the resulting burden of disease has been underestimated. Plasmodium ovale curtisi Duffy binding protein domain region II (PocDBP-RII) is an essential ligand for reticulocyte recognition and host cell invasion by P. ovale curtisi. However, the genomic variation, antigenicity and immunogenicity of PocDBP-RII remain major knowledge gaps. A total of 93 P. ovale curtisi samples were collected from migrant workers who returned to China from 17 countries in Africa between 2012 and 2016. The genetic polymorphism, natural selection and copy number variation (CNV) were investigated by sequencing and real-time PCR. The antigenicity and immunogenicity of the recombinant PocDBP-RII (rPocDBP-RII) protein were further examined, and the humoral and cellular responses of immunized mice were assessed using protein microarrays and flow cytometry. Efficiently expressed and purified rPocDBP-RII (39 kDa) was successfully used as an antigen for immunization in mice. The haplotype diversity (Hd) of PocDBP-RII gene was 0.105, and the nucleotide diversity index (π) was 0.00011. No increased copy number was found among the collected isolates of P. ovale curtisi. Furthermore, rPocDBP-RII induced persistent antigen-specific antibody production with a serum IgG antibody titer of 1: 16,000. IFN-γ-producing T cells, rather than IL-10-producing cells, were activated in response to the stimulation of rPocDBP-RII. Compared to PBS-immunized mice (negative control), there was a higher percentage of CD4+CD44highCD62L- T cells (effector memory T cells) and CD8+CD44highCD62L+ T cells (central memory T cells) in rPocDBP-RII‑immunized mice. PocDBP-RII sequences were highly conserved in clinical isolates of P. ovale curtisi. rPocDBP-RII protein could mediate protective blood-stage immunity through IFN-γ-producing CD4+ and CD8+ T cells and memory T cells, in addition to inducing specific antibodies. Our results suggested that rPocDBP-RII protein has potential as a vaccine candidate to provide assessment and guidance for malaria control and elimination activities.


Quality-of-care processes in geriatric assessment units: principles, practice, and outcomes.
To assess quality-of-care processes and to examine whether care processes are associated with short-term postdischarge outcomes in older vulnerable hospitalized patients. Retrospective study. Forty-nine Geriatric Assessment Units. Patients aged 65 and older who were admitted to a Geriatric Assessment Unit for a fall with trauma. Three care processes (comprehensiveness, informational continuity, patient-centered care) assessed through chart audit; three-month postdischarge outcomes (emergency department visit, hospital readmission, and death) obtained from national databases. A total of 934 hospitalization records were included. Mean comprehensiveness and informational continuity scores were 55% ± 12% and 42% ± 16%, respectively. Items related to geriatric global assessment (eg, functional autonomy) were particularly overlooked. Patient-centered care was poorly provided, with only 24% of hospitalization records showing evidence of advance care directives and at least one patient/family meeting with the physician to discuss clinical evolution. For the three care processes, a large variability among Geriatric Assessment Units was observed. Better comprehensiveness of care was associated with lowered short-term mortality (OR = 0.73, 95% CI = 0.55-0.96, P = .023), whereas higher scores on informational continuity was associated with fewer emergency department visits (OR = 0.91, 95% CI = 0.82-1.00, P = .046), hospital readmissions (OR = 0.84, 95% CI = 0.74-0.94, P = .003), and mortality (OR = 0.72, 95% CI = 0.59-0.88, P = .002). Patient-centered care was not associated with any of the postdischarge outcomes. A large gap between geriatric care principles and practice in Geriatric Assessment Units has been observed. Our results show that improvement in care processes may be translated to decreased short-term health services use and mortality.


Septic bursitis.
Nine cases of septic bursitis are presented, and the literature on the subject comprehensively reviewed, with an emphasis on the clinical manifestations of septic bursitis in various anatomic locations. Physical activities associated with increased susceptibility to septic bursitis and systemic conditions that increase the severity of septic bursitis are catalogued. Analysis of the microbiology of cases reported in the literature demonstrates that greater than 80% of cases of septic bursitis are caused by Staphylococcus aureus and other gram-positive organisms. However, a wide variety of gram-negative microorganisms, fungi, and other infectious agents have been reported to cause septic bursitis and may lead to complications in diagnosis and treatment. The nine cases reported here demonstrate the potential severity of septic bursitis and emphasize that significant systemic complications may result from this common musculoskeletal infection. Indications for hospitalization and/or intravenous antibiotic therapy for septic bursitis include the presence of fulminant local infection, evidence for systemic toxicity, or infection in an immunocompromised patient. Patients who fail to respond to intravenous antibiotics and percutaneous aspiration of the bursa may require surgical drainage or bursectomy by one of several methods that have been proposed. There is some recent evidence that intrabursal corticosteroid injection for therapy of nonseptic subcutaneous bursitis may be more effective than systemic antiinflammatory medication or simple bursa aspiration.


Faf1 is expressed during neurodevelopment and is involved in Apaf1-dependent caspase-3 activation in proneural cells.
Fas-associated factor 1 (Faf1) has been described as a Fas-binding pro-apoptotic protein and as a component of the death-inducing signaling complex (DISC) in Fas-mediated apoptosis. Faf1 is able to potentiate Fas-induced apoptosis in several cell lines, although its specific functions are still not clear. Here we show that Faf1 is highly expressed in several areas of the developing telencephalon. Its expression pattern appears to be dynamic at different embryonic stages and to be progressively confined within limited territories. To decipher the specific role of Faf1 in developing brain, we used cDNA over-expression and mRNA down-regulation experiments to modulate Faf1 expression in telencephalic neural precursor cells, and we showed that in neural cell death Faf1 acts as a Fas-independent apoptotic enhancer. Moreover, we found that Faf1 protein level is down-regulated during apoptosis in a caspase- and Apaf1-dependent manner.


Crystal structure of a hypothetical protein, TTHA0829 from Thermus thermophilus HB8, composed of cystathionine-β-synthase (CBS) and aspartate-kinase chorismate-mutase tyrA (ACT) domains.
TTHA0829 from Thermus thermophilus HB8 has a molecular mass of 22,754 Da and is composed of 210 amino acid residues. The expression of TTHA0829 is remarkably elevated in the latter half of logarithmic growth phase. TTHA0829 can form either a tetrameric or dimeric structure, and main-chain folding provides an N-terminal cystathionine-β-synthase (CBS) domain and a C-terminal aspartate-kinase chorismate-mutase tyrA (ACT) domain. Both CBS and ACT are regulatory domains to which a small ligand molecule can bind. The CBS domain is found in proteins from organisms belonging to all kingdoms and is observed frequently as two or four tandem copies. This domain is considered as a small intracellular module with a regulatory function and is typically found adjacent to the active (or functional) site of several enzymes and integral membrane proteins. The ACT domain comprises four β-strands and two α-helices in a βαββαβ motif typical of intracellular small molecule binding domains that help control metabolism, solute transport and signal transduction. We discuss the possible role of TTHA0829 based on its structure and expression pattern. The results imply that TTHA0829 acts as a cell-stress sensor or a metabolite acceptor.


Rapid technique of occlusion of the venae cavae for total cardiopulmonary bypass during repeat cardiac operations.
A new technique of occlusion of the venae cavae utilizing a cannula with an inflatable balloon cuff is described.


Multiple outcome assessment in a study of the cost-effectiveness of clozapine in the treatment of refractory schizophrenia. Department of Veterans Affairs Cooperative Study Group on Clozapine in Refractory Schizophrenia.
To develop new methods for combining results from multiple outcome domains and to demonstrate their application in a study of the cost-effectiveness of clozapine in treating hospitalized patients with refractory schizophrenia. Interview assessments, and administrative utilization and cost data, concerning 423 patients with refractory schizophrenia who had been hospitalized for 30-364 days during the year before study entry, at 15 VA medical centers. A 12-month double-blind trial compared clozapine (n = 205) and haloperidol (n = 218) in the treatment of refractory schizophrenia. Data from standard assessment instruments, gathered at baseline and at 6 weeks, and at 3, 6, 9, and 12 months, were used to develop a Composite Health Index for Schizophrenia, a measure that addresses outcome in six domains, weighted by patient or provider preferences. Cumulative improvement was estimated by computing the area under the improvement curve. This measure was then combined with cost data, reflecting consumption of societal resources to estimate incremental cost-effectiveness ratios. Clozapine was significantly more effective than haloperidol on measures of symptoms (p = .02) and side effects (p < .0001), with nonsignificant trends in the positive direction on community role functioning (p = .06), family relationships (p = .23), social relationships (p = .30), and daily activities (p = .20). Clozapine was also more effective than haloperidol on the one-year cumulative Composite Health Index for Schizophrenia (p < .0001 for all weighting schemes). After converting this measure to a 0-1 Worst Health-Good Health Scale analogous to Quality Adjusted Life Years, clozapine was found to yield a small improvement of .049 Worst Health-Good Health Units as compared to an improvement of only .027 Units for haloperidol (p < .0001). Average annual costs were $2,733 lower for clozapine (95% C.I. = -$9,220 to $3,754). Although clozapine was significantly more effective than haloperidol, the summary cost-effectiveness ratio had a wide 95 percent confidence interval ranging from -$431,585 to $177,352. Methods demonstrate an approach to using conventional disease-specific measures to evaluate the cumulative effectiveness of novel treatments for psychotic disorders and for expressing their economic effect as cost-effectiveness ratios. Among high hospital users with refractory schizophrenia, clozapine is more cost-effective than standard treatment, although the magnitude of its effect is small and there is considerable uncertainty about the cost estimates.


Peroneal Tendon Instability in Intra-Articular Calcaneus Fractures: A Retrospective Comparative Study and a New Surgical Technique.
To compare the prevalence of peroneal tendon instability as determined by intraoperative evaluation versus preoperative computed tomography (CT) scans, and to identify specific risk factors that correlate with tendon instability. Retrospective comparative study. Level 1 trauma hospital. Patients with operatively treated intra-articular calcaneus fractures managed between January 1, 2002 and December 31, 2012 were reviewed for evidence of peroneal tendon instability. Of 254 fractures, 155 intra-articular calcaneus fractures met inclusion criteria and were available for final analysis. Operative notes were reviewed to confirm intraoperative testing for superior peroneal retinaculum (SPR) integrity and peroneal tendon stability. Preoperative CT scan and plain radiographs were evaluated for presence of peroneal tendon dislocation, fibular fracture or "fleck" sign, excessive lateral wall displacement, and/or calcaneal fracture-dislocation. Peroneal tendon stability was determined with intraoperative assessment of the intact SPR and its confluence with the peroneal tendon sheath. The incidence of peroneal tendon instability on intraoperative assessment was compared with preoperatively identified tendon dislocation on CT scan. Prevalence of peroneal tendon dislocation was determined using each diagnostic method. Risk factors for tendon instability were identified using a multivariate regression model. There was significantly higher prevalence of peroneal tendon instability as determined by preoperative imaging (30%; n = 47/155) compared with intraoperative retinaculum testing (11.6%; n = 18/155) (P < 0.001). Intraoperative tendon instability was significantly associated with increased fracture classification severity, fibular fracture/"fleck" sign, and fracture-dislocation. Intraoperative evaluation of the SPR should be used in conjunction with preoperative imaging for diagnosis of peroneal instability in the setting of operatively treated, intra-articular calcaneus fractures. Diagnostic Level IV. See Instructions for Authors for a complete description of levels of evidence.


Inhibitory effect of oestradiol on activation of rat hepatic stellate cells in vivo and in vitro.
Hepatic stellate cells play a key role in the pathogenesis of hepatic fibrosis. To examine the inhibitory effect of oestradiol on stellate cell activation. In vivo, hepatic fibrosis was induced in rats by dimethylnitrosamine or pig serum. In vitro, rat stellate cells were activated by contact with plastic dishes resulting in their transformation into myofibroblast-like cells. In the dimethylnitrosamine and pig serum models, treatment with oestradiol at gestation related doses resulted in a dose dependent suppression of hepatic fibrosis with restored content of hepatic retinyl palmitate, reduced collagen content, lower areas of stellate cells which express alpha smooth muscle actin (alpha-SMA) and desmin, and lower procollagen type I and III mRNA levels in the liver. In cultured stellate cells, oestradiol inhibited type I collagen production, alpha-SMA expression, and cell proliferation. These findings suggest that oestradiol is a potent inhibitor of stellate cell transformation. The antifibrogenic role of oestradiol in the liver may contribute to the sex associated differences in the progression from hepatic fibrosis to cirrhosis


Rapid antimicrobial susceptibility profiling using impedance spectroscopy.
The present antibiotic susceptibility testing (AST) techniques based on bacterial culture, gene amplification and mass spectrometry are highly time consuming, labour intensive or expensive. Impedance spectroscopy is an emerging tool for rapid bacterial analysis as it is label-free, real-time, affordable and high-throughput. The over-reliance of this technique on complex chip designs and cell enrichment strategies has, however, slowed its foray into clinical AST. We demonstrate a label-free approach in which a low conductivity zwitterionic buffer is used for boosting impedance sensitivity in simple interdigitated electrodes (IDEs) allowing rapid AST in just 20 min without any liquid flow, biofunctionalization or cell enrichment steps. The detection principle relies on measuring changes in solution resistance due to antibiotic-induced bacterial cell death or growth. While the death-based approach is faster (20 min), it's restricted to surface-acting bactericidal antibiotics. The cell growth approach is longer (60-80 min) but more versatile as it applies to all drug types. Results for antibiotic sensitivity analysis and minimum inhibitory concentration (MIC) determination are illustrated for Escherichia coli, Klebsiella pneumoniae and Staphylococcus aureus against a wide class of antibiotics (penicillins, cephalosporins, polymyxins, carbapenems etc.).


Increased expression of endothelial cell nitric oxide synthase (ecNOS) in afferent and glomerular endothelial cells is involved in glomerular hyperfiltration of diabetic nephropathy.
The overproduction of nitric oxide (NO) is reported in the diabetic kidney and considered to be involved in glomerular hyperfiltration. The precise mechanism of NO production in the diabetic kidney is, however, not known. In this report, we compare the localization of endothelial cell nitric oxide synthase (ecNOS) isoform expression in the kidney tissue of streptozotocin (STZ)-induced diabetic rats and 5/6 nephrectomized rats and clarify the pivotal role of ecNOS for the glomerular hyperfiltration in the early stages of diabetic nephropathy. In diabetic rats, the diameters of afferent arterioles, the glomerular volume, creatinine clearance, and urinary NO2/NO3 were increased after the induction of diabetes. Efferent arterioles were, however, not altered. Insulin or L-NAME treatment returned the diameters of afferent arterioles, glomerular volume, creatinine clearance, and urinary NO2/NO3 to normal. The expression of ecNOS in afferent arterioles and glomeruli of diabetic rats increased during the early stages of the disease, but was not altered in efferent arterioles. Treatment with either insulin or L-NAME decreased ecNOS expression in afferent arterioles and in glomeruli. In contrast, the ecNOS expression was upregulated in both afferent and efferent arterioles and in the glomeruli of 5/6 nephrectomized rats, where the dilatation of afferent and efferent arterioles and glomerular enlargement were observed. Treatment with L-NAME ameliorated the ecNOS expression and dilatation of arterioles. We conclude that enhanced NO synthesis by ecNOS in afferent arterioles and glomerular endothelial cells in response to the hyperglycaemic state could cause preferential dilatation of afferent arterioles, which ultimately induces glomerular enlargement and glomerular hyperfiltration.


Anaerobic degradation and dehalogenation of chlorosalicylates and salicylate under four reducing conditions.
The anaerobic biodegradability and transformation of the mono-and dichlorinated salicylates (2-hydroxybenzoates) was examined under denitrifying, Fe (III) reducing, sulfate reducing and methanogenic conditions. 3,6-Dichlorosalicylate and 6-chlorosalicylate are anaerobic microbial metabolites of dicamba, a widely used herbicide. Anaerobic microcosms were established with dicamba treated soil from Wyoming, and golf course drainage stream sediments from New Jersey, which were each spiked with salicylate, 3,6-dichlorosalicylate or one of the four monochlorosalicylate isomers. Salicylate was degraded under denitrifying, sulfidogenic and methanogenic conditions. In methanogenic enrichments 5-chlorosalicylate and 3-chlorosalicylate were reductively dehalogenated to salicylate which was then utilized. Dehalogenation of monochlorinated salicylates to salicylate was also observed in denitrifying chlorosalicylate degrading cultures. The study revealed that the position of the chlorine substituent as well as the predominant electron accepting process affect the rate and extent of chlorosalicylate degradation in anoxic environments.


[Inequities in health: socio-demographic and spatial analysis of breast cancer in women from Córdoba, Argentina].
To identify sociodemographic determinants associated with the spatial distribution of the breast cancer incidence in the province of Córdoba, Argentina, in order to reveal underlying social inequities. An ecological study was developed in Córdoba (26 counties as geographical units of analysis). The spatial autocorrelation of the crude and standardised incidence rates of breast cancer, and the sociodemographic indicators of urbanization, fertility and population ageing were estimated using Moran's index. These variables were entered into a Geographic Information System for mapping. Poisson multilevel regression models were adjusted, establishing the breast cancer incidence rates as the response variable, and by selecting sociodemographic indicators as covariables and the percentage of households with unmet basic needs as adjustment variables. In Córdoba, Argentina, a non-random pattern in the spatial distribution of breast cancer incidence rates and in certain sociodemographic indicators was found. The mean increase in annual urban population was inversely associated with breast cancer, whereas the proportion of households with unmet basic needs was directly associated with this cancer. Our results define social inequity scenarios that partially explain the geographical differentials in the breast cancer burden in Córdoba, Argentina. Women residing in socioeconomically disadvantaged households and in less urbanized areas merit special attention in future studies and in breast cancer public health activities.


Building the Case for Quality Improvement.
Great improvements have been made by quality improvement teams. National trends towards using quality and value metrics in reimbursement suggest that physicians and advanced practitioners caring for children and adolescents will benefit from knowing and using quality improvement methods. These methods will also help as transparency of quality data becomes more commonplace.


Anthracycline chemicals with anthracyclinone structure exert antitumor effects by inhibiting angiogenesis and lymphangiogenesis in a xenografted gastric tumor model.
It is vital to screen or develop alternative therapeutic drugs with higher curative characteristics and fewer side effects for the clinical treatment of gastric cancer. Gastric cancer cells were exposed to different auramycin G doses while determining the impact on cell viability, migration, and invasion. Then the antitumor effects of auramycin G, 5-fluorouracil (5-Fu) and their combination were evaluated. Furthermore, the molecular mechanisms of angiogenesis and lymphangiogenesis regulated by auramycin G and its analogs were investigated. Auramycin G inhibited cell viability in a dose-dependent manner, with a 50% inhibitory concentration of 23.72 ± 6.36 mg/L and 32.54 ± 5.91 mg/L for AGS and MGC803 cells, respectively. The migration and invasion of gastric cancer cells were significantly inhibited by 10 mg/L auramycin G, which was consistent with the down-regulation of the VEGFR2-VEGFA-pPI3K-pAkt-pErk1 and VEGFR3-VEGFC-pPI3K-pAkt-pmTOR proteins. Notably, the average tumor weights were significantly reduced in both the auramycin G (2.21 ± 0.45 g) of 50 mg/kg body weight and auramycin G + 5-fluorouracil (5-Fu) groups (1.33 ± 0.28 g), compared with the control (3.73 ± 0.56 g). Considering that auramycin G decreased the growth of blood and lymphatic vessels while reducing the degree of tumor malignancy, it effectively suppressed tumors by regulating the angiogenic and lymphangiogenic pathways. The present study confirmed that auramycin G displayed a prominent antitumor activity in gastric tumor models, both in vitro and in vivo. Moreover, it was confirmed that auramycin G played a specific role in certain gastric cancer cell types, while the mechanism was validated to be associated with angiogenesis- and lymphangiogenesis-related pathway suppression.


Comparison of preoperative evaluation of malignant low-level biliary obstruction using plain magnetic resonance and coronal liver acquisition with volume acceleration technique alone and in combination.
To evaluate the clinical value of plain magnetic resonance (MR) imaging (including magnetic resonance cholangiopancreatography, MRCP) and coronal liver acquisition with volume acceleration (LAVA) technique in the diagnosis and preoperative assessment of malignant low-level biliary obstruction. Forty-one patients with confirmed malignant low-level biliary obstruction were examined by plain MR, MRCP and coronal LAVA techniques. Group 1, plain MR (including MRCP); group 2, coronal LAVA; group 3, plain MR and coronal LAVA. Assessments included positioning, qualitative diagnosis and preoperative evaluation. The results were compared with pathological, endoscopic retrograde cholangiopancreatography or percutaneous transhepatic cholangiography results. There were 14 pancreatic adenocarcinoma, 12 distal common bile duct carcinoma, 10 ampullary carcinoma, and 5 duodenal carcinoma cases. There was no significant difference in accuracy of the three groups' positioning diagnoses, 87.8, 90.2, and 92.7 %, respectively. The accuracy of the qualitative diagnoses was lower in group 1 at 78.0 %, but not significantly different in groups 2 and 3 at 92.7 and 95.1 %, respectively (P = 0.031, and 0.039, group 1 vs groups 2 and 3, respectively). Thirty-three patients underwent open surgery. There were 19 adjacent organ involvements, 9 vascular involvements, 13 lymph node metastases and 6 liver metastases. 22 patients were verified surgically and histologically for resectable lesions. Plain MR with coronal LAVA imaging showed 85.4 % accuracy, 90.9 % sensitivity, 78.9 % specificity, 83.3 % positive and 88.2 % negative predictive value for resectability. Plain MR and coronal LAVA techniques are potential noninvasive tools for diagnosis and preoperative assessment of malignant low-level biliary obstruction.


A protective role for the human SMG-1 kinase against tumor necrosis factor-alpha-induced apoptosis.
The human suppressor of morphogenesis in genitalia-1 (hSMG-1) protein kinase plays dual roles in mRNA surveillance and genotoxic stress response pathways in human cells. Here, we report that small interfering RNA-mediated depletion of hSMG-1, but not ATM, ATR, hUpf1, or hUpf2, in human U2OS osteosarcoma cells markedly increases the magnitude and accelerates the rate of apoptosis induced by tumor necrosis factor-alpha (TNFalpha) stimulation. The increase in TNFalpha-mediated cell killing observed in hSMG-1-depleted cells is not related to the suppression of nonsense-mediated mRNA decay or to the inhibition of TNFalpha-induced NF-kappaB activation. Rather, we observed that loss of hSMG-1 accelerates the degradation of the long form of the FLICE-inhibitory protein (FLIP(L)), an inhibitor of death-inducing signaling complex-mediated caspase-8 activation, in TNFalpha-treated cells. These results suggest that hSMG-1 plays an important role in cell survival during TNFalpha-induced stress.


Socioeconomic and Racial Disparities in Cancer Stage at Diagnosis, Tumor Size, and Clinical Outcomes in a Large Cohort of Women with Breast Cancer, 2007-2016.
Socioeconomic and treatment factors contribute to diagnosis of early-stage (local-stage) breast cancer, as well as excess deaths among African American women. We evaluated socioeconomic and treatment predictive factors for early-stage breast cancer among African American women compared to Caucasian women. A secondary aim evaluated predictors and overall risks associated with all-cause and breast cancer-specific mortality. We used retrospective cohort population-based study data from the Surveillance, Epidemiology, and End Results (SEER) Program on 547,703 women aged ≥ 20 years diagnosed with breast cancer primary tumors from 2007 to 2016. Statistical analysis used logistic regression to assess predictors of early-stage breast cancer and Cox proportional hazards regression for mortality risks. African American women were more likely to be diagnosed at advanced-stage, had larger tumor size at diagnosis, and received less cancer-directed surgery, but more chemotherapy than Caucasian women. Insured women (> 50%) were more likely to be diagnosed at early-stage and to have smaller tumors (p < 0.05). Education level, poverty level, and household income had no impact on racial disparities or socioeconomic disparities in women diagnosed at early stage. We found increased risks for all-cause mortality (hazard ratio = 1.18; 95% confidence interval, 1.16-1.21) and breast cancer-specific mortality (HR = 1.22; 95% CI, 1.19-1.25) among African American women compared to Caucasian women after adjusting for demographic, socioeconomic, and treatment factors. In this population-based study using the most recent SEER data, African American women with breast cancer continued to exhibit higher all-cause mortality and breast cancer-specific mortality compared to Caucasian women.


Happily partnered older adults' relationship-enhancing behaviours.
Relationship-enhancing behaviours that contribute to older adults' well-being are scarcely considered in "active ageing" discourses despite relationship quality having been repeatedly linked to health outcomes. This paper explores such behaviours in older adults. Cross-sectional data were collected in 2016 from 168 partnered baby boomers (born 1946 to 1965) using an online survey. The 36 qualitative and quantitative questions were analysed using mixed methods. Participants were predominantly women (85%), with a mean age of 62 years (SD = 5.2). Relationship-enhancing behaviours included verbal and non-verbal cues, physical affection and pleasurable sexual activities. A couple's shared bed was an important relationship setting. For happily partnered older adults, relationship quality improves personal well-being. As a social determinant of healthy ageing, health policies and programs are needed to support older adults' relationship quality. To this end, the development of targeted relationship interventions for delivery in health settings is warranted.


The prognostic impact of RAS on overall survival following liver resection in early versus late-onset colorectal cancer patients.
The impact of molecular aberrations on survival after resection of colorectal liver metastases (CLM) in patients with early-age-onset (EOCRC) versus late-age-onset colorectal cancer (LOCRC) is unknown. Patients who underwent liver resection for CLM with known RAS, BRAF and MSI status were retrospectively studied. The prognostic impact of RAS mutations by age was analysed with age as a categorical variable and a continuous variable. The study included 573 patients, 192 with EOCRC and 381 with LOCRC. The younger the age of onset of CRC, the greater the negative impact on overall survival of RAS mutations in the LOCRC, EOCRC, and ≤40 years (hazard ratio (HR), 1.64 (95% confidence interval (CI), 1.23-2.20), 2.03 (95% CI, 1.30-3.17), and 2.97 (95% CI, 1.44-6.14), respectively. Age-specific mortality risk and linear regression analysis also demonstrated that RAS mutations had a greater impact on survival in EOCRC than in LOCRC (slope: -4.07, 95% CI -8.10 to 0.04, P = 0.047, R2 = 0.08). Among patients undergoing CLM resection, RAS mutations have a greater negative influence on survival in patients with EOCRC, more so in patients ≤40 years, than in patients with LOCRC and should be considered as a prognostic factor in multidisciplinary treatment planning.


Utilisation of pH stacking in conjunction with a highly absorbing chromophore, 5-aminofluorescein, to improve the sensitivity of capillary electrophoresis for carbohydrate analysis.
This study explores the use of pH stacking in conjunction with 5-aminofluorescein as a derivatization agent for the sensitive analysis of simple sugars such as glucose, lactose and maltotriose by capillary electrophoresis (CE). The derivatization agent was selected on the basis of its extremely high molar absorptivity, its compatibility with a 488nm light-emitting diode (LED) and the fact that it has two ionizable groups making it compatible with on-line stacking using a dynamic pH junction. The influence of both acetic and formic acids at concentrations of 0.19, 0.019 and 0.0019molL(-1) were investigated with regard to both derivatization efficiency and the ability to stack using a dynamic pH junction. Superior sensitivity and resolution was obtained in formic acid over acetic acid. Substantially lower peaks were obtained with 0.19molL(-1) formic acid when compared to 0.019 and 0.0019molL(-1) concentrations, which was confirmed by computer simulation studies to be due to the inadequate movement of the pH boundary for stacking. Further simulation studies combined with experimental data showed the separation with the best resolution and greatest sensitivity when the carbohydrates were derivatized with the 0.095molL(-1) formic acid. Utilisation of stacking via dynamic pH junction mode in conjunction with LED detection enabled efficiencies of 150,000 plates and detection limits in the order of 8.5x10(-8)molL(-1) for simple sugars such as glucose, lactose and maltotriose hydrate. The current system also demonstrates a 515 times improvement in sensitivity when compared to using a normal deuterium lamp, and 16 times improvement over other systems using LEDs.


Risk Factors Associated with a Dengue Fever Outbreak in Islamabad, Pakistan: Case-Control Study.
On October 23, 2016, 79 dengue fever cases were reported from the Union Council Tarlai to Federal Disease Surveillance and Response Unit Islamabad. A team was established to investigate the suspected dengue outbreak. The aim of this study was to determine the extent of the outbreak and identify the possible risk factors. Active case finding was performed through a house-to-house survey. A case was defined as an acute onset of fever ≥38℃ in a resident of Tarlai from October 2 to November 11, 2016, with a positive dengue virus (nonstructural protein, NS-1) test and any of the two of following signs and symptoms: retroorbital/ocular pain, headache, rash, myalgia, arthralgia, and hemorrhagic manifestations. A structured questionnaire was used to collect data. Age- and sex-matched controls (1:1) were identified from residents in the same area as cases. Blood samples were taken and sent to the National Institute of Health for genotype identification. During the active case search, 145 cases of dengue fever were identified by surveying 928 houses from October 23 to November 11, 2016. The attack rate (AR) was 17.0/10,000. The mean age was 34.4 (SD 14.4) years. More than half of the cases were male (80/145, 55.2%). Among all cases, 29% belonged to the 25-34 years age group and the highest AR was found in the 35-44 years age group (35.6/10,000), followed by the 55-64 years age group (35.5/10,000). All five blood samples tested positive for NS-1 (genotype DENV-2). The most frequent presenting signs/symptoms were fever and headache (both 100%). Stagnant water around houses (odds ratio [OR] 4.86, 95% CI 2.94-8.01; P<.001), presence of flower pots in the home (OR 2.73, 95% CI 1.67-4.45; P<.001), and open water containers (OR 2.24, 95% CI 1.36-3.60; P<.001) showed higher odds among cases. Conversely, use of bed nets (OR 0.44, 95% CI 0.25-0.77; P=.003), insecticidal spray (OR 0.33, 95% CI 0.22-0.55; P<.001), door screens (OR 0.27, 95% CI 0.15-0.46; P<.001), mosquito coil/mat (OR 0.26, 95% CI 0.16-0.44; P<.001), and cleanliness of the house (OR 0.12, 95% CI 0.05-0.26; P<.001) showed significant protective effects. Stagnant water acting as breeding grounds for vectors was identified as the probable cause of spread of the dengue outbreak. Establishment of surveillance and an early reporting system along with use of protective measures against the vector are strongly recommended.


Management of corneal neurotrophic ulcers with Cacicol®-RGTA (ReGeneraTing Agent): a case series.
Neurotrophic corneal ulcers are difficult to treat, and the conventional treatment often results in failure. A new matrix regenerating agent ("ReGeneraTing Agents"), Cacicol® (Laboratoires Théa), has demonstrated good results over the last few years. Therefore, the aim of this study was to evaluate the response to Cacicol® in a series of cases with neurotrophic corneal ulcers. Retrospective case series looking at 11 patients with corneal ulcers unresponsive to conventional therapy that underwent treatment with Cacicol®. One cycle included 1 drop every two days for 5 days. The range of conventional therapy prior to Cacicol® was 0-91 days. On introducing Cacicol® 82% (9/11) of the cases were cured, and 18% (2/11) failed, requiring an amniotic membrane transplant or penetrating keratoplasty. The healing only required one cycle of Cacicol® in 67% (6/9) of the patients. More than one cycle of Cacicol® was needed in 45% (5/11) patients. One corneal bacterial ulcer responded favourably and one case related to Acanthamoeba did not respond. Most of the patients improved or maintained their visual acuity. Cacicol® was a useful therapy in a high number of difficult neurotrophic corneal ulcers, including corneal infections. Some cases may require more than one cycle of Cacicol® or used as first-line treatment in order to achieve the desired result.


Low intensity light treatment improves purple kale (Brassica oleracea var. sabellica) postharvest preservation at room temperature.
Purple Kale is a vegetable of the Brassicaceae family whose are popularly consumed in recent years due to their high level of healthy components. For consumption, matures leaves are harvested and postharvest senescence is induced. Changes in color leaves due to chlorophyll degradation are the main visible symptoms of postharvest senescence, but there are other changes that affect the nutritional quality of kale. The aim of this study was to investigate if low intensity light pulses could be used to delay postharvest senescence of purple kale stored at room temperature. Daily treatments with 1 h pulses of white or red light were performed. Irradiated samples had approximately 40% higher chlorophyll and protein and more of 20% higher antioxidant capacity and soluble sugar content than control samples regardless of light quality used in treatment (white or red). Both light treatments improve the appearance and quality of kale during storage at room temperature.


Reliability of reporting self-measured blood pressure values by hypertensive patients.
For self-measurement of blood pressure to be useful, patient reporting of test results must be reliable and accurate. Until now no study directly measured the accuracy and reliability of patients' reporting of self-measured blood pressure values. Thirty hypertensive patients (69 +/- 11 years) were instructed to measure blood pressure at home over 14 days with the highly accurate Omron IC monitor and to keep a record of all readings in a patient logbook. To assess the reliability of the records, patients were not informed about the memory capacity of the device. We compared automatically stored blood pressure readings with the respective logbook entries to analyze deletion (under-reporting), addition (over-reporting), and precision of reporting of test results. The prevalent pattern was under-reporting, averaging 36% +/- 24% (3% to 89%), which occurred significantly more than over-reporting (9% +/- 11%; 0% to 38%). The precision of reporting (identical values at corresponding times) was 76% +/- 34% (0% to 100%). This observer error did not affect group comparisons of automatically stored values and logbook entries, although the estimated limits of agreement were wide. Blood pressure control, duration of hypertension, age, or previous use of self-measurement and patterns of logbook entries were not found to be predictive of the patients' reliability. Our results demonstrate a substantial observer error in the reporting of self-measured blood pressure values. This bias may be reduced by memory-equipped blood pressure devices.


Lower extremity pseudoaneurysms and their interventional radiological management: a pictorial review.
Lower extremity pseudoaneurysms (PsAs) are mostly developed after traumatic or iatrogenic injury to the arteries. Unless treated, they can be complicated by adjacent mass effects, distal embolism, secondary infection, and rupture. Imaging helps in the diagnosis and planning of therapeutic intervention. Ultrasonography (USG) is often diagnostic, while CT angiography aids in vascular mapping required for intervention. Image-guided therapy offers to manage these pseudoaneurysms in a minimally invasive approach, obviating the need for surgery. A smaller, superficial, and narrow-necked PsA can easily be managed with local USG-guided compression or thrombin injection. When the percutaneous approach is not a feasible option, PsA from expendable arteries can also be managed with coiling or glue injection. Wide-necked PsA from an unexpendable artery necessitates stent graft placement, although coiling of the neck may be a viable and cheaper alternative for a long- and narrow-necked PsA. Presently, vascular closure devices are also used to seal a small arterial rent through a direct percutaneous approach. This pictorial review entails various techniques to deal with lower extremity pseudoaneurysms. An idea about the various intervention radiological approaches will help in choosing appropriate methods to tackle lower extremity pseudoaneurysms.


[Synthesis and identification of the hapten and complete antigens for Zearalenone].
To synthesize and identify the hapten and complete antigens for Zearalenone for the purpose of preparation of anti-Zearalenone antibodies. Zearalenone and carboxymethoxylamine hemihydrochloride were incubated to synthesize the hapten ZEN-oxime. The ZEN-oxime was identified by thin layer chromatography (TLC), high performance liquid chromatographic (HPLC) and liquid chromatography-tandem mass spectrometry (LC-MSn). The ZEN-oxime was further conjugated to bovine serum albumin (BSA) or ovalbumin (OVA) to form the complete antigens by NHS ester method. The complete antigens were identified by ultraviolet spectrum, 2, 4, 6-trinitrobenzene sulfonicacid method (TNBS) and immunological analysis. The results indicated that the hapten and complete antigens were prepared successfully. The hapten and complete antigens for Zearalenone have been successfully synthesized and identified by several methods, which enables further preparation of anti-Zearalenone antibodies.


A putative kinetic model for substrate metabolisation by Drosophila acetylcholinesterase.
Insect acetylcholinesterase, an enzyme whose catalytic site is located at the bottom of a gorge, can metabolise its substrate in a wide range of concentrations (from 1 microM to 200 mM) since it is activated at low substrate concentrations. It also presents inhibition at high substrate concentrations. Among the various rival kinetic models tested to analyse the kinetic behaviour of the enzyme, the simplest able to explain all the experimental data suggests that there are two sites for substrate molecules on the protein. Binding on the catalytic site located at the bottom of the gorge seems to be irreversible, suggesting that each molecule of substrate which enters the active site gorge is metabolised. Reversible binding at the peripheral site of the free enzyme has high affinity (2 microM), suggesting that this binding increases the probability of the substrate entering the active site gorge. Peripheral site occupation decreases the entrance rate constant of the second substrate molecule to the catalytic site and strongly affects the catalytic activity of the enzyme. On the other hand, catalytic site occupation lowers the affinity of the peripheral site for the substrate (34 mM). These effects between the two sites result both in apparent activation at low substrate concentration and in general inhibition at high substrate concentration.


Anti-platelet and anti-thrombotic effects of OP-41483.alpha-CD, a prostacyclin analogue, in experimental animals.
The effects of OP-41483.alpha-CD, 5(E)-6,9-deoxa-6,9 alpha-methylene-15-cyclopentyl-16,17,18,19,20-pentanor prostacyclin (PGI2).alpha-cyclodextrin clathrate, on platelet function and experimental thrombosis were studied. In human platelets, OP-41483 inhibited aggregation induced by adenosine diphosphate (ADP) or collagen, promoted disaggregation, and elevated cyclic adenosine monophosphate (cAMP) levels in vitro at the same order of concentrations. The equipotent antiaggregatory activity of OP-41483 to human platelets was observed in monkey platelets in vitro. Furthermore, intravenous administration of OP-41483 to monkeys, unlike PGI2, showed the antiaggregatory effect on platelets but with less effect on blood pressure, suggesting that a differential sensitivity to OP-41483 between platelet function and vascular tone exists in monkeys. In rabbits, OP-41483.alpha-CD attenuated platelet aggregation induced by ADP, collagen and platelet activating factor (PAF), decreased circulating platelet aggregates, and inhibited platelet adhesiveness to de-endothelialized blood vessels. These results suggest that the anti-thrombotic effects of OP-41483 are associated with its potent antiplatelet activities mainly because of the elevation of cAMP levels in the platelets. The potent anti-thrombotic and less hypotensive effects of this compound may be useful for various thrombotic disorders.


Staphylococcus aureus mobile genetic elements.
Among the bacteria groups, most of them are known to be beneficial to human being whereas only a minority is being recognized as harmful. The pathogenicity of bacteria is due, in part, to their rapid adaptation in the presence of selective pressures exerted by the human host. In addition, through their genomes, bacteria are subject to mutations, various rearrangements or horizontal gene transfer among and/or within bacterial species. Bacteria's essential metabolic functions are generally encoding by the core genes. Apart of the core genes, there are several number of mobile genetic elements (MGE) acquired by horizontal gene transfer that might be beneficial under certain environmental conditions. These MGE namely bacteriophages, transposons, plasmids, and pathogenicity islands represent about 15% Staphylococcus aureus genomes. The acquisition of most of the MGE is made by horizontal genomic islands (GEI), recognized as discrete DNA segments between closely related strains, transfer. The GEI contributes to the wide spread of microorganisms with an important effect on their genome plasticity and evolution. The GEI are also involve in the antibiotics resistance and virulence genes dissemination. In this review, we summarize the mobile genetic elements of S. aureus.


Screening and identification of lactic acid bacteria with antimicrobial abilities for aquaculture pathogens in vitro.
This study aimed to evaluate the antibacterial properties of nine lactic acid bacterial strains. The agar diffusion method (Oxford cup method) was used to assess the antimicrobial activity against pathogenic bacteria in aquaculture. The results showed that all selected strains inhibited the growth of Photobacterium damsel, Vibrio alginolyticus, Listonella anguillarum, Edwardsiella ictaluri, Aeromonas hydrophila, V. arahaemolyticus, Edwardsiella tarda and V. harveyi, but did not inhibit the growth of Metschnikowia bicuspidata. Among these strains of lactic acid bacteria, r1 was selected for its obvious antibacterial activity against eight kinds of pathogenic bacteria by 96-well plate method. Its inhibitory rate reached 96%, and it could inhibit the growth of six pathogenic bacteria at 121 ℃, 20 min and pH 3.5-4.0. It was identified as Lactiplantibacillus plantarum by morphological observation and 16S rRNA sequencing analysis. Because strain r1 was isolated from culture ponds and exerted strong inhibitory effects on pathogenic bacteria, it holds potential as an agent to prevent and control infectious diseases in aquaculture. This study provides a foundation for the development and utilization of probiotics in aquaculture.


Surgical resection improves overall survival of patients with small bowel leiomyosarcoma.
Small bowel leiomyosarcoma (SB LMS) is a rare disease with few studies characterizing its outcomes. This study aims to evaluate surgical outcomes for patients with SB LMS. The National Cancer Database was queried from 2004 to 2016 to identify patients with SB LMS who underwent surgical resection. The primary outcome was overall survival. A total of 288 patients with SB LMS who had undergone surgical resection were identified. The median age was 63, and the majority of patients were female (56%), White (82%), and had a Charlson comorbidity score of zero (76%). Eighty-one percent of patients had negative margins following surgical resection. Fourteen percent of patients had metastatic disease at the time of diagnosis. Nineteen percent of patients received chemotherapy and 3% of patients received radiation. One-year overall survival was 77% (95% CI: 72-82%) and 5-year overall survival was 43% (95% CI: 36-49%). Higher grade (HR: 1.98, 95% CI: 1.10-3.55, p = 0.02) and metastatic disease at diagnosis (HR: 2.57, 95% CI: 1.45-4.55, p = 0.001) were independently associated with higher risk of death. SB LMS is a rare disease entity, with treatment centering on complete surgical resection. Our results demonstrate that overall survival is higher than previously thought. Timely diagnosis to allow for complete surgical resection is key, and investigation into the possible role of chemotherapy or radiation therapy is needed.


Ovarian cancer: Novel mechanisms and therapeutic targets regarding the microenvironment in the abdominal cavity.
Ovarian cancer is an intractable disease that is mostly diagnosed at an advanced stage and has a high recurrence rate. The early development of characteristic peritoneal dissemination via ascites contributes to a poor prognosis. Based on the "seed and soil" theory, ovarian cancer is considered to form a disseminated tumor that interacts with the peritoneum; superficial mesothelial cells are structurally important. Thus far, we have reported that peritoneal mesothelial cells, which originally are ecological defenses, transform into ovarian cancer-associated mesothelial cells, which are allies of cancer. They are found to be actively involved in the formation of a friendly "soil" that promotes the survival of "seeds" of ovarian cancer cells. We also demonstrated that the progression of ovarian cancer and the induction of its refractory nature are partially mediated through competition and cooperation between ovarian cancer and mesothelial cells. We believe that it is necessary to shift the aim of treatment strategies from solely targeting cancer cells to focusing on the crosstalk between the surrounding environment and ovarian cancer, an approach that ultimately aims to achieve "coexistence" with cancer through disease control.


A three-year evaluation of metabolic changes in Singaporean Norplant-2 rod acceptors.
In this longitudinal study involving 100 Singaporean women, the effects of Norplant-2 rods on metabolic function were evaluated. With respect to liver function, the results indicate possible hepatocellular dysfunction as evidenced by a significant rise in serum bilirubin and a significant fall in total proteins and globulin during the three years of use. As regards lipid metabolism total triglycerides, cholesterol and LDL cholesterol were significantly decreased as compared to their preinsertion values at the end of three years. The HDL-cholesterol was also significantly decreased during the second and third year of use. Despite this, the HDL-cholesterol/total-cholesterol-HDL-cholesterol remained above 0.200. Thus, though speculative, it still appears to indicate that use of Norplant-2 rods is not directly contributory to cardiovascular risk. The use of Norplant-2 was not associated with any significant effect on carbohydrate metabolism after three years of use.


Long Term Treatment Results for Deep Infections of Total Knee Arthroplasty.
This study aims to identify the long-term outcomes of total knee arthroplasty (TKA) treated for deep infection. 3270 consecutive primary and 175 revision TKAs were followed prospectively. There were 39 deep infections (1.16%): 29 primary (0.9%) and 10 revision (5.7%) cases. Two-stage resection and re-implantation procedure was performed in 13 primary cases with 10/13 (77%) successfully resolved. Early (<1 month) Irrigation and Debridement (I&D) was performed in 16 primary cases with 100% success. Late (>4 months) I&D was performed in 6 cases with 5/6 (83.3%) successful. Infection following revision TKA resulted in poor outcomes with both two-stage (2/4 successful) and I&D (2/6 successful). Deep infection after primary TKA can be successfully resolved with I&D and appropriate antibiotic treatment in the early postoperative course.


Embracing covariation in brain evolution: large brains, extended development, and flexible primate social systems.
Brain size, body size, developmental length, life span, costs of raising offspring, behavioral complexity, and social structures are correlated in mammals due to intrinsic life-history requirements. Dissecting variation and direction of causation in this web of relationships often draw attention away from the factors that correlate with basic life parameters. We consider the "social brain hypothesis," which postulates that overall brain and the isocortex are selectively enlarged to confer social abilities in primates, as an example of this enterprise and pitfalls. We consider patterns of brain scaling, modularity, flexibility of brain organization, the "leverage," and direction of selection on proposed dimensions. We conclude that the evidence supporting selective changes in isocortex or brain size for the isolated ability to manage social relationships is poor. Strong covariation in size and developmental duration coupled with flexible brains allow organisms to adapt in variable social and ecological environments across the life span and in evolution.


The rising prevalence of asthma: true increase, diagnostic exchange or diagnostic accuracy?
In the midst of frequent reports about "the asthma epidemic," results from a number of studies by the manitoba centre for health policy have shown stable or decreasing prevalence of an overall indicator of respiratory diseases which includes asthma. To resolve these apparently contrary findings, we conducted a time trend analysis using administrative data. results revealed significant potential for diagnostic exchange: asthma prevalence increased, but that of bronchitis decreased.


A Facile Way to Fabricate High-Performance Solution-Processed n-MoS2/p-MoS2 Bilayer Photodetectors.
Two-dimensional (2D) material has many advantages including high carrier mobilities and conductivity, high optical transparency, excellent mechanical flexibility, and chemical stability, which made 2D material an ideal material for various optoelectronic devices. Here, we developed a facile method of preparing MoS2 nanosheets followed by a facile liquid exfoliation method via ethyl cellulose-assisted doping and utilizing a plasma-induced p-doping approach to generate t effectively the partially oxided MoS2 (p-MoS2) nanosheets from the pristine n-type nanosheets. Moreover, an n-p junction type MoS2 photodetector device with the built-in potentials to separate the photogenerated charges is able to significantly improved visible light response. We have fabricated photodetector devices consisting of a vertically stacked indium tin oxide (ITO)/pristine n-type MoS2 nanosheets/p-MoS2/Ag structure, which exhibit reasonably good performance illumination, as well as high current values in the range of visible wavelength from 350 to 600 nm. We believe that this work provides important scientific insights for photoelectric response properties of emerging atomically layered 2D materials for photovoltaic and other optoelectronic applications.


[Structured concept for the establishment of a broad and ambulatory care of patients with type 2 diabetes: one-year evaluation of a regional teaching organization].
The increasing prevalence of diabetes mellitus and its long-term complications are associated with an expanding social medical problem. In order to originate an established teaching and training program on a physician-based level in short time, three specialist diabetes centers from Lübeck transferred their concept to a diabetes organization based on 17 physicians who had only rarely undertaken any diabetes teaching before. We investigated the achievement and effectiveness of this concept in a prospective multicenter evaluation one year after the patients had received structured diabetes teaching by the organization. Physicians and their teaching staff were trained by the specialists from the diabetes centers according to an official agreement. Patients were treated by each practice, while the diabetes teaching was done centrally by the organization through a diabetes assistant/dietician based on a modified official diabetes teaching and training program (ZI-program). 230 of 250 patients (120 male, 110 female) were reinvestigated one year after they had received the teaching. The group consisted of 179 non-insulin-treated (NIB; 94 via physicians, 85 via specialists) and 51 insulin-treated (IB; 19 via physicians, 32 via specialists) participants. The average age of NIB was 60.4+/-9.8 years, while IBs were 68.8+/-7.3 years old. HbA (1c) values were reduced in both groups, NIB and IB, by approximately 1% (NIB: 7.59+/-1.97% to 6.59+/-1.84%; IB: 8.47+/-1.35% to 7,36+/-1,38 %; p < 0,001). In the NIB-group the BMI was reduced by 0,64+/-0,14 kg x m (-2), whereas it was increased in the IB-group by 0.33+/-0.24 kg x m(-2) (NIB: 30.55+/-0.40 to 29.91+/-0.39 kg x m(-2), p < 0.001; IB: 28.83+/-0.74 to 29.16+/-0.75 kg x m(-2), p = 0.82). The transfer of established teaching and training concepts of specialist diabetes centers to a newly founded, physician-based diabetes organization resulted in a broad, effective and long-lasting medical care of patients with type 2 diabetics treated without or with insulin. The results are superior to those of other evaluations based on diabetes training ZI-programs.


A kinetically stable plant subtilase with unique peptide mass fingerprints and dimerization properties.
Milin, a potent molluscicide from the latex of Euphorbia milii, holds promise in medicinal biochemistry. Electrophoresis, size exclusion chromatography, mass spectrometry and other biochemical characteristics identify milin as a homodimeric, plant subtilisin-like serine protease, the first of its kind. The subunits of milin are differentially glycosylated affecting dimer association, solubility and proteolytic activity. The dimeric dissociation is SDS-insensitive and strongly temperature dependent but does not appear to be linked by disulfide bridges. N-terminal sequence of acid hydrolyzed peptide fragments shows no homology to known serine protease. Peptide mass fingerprinting and de novo sequencing of the tryptic fragments also did not identify putative domains in the protein. Milin seems to be a novel plant enzyme with subunit association partly similar to human herpes virus serine proteases and partly to penicillin binding proteins. Its behaviour on SDS-PAGE gels and other properties is like "kinetically stable" proteins. Such subunit association and properties might play a critical role in its physiological function and in controlling Schistosomiasis.


Generation of an expression library in the baculovirus expression vector system.
The construction and screening of a small cDNA library consisting of 2 x 10(4) clones in the baculovirus expression vector system are described. This library consists of antibody heavy chain sequences isolated from the spleen of a mouse immunized with tetanus toxoid fragment C. A portion of this library was used to produce a pool of recombinant baculoviruses which were screened for production of antibody fragments reactive to tetanus toxoid without prior expression in Escherichia coli. The pool of 30 clones was found to contain at least 6 different populations of antibody indicating that diversity existed within the library. Positive clones were isolated from the baculovirus system and confirmed as being capable of producing a tetanus reactive antibody by expression as a beta-lactamase fusion protein in E. coli. One of these clones was returned to the baculovirus system using a different transfer vector, and tetanus binding reconfirmed. The results presented here show that the concept of the construction and screening of a baculovirus expression library is feasible even with 'difficult' proteins, such as antibody heavy chain fragments, and that the baculovirus expression vector system has the potential to produce cDNA expression libraries which can be screened directly for the desired protein.


Participatory Action Research (PAR) - to better understand the experiences of nurse academics working in a team.
There is considerable literature outlining the high levels of occupational stress nurse academics experience, and the potential effect of workplace pressure on mental health and wellbeing. To support the notion that to succeed in an academic environment, academics are more successful when working in a team, two academics conducted a Participation Action Research study. The PAR study was developed in line with a Clinical Skill Project to better understand the experiences of nurse academics working in a team. The Clinical Skills Project involved the write up of 40 nursing skills for publication. Twenty-seven academics were recruited into the project and allocated skills to write, in teams of 2-3, according to clinical expertise and interest. The Participatory Action Research (PAR) approach formed the framework for the project, as well as, provided an opportunity for the nurse academics to 'come together' at fortnightly team meetings to discuss the project and talk about their experience working in a team. Using the PAR cyclical process of observing, reflecting, planning, and acting there was ongoing opportunity for the academic nurses to discuss, question and share knowledge about academic practices. These Interactive reflections were recorded in a team reflective diary during the meetings. Participants were also asked to reflect on their individual experience of working in the team, before, during and after the project. At the completion of the project all reflective comments were transcribed to form a combined narrative. Thematic and content analysis was then undertaken to identify any similarities and or differences in academic staff experience. The analysis revealed the following key themes. Working in a team creates better staff relationships, Working in a team can change workplace culture and Working in a team can Improve staff health and well-being.


The effect of decreasing computed tomography dosage on radiostereometric analysis (RSA) accuracy at the glenohumeral joint.
Standard, beaded radiostereometric analysis (RSA) and markerless RSA often use computed tomography (CT) scans to create three-dimensional (3D) bone models. However, ethical concerns exist due to risks associated with CT radiation exposure. Therefore, the aim of this study was to investigate the effect of decreasing CT dosage on RSA accuracy. Four cadaveric shoulder specimens were scanned using a normal-dose CT protocol and two low-dose protocols, where the dosage was decreased by 89% and 98%. 3D computer models of the humerus and scapula were created using each CT protocol. Bi-planar fluoroscopy was used to image five different static glenohumeral positions and two dynamic glenohumeral movements, of which a total of five static and four dynamic poses were selected for analysis. For standard RSA, negligible differences were found in bead (0.21±0.31mm) and bony landmark (2.31±1.90mm) locations when the CT dosage was decreased by 98% (p-values>0.167). For markerless RSA kinematic results, excellent agreement was found between the normal-dose and lowest-dose protocol, with all Spearman rank correlation coefficients greater than 0.95. Average root mean squared errors of 1.04±0.68mm and 2.42±0.81° were also found at this reduced dosage for static positions. In summary, CT dosage can be markedly reduced when performing shoulder RSA to minimize the risks of radiation exposure. Standard RSA accuracy was negligibly affected by the 98% CT dose reduction and for markerless RSA, the benefits of decreasing CT dosage to the subject outweigh the introduced errors.


Assessment of membrane damage in continuous cultures of mammalian cells.
The present studies were aimed at evaluating procedures for assessing the effect of chemicals on the integrity of the plasma membrane in continuous cell cultures. The degree of membrane damage was monitored by determining the 'leakage' of alpha-[3H]aminoisobutyric acid ([3H]AIB) and [14C]deoxy-2-fluoro-D-glucose ([14C]FdG) from the prelabelled cells. These parameters were compared to the loss of lactate dehydrogenase (LDH) from the cells and the decrease in the intracellular level of K+. Triton X-100, sodium dodecylsulfate (SDS), phospholipase C and nystatin which are known to affect membranes by different mechanisms served as test agents. In parallel, we monitored the effects of the chemicals on the viability of the cells. The following results were obtained: (1) The two radioactive markers [3H]AIB and [14C]FdG were found to be suitable to probe for damages of the plasma membrane in a variety of continuous cell lines which differ widely in their phenotype, rate of growth and degree of differentiation. (2) The leakage of the two markers could conveniently be monitored by double labelling techniques. (3) The loss from the cells of the 3 markers of smaller molecular size, K+, [3H]AIB, [14C]FdG, differed considerably depending on the test agent used. (4) Intracellular K+ level and [3H]AIB leakage generally appeared to follow a similar pattern, whereas [14C]FdG leakage may have shown a distinctly different response. (5) The leakage of LDH was an insensitive indicator for membrane damage. (6) No clear relationship was detectable between a particular leakage pattern of the markers and the loss of cellular viability.


Severe mental retardation in a Swedish county. I. Epidemiology, gestational age, birth weight and associated CNS handicaps in children born 1959--70.
In a unselected series of children born in 1959--70 with severe mental retardation (MR)---defined as IQ less than 50---in a Swedish county, the incidence, prevalence, gestational length, birth weight and associated CNS handicaps were analysed. The cumulative incidence at 1-16 years of age was calculated at 3.3% and the prevalence at 11-16 years at 2.8%. These figures were lower than in most other previous studies. In the great majority of cases the pathogenesis was of prenatal origin. The mean gestational lengths and birth weights were decreased compared with those of an average Swedish population. Severe MR affected large and small for date babies more often than could be expected. On the other hand, babies, with a low birth weight, appropriate for gestational age, and with an uncomplicated history, were found not to run a special risk of severe MR. Among the 122 children, 42% had one or more associated CNS handicaps---epilepsy (30%) and cerebral palsy (18%) being the most common.


Abdominoscrotal hydrocele in infant with hydronephrosis.
A case is presented of an unusually large abdominoscrotal hydrocele with secondary left ureterohydronephrosis owing to contiguous pressure. The technique that made the preoperative diagnosis apparent is described.


Congenital craniopharyngioma: a case report and literature review.
Although craniopharyngiomas are congenital tumors, they are rarely diagnosed in the prenatal or early neonatal period. Sometimes they are very large, debilitating and life-threatening, as in the case discussed here. A 21-month-old girl was referred for craniopharyngioma that had been diagnosed at 5 months because of neurologic complications. The pregnancy and birth were considered to be unremarkable. The birth weight was 4 kg, length 53 cm, head circumference 38 cm (n=35±1). Brain CT revealed active hydrocephalus caused by a very large solid, cystic and calcified supra sellar mass. MRI confirmed the process measuring 5 cm in height, multidirectional, diving into pituitary sella, displacing the brainstem. After several resections and reservoir drainage, the patient was blind, hemiparetic and she convulsed frequently. The patient died when she was 2. The large head circumference at birth, the size of the tumor, blindness, and hemiparesis observed before the age of 5 months suggested an antenatal process unnoticed because of inadequate gestational monitoring.


LC determination of the anti-ulcer agent CDRI-85/92 in rat serum.
CDRI-85/92 is a new potent anti-ulcer compound developed by Central Drug Research Institute, Lucknow (India). This compound is in advanced stage of preclinical trials. A High-performance liquid chromatographic (HPLC) method was developed and validated for the analysis of CDRI-85/92 using rat serum. The HPLC analysis, applicable to 0.5-ml volumes of serum, involved protein precipitation of serum samples with acetonitrile (1:3 v/v) followed by centrifugation and separation on a C-18 column and the use of UV detector at the wavelength 250 nm. The method was sensitive with a lowest limit of quantitation (LLOQ) of 1.25 ng ml(-1) in rat serum and the recovery was more than 96%. The linearity was satisfactory as indicated by correlation of >0.99, in addition to the visual examination of the calibration curves. The precision and accuracy were acceptable as indicated by relative standard deviation (R.S.D.) ranging from 4.15 to 8.21%, bias values ranging from 2.96 to 11.18%. In-process stability evaluation showed the stability of the compound in processed samples lasted up to 168 h. The method was applied for analysing CDRI-85/92 in rat serum after administration of single oral or iv bolus dose of 20 mg kg(-1). The robustness/ruggedness of the HPLC procedure was tested using different HPLC instrumentation and column of different make. The assay was found to be sensitive (limit of quantification was 1.25 ng ml(-1)), specific (retention time for CDRI-85/92 is 7.5 min), accurate (% bias is <12%), precise (% R.S.D. is <10%), robust (no significant change in peak profile in two HPLC Instruments) and reliable for use in pharmacokinetic or toxicokinetic studies.


Amikacin in the treatment of pulmonary tuberculosis.
Sensitivity tests on strains from 11 patients with pulmonary tuberculosis, previously treated with kanamycin and/or capreomycin, showed incomplete cross-resistance between amikacin and capreomycin but complete cross-resistance between amikacin and kanamycin. Treatment with amikacin of 4 patients with multiply resistant strains resulted in no response as assessed by sputum smears and cultures, but resistance emerged to amikacin, kanamycin and capreomycin. Amikacin has no role in the treatment of tuberculosis as it cannot be given as an alternative to kanamycin, has no advantages over it and is more expensive.


Correction of metabolic abnormalities in a mouse model of glycogen storage disease type Ia by CRISPR/Cas9-based gene editing.
Glycogen storage disease type Ia (GSD-Ia), deficient in glucose-6-phosphatase-α (G6PC), is characterized by impaired glucose homeostasis and a hallmark of fasting hypoglycemia. We have developed a recombinant adeno-associated virus (rAAV) vector-mediated gene therapy for GSD-Ia that is currently in a phase I/II clinical trial. While therapeutic expression of the episomal rAAV-G6PC clinical vector is stable in mice, the long-term durability of expression in humans is currently being established. Here we evaluated CRISPR/Cas9-based in vivo genome editing technology to correct a prevalent pathogenic human variant, G6PC-p.R83C. We have generated a homozygous G6pc-R83C mouse strain and shown that the G6pc-R83C mice manifest impaired glucose homeostasis and frequent hypoglycemic seizures, mimicking the pathophysiology of GSD-Ia patients. We then used a CRISPR/Cas9-based gene editing system to treat newborn G6pc-R83C mice and showed that the treated mice grew normally to age 16 weeks without hypoglycemia seizures. The treated G6pc-R83C mice, expressing ≥ 3% of normal hepatic G6Pase-α activity, maintained glucose homeostasis, displayed normalized blood metabolites, and could sustain 24 h of fasting. Taken together, we have developed a second-generation therapy in which in vivo correction of a pathogenic G6PC-p.R83C variant in its native genetic locus could lead to potentially permanent, durable, long-term correction of the GSD-Ia phenotype.


Epigenetic events in normal colonic mucosa surrounding colorectal cancer lesions.
Gene inactivation by promoter hypermethylation has been demonstrated in the colonic mucosa of colorectal cancer (CRC) patients. However, current data do not prove direct involvement of this epigenetic modification in the early stages of CRC. Promoter methylation profiles of E-cadherin, hMLH1, MGMT, p16(INK4a), p15(INK4b) and p14(ARF); mutations of K-ras, B-raf and TP53 and microsatellite instability (MSI) were examined in normal and cancerous colonic mucosal tissue in 82 CRC patients using methylation-specific PCR assays. Methylation of hMLH1 and MGMT in normal mucosa correlated significantly with MSI and K-ras activation in neighbouring cancerous mucosal tissues. Similarly, poorly differentiated tumours were associated with methylated p16(INK4a) and E-cadherin in neighbouring normal colonic tissues (NCTs). Our results indicate that epigenetic changes in mucosa surrounding colorectal neoplastic lesions may describe a 'field cancerisation' phenomenon that may occur previous to genetic alterations in early stages of carcinogenesis.


Iridium-Catalyzed B-H Bond Insertion Reactions Using Sulfoxonium Ylides as Carbene Precursors toward α-Boryl Carbonyls.
An iridium-catalyzed B-H bond insertion reaction between borane adducts and sulfoxonium ylides to afford α-boryl carbonyls has been developed. The starting materials are safe and readily available. In addition, analogues of sulfoxonium ylides, such as sulfonium salts and sulfonium ylides could also be amenable to the reaction.


Data of pre-clinical and early clinical trials of acriflavine and hydroxy-methyl-ellipticine reviewed, enriched by the experience of their use for 18 months to 6 years in combinations with other HIV1 virostatics.
Two virostatics which we discovered in 1990, acriflavine (ACF) and hydroxy-methyl-ellipticine (HEL) and shown active on HIV1 resistant to AZT have been introduced into combinations of four virostatics selected among ten available: themselves, plus zidovudine, zalcitabine, didanosine, lamivudine, stavudine, saquinavir, ritonavir, indinavir, the combinations were applied in 3-week sequences, differing from each other by drug rotation. Those which contained ACF may have more often a CD34 decrease than those containing neither ACF nor HEL, and they present more often a CD4 increase. No significant difference as far as side effects or beneficial effects could be detected after 18 months to 6 years, between sequences containing ACF or HEL or both, and sequences not containing any one of them.


Circulating serotonin in vertebrates.
The role of circulating serotonin is unclear and whether or not serotonin is present in the blood of non-mammalian species is not known. This study provides the first evidence for the presence of serotonin in thrombocytes of birds and three reptilian species, the endothermic leatherback sea turtle, the green sea turtle and the partially endothermic American alligator. Thrombocytes from a fresh water turtle, American bullfrog, Yellowfin tuna, and Chinook salmon did not contain serotonin. Serotonin is a vasoactive substance that regulates skin blood flow, a major mechanism for endothermic body temperature regulation, which could explain why circulating serotonin is present in warm-blooded species. The temperature sensitivity of human blood platelets with concomitant changes in serotonin content further supports a link between circulating serotonin and thermoregulation. Phylogenetic comparison of the presence of circulating serotonin indicated an evolutionary divergence within reptilian species that might coincide with the emergence of endothermy.


Effect of prenatal exposure to phenobarbital on the development of monoamine oxidase and glucocorticoids.
1. Fetal exposure to phenobarbital (PB, 30 mg/kg) 2-5 days prior to parturition was conducted in Sprague-Dawley rats. The fetal exposure to PB resulted in: (a) Significant increase (P less than 0.01) in body wt at 23 and 42 days of age; (b) Significant increase (P less than 0.01) in brain wt at all ages studied; (c) Significant decline (P less than 0.05) in liver monoamine oxidase at day 13 of age; (d) Significant (P less than 0.05) increase in plasma corticosterone levels at days 23 and 42.


The burden of acute conjunctivitis attributable to ambient particulate matter pollution in Singapore and its exacerbation during South-East Asian haze episodes.
Urban air quality in South-East Asia is influenced by local and transboundary sources of air pollutants. Research studies have well characterized the short-term effects of air pollution on cardiovascular and respiratory health but less so on ocular health. We investigated the relationship between air pollution and acute conjunctivitis in Singapore, a tropical city-state located in South-East Asia. Assuming a negative-binomial distribution, we examined the short-term associations between all-cause acute conjunctivitis reports from 2009 to 2018 and contemporaneous ambient air pollutant concentrations using a time-series analysis. In separate pollutant models for PM2.5 and PM10, we fitted fractional polynomials to investigate the linearity between air pollutant exposures and conjunctivitis, adjusting for long-term trend, seasonality, climate variability, public holidays, immediate and lagged exposure effects, and autocorrelation. There were 261,959 acute conjunctivitis reports over the study period. Every 10 μg/m3 increase in PM2.5 was associated with a 3.8% (Incidence Rate Ratio (IRR): 1.038, 95% Confidence Interval (CI): 1.029-1.046, p < 0.001) cumulative increase in risk of conjunctivitis over the present and subsequent week. Every 10 μg/m3 increase in PM10 was associated with a 2.9% (Incidence Rate Ratio (IRR): 1.029, 95% Confidence Interval (CI): 1.022-1.036, p < 0.001) cumulative increase in risk of conjunctivitis over the present and subsequent week. Acute conjunctivitis reports exhibited an inverse dependence on ambient air temperature and relative humidity variability. Approximately 3% of all acute conjunctivitis reports were attributable to PM2.5. Particulate matter attributed acute conjunctivitis was disproportionately higher during transboundary haze episodes. Our study strengthens the evidence linking particulate matter exposure to an increased risk of conjunctival disease, with a disproportionately higher disease burden during South-East Asia transboundary haze episodes. Our findings underscore the importance of reducing the health impact of indigenous and transboundary sources of ambient particulate matter pollution.


Enhanced chromatin dynamics by FACT promotes transcriptional restart after UV-induced DNA damage.
Chromatin remodeling is tightly linked to all DNA-transacting activities. To study chromatin remodeling during DNA repair, we established quantitative fluorescence imaging methods to measure the exchange of histones in chromatin in living cells. We show that particularly H2A and H2B are evicted and replaced at an accelerated pace at sites of UV-induced DNA damage. This accelerated exchange of H2A/H2B is facilitated by SPT16, one of the two subunits of the histone chaperone FACT (facilitates chromatin transcription) but largely independent of its partner SSRP1. Interestingly, SPT16 is targeted to sites of UV light-induced DNA damage-arrested transcription and is required for efficient restart of RNA synthesis upon damage removal. Together, our data uncover an important role for chromatin dynamics at the crossroads of transcription and the UV-induced DNA damage response.


Functional analysis and regulation of the malate synthase from Chlamydomonas reinhardtii.
Malate synthase (EC 18.104.22.168, formerly EC 126.96.36.199) has been investigated in the unicellular green algae Chlamydomonas reinhardtii. The molecular characteristics and the regulation of gene expression have been investigated for the enzyme. A full-length malate synthase cDNA has been isolated, containing an open reading frame of 1,641 bp encoding a polypeptide of 546 amino acids. This protein shares the conserved signature of the malate synthase family, along with the catalytic residues essential for enzymatic activity and a C-terminal motif that matches the consensus for glyoxysome import. Functionality studies have been facilitated by heterologous expression of the malate synthase cDNA in Escherichia coli. The remarkable metabolic versatility of the alga has been used to analyse the metabolic control of malate synthase gene expression. The data strongly support the role of acetate and light as the main regulatory effectors, and the existence of cross-talk between the two signalling pathways.


Tritiated thymidine autoradiographic study on histogenesis and spreading of intestinal metaplasia in human stomach.
The non-diseased portions of the antral mucosa of patients suffering from gastric cancer or ulcer were biopsied. The biopsy specimens were then labelled with 3H-thymidine in vitro, and distribution of the labelled epithelial cells in the normal pyloric and in the intestinalized mucosa was studied with autoradiography, and modes of histogenesis and spreading of the intestinal metaplasia were studied, and kinetic characteristics of the intestinalized mucosa were discussed. In the normal pyloric mucosa, the labelled cells were confined to the isthmus region (the middle one-third level of the mucosa), indicating that the surface epithelial and the pyloric glandular cells are normally replaced from the isthmus region. On the other hand, a zone of the labelled cells was found at the lower one-third level in the intestinalized mucosa. The absorptive and the goblet cells in the intestinalized mucosa appear to be renewed by about 70 hours in a fashion similar to that of the small intestine. Microscopic and autoradiographic analysis of the antral mucosa in the course of intestinalization indicates that the intestinal metaplasia begins in the isthmus region of the pyloric glandular tubules of an intact mucosa unaffected by gross injury through transformation of the generative cells from a pyloric to an intestinal pattern. This permits the pyloric lining cells to be replaced with intestinal villous cells and also permits the generative cell zone of the intestinal tubules to shift from the isthmus to the base of the gland until the process is complete. The downward shift of the intestinal tubules occurs in a framework of one of the branched pyloric glands and other glands disappear, resulting in a change of mucosal architectures of the antrum from a branched to a simple tubular gland. The intestinal metaplasia spreads in the mucosa through multi-focal (and sporadical) transformation of the neck generative cells in individual glandular tubules.


Epidermal growth factor receptors and prognosis in primary breast cancer.
A retrospective study was performed on 109 human breast tumors stored in liquid nitrogen in order to assess the prognostic value of epidermal growth factor receptor (EGF-R) (median patient follow-up 5 years). A significant inverse relationship was observed between EGF-R and both estrogen (ER) and progesterone receptors (PR). Univariate analysis showed a trend towards a shorter metastasis-free survival both in the overall population and in node-negative patients with EGF-R positive tumors. Multivariate analysis of the overall population showed that lymph-node involvement and PR status were the only significant variables in predicting metastasis-free survival. However, in patients receiving no adjuvant treatment (hormone therapy or chemotherapy). EGF was the only significant variable in the multivariate Cox analysis. No c-erbB-1 amplification was detected in these tumors.


Small molecule induction of MSH2-dependent cell death suggests a vital role of mismatch repair proteins in cell death.
Avoidance of apoptosis is one of the hallmarks of cancer development and progression. Chemotherapeutic agents aim to initiate an apoptotic response, but often fail due to dysregulation. MSH proteins are capable of recognizing cisplatin damage in DNA and participate in the initiation of cell death. We have exploited this recognition and computationally simulated a MutS homolog (MSH) "death conformation". Screening and docking experiments based on this model determined that the MSH2-dependent cell-death pathway can be induced by a small molecule without DNA damage, reserpine. Reserpine was identified via virtual screening on structures obtained from molecular dynamics as a small molecule that selectively binds a protein "death" conformation. The virtual screening predicts that this small molecule binds in the absence of DNA. Cell biology confirmed that reserpine triggers the MSH2-dependent cell-death pathway. This result supports the hypothesis that the MSH2-dependent pathway is initiated by specific protein conformational changes triggered by binding to either DNA damage or small compound molecules. These findings have multiple implications for drug discovery and cell biology. Computational modeling may be used to identify and eventually design small molecules that selectively activate particular pathways through conformational control. Molecular dynamics simulations can be used to model the biologically relevant conformations and virtual screening can then be used to select for small molecules that bind specific conformations. The ability of a small molecule to induce the cell-death pathway suggests a broader role for MMR proteins in cellular events, such as cell-death pathways, than previously suspected.


Minimal access spinal surgery (MASS) in treating thoracic spine metastasis.
A retrospective study was conducted. This study aims to analyze the feasibility and efficacy of using minimal access spinal surgery (MASS) for managing thoracic spine metastasis. Literature regarding minimally invasive surgical treatment for thoracic spine metastasis is sparse. In the past decade, the role of minimally invasive or endoscopic technique in managing metastatic thoracic disease has evolved. From February 1997 to March 2003, 46 patients with spine metastases, from T3-T12, were enrolled in this study. There were 29 patients undergoing MASS. Seventeen patients received standard thoracotomy (ST) in the early study period served as the control group. The indications for MASS include intractable back pain and/or neurologic deficits or neurologic deterioration during or after radiotherapy. Inclusion criteria for this study included tumor limited to one or two vertebral segments. In the MASS and ST groups, no patient died as a result of an immediate intraoperative event. The mean operative blood loss was 1,110 versus 1,162 mL (P = 0.63), and the mean operative length was 179 versus 180 minutes (P = 0.54). Complication rates and 1-year, 2-year, and overall survival rates were comparable and the mean grade of neurologic recovery was 1.2 on the Frankel scale in both groups. Only 6.9% of MASS patients required a 2-day postoperative ICU stay compared with 88% of ST patients (P < 0.0001). The MASS technique is safe and effective and has proved to be an excellent alternative in managing thoracic spine metastasis. Surgeons may use progressively smaller incisions (5-6 cm in length) for the procedure. The learning curve for performing MASS procedures was not steep.


Transrectal repair of rectocele: an extended armamentarium of colorectal surgeons. A report of 355 cases.
Colorectal surgeons are frequently faced with rectocele patients who have distressing bowel difficulty and anorectal complaints. In 1977, a new technique of transrectal repair of rectocele operating through a standard Fansler operating speculum was developed. The principle of the repair is based on the technique of Sullivan, as described elsewhere. The main difference is in dealing with the mucosal prolapse. A total of 355 cases of transrectal repair of rectocele was compiled for study covering a period from 1977 to 1982. Ninety-eight percent of patients have improved. Only 2 percent reported no improvement after surgery. There was a 5.6 percent overall infection rate. With refinement of the technique, no infection has been observed in the last 96 cases of the series.


In vitro anticancer activities of Schiff base and its lanthanum complex.
Schiff base metal complexes are well-known to intercalate DNA. The La(III) complexes have been synthesized such that they hinder with the role of the topoisomerases, which control the topology of DNA during the cell-division cycle. Although several promising chemotherapeutics have been developed, on the basis of Schiff base metal complex DNA intercalating system they did not proceed past clinical trials due to their dose-limiting toxicity. Herein, we discuss an alternative compound, the La(III) complex, [La(L(1))2Cl3]·7H2O based on a Schiff base ligand 2,3-dihydro-1H-indolo-[2,3-b]-phenazin-4(5H)-ylidene)benzothiazole-2-amine (L(1)), and report in vitro cell studies. Results of antitumor activity using cell viability assay, reactive oxygen species (ROS) generation and nuclear condensation in PC-3 (Human, prostate carcinoma) cells show that the metal complex is more potent than ligand. La(III) complexes have been synthesized by reaction of lanthanum(III) salt in 1:2M ratio with ligands L(1) and 3-(ethoxymethylene)-2,3-dihydro-1H-indolo[2,3-b]-phenazin-4(5H)-ylidene)benzathiazole-2-amine (L(2)) in methanol. The ligands and their La(III) complexes were characterized by molar conductance, magnetic susceptibility, elemental analyses, FT-IR, UV-Vis, (1)H/(13)C NMR, thermogravimetric, XRD, and SEM analysis.


Maternity services for rural and remote Australia: barriers to operationalising national policy.
In Australia, many small birthing units have closed in recent years, correlating with adverse outcomes including a rise in the number of babies born before arrival to hospital. Concurrently, a raft of national policy and planning documents promote continued provision of rural and remote maternity services, articulating a strategic intent for services to provide responsive, woman-centred care as close as possible to a woman's home. The aims of this paper are to contribute to an explanation of why this strategic intent is not realised, and to investigate the utility of an evidence based planning tool (the Toolkit) to assist with planning services to realise this intent. Interviews, focus groups and a group information session were conducted involving 141 participants in four Australian jurisdictions. Field notes and reports were thematically analysed. We identified barriers that helped explain the gap between strategic intent and services on the ground. These were absence of informed leadership; lack of knowledge of contemporary models of care and inadequate clinical governance; poor workforce planning and use of resources; fallacious perceptions of risk; and a dearth of community consultation. In this context, the implementation of policy is problematic without tools or guidance. Barriers to operationalising strategic intent in planning maternity services may be alleviated by using evidence based planning tools such as the Toolkit.


LOXL2 promotes aggrecan and gender-specific anabolic differences to TMJ cartilage.
In the United States, 5-12% of adults have at least one symptom of temporomandibular joint (TMJ) disorders, including TMJ osteoarthritis (TMJ-OA). However, there is no chondroprotective agent that is approved for clinical application. We showed that LOXL2 is elevated in the regenerative response during fracture healing in mice and has a critical role in chondrogenic differentiation. Indeed, LOXL2 is an anabolic effector that attenuates pro-inflammatory signaling in OA cartilage of the TMJ and knee joint, induces chondroprotective and regenerative responses, and attenuates NF-kB signaling. The specific goal of the study was to evaluate if adenoviral delivery of LOXL2 is anabolic to human and mouse TMJ condylar cartilage in vivo and evaluate the protective and anabolic effect on cartilage-specific factors. We employed two different models to assess TMJ-OA. In one model, clinical TMJ-OA cartilage from 5 different samples in TMJ-OA cartilage plugs were implanted subcutaneously in nude mice. Adenovirus LOXL2 -treated implants showed higher mRNA levels of LOXL2, ACAN, and other anabolic genes compared to the adenovirus-Empty-treated implants. Further characterization by RNA-seq analysis showed LOXL2 promotes proteoglycan networks and extracellular matrix in human TMJ-OA cartilage implants in vivo. In order to evaluate if LOXL2-induced functional and sex-linked differences, both male and female four-month-old chondrodysplasia (Cho/+) mice, which develop progressive TMJ-OA due to a point mutation in the Col11a1 gene, were subjected to intraperitoneal injection with Adv-RFP-LOXL2 every 2 weeks for 12 weeks. The data showed that adenovirus delivery of LOXL2 upregulated LOXL2 and aggrecan (Acan), whereas MMP13 expression was slightly downregulated. The fold change expression of Acan and Runx2 induced by Adv-RFP-LOXL2 was higher in females compared to males. Interestingly, Adv-RFP-LOXL2 injection significantly increased Rankl expression in male but there was no change in females, whereas VegfB gene expression was increased in females, but not in males, as compared to those injected with Adv-RFP-Empty in respective groups. Our findings indicate that LOXL2 can induce specifically the expression of Acan and other anabolic genes in two preclinical models in vivo. Further, LOXL2 has beneficial functions in human TMJ-OA cartilage implants and promotes gender-specific anabolic responses in Cho/+ mice with progressive TMJ-OA, suggesting its merit for further study as an anabolic therapy for TMJ-OA.


Complete Genome Sequence of the Arcobacter butzleri Cattle Isolate 7h1h.
Arcobacter butzleri strain 7h1h was isolated in the United Kingdom from the feces of a clinically healthy dairy cow. The genome of this isolate was sequenced to completion. Here, we present the annotation and analysis of the completed 7h1h genome, along with a comparison of this genome to the existing A. butzleri genomes.