Effect of liquid-based cytology fixing solution on immunocytochemistry: Efficacy of antigen retrieval in cytologic specimens.
Immunocytochemistry (ICC) is an indispensable technique to improve diagnostic accuracy. ICC using liquid-based cytology (LBC)-fixed specimens has been reported. However, problems may arise if the samples are not fixed appropriately. We investigated the relationship between the LBC fixing solution and ICC and the usefulness of antigen retrieval (AR) in LBC specimens. Specimens were prepared from five types of LBC-fixed samples using cell lines and the SurePath™ method. ICC was performed using 13 antibodies and analyzed by counting the number of positive cells in the immunocytochemically stained specimens. Insufficient reactivity was observed using ICC without heat-induced AR (HIAR) in nuclear antigens. The number of positive cells increased in ICC with HIAR. The percentage of positive cells was lower in CytoRich™ Blue samples for Ki-67 and in CytoRich™ Red and TACAS™ Ruby samples for estrogen receptor and p63 than in the other samples. For cytoplasmic antigens, the percentage of positive cells for no-HIAR treatment specimens was low in the three antibodies used. In cytokeratin 5/6, the number of positive cells increased in all LBC specimens with HIAR, and the percentage of positive cells in CytoRich™ Red and TACAS™ Ruby samples was significantly lower (p < .01). For cell membrane antigens, CytoRich™ Blue samples had a lower percentage of positive cells than the other LBC-fixed samples. The combination of detected antigen, used cells, and fixing solution may have different effects on immunoreactivity. ICC using LBC specimens is a useful technique, but the staining conditions should be examined before performing ICC.


Septic knee arthritis after intra-articular hyaluronate injection. Two case reports.
Intraarticular sodium hyaluronate injection to treat osteoarthritis is associated with minor side effects. Infections seem uncommon. We report two cases of septic knee arthritis. One patient was an 80-year-old woman who was admitted for Staphylococcus aureus knee arthritis after several intraarticular injections of sodium hyaluronate and corticosteroids. In the other patient, a 78-year-old woman, Neisseria mucosa knee arthritis occurred after a single sodium hyaluronate injection. Faultless aseptic technique is essential when administering hyaluronate viscosupplementation. Patients should be informed of the risk of septic arthritis.


Erythritol sprays reduce Drosophila suzukii infestation without impacting honey bee visitation nor fruit quality.
Spotted-wing drosophila, Drosophila suzukii, is an economic pest of small fruits and cherries. Insecticides primarily control this pest while alternative controls are in development. Laboratory studies show that erythritol is insecticidal to D. suzukii and other pests while approved for human consumption. Moreover, erythritol combined with sucrose or non-caloric sucralose can stimulate feeding and quicken mortality. Before growers can use erythritol, the impact on crop protection, non-target insects, and fruit quality need evaluation. In three blueberry and cherry field cage trials, oviposition on fruit sprayed with erythritol:sucrose or erythritol:sucralose formulations was lowered by 59%-81% compared with unsprayed controls. Fly infestation (larval or adult counts from fruit) was 90% lower in a greenhouse blueberry trial, and 49% lower in an open field blueberry trial with 2 m erythritol : 0.5 m sucrose. Infestation was also 57% lower in an open field cherry trial with 1.5 m erythritol:0.5 m sucrose. Other field trials with very low pest pressure or frequent rains revealed no differences from controls. Field trials consistently revealed that honey bees did not preferentially visit plants sprayed with either erythritol formulation, although yellow jackets visited plants sprayed with erythritol:sucrose more frequently. Erythritol formulations consistently led to more leaf spotting, but there was no reduction in the quality of treated blueberries or cherries in terms of mold development, firmness, diameter, epidermal penetration force, and Brix° (total soluble solids) at harvest. Eleven trials conducted over four years show that erythritol formulations can reduce D. suzukii pressure without attracting foraging honey bees nor negatively impacting fruit quality. © 2023 Society of Chemical Industry. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.


Concordant correlation of LIV-1 and E-cadherin expression in human breast cancer cell MCF-7.
The recent report highlighted a significant association between signal transducer and activator of transcription 3 (STAT3) and Snail and LIV-1 (SLC39A6 or ZIP6), the breast cancer-associated protein that belongs to a new subfamily of zinc transporters. LIV-1 is a downstream target of STAT3, both in zebrafish and mammalian cells and provides control over epithelial-mesenchymal transition (EMT). Crucially, these observations link LIV-1, previously demonstrated to be associated with lymph node metastasis in breast cancer, to genes with a proven role in development. A putative role of LIV-1 as a regulator of E-cadherin that modulates the cell-cell adhesion is thus inferred. In present study, the correlation of LIV-1 and E-cadherin expression in human breast cancer cell MCF-7 and the effect of LIV-1 expression on the cell growth were assessed to explore the possible mechanisms associated with this observation in breast cancer. It was shown that the silencing of LIV-1 would induce the down-expression of E-cadherin. There was opposite results if the cells were overexpressed with LIV-1. In addition, the results showed that promotion effect after silencing of LIV-1 and inhibition effect after overexpression of LIV-1 in transfected cells. To our knowledge, this is the first evidence that the expression of E-cadherin could be regulated by the zinc transporter LIV-1. The results suggest that there is an association of LIV-1 expression with less aggressive tumors due to high E-cadherin expression because of high LIV-1 expression. LIV-1 may be a regulator of E-cadherin.


The effect of hyperbaric oxygen therapy on retina, choroidal thickness, and choroidal vascularity index.
To determine the acute and cumulative effect of hyperbaric oxygen therapy (HBOT) on retina and choroid tissue in healthy eyes. Thirty-five subjects who were planned to undergo HBOT for non-ophthalmologic indications comprised the population of this prospective study. Central macular thickness (CMT), retinal nerve fiber layer (RNFL), and choroidal thickness (CT) (3 points: subfoveal area, 500 µm nasal and fovea temporal) were measured using spectral-domain optical coherence tomography (SD-OCT) before HBOT and half an hour after the 1st and 20th sessions of HBOT. The subfoveal choroidal area was segmented using ImageJ software with the binarization technique on enhanced depth imaging (EDI) OCT images. Choroidal area (CA), luminal area (LA), and stromal area (SA) were calculated. Choroidal vascularity index (CVI) was determined as the ratio between LA and CA. The right eyes of 35 patients aged between 22 and 59 years were enrolled in the study. The mean CMT values of the patients were 259.36 ± 22.31 µm, 256.94 ± 22.72 µm, and 254.58 ± 23.02 µm before HBOT, after the 1st session, and after the 20th session, respectively. The change in CMT values before and after HBOT was statistically significant (p=0.001). When the patients' RNFL, CT, CA, SA, LA, and CVI changes before and after the HBOT were examined, no statistically significant difference was found (p>0.05). Our study jointly evaluates the effect of HBOT on the vascular and stromal components of the choroid and macula in healthy eyes. Due to its thinning effect on the macula, it can be preferred as an adjunctive and facilitating treatment option in addition to current treatments in patients with macular edema due to retinal vascular disorders.


Quantum chemical density functional theory studies on the molecular structure and vibrational spectra of Gallic acid imprinted polymers.
Gallic acid (GA) is known by its antioxidant, anticarcinogenic properties and scavenger activity against several types of harmful free radicals. Molecularly imprinted polymers (MIPs) are used in separation of a pure compound from complex matrices. A stable template-monomer complex generates the MIPs with the highest affinity and selectivity for the template. The quantum chemical computations based on density functional theory (DFT) was used on the template Gallic acid (GA), monomer acrylic acid (AA) and GA-AA complex to study the nature of interactions involved in the GA-AA complex. B3LYP/6-31+G(2d,2p) model chemistry was used to optimize their structures and frequency calculations. The effect of porogen acetonitrile (ACN) on complex formation was included by using polarizable continuum model (PCM). The results demonstrated the formation of a stable GA-AA complex through the intermolecular hydrogen bonding between carboxylic acid groups of GA and AA. The Mulliken atomic charge analysis and simulated vibrational spectra also supported the stable hydrogen bonding interaction between the carboxylic acid groups of GA and AA with minimal interference of porogen ACN. Further, simulations on GA-AA mole ratio revealed that 1:4 GA-AA was optimum for synthesis of MIP for GA.


Prevalence of erm genes encoding macrolide-lincosamide-streptogramin (MLS) resistance among clinical isolates of Staphylococcus aureus in a Turkish university hospital.
This study investigated the prevalence of the erm(A), erm(B) and erm(C) genes among 122 MLS-resistant clinical isolates of Staphylococcus aureus from a Turkish university hospital. Of these isolates, 44 were inducibly resistant and 78 were constitutively resistant. The presence of one or more erm genes was demonstrated in 114 isolates; the erm(C) gene was detected in 97 isolates, and the erm(A) gene was detected in 96 isolates. Seventy-eight isolates harboured both erm(A) and erm(C). The combination of erm(A), erm(B) and erm(C) genes was detected in only one isolate.


Persistent Pain After Wrist or Hand Fracture: Development and Validation of a Prognostic Model.
Worldwide, the incidence of wrist fracture is increasing. There are currently no externally validated prognostic models to inform early decision making for these patients. To develop and validate a prognostic model from a comprehensive range of candidate prognostic factors that can identify patients who are at risk of developing persistent pain following wrist or hand fracture. We developed and validated a prognostic model using secondary data derived from a prospective cohort study (n = 715), with recruitment sites in 3 metropolitan hospitals in Sydney, Australia. The primary outcome was persistent pain 4 months following the injury. The current study used a backward stepwise regression analysis to develop the model in 2 hospitals (n = 408) and externally validate it in a third hospital (n = 307). To determine the accuracy of the model, we assessed calibration and discrimination in accordance with the PROGnosis RESearch Strategy framework. Complete data were available for 95% of the cohort. Of 14 candidate variables, the final model contained 2 prognostic factors: patient age and pain intensity reported at initial presentation. The area under the receiver operating characteristic curve was 0.63 (95% confidence interval: 0.56, 0.69) in the development sample and 0.61 (95% confidence interval: 0.51, 0.70) in the validation sample. The model systematically overestimated risk (intercept, -1.13; slope, 0.73). We developed and externally validated a prognostic model to predict persistent pain 4 months after a wrist or hand fracture. Future studies are needed to assess whether the accuracy of this model can be improved by updating and validating it in local settings. Prognosis, level 1b. J Orthop Sports Phys Ther 2019;49(1):28-35. Epub 12 Sep 2018. doi:10.2519/jospt.2019.8342.


Cerebrospinal fluid findings in neurological manifestations of Lyme disease.
The cerebrospinal fluid (CSF) findings in 21 patients with different manifestations of Lyme disease are presented. 15 patients exhibited CSF changes including a lymphoplasmocytic pleocytosis and a CSF protein profile indicating a barrier leakage combined with an intrathecal immunoglobulin synthesis. Six patients-mainly suffering from cranial neuritis-had a normal CSF.


Adjustment of homosexual and heterosexual women: a cross-national replication.
British homosexual and heterosexual women were evaluated on the same adjustment inventories used with two similar U.S. groups. The results of both studies were quite parallel, and the findings again supported similarities rather than differences in adjustment between homosexuals and heterosexuals.


Psychometric properties of the Death Anxiety Scale (DAS) among terminally ill cancer patients.
Research conducted with the terminally ill population in relation to death anxiety is rare and mostly outdated. The purpose of this study was to evaluate the psychometric properties of the widely used Death Anxiety Scale (DAS) on a sample of terminal cancer patients.Additionally, validation studies of the DAS have exclusively used traditional statistical methods for analysis. The current study utilized an item response theory technique (IRT), namely the Rasch Rating Scale model for data analysis. The methodology employed may be useful for other researchers conducting validation studies from an IRT perspective.


Effects of low doses of aspirin, 10 mg and 30 mg daily, on bleeding time, thromboxane production and 6-keto-PGF1 alpha excretion in healthy subjects.
To compare the long term effects of two low doses of aspirin taken daily, we performed a placebo-controlled cross-over study in 19 normal subjects. Aspirin 10 mg daily for 3 weeks caused a significant inhibition by 61 +/- 12 percent of platelet thromboxane B2 generation but had no effect on the Simplate bleeding time. Aspirin 30 mg daily for 3 weeks reduced thromboxane B2 production by 94 +/- 5 percent and caused a significant prolongation of the bleeding time, 1.6 times the control value. No cumulative inhibitory effects were observed after the first week of treatment. Both doses did not effect the urinary excretion of 6-keto-PGF1 alpha.


Rivaroxaban versus nadroparin for thromboprophylaxis following thoracic surgery for lung cancer: A randomized, noninferiority trial.
The benefit of rivaroxaban in thromboprophylaxis after oncologic lung surgery remains unknown. To evaluate the efficacy and safety of rivaroxaban, patients who underwent thoracic surgery for lung cancer were enrolled, and randomly assigned to rivaroxaban or nadroparin groups in a 1:1 ratio; anticoagulants were initiated 12-24 h after surgery and continued until discharge. Four hundred participants were required according to a noninferiority margin of 2%, assuming venous thromboembolism (VTE) occurrence rates of 6.0% and 12.6% for patients in the rivaroxaban and nadroparin groups, respectively. The primary efficacy outcome was any VTE during the treatment and 30-day follow-up periods. The safety outcome was any on-treatment bleeding event. Finally, 403 patients were randomized (intention-to-treat [ITT] population), with 381 included in per-protocol (PP) population. The primary efficacy outcomes occurred in 12.5% (25/200) of the rivaroxaban group and 17.7% (36/203) of the nadroparin group (absolute risk reduction, -5.2%; 95% confidence interval [CI], [-12.2-1.7]), indicating the noninferiority of rivaroxaban in ITT population. Sensitivity analysis was performed in the PP population and yielded similar results, confirming the noninferiority of rivaroxaban. In the safety analysis population, the incidence of any on-treatment bleeding events did not differ significantly between the groups (12.2% for rivaroxaban vs. 7.0% for nadroparin; relative risk [RR], 1.9; 95% CI, [0.9-3.7]; p = .08), including major bleeding (9.7% vs. 6.5%; RR, 1.6 [95% CI, 0.9-3.7]; p = .24), and nonmajor bleeding (2.6% vs. 0.5%; RR, 5.2 [95% CI, 0.6-45.2]; p = .13). Rivaroxaban for thromboprophylaxis after oncologic lung surgery was shown to be noninferior to nadroparin.


Lipodystrophy and adrenal insufficiency: potential mediators of peripheral neuropathy in HIV infection?
The mechanisms behind certain co-morbid conditions associated with chronic HIV disease still remain elusive. HIV-associated peripheral neuropathy is one among those rarely studied manifestations in HIV-1 infection. Numerous underlying factors associated with peripheral neuropathy have been described in HIV disease. Herein, we hypothesized certain heretofore undescribed potential mechanisms that lead to HIV associated neuropathy. Being a multifactoral manifestation, HIV-associated neuropathy is presumed to have an association with physiological factors namely, adrenal inadequacy/steroid resistance and lipodystrophy-induced cushion-effect loss in peripheral nerves. Therefore, management of the adrenals with steroids at the time-point of high inflammatory burden thereby preventing lipodystrophy by selecting the optimum treatment regimen could markedly alleviate the severity of HIV-associated neuropathic manifestations.


Dihydromyricetin improves social isolation-induced cognitive impairments and astrocytic changes in mice.
Social isolation induces stress, anxiety, and mild cognitive impairment that could progress towards irreversible brain damage. A probable player in the mechanism of social isolation-induced anxiety is astrocytes, specialized glial cells that support proper brain function. Using a social isolation mouse model, we observed worsened cognitive and memory abilities with reductions of Object Recognition Index (ORI) in novel object recognition test and Recognition Index (RI) in novel context recognition test. Social isolation also increased astrocyte density, reduced astrocyte size with shorter branches, and reduced morphological complexity in the hippocampus. Dihydromyricetin, a flavonoid that we previously demonstrated to have anxiolytic properties, improved memory/cognition and restored astrocyte plasticity in these mice. Our study indicates astrocytic involvement in social isolation-induced cognitive impairment as well as anxiety and suggest dihydromyricetin as an early-stage intervention against anxiety, cognitive impairment, and potential permanent brain damage.


First evidence of Pezoloma ericae in Australia: using the Biomes of Australia Soil Environments (BASE) to explore the Australian phylogeography of known ericoid mycorrhizal and root-associated fungi.
The prominent ericoid mycorrhizal fungus, Pezoloma ericae, has not been found in Australia to date. In the present study, internal transcribed spacer (ITS) data from the Biomes of Australia Soil Environments (BASE) was searched for evidence of P. ericae and other known ericoid mycorrhizal and root-associated taxa. ITS sequences with high identity to P. ericae, Meliniomyces bicolor, Meliniomyces variabilis, Cairneyella sp. 2, Cadophora finlandica and Woollsia mycorrhizal fungus VI were identified and their distribution in Australia visualised. This is the first evidence that P. ericae, M. bicolor and M. variabilis very likely occur on the Australian continent and provides a set of locations from which to seek isolates for further characterisation. The presence of P. ericae in South America, South Africa, and now Australia suggests a broad and ancient Gondwanan distribution for this well-studied species.


Reducing neuropathies between the 2020 and 2021 Covid-19 surges in a large UK intensive care unit: A quality improvement project.
Peripheral nerve injuries (PNIs) can be acquired by patients in intensive care unit (ICU) who are critically unwell with Covid pneumonitis. Prone position ventilation has been linked to this life-changing complication. To reduce the occurrence and severity of PNIs for patients with Covid pneumonitis requiring prone positioning whilst sedated and ventilated in ICU. This study is a quality improvement project that evolved over the course of the first two surges of Covid pneumonitis admissions within the ICU at the Queen Elizabeth Hospital Birmingham (Surge 1: March 2020-July 2020, 93 prone ventilation survivors; Surge 2: September 2020-May 2021, 309 prone ventilation survivors). Implementation of updated prone positioning guidelines that aimed to reduce the risk of PNI. This was supplemented by face-to-face teaching for ICU professionals. The number of patients who sustained PNI and the severity of such injuries were recorded. During the first surge 21 patients (22.6%) had at least one high grade PNI. During the second surge there were 12 patients (3.9%) sustaining an intermediate or high grade PNI. For PNI patients, there was an increase in the mean proning episodes (6-13) and duration (17.8-18.6 h). This represents an 82% reduction in PNI cases. High grade injuries reduced from 14/21 (66%) to 4/12 (33%). Optimizing the position of patients in the prone position in ICU with Covid pneumonitis may be key in reducing the development of PNI. Changes to pharmacological management may have influenced the results seen in this study. Clinicians working within ICU with acutely unwell patients with Covid pneumonitis should acknowledge the heightened risk of PNI and take relevant steps to reduce the risk of injury acquisition.


Occupational diesel exhaust exposure as a risk factor for chronic obstructive pulmonary disease.
Chronic obstructive pulmonary disease (COPD) is a major source of morbidity and mortality worldwide. Although cigarette smoking is the major cause of COPD, occupational exposures have emerged as an important risk factor, especially in nonsmokers. In this review, we assess the state of the literature on the association of COPD with a specific occupational exposure, diesel exhaust. A large body of literature links general occupational exposures to dust and fumes with an increased risk of COPD, particularly in nonsmokers. Few studies, however, have explicitly examined the role of occupational diesel exhaust exposures to COPD risk. Suggestive recent findings link occupational diesel exposures to an increased risk of COPD. The available literature directly examining the effects of occupational diesel exhaust on risk of COPD is quite small, but does suggest that increasing exposures are associated with increasing risk. Additional research, with more advanced exposure metrics, is needed to fully elucidate this association.


Incidence and risk factors of portomesenteric venous thrombosis after colorectal surgery for cancer in the elderly population.
Although it is known that portomesenteric venous thrombosis (PMVT) is associated with total colectomy and proctocolectomy in young patients with inflammatory bowel disease, little is known about incidence and risk factors of PMVT among the elderly population undergoing colorectal surgery for cancer. Data of elderly patients (> 70 years) undergoing surgery for colorectal cancer were retrospectively registered. The occurrence of PMVT was correlated with the patients' characteristics and operative variables. Data collected included age, sex, obesity, ASA score, tumor degree, type of surgical resection, surgical approach (laparoscopic or open), and duration of surgery (from skin incision to the application of dressings). A total of 137 patients > 70 years who underwent surgery for colorectal cancer and developed an acute intraabdominal process with suggestive symptoms, needing a CT scan, were included. Three of these patients (2.1%) had portomesenteric venous thrombosis during the study period, which was proved with CT scan. There were no significant patients' characteristics or operative variables between patients with or without the occurrence of PMVT after surgery. Of interest, only operative time was significantly higher in patients with PMVT after surgery (256 ± 40 vs 140 ± 41, p < 0.001). PMVT as a cause of abdominal pain after colorectal surgery for cancer in the elderly population is uncommon. An index of suspicion for PMVT in an elderly postoperative colorectal cancer patient with sudden onset of abdominal pain must be maintained.


Perineal wound healing after abdominoperineal resection for rectal cancer: a retrospective cohort study.
Delayed perineal wound healing is a common complication after abdominoperineal resection (APR) in rectal cancer. The primary aim of this study was to evaluate the number of patients with delayed wound healing after APR. Secondary aims were to identify risk factors, and describe treatment. Prospectively collected data from the Swedish Colorectal Cancer Registry (SCRCR) was used for retrospective analysis of APR performed at Skåne University Hospital Malmö between 2013 and 2018. Medical charts were retrospectively reviewed. Delayed healing was defined as non-healed perineal wound 30 days postoperatively. Patients undergoing extralevator APR requiring reconstruction were excluded. Statistical analysis was made using SPSS. Risk factors for impaired wound healing were analyzed using a multivariable model. A total of 162 patients were included, of which 114 underwent standard APR (sAPR) and 48 patients intersphincteric APR (isAPR). In the total population, 69% (111/162) were male, with median age 71 (26-87). The overall healing rate was 52% (85/162); 44% (50/114) in sAPR vs 73% (35/48) in isAPR (P < 0.001). Risk factors for impaired healing after multivariable analysis were BMI > 30 (OR 7.0; CI 95% 1.8-26.2, P = 0.004), reoperation (OR 7.9; CI 95% 1.6-39.8, P = 0.013), neoadjuvant radiotherapy (OR 5.2; CI 95% 1.02-25.1, P = 0.047) and sAPR (OR 2.598; CI 95% 1.05-6.41, P = 0.038). Eight percent (13/162) required an intervention (Clavien-Dindo ≥ 3). Delayed perineal wound healing is a frequent complication after APR but the majority could be treated conservatively. Several risk factors were identified. Further studies aiming at interventions reducing delayed perineal wound healing after APR are warranted.


Analysis of 41 suicide attempts by wrist cutting: a retrospective analysis.
Self-cutting injuries have a low mortality rate, but this type of injuries has special clinical significance because they have the potential of leading to devastating disability and repeated suicide attempts. The purpose of this study is to analyze the nature and outcomes of wrist-cutting injuries. A retrospective study was designed in order to investigate 41 suicide attempts by wrist cutting attended to Uludag University Faculty of Medicine Emergency Department between June 2008 and December 2014. The patients were analyzed for age, gender, alcohol intake, psychological state, prior suicide attempts, and clinical features such as injury side, injury pattern, and used tool. It was seen that the severity of wrist-cutting injury variates between gender and age. Alcohol or drug consumption and having a diagnosed psychiatric disorder create a higher risk for extensive wrist lacerations. It was seen that skin only lacerations were most likely to repeat the act and therefore are most in need of psychiatric intervention. Level III, retrospective study.


Phase 1 study of the safety, pharmacokinetics, and preliminary efficacy of CA102N as monotherapy and in combination with trifluridine-tipiracil in patients with locally advanced or metastatic solid tumors.
CA102N is a covalently bound conjugate of modified nimesulide (Nim) and NaHA, the sodium salt of hyaluronic acid (HA). HA is a natural ligand of cluster of differentiation 44 (CD44), which is over-expressed in colorectal cancer (CRC). CA102N is designed to deliver nimesulide directly to the tumor via the interaction of HA and CD44. A Phase 1, 2-part (dose escalation, dose expansion), non-randomized, open-label, first-in-human study of CA102N, as monotherapy and in combination with trifluridine-tipiracil, was conducted in patients with locally advanced or metastatic solid tumors. The CA102N doses evaluated were 0.36 mg/kg, 0.54 mg/kg, and 0.72 mg/kg Nim equivalent. The primary endpoints were dose-limiting toxicities (DLTs) in Cycle 1 as well as serious adverse events (SAEs) and treatment-emergent adverse events (TEAEs) throughout the study; secondary endpoints were pharmacodynamics parameters, objective tumor response, and urinary pharmacodynamics markers of target inhibition. Between April 2019 and October 2021, 37 patients were enrolled in 3 US centers. No DLTs were observed in Part 1, and 0.72 mg/kg Nim equivalent was the dose selected for Part 2. In total, 52 TEAEs in 18 patients were CA102N-related; 4 (in 3 patients) were ≥ Grade 3. Exploratory analysis in the dose expansion cohort revealed a median progression-free survival of 3.7 (1.0, 6.77) months. Based on this study, CA102N as monotherapy or in combination with trifluridine-tipiracil, was safe and well-tolerated at the recommended Phase 2 dose of 0.72 mg/kg Nim equivalent in patients with locally advanced or metastatic solid tumors. Preliminary evidence of antitumor activity in CRC warrants further clinical development. (ClinicalTrials.gov registration number: NCT03616574. Registration date: August 6, 2018).


Gender-specific spatio-temporal patterns of colorectal cancer incidence in Navarre, Spain (1990-2005).
In the last ten to twenty years, a stabilization or decline in colorectal cancer (CRC) incidence has been observed in some countries across the world but not in Spain. Our objective here is to assess the gender-specific CRC spatio-temporal pattern in the health areas of Navarre, a Spanish province, during the period 1990-2005. For each gender, a model with spatio-temporal CAR (Conditional Autoregressive) distributions is used for smoothing the incidence risks. Smoothing is carried out in two dimensions: space and time, allowing for a different time evolution in each health area. An estimated incidence trend curve for each health area and the corresponding confidence bands are obtained. To analyze the evolution of the geographical patterns of CRC incidence risks, maps are also provided. In both genders, CRC shows an increasing trend in most of the areas. In the second half of the period 1998-2005 most of the areas have risks above one although not all statistically significant. In general females present equal or lower risks than males in all areas during the studied period. Colorectal cancer incidence risk is still increasing in the health areas of Navarre. Promoting healthful lifestyles for primary prevention and early detection programs could help to reverse the trend in the province.


The Short-Term Effect of Slope Walking on Soleus H-Reflexes in People with Multiple Sclerosis.
Downslope walking (DSW) causes H-reflex depression in healthy adults, and thus may hold promise for inducing spinal reflex plasticity in people with Multiple Sclerosis (PwMS). The study purpose was to test the hypothesis that DSW will cause acute depression of spinal excitability in PwMS. Soleus H-reflexes were measured in PwMS (n = 18) before and after 20 min of treadmill walking during three visits. Participants walked on a different slope each visit [level: 0% level walking (LW), upslope: +7.5% treadmill walking with an upslope (USW) or downslope: -7.5% (DSW)]. The soleus Hmax/Mmax ratio was used to measure spinal excitability. Heart rate and ratings of perceived exertion (RPE) were measured during walking. DSW induced the largest change in spinal excitability (a 26.7% reduction in soleus Hmax/Mmax (p = 0.001)), although LW also reduced Hmax/Mmax (-5.3%, p = 0.05). Heart rate (p < 0.001) was lowest for DSW, and RPE for DSW did not exceed "Fairly light". DSW evokes short-term spinal plasticity in PwMS, while requiring no greater effort than LW. Our results suggest that PwMS retain the capacity for DSW-induced short-term spinal reflex modulation previously found in healthy adults. These results may provide a foundation for further investigation of long-term effects of DSW on spinal reflex plasticity and functional ability in PwMS.


Nurses' responses to do-not-resuscitate orders in the neonatal intensive care unit.
A statewide survey of nurses in perinatal centers was conducted to assess the prevalence of do-not-resuscitate (DNR) policies in neonatal intensive care units (NICUs) and to examine factors influencing nurses in those centers in their compliance with DNR orders. Three nurses in each of 10 perinatal centers were asked to complete a questionnaire on DNR policies and nurses' compliance and to respond to four hypothetical clinical situations. Eighteen of the 27 responding nurses reported the existence of a DNR policy. Factors affecting compliance with DNR orders were agreement that the infant should not be resuscitated (n = 24) or respect for the parents' wishes (n = 19). Nurses' intention to resuscitate despite a DNR order varied, depending on the description of the infant. Multiple regression analyses showed that subjective norms (beta = .41 to .82) rather than attitudes (beta = .17 to .39) exerted a more powerful influence on nurses' decisions not to resuscitate.


Localizing sensory and cognitive systems for pre-attentive visual deviance detection: an sLORETA analysis of the data of Kimura et al. (2009).
Pre-attentive deviance detection in the visual environment has been known to be reflected by an event-related brain potential (ERP) component, deviant-related negativity. Recently, however, we demonstrated that deviant-related negativity comprises two, temporally and spatially overlapping ERP components, by using an experimental protocol consisting of oddball and equiprobable sequences [M. Kimura, J. Katayama, H. Ohira, E. Schröger, Visual mismatch negativity: new evidence from the equiprobable paradigm, Psychophysiology 46 (2009) 402-409]: (1) visual N1 that reflects a sensory, refractoriness-based deviance detection system and (2) visual mismatch negativity (MMN) that reflects a cognitive, memory-comparison-based deviance detection system. In the present paper, we further elucidated the neural generators of the visual N1 and visual MMN with standardized low-resolution brain electromagnetic tomography (sLORETA). Results showed that the visual N1 was involved in neural activations of the primary and nonprimary visual areas, while the visual MMN was involved in neural activations of the nonprimary visual areas and the prefrontal areas. These results suggest that the sensory and cognitive deviance detection systems subserved by distinct neural structures underlie our efficient pre-attentive visual deviance detection.


Successful use of venovenous extracorporeal membrane oxygenation in accidental hypothermic cardiac arrest.
Cardiopulmonary bypass is usually used for rewarming and for providing cardiac support in patients with severe hypothermia and cardiovascular instability. We report the first case of accidental severe hypothermia associated with prolonged cardiac arrest that was successfully managed by venovenous extracorporeal membrane oxygenation.


The effect of environmental pressure and resin cements on the push-out bond strength of a quartz fiber post to teeth root canals.
To evaluate the effect of environmental pressure changes on the bond strength between a fiber post and one of three resin cements using different mixing methods and modes of application. Sixty single-canal human teeth were divided into three groups (n = 20) and endodontically treated. Post spaces were prepared, and a quartz fiber post was secured with either a self-adhesive machine-mixed cement (RelyX Unicem, Aplicap), a self-adhesive hand-mixed cement (RelyX Unicem), or a self-etching dual-cured resin cement (Panavia F2). Half of each group was subjected to 24 pressure cycles from 0 to 5 atmospheres. The mean push-out bond strength of the posts was calculated and statistically analyzed using ANOVA and Tukey tests (α = 0.05). Regardless of the pressure, Unicem Aplicap achieved the highest bond strength (P < 0.05). The bond strengths of all groups were significantly lower after they were subjected to the pressure cycles (P < 0.003), and they were lower in the apical regions. Bond strengths between the fiber post and root canal can be affected by environmental pressure while the type of resin cements, their mixing methods and modes of application incorporated lower porosity, achieving higher bond strength.


Severe partial ureteric obstruction in newborn rats can produce renal dysplasia.
To investigate whether partial unilateral ureteric obstruction (PUUO) produces renal dysplasia in newborn rats. Left mild (in 31) or severe (in 34) PUUO was induced in 2-day-old rats by embedding a quarter or two-thirds of the ureter into the psoas muscles, respectively. Sham-operated control rats (36) were assessed in parallel. Kidney morphology, renal parenchymal weight and histology were examined 24 weeks and 30 months afterward. There was significant pelvic dilatation in all obstructed kidneys; four kidneys were dysplastic in those severely obstructed, with a significant decrease in renal volume. There were three dysplastic kidneys after 6 months and one at 30 months. The in vitro dysplastic kidney weight was 36% of the control kidneys. Microscopy showed primitive glomerular and tubular structures, with renal parenchymal developmental disorganization and marked fibrosis. The glomeruli, tubules and collecting ducts were deficient in number and had often undergone cystic changes. Columnar tubular epithelium and peritubular mesenchymal collars were present. There was no renal dysplasia in the mildly obstructed and sham-operated rats. The parenchymal weight of the kidneys contralateral to the dysplastic kidneys was significantly higher than in the controls (P < 0.001). Severe PUUO can produce renal dysplasia in newborn rats. However, only 12% with severe obstruction had renal dysplasia, indicating that the cause of renal dysplasia might also be related to other factors.


An integrated investigation on anaerobic membrane-based thickening of fecal sludge and the role of extracellular polymeric substances (EPS) in solid-liquid separation.
Pre-thickening or primary treatment of fecal sludge (FS) is a major bottleneck in designing fecal sludge treatment plants. This research demonstrates a practical analysis to improve the thickening efficiency of FS using woven fiber microfiltration membrane. A laboratory-scale anaerobic membrane-based thickening tank (MBTT) was investigated. Firstly, the system was operated with unconditioned FS at a flux range of 1-3 L/m2h. Secondly, the system was operated at an optimized flux of 2 L/m2h with conditioners, chitosan, and charcoal dust, at their optimized dosages reported in previous studies. It was observed that the solids accumulation in MBTT was linear and was specific to net solids accumulation. Feed FS was thickened to around 15% of total solids (TS) in 9-14 days. The overall solids accumulation rate was higher with conditioned FS. The less EPS accumulation and higher dewaterability in conditioned FS reduced the brushing frequency of the membrane and consequently, the average filtration duration per cycle was increased. Strong correlations of dewatering time with floc size, EPS, and electrical conductivity, indicated that higher EPS in FS tends to form flocs which can increase the dewatering rate in unstabilized FS. In permeate, the average TS and CODt removal observed were 72-78% and 87-91%, respectively.


Delayed calcium dysregulation in neurons requires both the NMDA receptor and the reverse Na+/Ca2+ exchanger.
Glutamate-induced delayed calcium dysregulation (DCD) is a causal factor leading to neuronal death. The mechanism of DCD is not clear but Ca2+ influx via N-methyl-d-aspartate receptors (NMDAR) and/or the reverse plasmalemmal Na+/Ca2+ exchanger (NCXrev) could be involved in DCD. However, the extent to which NMDAR and NCX(rev) contribute to glutamate-induced DCD is uncertain. Here, we show that both NMDAR and NCX(rev) are critical for DCD in neurons exposed to excitotoxic glutamate. In rat cultured hippocampal neurons, 25 μM glutamate produced DCD accompanied by sustained increase in cytosolic Na+ ([Na+]c) and plasma membrane depolarization. MK801 and memantine, noncompetitive NMDAR inhibitors, added shortly after glutamate, completely prevented DCD whereas AP-5, a competitive NMDAR inhibitor, failed to protect against DCD. None of the tested inhibitors lowered elevated [Na+]c or restored plasma membrane potential. In the experiments with NCX reversal by gramicidin, MK801 and memantine robustly inhibited NCXrev while AP-5 was much less efficacious. In electrophysiological patch-clamp experiments MK801 and memantine inhibited NCXrev-mediated ion currents whereas AP-5 failed. Thus, MK801 and memantine, in addition to NMDAR, inhibited NCXrev. Inhibition of NCXrev either with KB-R7943, or by collapsing Na+ gradient across the plasma membrane, or by inhibiting Na+/H+ exchanger with 5-(N-ethyl-N-isopropyl) amiloride (EIPA) and thus preventing the increase in [Na+]c failed to preclude DCD. However, NCXrev inhibition combined with NMDAR blockade by AP-5 completely prevented DCD. Overall, our data suggest that both NMDAR and NCXrev are essential for DCD in glutamate-exposed neurons and inhibition of individual mechanism is not sufficient to prevent calcium dysregulation.


The isothermal Boltzmann-Gibbs entropy reduction affects survival of the fruit fly Drosophila melanogaster.
To the best of our knowledge, this is the first experimental evidence of the effect of isothermal changes in entropy on a living organism. In greater detail, the effect of the reduction of the total Boltzmann-Gibbs entropy (S) of the aquatic environment on the survival rate and body mass of the fruit fly Drosophila melanogaster was investigated. The tests were carried out in standard thermodynamic states at room temperature of 296.15 K and ambient atmospheric pressure of 1 bar. Two variants of entropy reduction (ΔS) were tested for ΔS = 28.49 and 51.14 J K-1 mol-1 compared to the blind and control samples. The entropy level was experimentally changed, using the quantum system for isothermal entropy reduction. This system is based on quantum bound entanglement of phonons and the phenomenon of phonon resonance (interference of phonon modes) in condensed matter (Silicon dioxide (SiO2) and single crystals of Silicon (Si0), Aluminum (Al0) plates ("chips"), glass, and water). All studied organisms were of the same age (1 day). Mortality was observed daily until the natural death of the organisms. The investigations showed that changes in the Boltzmann-Gibbs entropy affected the survival and body mass of the fruit flies. On the one hand, the reduction in entropy under isothermal conditions in the aquatic environment for ΔS = 28.49 J K-1 mol-1 resulted in an extension of the lifespan and an increase in the body mass of female fruit flies. On the other hand, the almost twofold reduction in this entropy for ΔS = 51.14 J K-1 mol-1 shortened the lives of the males. Thus, the lifespan and body mass of flies turned out to be a specific reaction of metabolism related to changes in the entropy of the aquatic environment.


Proposal of early CT morphological criteria for response of liver metastases to systemic treatments in gastroenteropancreatic neuroendocrine tumors: Alternatives to RECIST.
RECIST 1.1 criteria are commonly used with computed tomography (CT) to evaluate the efficacy of systemic treatments in patients with neuroendocrine tumors (NETs) and liver metastases (LMs), but their relevance is questioned in this setting. We aimed to explore alternative criteria using different numbers of measured LMs and thresholds of size and density variation. We retrospectively studied patients with advanced pancreatic or small intestine NETs with LMs, treated with systemic treatment in the first-and/or second-line, without early progression, in 14 European expert centers. We compared time to treatment failure (TTF) between responders and non-responders according to various criteria defined by 0%, 10%, 20% or 30% decrease in the sum of LM size, and/or by 10%, 15% or 20% decrease in LM density, measured on two, three or five LMs, on baseline (≤1 month before treatment initiation) and first revaluation (≤6 months) contrast-enhanced CT scans. Multivariable Cox proportional hazard models were performed to adjust the association between response criteria and TTF on prognostic factors. We included 129 systemic treatments (long-acting somatostatin analogs 41.9%, chemotherapy 26.4%, targeted therapies 31.8%), administered as first-line (53.5%) or second-line therapies (46.5%) in 91 patients. A decrease ≥10% in the size of three LMs was the response criterion that best predicted prolonged TTF, with significance at multivariable analysis (HR 1.90; 95% CI: 1.06-3.40; p = .03). Conversely, response defined by RECIST 1.1 did not predict prolonged TTF (p = .91), and neither did criteria based on changes in LM density. A ≥10% decrease in size of three LMs could be a more clinically relevant criterion than the current 30% threshold utilized by RECIST 1.1 for the evaluation of treatment efficacy in patients with advanced NETs. Its implementation in clinical trials is mandatory for prospective validation. Criteria based on changes in LM density were not predictive of treatment efficacy. CLINICAL TRIAL REGISTRATION: Registered at CNIL-CERB, Assistance publique hopitaux de Paris as "E-NETNET-L-E-CT" July 2018. No number was assigned. Approved by the Medical Ethics Review Board of University Medical Center Groningen.


Simultaneous determination of seven unconjugated steroids in maternal venous and umbilical arterial and venous serum in elective and emergency cesarean section at term.
In order to assess specific gluco- and mineralocorticoid functions in both mother and fetoplacental unit in relation to the presence or absence of labor, serum levels of unconjugated aldosterone (A), corticosterone (B), deoxycorticosterone (DOC), progesterone (P), 17-hydroxyprogesterone (17-OHP), cortisol (F), and cortisone (E) were determined simultaneously. These levels were determined by specific radioimmunoassays in two groups of 24 paired maternal venous and umbilical arterial and venous samples obtained at term delivery by either elective (Group I, N = 8) or emergency (Group II, N = 8) cesarean section. In Group II, after spontaneous labor, mean maternal serum levels of all steroids investigated exceeded those found in Group I (not in labor). These increases were most pronounced (p less than 0.005) in F (74%) and DOC (106%) levels demonstrating stimulation of both the glucocorticoid (cortisol)--and the mineralocorticoid (aldosterone)--producing pathways of the maternal adrenals by spontaneous labor. Arteriovenous differences in umbilical steroid levels revealed in both groups the placental origin of P, 17-OHP, and E (p less than 0.05 to 0.005), with greater (more negative) mean AV differences after labor (Group II). The negative AV difference of DOC, B, A, and F found in Group I, however, decreased after labor and became even positive in the cases of B and F, reflecting the close relationship between spontaneous labor and the fetal adrenal's active production not only of the glucocorticoids B and F, but also, to a lesser extent, of the mineralocorticoids DOC and aldosterone.


Asymptomatic GBS bacteriuria during antenatal visits: To treat or not to treat?
Inconsistencies persist regarding the efficacy of treating asymptomatic group B Streptococcus bacteriuria in pregnant individuals with colony counts below 10 (100,000) CFU/mL. Despite these discrepancies, treatment still occurs. This article examines the role of screening and treatment, evidence-based guidelines, and practice patterns to provide clarification and resolve local practice disparities.


ESR/ERS white paper on lung cancer screening.
Lung cancer is the most frequently fatal cancer, with poor survival once the disease is advanced. Annual low-dose computed tomography has shown a survival benefit in screening individuals at high risk for lung cancer. Based on the available evidence, the European Society of Radiology and the European Respiratory Society recommend lung cancer screening in comprehensive, quality-assured, longitudinal programmes within a clinical trial or in routine clinical practice at certified multidisciplinary medical centres. Minimum requirements include: standardised operating procedures for low-dose image acquisition, computer-assisted nodule evaluation, and positive screening results and their management; inclusion/exclusion criteria; expectation management; and smoking cessation programmes. Further refinements are recommended to increase quality, outcome and cost-effectiveness of lung cancer screening: inclusion of risk models, reduction of effective radiation dose, computer-assisted volumetric measurements and assessment of comorbidities (chronic obstructive pulmonary disease and vascular calcification). All these requirements should be adjusted to the regional infrastructure and healthcare system, in order to exactly define eligibility using a risk model, nodule management and a quality assurance plan. The establishment of a central registry, including a biobank and an image bank, and preferably on a European level, is strongly encouraged. • Lung cancer screening using low dose computed tomography reduces mortality. • Leading US medical societies recommend large scale screening for high-risk individuals. • There are no lung cancer screening recommendations or reimbursed screening programmes in Europe as of yet. • The European Society of Radiology and the European Respiratory Society recommend lung cancer screening within a clinical trial or in routine clinical practice at certified multidisciplinary medical centres. • High risk, eligible individuals should be enrolled in comprehensive, quality-controlled longitudinal programmes.


[Combined treatment of prostatic adenoma with the 80 Watt KTP-laser and low-pressure transurethral resection].
The purpose of this prospective study is to determine the effectiveness of method for vaporisation and elimination of the prostate adenoma. The results are analysed that obtain when combining this Laser-method with the resection at low pressure. 151 patients with BPH symptomatic were treated between August 2004 and january 2006 with the KTP-Laser or combined with low pressure TURP. The additional Resection was carried out in those patients with large adenomas or to have accentuated middle lobule. The ablative effect was controlled at the end of the operation with TRUS (transrectal ultrasound). 151 patients were divided in 2 groups, group 1 (n:43) those with single laser treatment and group 2 (n: 108) with combined treatment. The control of the post-miccional peak-flow demonstrates an increase of 65,6% in group 1, and of 122,4 % in group 2. Our study reveals the advantages of combining both operative procedures to mainly obtain a better result in the ablation of the prostate adenoma in prostates of great size.


Balance of amino acids in the pregnant human uterus at term.
The nutritive and metabolic state of the human uterus at term is evaluated by measuring the uptake and release of amino acids. The subjects are ten healthy women with normal pregnancy undergoing elective caesarean section at term, before onset of labour. Free amino acids in arterial (radial artery) and venous (plexus of the uterine and ovarian veins) blood are determined and arteriovenous (AV) differences in each amino acid across the uterus are calculated. Generally the AV differences are negative, i.e. uterus at term releases amino acids in most cases. The human pregnant uterus at term is characterized by a release of amino acids rather than uptake. This indicates that they are in excess and are not needed in anabolic processes or as a fuel, even when the uterine tissue at term is supposed to be preparing for its grand performance, i.e. the delivery.


GABA(B) autoreceptor-mediated cell type-specific reduction of inhibition in epileptic mice.
GABA(B) receptors (GABA(B)Rs) mediate slow inhibitory effects on neuronal excitability and synaptic transmission in the brain. However, the GABA(B)R agonist baclofen can also promote excitability and seizure generation in human patients and animals models. Here we show that baclofen has concentration-dependent effects on the hippocampal network in a mouse model of mesial temporal lobe epilepsy. Application of baclofen at a high dose (10 mg/kg i.p.) reduced the power of γ oscillations and the frequency of pathological discharges in the Cornu Ammonis area 3 (CA3) area of freely moving epileptic mice. Unexpectedly, at a lower dose (1 mg/kg), baclofen markedly increased γ activity accompanied by a higher incidence of pathological discharges. Intracellular recordings from CA3 pyramidal cells in vitro further revealed that, although at a high concentration (10 µM), baclofen invariably resulted in hyperpolarization, at low concentrations (0.5 µM), the drug had divergent effects, producing depolarization and an increase in firing frequency in epileptic but not control mice. These excitatory effects were mediated by the selective muting of inhibitory cholecystokinin-positive basket cells (CCK(+) BCs), through enhanced inhibition of GABA release via presynaptic GABA(B)Rs. We conclude that cell type-specific up-regulation of GABA(B)R-mediated autoinhibition in CCK(+) BCs promotes aberrant high frequency oscillations and hyperexcitability in hippocampal networks of chronic epileptic mice.


Genotypic analysis using a Y-chromosome-specific probe following bone marrow transplantation.
To monitor successful engraftment after bone marrow transplantation, we performed Southern hybridization analysis or dot blot analysis of DNA in a set of sex-mismatched cases using a Y-chromosome-specific DNA probe (pHY10). This method was extremely sensitive and rapid for checking which cells contain the Y-chromosome. Using this probe, analysis of cells from peripheral blood and bone marrow after transplantation demonstrated the usefulness of confirming engraftment of donor cells and of detecting mixed lymphohematopoietic chimerism.


Cell-free translation of peptides and proteins: from high throughput screening to clinical production.
In the past decade, in vitro transcription/translation technologies have emerged as discovery tools for screening large protein expression libraries, for the selection of engineered polypeptide libraries, and as alternatives to conventional heterologous expression for protein production. Therapeutic proteins and peptides discovered using ribosome-based display methods that link genetic information to the encoded polypeptide generated by cell-free extracts, or purified translation components, are beginning to move forward into human clinical trials. This review details the significant progress in in vitro translation for novel protein and non-natural amino acid containing peptide discovery platforms, as well as advances in the clinical-scale production of therapeutic proteins using cell-free transcription/translation.


Identification of a novel somatic mutation of POU6F2 by whole-genome sequencing in prolactinoma.
Pituitary adenomas (PAs) are one of the most common intracranial tumors; approximately half of PAs are prolactin (PRL)-secreting PAs (prolactinomas). The genetic alterations prevalent in prolactinomas are unknown. Here, we present a patient with an extremely aggressive and giant prolactinoma accompanied by serious destruction of the surrounding bone mass. This patient exhibited resistance to dopaminergic drugs. Through whole-genome sequencing, we identified two novel somatic mutations in the POU6F2 gene (NM_001166018.2: c. 839 C>T; NM_001166018.2: c. 875A>G). This report is the first to identify these somatic mutations in the POU6F2 gene in a prolactinoma. We found that these two mutations obviously decreased the expression level of POU6F2. Inhibition of POU6F2 activity increased the cell proliferation and PRL secretion in rat pituitary cells, but proliferation and PRL secretion were decreased in cells with POU6F2 overexpression. POU6F2 might play a crucial role in the development of prolactinomas and may be a promising target for developing new therapies against prolactinomas.


A collection of enhancer trap insertional mutants for functional genomics in tomato.
With the completion of genome sequencing projects, the next challenge is to close the gap between gene annotation and gene functional assignment. Genomic tools to identify gene functions are based on the analysis of phenotypic variations between a wild type and its mutant; hence, mutant collections are a valuable resource. In this sense, T-DNA collections allow for an easy and straightforward identification of the tagged gene, serving as the basis of both forward and reverse genetic strategies. This study reports on the phenotypic and molecular characterization of an enhancer trap T-DNA collection in tomato (Solanum lycopersicum L.), which has been produced by Agrobacterium-mediated transformation using a binary vector bearing a minimal promoter fused to the uidA reporter gene. Two genes have been isolated from different T-DNA mutants, one of these genes codes for a UTP-glucose-1-phosphate uridylyltransferase involved in programmed cell death and leaf development, which means a novel gene function reported in tomato. Together, our results support that enhancer trapping is a powerful tool to identify novel genes and regulatory elements in tomato and that this T-DNA mutant collection represents a highly valuable resource for functional analyses in this fleshy-fruited model species.


Deficiency of hydrogen sulfide production and pregnancy rate in an experimental model: Association with preterm delivery.
Pro-inflammatory phenomena drive preterm delivery (PTD). Hydrogen sulfide is a gasotransmitter with anti-inflammatory properties produced through the activity of the enzyme cystathionine-γ-lyase (CSE), and its impact was studied in models of normal delivery and PTD in mice. Female CSE+/+ and CSE-/- mice were mated with male CSE+/+ mice; mating was done with drinking water unsupplemented and supplemented with cysteine. The pregnancy rate was monitored. PTD was induced by the intraperitoneal injection of bacterial lipopolysaccharide (LPS) on day 14.5 of pregnancy. Mice were sacrificed for tissue collection and splenocyte isolation after 6 and 12 h. Isolated splenocytes were stimulated for the production of tumor necrosis factor-alpha (TNFα), interleukin (IL)-10 and interferon-gamma (IFNγ); TNFα and vascular endothelial growth factor (VEGF) were measured in the fetuses and the placenta. The successful pregnancy rate was lower in CSE-/- mice and it was restored with cysteine supplementation. CSE deficiency was associated with higher tissue concentrations of TNFα in the fetuses, attenuated IL-10 responses and higher IFNγ production from splenocytes. CSE deficiency was not associated with PTD. Following PTD induction, CSE-/- mice did not show attenuated IL-10 responses but the production of TNFα and IFNγ was lowered over-time; placental VEGF was also increased over-time. CSE deficiency has an unfavorable impact on pregnancy. H2 S deficiency through CSE does not drive PTD but mediates pro-inflammatory phenomena in fetuses.


Genetic similarity between cancers and comorbid Mendelian diseases identifies candidate driver genes.
Despite large-scale cancer genomics studies, key somatic mutations driving cancer, and their functional roles, remain elusive. Here, we propose that analysis of comorbidities of Mendelian diseases with cancers provides a novel, systematic way to discover new cancer genes. If germline genetic variation in Mendelian loci predisposes bearers to common cancers, the same loci may harbour cancer-associated somatic variation. Compilations of clinical records spanning over 100 million patients provide an unprecedented opportunity to assess clinical associations between Mendelian diseases and cancers. We systematically compare these comorbidities against recurrent somatic mutations from more than 5,000 patients across many cancers. Using multiple measures of genetic similarity, we show that a Mendelian disease and comorbid cancer indeed have genetic alterations of significant functional similarity. This result provides a basis to identify candidate drivers in cancers including melanoma and glioblastoma. Some Mendelian diseases demonstrate 'pan-cancer' comorbidity and shared genetics across cancers.


Kidney-specific proteins in patients receiving aprotinin at high- and low-dose regimens during coronary artery bypass graft with cardiopulmonary bypass.
The aim was to determine whether the administration of aprotinin can cause deleterious effects on renal function in cardiac surgery with cardiopulmonary bypass (CPB). Sixty consecutive patients with normal preoperative renal function undergoing elective coronary artery bypass surgery with CPB using the same anaesthetic; CPB and surgical protocols were randomized into three groups. Patients received placebo (Group 1), low-dose aprotinin (Group 2) or high-dose aprotinin (Group 3). Renal parameters measured were plasma creatinine, alpha1-microglobulin and beta-glucosaminidase (beta-NAG) excretion. Measurements were performed before surgery, during CPB and 24 and 72 h, and 7 and 40 days postoperatively. In the three groups, alpha1-microglobulin and beta-NAG excretions significantly increased during CPB, at 24 and 72 h, and 7 days postoperatively (P < 0.05) and had returned to preoperative levels at postoperative day 40. Plasma creatinine levels were within normal values at times recorded. In Groups 2 and 3, alpha1-microglobulin excretion during CPB was significantly higher than in Group 1 (P < 0.001), and 24h after surgery it still remained significantly higher in Group 3 compared to Groups 1 and 2 (P < 0.05). Aprotinin caused a significant increase in alpha1-microglobulin excretion but not in beta-NAG excretion during CPB, which may be interpreted as a greater renal tubular overload without tubular damage. This effect persisted for 24 h after surgery when high-dose aprotinin doses had been administered. Creatinine plasma levels were not sensitive to detect these prolonged renal effects in our study.


Cortisol and testosterone dynamics following exhaustive endurance exercise.
Cortisol (C) and testosterone (T) are impacted significantly by prolonged endurance exercise with inverse responses. Increases in C are witnessed concurrently with decrements in T, possibly impacting recovery. This study was conducted to assess the dynamics of C and free T (fT) concentration and recovery time following an exhaustive endurance exercise session (EES). 12 endurance-trained males (X ± SD: VO2max 66.3±4.8 ml/kg/min, age 22.8 ± 3.1 years, body fat 11.0 ± 1.4 %, training 7.1 ± 3.2 years) completed a treadmill EES at ventilatory threshold (74.7 ± 4.6 % of VO2max; 96.9 ± 10.8 min). Basal blood C and fT were collected at baseline: -48, -24 h, and immediately before (0 h) the EES as well as immediately (+0 h), +24 h, +48 h, and +72 h after the EES. Blood glucose (G) was measured to confirm no undue influence on C. Statistically data were analyzed with repeated measures ANOVA (LSD post hoc). C (nmol/L) increased significantly from -48 h (321 ± 59) to +0 h (701 ± 178) (p < 0.001), and displayed a baseline overshoot with +24 h (209 ± 67) being significantly lower than -48 and +0 h (p < 0.03). fT (pmol/L) decreased significantly from -48 h (161 ± 40) to +0 h (106 ± 38) (p < 0.01) and remained lower at +24 h (110 ± 33) and +48 h (129 ± 30) (p < 0.001). G remained stable throughout. A moderately negative correlation (r = -0.636, p < 0.026) was found between C and fT at +0 h. EES recovery may require 48 h for C and 72 h for fT to return to baseline values. Furthermore, C and fT were only correlated immediately post-exercise. Future research should perform more frequent measurements throughout time course.


A case of primary amebic meningoencephalitis caused by Naegleria fowleri in Bangladesh.
We present the first recognized case of primary amebic meningoencephalitis (PAM) caused by Naegleria fowleri in a 15-year-old male from Bangladesh. He performed daily nasal rinsing with untreated ground water and bathed in untreated ground water or river water, which likely exposed him to N. fowleri.


Intrinsic carpal ligaments on MR and multidetector CT arthrography: comparison of axial and axial oblique planes.
To compare axial and oblique axial planes on MR arthrography (MRA) and multidetector CT arthrography (CTA) to evaluate dorsal and volar parts of scapholunate (SLIL) and lunotriquetral interosseous (LTIL) ligaments. Nine cadaveric wrists of five male subjects were studied. The visibility of dorsal and volar parts of the SLIL and LTIL was graded semi-quantitatively (good, intermediate, poor) on MRA and CTA. The presence of a ligament tear was determined on arthrosocopy and sensitivity, specificity and accuracy of tear detection were calculated. Oblique axial imaging was particularly useful for delineating dorsal and volar parts of the LTIL on MRA with overall 'good' visibility increased from 11 % to 78 %. The accuracy of MRA and CTA in revealing SLIL and LTIL tear was higher using the oblique axial plane. The overall accuracy for detecting SLIL tear on CTA improved from 94 % to 100 % and from 89 % to 94 % on MRA; the overall accuracy of detecting LTIL tear on CTA improved from 89 % to 100 % and from 72 % to 89 % on MRA CONCLUSION: Oblique axial imaging during CT and MR arthrography improves detection of tears in the dorsal and volar parts of both SLIL and LTIL. • Oblique axial imaging improves SLIL and LTIL visibility and tear detection. • This improvement is greater for the LTIL than for the SLIL ligament. • Overall, CT arthrography performed better than MR arthrography.


Postoperative cancer treatments: In-situ delivery system designed on demand.
The keys to the prevention of tumor recurrence after operation are the elimination of residual tumor cells and the reversal of microenvironments that induce recurrence. In the formulation of a treatment scheme, building an appropriate drug delivery system is essential. An in-situ drug delivery system (ISDDS) is regarded as an effective treatment route for postoperative use that increases drug delivery efficiency and mitigates side-effects. ISDDS technology has been considerably improved through a clearer understanding of the mechanisms of postoperative recurrence and the development of drug delivery materials. This paper describes the initiation and characteristics of postoperative recurrence mechanisms. Based on this information, design principles for ISDDS are proposed, and a variety of practical drug delivery systems that fulfil specific therapeutic needs are presented. Challenges and future opportunities related to the application of in-situ drug carriers for inhibiting cancer recurrence are also discussed.


Cost-effectiveness of beer versus red wine for the prevention of symptomatic coronary artery disease.
Until now, red wine has been the cardioprotective beverage of choice, but the convenience and lack of adverse effects make beer a more cost-effective, safe and widely available choice. A paucity of evidence in support of this led to our study. During a 6-month period, 11,780 consecutive patrons at 18 randomly selected urban and community liquor distributors were recruited. Participants were randomly assigned to receive either beer or wine daily for 5 years. Of the 10,078 people who met the inclusion criteria, 5033 were assigned to receive red wine and 5039 to receive beer every day. Effectiveness and adverse effects were equal in the 2 groups. However, costs for beer were substantially lower. In view of its effectiveness, low cost, acceptable adverse-event profile and the fact that it is available in convenient single-dose dispensers, beer should replace red wine as the cardioprotective beverage of choice.


HPLC-UV analytical validation of a method for quantification of progesterone in ex vivo trans-corneal and trans-scleral diffusion studies.
Progesterone (PG) diminishes free radical damage and thus can afford protection against oxidative stress affecting the retina. The therapeutic use of PG is limited because it is a highly hydrophobic steroid hormone with very low solubility in water. This is the main drawback for the therapeutic application of PG at ocular level. The aims of this study were: (i) to analyze if PG causes ocular irritation (ii) to validate a HPLC method to determine PG in ex vivo studies and (iii) to evaluate PG permeation through cornea and sclera. A high performance liquid chromatographic method was developed and validated to detect PG incorporated to β-cyclodextrin using a Waters Sunfire C18 (150 × 4.6 mm) reverse-phase column packed with 5 μm silica particles using a mobile phase consisted of a mixture of acetonitrile (ACN) and pure water 80:20 (v/v), pH 7.4. The limit of detection and the limit of quantification for 50 μL injection of PG were found to be 0.42 and 1.26 μg/mL, respectively. The calibration curve showed excellent linearity over the concentration range (0.5 μg/mL to 100 μg/mL). As proof of concept, ex-vivo experiments to investigate PG permeation through cornea and sclera with vertical diffusion cells were carried out to quantify PG diffusion. Ex vivo experiments demonstrate its applicability to investigate permeation levels of PG from 6.57 ± 0.37 μg/cm2 at cornea and 8.13 ± 0.85 μg/cm2 sclera. In addition, at the end of diffusion studies the amount of PG retained in each tissue was also quantified, and it was 40.87 ± 9.84 μg/cm2 (mean ± SD; n = 6) in cornea and 56.11 ± 16.67 μg/cm2 (mean ± SD; n = 6) in sclera.


Breakdown of Scaling and Friction Weakening in Intermittent Granular Flow.
Many materials are produced, processed and stored as grains, while granularity of matter can be crucial in triggering potentially catastrophic geological events like landslides, avalanches and earthquakes. The response of grain assemblies to shear stress is therefore of utmost relevance to both human and natural environment. At low shear rate a granular system flows intermittently by distinct avalanches. In such state the avalanche velocity in time is expected to follow a symmetrical and universal average behavior, whose dependence on the slip size reduces to a scale factor. Analyzing data from long lasting experiments, we observe a breakdown of this scaling: While in short slips velocity shows indeed a self-similar and symmetric profile, it does not in long slips. The investigation of frictional response in these different regimes evidences that this breakdown can be traced back to the onset of a friction weakening, which is of dynamical origin and can amplify instabilities exactly in this critical state, the most frequent state for natural hazards.


Normal aerobic and anaerobic exercise data for North American school-age children.
The purpose of this study was to establish normative data for untrained, healthy North American children by means of the James protocol for bicycle ergometry. Data were obtained on 151 of 185 children (70 girls and 81 boys). Their ages ranged from 7 years 6 months to 12 years 9 months. All subjects were divided into groups by gender and body surface area (BSA). Maximum heart rates were greater in girls. The mean difference between maximum and recovery heart rates differed significantly by gender, girls taking longer to recover than boys. Maximum oxygen consumption (measured in cubic centimeters per minute per kilogram body weight) did not differ in boys and girls. Ventilatory anaerobic threshold (VAT) occurred when there was an isolated increase in the slope for ventilatory equivalent for oxygen consumption (VE/VO2) with no change in the slope for ventilatory equivalent for carbon dioxide production (VE/VCO2) when both were plotted against time. Absolute oxygen consumption (VO2) at VAT increased with BSA in both sexes, and, when normalized to body size and expressed as a percent of VO2 maximum, no significant difference was observed between the sexes. These data may be used in the fitness evaluations of preadolescent children from North America.


An inducible expression vector for both fission and budding yeast.
We have developed a vector system for inducible gene expression in both fission yeast (Schizosaccharomyces pombe) and budding yeast (Saccharomyces cerevisiae). The autonomously replicating expression vector contains multiple glucocorticoid response elements, rendering a linked promoter inducible 20-70-fold by glucocorticoid hormones in the presence of the mammalian glucocorticoid receptor. A polylinker with several unique cloning sites allows insertion of cDNAs of interest. Glucocorticoids are gratuitous signalling molecules in yeast, exerting little or no effect on the expression of genes other than those fused to the regulated promoter.


Regional distribution of cholecystokinin receptors in primate cerebral cortex determined by in vitro receptor autoradiography.
Cholecystokinin (CCK) is a putative peptide neurotransmitter present in high concentration in the cerebral cortex. By using techniques of in vitro receptor autoradiography, CCK binding sites in primate cortex were labeled with 125I-Bolton-Hunter-labeled CCK-33 (the 33-amino-acid C-terminal peptide) and 3H-CCK-8 (the C-terminal octapeptide). Biochemical studies performed on homogenized and slide-mounted tissue sections showed that the two ligands labeled a high-affinity, apparently single, saturable site. Autoradiography revealed that binding sites labeled by both ligands were anatomically indistinguishable and were distributed in two basic patterns. A faint and diffuse label characterized portions of medial prefrontal cortex, premotor and motor cortices, the superior parietal lobule, and the temporal pole. In other cortical areas the pattern of binding was layer-specific; i.e., binding sites were concentrated within particular cortical layers and were superimposed upon the background of diffuse label. Layer-specific label was found in the prefrontal cortex, anterior and posterior cingulate gyrus, somatosensory cortex, inferior parietal lobule, retrosplenial cortex, insula, temporal lobe cortices, and in the primary visual and adjacent visual association cortices. The areal and laminar localization of layer-specific CCK binding sites consistently coincided with the cortical projections of thalamic nuclei. In prefrontal cortex, CCK binding sites were present in layers III and IV, precisely paralleling the terminal fields of thalamocortical projections from the mediodorsal and medial pulvinar nucleus of the thalamus. In somatosensory cortex, the pattern of CCK binding in layer IV coincided with thalamic inputs arising from the ventrobasal complex, while in the posterior cingulate gyrus, insular cortex, and retrosplenial cortex, layer IV and lower III binding mirrored the laminar distribution of cortical afferents of the medial pulvinar. CCK binding in layers IVa, IVc alpha, IVc beta, and VI of primary visual cortex corresponded to the terminal field disposition of lateral geniculate neurons, whereas in adjacent visual association cortex, binding in layers III, IV, and VI faithfully followed the cortical distribution of projections from the inferior and lateral divisions of the pulvinar nucleus of the thalamus. We interpret the diffusely labeled binding sites in primate cortex as being associated with the intrinsic system of CCK-containing interneurons that are distributed throughout all layers and areas of the cortex. The stratified binding sites, however, appear to be associated with specific extrinsic peptidergic projections.(ABSTRACT TRUNCATED AT 400 WORDS)


Alpha-thalassemia.
The current concepts of alpha-thalassemia including incidence, genetics, clinical spectrum and diagnosis are reviewed. Speculation concerning clinical application of the molecular biology of alpha-thalassemia is also presented.


Morphology of the cardiac conduction system in patients with electrophysiologically proven dual atrioventricular nodal pathways.
Although the electrophysiologic criteria for dual atrioventricular nodal pathways are well established, the anatomical substrate is still unclear. We examined the hearts from 10 patients who had been studied electrophysiologically prior to cardiac transplantation. All 10 patients were male, aged 22 to 60 years. Nine of the 10 patients had dual atrioventricular nodal pathways according to accepted criteria. Histologic studies of the atrioventricular conduction system showed normal structure of the atrioventricular node in all 10 hearts, with minor variations within the node in 3 cases, within the penetrating bundle in 3 cases, and within the nonbranching bundle in 3 cases. The atrial approaches to the atrioventricular node were generally scanty in 6 hearts. The solitary case that was shown electrophysiologically to lack dual pathways had no obvious difference in the structure of the nodal area other than sparsity of transitional cells. We were unable to locate any extranodal atrial tracts as described by other investigators. The anatomical substrate for conduction over dual pathways may be too subtle to be detected by gross morphologic studies. Since dual pathways were unmasked in all patients but one during electrophysiologic studies, it may be that the potential for these pathways is ubiquitous.


A new mathematical equation relating activation energy to bond angle and distance: A key for understanding the role of acceleration in lactonization of the trimethyl lock system.
AM1 semi-empirical molecular orbital and ab initio HF at the 6-31G level calculations for the lactonization processes of 12 different hydroxy acids (1a-1l) which differ in their structural features have been conducted. The calculations obtained reveal the following: (1) The rate-limiting step in the lactonization process is formation of a tetrahedral intermediate and not its collapse as was previously reported. (2) The rate-limiting step in both the acid-catalyzed and uncatalyzed lactonization is composed of two successive steps: approach of the hydroxyl toward the carbonyl carbon until it reaches a distance of 1.4 -1.5A, followed by proton transfer from the ether-type oxygen to one of the hydroxyls in the tetrahedral intermediate. Calculations of the activation energies for formation of the tetrahedral intermediate in the 12 hydroxy acids studied indicate: (1) A linear relationship exists between the change in enthalpic energy (E) and the ratio of the attack angle (nucleophilic-oxygen/carbonyl-carbon/alphalambdapietaalpha-carbon) to the distance (nucleophilic-oxygen/carbonyl-carbon) termed alpha/r; (2) The slope (S) of E vs. alpha/r plots depend on the nature of the hydroxy acids. Furthermore, plots of S values against the experimental rate values (log k(exp)) show a linear correlation with a high correlation coefficient. The combined results suggest that hydroxy acids with low S values have high k(exp) values due to enthalpic proximity effects.


Increased production of biomass-degrading enzymes by double deletion of creA and creB genes involved in carbon catabolite repression in Aspergillus oryzae.
In a previous study, we reported that a double gene deletion mutant for CreA and CreB, which constitute the regulatory machinery involved in carbon catabolite repression, exhibited improved production of α-amylase compared with the wild-type strain and single creA or creB deletion mutants in Aspergillus oryzae. Because A. oryzae can also produce biomass-degrading enzymes, such as xylolytic and cellulolytic enzymes, we examined the production levels of those enzymes in deletion mutants in this study. Xylanase and β-glucosidase activities in the wild-type were hardly detected in submerged culture containing xylose as the carbon source, whereas those enzyme activities were significantly increased in the single creA deletion (ΔcreA) and double creA and creB deletion (ΔcreAΔcreB) mutants. In particular, the ΔcreAΔcreB mutant exhibited >100-fold higher xylanase and β-glucosidase activities than the wild-type. Moreover, in solid-state culture, the β-glucosidase activity of the double deletion mutant was >7-fold higher than in the wild-type. These results suggested that deletion of both creA and creB genes could also efficiently improve the production levels of biomass-degrading enzymes in A. oryzae.


Digital image analysis versus clinical assessment of wound epithelialization: a validation study.
To evaluate the progress in wound healing, wound assessment is mandatory. Epithelialization is traditionally assessed subjectively by the clinician. In a previous study, subjective assessment of epithelialization was shown to be reliable. In this study, reliability of epithelialization measured by digital image analysis was investigated and then, we validated the subjective evaluation by comparing this assessment to measurements with digital image analysis. Clinicians assessed epithelialization in 50 burn wounds that were treated with a split skin graft. Epithelialization of these wounds was also measured by three observers using digital image analysis. Reliability of digital image analysis was tested using the intraclass correlation (IC). To test validity, subjective clinical assessment was correlated with digital image analysis (IC). The results showed that interobserver reliability of epithelialization measured by digital image analysis was good (IC coefficient 0.74). Subjective clinical assessment of epithelialization showed a strong correlation with digital image analysis (IC coefficient 0.80). In conclusion, subjective clinical evaluation of wound epithelialization is as good as an objective measure, in this study digital image analysis. Since digital image analysis is more time-consuming, we recommend the use of the subjective evaluation for daily practice.


Skeletal turnover, bone mineral density, and fractures in male chronic abusers of alcohol.
Chronic alcohol abuse is a risk factor for osteoporosis and fractures, whose pathogenesis is still unclear. We investigated the influence of alcoholism and other risk factors on calcium and skeletal metabolism, bone mineral density (BMD), and fractures. In 51 chronic male alcoholics without liver failure and 31 healthy controls, serum total and ionised calcium, phosphate, creatinine, 25-hydroxy vitamin D (25OHD), PTH, total (ALP) and bone-specific (BALP) alkaline phosphatase, osteocalcin (BGP), carboxy-terminal telopeptide of type I collagen (beta-CTx), osteoprotegerin (OPG) and receptor activator of nuclear factor kappa B ligand (RANKL) were assessed. In patients only, we also measured serum testosterone, 17-beta estradiol, LH, and IGF-I. BMD was measured by dual energy x-ray absorptiometry at lumbar spine (LS-) and femur [neck (FN-) and total hip (TF-)]. Vertebral fractures were identified by a semiquantitative method on thoraco-lumbar spine x-ray, non-vertebral fractures (as life-style factors) by history. Alcoholics were leaner, had significantly higher ALP and BALP, and lower BGP and 25OHD levels than controls. No significant difference in other calcium and bone metabolism parameters was found. OPG/RANKL ratio was significantly higher in alcoholics. Beta-CTx negatively correlated with abuse duration. OPG positively correlated with daily alcohol assumption and with indexes of liver cytolysis. Though LS-, FN- and TF-BMD of alcoholics and controls did not significantly differ, patients had a much higher prevalence of vertebral fractures. The same was found considering both vertebral and non-vertebral fractures. Ethanol-induced skeletal damage seems mainly dependent on negative effects on bone formation. Lifestyle factors and traumas likely contribute to the high fracture incidence of alcohol abusers, independently of BMD.


A potent platelet aggregation inducer purified from Trimeresurus mucrosquamatus snake venom.
A non-coagulant platelet aggregation inducer (called platelet 'aggregoserpentin') was isolated from Trimeresurus mucrosquamatus snake venom by CM-Sephadex chromatography and purified by gel filtration. It was homogeneous as judged by the ultracentrifugal analysis and electrophoresis on polyacrylamide gel and cellulose acetate membrane. The molecular weight was estimated to be 68 000 as judged by the SDS-polyacrylamide gel electrophoresis and gel filtration on Sephadex G-75. The ultracentrifugal analysis gave 3.19 Svedberg units. It was a protein-polysaccharide complex containing 340 amino acid residues and 50% carbohydrate per molecule. The isoelectric point was pH 5.4. It did not possess any of the hydrolase enzymatic properties which were found in the crude venom. The minimal concentration of 'aggregoserpentin' necessary to induce platelet aggregation was 10 ng/ml, about one four-hundredth of that of the crude venom. It did not cause lysis of platelets because lactate dehydrogenase was not found in supernatant after complete aggregation. An intravenous injection of 'aggregoserpentin' (35 microgram/kg) into rabbit ear marginal vein caused marked decrease of platelet number to approx. 10-20% of that of the control.


Hepatitis C virus genotypes in two different patient cohorts in Johannesburg, South Africa.
Previous studies in South African patients have shown that hepatitis C virus (HCV) prevalence is low (2.6%) and genotype 5 is the dominant genotype. This is the first sequence-based genotype study from this country on two different patient groups (haemophiliacs (H) and liver disease (LD) patients) over two time periods (2000-2002 and 2007). Genotype 5 was found to be the dominant genotype in the LD groups, but genotype 1 dominated in the H group. Genotype 2, and a higher prevalence of genotype 3a, was present in the H group when compared to previous South African studies. Genotypes 3 and 4 have been described here in the LD groups for the first time in South Africa, with subtypes 4c and 4g being identified. A separate cluster of genotype 5 sequences were found to have only one adenine at nucleotide position 107 of the 5'UTR, as previously reported. Subtyping in the less conserved NS5B region was used to further characterize the 2000-2002 isolates and validate 5'UTR typing. The study shows that by using reliable methods of genotyping, the prevalence and frequencies of HCV genotypes can be monitored in South Africa for better diagnosis and treatment of the disease.


Preclinical study of transcervical upper mediastinal dissection for esophageal malignancy by robot-assisted surgery.
Robotic surgical systems are potentially applicable to transcervical mediastinal lymph dissection for esophageal malignancy. Robot-assisted surgery was performed on a male fresh-frozen human cadaver. Devices for single-port laparoscopic surgery were deployed via one small incision in the left clavicular area. The task for the robot-assisted surgery was the upper mediastinal dissection to the level of the left main bronchus and en bloc harvest of the lymph nodes adherent to the left recurrent laryngeal nerve. An up-angled 30° scope in the 6 o'clock port and two robotic arms from the 3 and 9 o'clock ports worked effectively together. No collisions of the devices inside the cadaveric body or unexpected traumatic events occurred. The robotic surgical system can be used safely for the upper mediastinal dissection. Copyright © 2016 John Wiley & Sons, Ltd.


Maternal and fetal insulin-like growth factor system and embryonic survival during pregnancy in rats: interaction between dietary chromium and diabetes.
Chromium (Cr) depletion may exacerbate hyperglycemia and negative outcomes of pregnancy in the streptozotocin (STZ) diabetic pregnant rat model through the regulation of the insulin-like growth factor (IGF) system. To test this hypothesis, 40 female rats, all fed a low Cr diet (i.e., 70 microgram Cr/kg diet ) from 21 d of age, were randomly assigned one of four treatments, applied on Day 1 of pregnancy, in a 2 x 2 factorial design: 1) very low Cr diet (40 microgram Cr/kg diet) + citrate buffer injection, 2) very low Cr diet + STZ injection (30 mg STZ/kg body wt in citrate buffer), 3) adequate Cr diet (2 mg Cr [from added CrK(SO4)2]/kg diet) + citrate buffer injectionand 4) adequate Cr diet + STZ injection. Blood and tissues were collected on Day 20 of pregnancy. Chromium depletion increased (P < 0.05) urinary hydroxyproline excretion, 22-kDa IGF binding protein (IGFBP) concentration and litter size but decreased (P < 0. 05) placental wt, percentage of protein per fetus, and fetal IGF-I and -II concentrations. Chromium had no effect (P > 0.10) on maternal hormones, 32-kDa IGFBP, glucose, or placental and fetal hydroxyproline concentrations. Diabetes decreased (P < 0.05) maternal wt gain, embryonic survival, litter size, mean pup wt and maternal insulin concentrations, increased (P < 0.05) maternal blood glucose, IGF-I concentrations and maternal hydroxyproline excretion but did not affect fetal concentrations of hormones, IGFBP, glucose or hydroxyproline. Interaction between chromium and diabetes tended (P < 0.10) to affect maternal IGF-II concentrations, but had no effect on other maternal or fetal variables. In conclusion, maternal chromium depletion did not exacerbate hyperglycemia or pregnancy outcome in STZ-induced diabetic rats, but may negatively affect fetal protein content by decreasing fetal IGF-II concentrations. Diabetes may negatively affect fetal growth through its effect on maternal glucose, insulin and IGF-I.


The impact of clinical trial design on cost-effectiveness analyses: illustration from a published study of the one-touch ultrasmart blood glucose meter for insulin-using diabetes patients.
One source of variation in cost-effectiveness analyses stems from the characteristics of the study upon which each is based. This report provides cost-effectiveness analyses using data from a recently published randomized clinical trial (RCT) comparing an integrated glucose meter/electronic logbook to a conventional glucose meter/paper logbook in helping to control hemoglobin A1c in type 1 or type 2 diabetes. RCT participants and health care professionals (HCPs) were "blinded" to results of meter downloads until week 16, when participants chose systems. They returned to "usual care" and could obtain meter results and share them with their HCPs. Those eligible returned 26-65 weeks later for an observational visit. The CORE Diabetes Model was used to estimate the 60-year cost-effectiveness of the electronic (vs. conventional) meter. With no price premium, the newer technology represented a dominant strategy (greater effectiveness/lower costs) based on the RCT alone or on the RCT + observational visit. With a $100.00/year premium, the incremental cost-effectiveness ratio was $28,053 based on the RCT, but the electronic monitor was dominant when simulations included observational visit results. One plausible reason for the greater benefits of the electronic monitor with the observational period included was the ability of patients and HCPs to make better clinical and lifestyle modifications based on fully available, formatted data. Because the advantages of the electronic meter are based on timely access to accurate feedback, the importance of naturalistic, unblinded studies for technology assessments can be appreciated. Addressing the methodological issues discussed here can help integrate clinical and economic outcomes for diabetes care innovations.


Dislodgment Resistance of Bioceramic and Epoxy Sealers: A Systematic Review and Meta-analysis.
The aim of the present systematic review was to evaluate if epoxy resin-based root canal sealers present superior push-out bond strength compared to calcium silicate-based root canal sealers. The inclusion criteria consisted of in vitro studies that compared the push-out bond strength of epoxy resin-based and calcium silicate-based sealers. A systematic search was performed in the following databases for articles published until February 2018: PubMed, ScienceDirect, Scopus, Web of Science, and OpenGrey. The quality assessment and data extraction of the selected articles were performed. A meta-analysis of the pooled data and the subgroups according to the root thirds was carried out using the RevMan software (P < .05). The search resulted in 2292 studies. After the duplicate studies were removed and the title and abstract were read, 20 studies were selected and 17 were considered as having a low risk of bias. The pooled meta-analysis comparing epoxy resin-based (n = 467) and paste-to-paste calcium silicate-based root canal sealers (n = 467) demonstrated higher mean push-out bond strength values (P < .001) for the epoxy resin-based root canal sealers; the heterogeneity among studies was 85% (I2). The comparisons between epoxy resin-based (n = 358) and premixed ready-to-use calcium silicate-based root canal sealers (n = 358) also demonstrated a significant difference between the sealers (P < .05), with an I2 of 95%. The subgroup analysis showed that only in the middle third, were increased bond strength values for epoxy resin-based sealer observed (P < .001), with an I2 of 94%. The epoxy resin-based sealer demonstratedhigher push-out bond strength than paste-to-paste calcium silicate-based root canal sealer regardless of the root third assessed. In addition, the epoxy resin-based sealer exhibited increased push-out bond strength in comparison with premixed ready-to-use calcium silicate-based root canal sealer when evaluating the middle third.


Prospective teachers' conceptions of assessment: a cross-cultural comparison.
This paper examines the responses of two sample of prospective teachers (New Zealand, n = 324; and Spain, n = 672) to the Teachers' Conceptions of Assessment inventory (English and Spanish respectively). The inventory captures four major intentions for assessment (i.e., improvement, irrelevance, school and student accountability). The conceptions of prospective teachers about the nature and purpose of assessment are relevant, given that (a) much educational assessment is carried out in classrooms; and (b) prospective teachers enter the teacher education programs with significant prior school experience of assessment as pupils. Results of confirmatory factor analysis indicated that the original model was inadmissible and that the best-fitting revised model was only configurally invariant between the two samples. It would appear that lack of teaching experience results in different responses for prospective teachers to those of practicing teachers. Moreover, differences in societal and cultural priorities for assessment use most likely explain the lack of invariance between samples.


A calcium-independent 5-lipoxygenase system in mast/basophil PT-18 cells.
Mammalian 5-lipoxygenase systems exist in inactive or cryptic states and have to be stimulated in order to metabolize exogenous [14C]arachidonic acid to 5-HETE and leukotrienes. In most cells, both the activation process and the 5-lipoxygenase activity are calcium-dependent. However, the cryptic 5-lipoxygenase system in the murine PT-18 mast/basophil cell line, which can be stimulated by 15-hydroxyeicosatetraenoic acid (15-HETE), is unusual. Studies with fura-2 loaded PT-18 cells indicate that increases in cytosolic calcium do not appear to correlate with enhanced 5-lipoxygenase product formation. Thus, both the calcium ionophore ionomycin and arachidonic acid increase cytosolic calcium levels but have very little effect on [14C]5-HETE formation, whereas 15-HETE induces large increases in [14C]5-HETE production but no concomitant enhancement in cytosolic calcium is observed. Chelation of extracellular calcium by 3 mM EGTA resulted in a 30-40% inhibition of [14C]5-HETE formation induced by 15 HETE, whereas 3 mM EGTA has no appreciable effect on a crude PT-18 5-lipoxygenase homogenate. These results indicate that in PT-18 cells, calcium does not appear to play an important role in either the 15-HETE-induced activation process, or the enzymatic activity of the cryptic 5-lipoxygenase system.


The evolution of imagination and the adaptive value of imaginary worlds.
Characterizing the cultural evolution of imaginary worlds as a hedonic but non-adaptive exaptation from evolved exploratory tendencies, Dubourg and Baumard defend too narrow a conception of the adaptive evolution of imaginary worlds. Imagination and its imaginary worlds are ancient and adaptive, allowing deliberation over actions, consequences, and futures worth aspiring to, often engendering the world we see around us.


Distinct quantitative computed tomography emphysema patterns are associated with physiology and function in smokers.
Emphysema occurs in distinct pathologic patterns, but little is known about the epidemiologic associations of these patterns. Standard quantitative measures of emphysema from computed tomography (CT) do not distinguish between distinct patterns of parenchymal destruction. To study the epidemiologic associations of distinct emphysema patterns with measures of lung-related physiology, function, and health care use in smokers. Using a local histogram-based assessment of lung density, we quantified distinct patterns of low attenuation in 9,313 smokers in the COPDGene Study. To determine if such patterns provide novel insights into chronic obstructive pulmonary disease epidemiology, we tested for their association with measures of physiology, function, and health care use. Compared with percentage of low-attenuation area less than -950 Hounsfield units (%LAA-950), local histogram-based measures of distinct CT low-attenuation patterns are more predictive of measures of lung function, dyspnea, quality of life, and health care use. These patterns are strongly associated with a wide array of measures of respiratory physiology and function, and most of these associations remain highly significant (P < 0.005) after adjusting for %LAA-950. In smokers without evidence of chronic obstructive pulmonary disease, the mild centrilobular disease pattern is associated with lower FEV1 and worse functional status (P < 0.005). Measures of distinct CT emphysema patterns provide novel information about the relationship between emphysema and key measures of physiology, physical function, and health care use. Measures of mild emphysema in smokers with preserved lung function can be extracted from CT scans and are significantly associated with functional measures.