Topical mitomycin C versus intralesional triamcinolone in the management of esophageal stricture due to caustic ingestion.
Esophageal stricture due to caustic ingestion is one of the most difficult problems to manage. Esophageal dilations are the usual treatment and they require a great number of sessions in the majority of cases. This implies time, risks for the patient, anguish for the relatives, and very often, frustration for the physician. To evaluate the efficacy of the application of topical mitomycin C and intralesional triamcinolone in the prevention of post-dilation esophageal stricture recurrence. A prospective, comparative, nonrandomized, and longitudinal study was conducted that compared a cohort of 16 patients treated with mitomycin C (2009-2012) with a retrospective cohort of 34 patients treated with triamcinolone (2002-2009). The patients treated with intralesional triamcinolone had a median of 11 dilations (minimum 4 and maximum 24), whereas the median in the patients treated with topical mitomycin C was 4.5 (minimum 3 and maximum 8). The groups were compared using the Mann-Whitney U test, finding a statistically significant difference of a two-tailed P<.001. In the multiple linear regression model, the dependent variable was the number of dilations and the independent variables were the type of lesion and treatment. The result was an R(2) .676 with a significance level of P<.001, in which the regression coefficient for treatment was B -.682 (95% CI -8.286 to -5.025) and the lesion grade was B .435 (95% CI 2.043- 4.573). The ANOVA result was an F 49.08 and a P<.001 and showed that the independent variables of type of lesion and treatment had a linear relation with the number of dilations, reinforcing the fact that our results were not due to chance. Topical mitomycin C considerably reduced the number of esophageal dilations compared with the use of intralesional triamcinolone to alleviate dysphagia, and therefore we suggest it as a treatment option in strictures due to caustic ingestion.


Utomilumab in Patients With Immune Checkpoint Inhibitor-Refractory Melanoma and Non-Small-Cell Lung Cancer.
Clinical/translational cancer immunotherapy. The goal of this study was to estimate the objective response rate for utomilumab in adults with immune checkpoint inhibitor (ICI)-refractory melanoma and non-small-cell lung cancer (NSCLC). Utomilumab was dosed intravenously every 4 weeks (Q4W) and adverse events (AEs) monitored. Tumor responses by RECIST1.1 were assessed by baseline and on-treatment scans. Tumor biopsies were collected for detection of programmed cell death ligand 1, CD8, 4-1BB, perforin, and granzyme B, and gene expression analyzed by next-generation sequencing. CD8+ T cells from healthy donors were stimulated with anti-CD3 ± utomilumab and compared with control. Patients with melanoma (n=43) and NSCLC (n=20) received utomilumab 0.24 mg/kg (n=36), 1.2 mg/kg (n=26), or 10 mg/kg (n=1). Treatment-emergent AEs (TEAEs) occurred in 55 (87.3%) patients and serious TEAEs in 18 (28.6%). Five (7.9%) patients discontinued owing to TEAEs. Thirty-two (50.8%) patients experienced treatment-related AEs, mostly grade 1-2. Objective response rate: 2.3% in patients with melanoma; no confirmed responses for patients with NSCLC. Ten patients each with melanoma (23.3%) or NSCLC (50%) had stable disease; respective median (95% confidence interval, CI) progression-free survival was 1.8 (1.7-1.9) and 3.6 (1.6-6.5) months. Utomilumab exposure increased with dose. The incidences of antidrug and neutralizing antibodies were 46.3% and 19.4%, respectively. Efficacy was associated with immune-active tumor microenvironments, and pharmacodynamic activity appeared to be blunted at higher doses. Utomilumab was well tolerated, but antitumor activity was low in patients who previously progressed on ICIs. The potential of 4-1BB agonists requires additional study to optimize efficacy while maintaining the tolerable safety profile.


Geographically differentiated pay in the labour market for nurses.
This novel application of spatial wage theory to health service labour markets analyses the competitiveness of nurse's pay and how this differs between local labour markets in Britain. A switching regression model is estimated to derive standardised spatial wage differentials (SSWDs) for nurses and their comparators. An SSWD gap is constructed and its relationship to vacancies estimated. A reduction in the gap in a local area is shown to result in an increase in the long-term vacancy rate for National Health Service (NHS) nurses. The competitiveness of nursing pay is shown to have a strong effect on the ability of the NHS to attract and retain nurses.


Posttraumatic stress symptoms in adolescent survivors of childhood cancer and their mothers.
We examined symptoms of posttraumatic stress disorder (PTSD) in adolescent survivors of childhood cancer and their mothers and the contribution of family functioning, including perceived emotional support and familial conflict, and individual factors including life stress and severity of disease to PTSD symptoms. Participants were 52 adolescent cancer survivors and their mothers and 42 healthy adolescent counterparts and their mothers. Findings revealed that mothers of cancer survivors endorsed more PTSD symptoms than did their healthy counterparts and that survivors and mothers also reported greater recent and past stressful life events. Although no survivors met clinical criteria for a PTSD diagnosis, over 36% endorsed mild subthreshold symptomatology. Findings are discussed in the context of understanding PTSD symptoms within a family systems framework.


Efficacy and safety of pembrolizumab and axitinib as first-line treatment for patients with advanced renal cell carcinoma: Real-world experience in Japan.
The objective of this study was to assess the clinical outcomes following combined treatment with pembrolizumab and axitinib as first-line therapy for patients with advanced RCC. This study retrospectively included 47 consecutive Japanese patients who were diagnosed with advanced RCC and subsequently received pembrolizumab and axitinib between February 2020 and January 2022. Efficacy and safety of this combined therapy in these patients were comprehensively investigated. The 47 included patients were classified into the following 3 groups by the IMDC system: favorable, 7 (14.9%); intermediate, 24 (51.1%) and poor, 16 (34.0%). Responses to this combined therapy in the 47 patients were as follows: CR, 8 (17.0%); PR, 20 (42.6%); SD, 16 (34.0%) and PD, 3 (6.4%); thus, the ORR was 59.6%. During the observation period, disease progression and death occurred in 19 (40.4%) and 9 (19.1%) patients, respectively, and the median PFS and OS were 18 months and not reached, respectively. Univariate analyses identified the following significant predictors for poor prognostic outcomes: lack of nephrectomy, liver metastasis, bone metastasis, elevated CRP and IMDC poor risk for PFS; and lack of nephrectomy, non-CCC and elevated CRP for OS. AEs and those corresponding to grade ≥ 3 occurred in all (100%) and 30 (63.8%) patients, respectively. To our knowledge, this is the first study focusing on real-world outcomes following pembrolizumab and axitinib for treatment-naïve advanced Japanese RCC patients, which showed the efficacy and safety of this combined therapy being similar or even superior to those in clinical trial.


Effectiveness and safety of olanzapine in the treatment of schizophrenia among Asian patients switching from conventional antipsychotics.
The objectives of this study were: (1) to investigate, in a clinical practice setting, the effectiveness of olanzapine in the treatment of schizophrenia among partially-responding, symptomatic Asian patients who switch from conventional antipsychotic treatment, (2) to assess the safety of olanzapine and (3) to assess the change in quality of life in Asian patients with schizophrenia who switch to olanzapine. Effectiveness, safety and quality of life were assessed in outpatients with schizophrenia (n=1267) who lacked symptomatic control with conventional antipsychotics and were switched to olanzapine therapy. Data for this prospective, observational study were collected for 12 months from Asian patients in China, Hong Kong, the Philippines, South Korea and Taiwan. Significant clinical improvements (P<0.05) were observed following 12 months of olanzapine treatment and 87.3% of the subjects responded to treatment at endpoint (i.e. Brief Psychiatric Rating Scale Total score reduced by > or =30% relative to baseline; last observation carried forward). Abnormal involuntary movements (mean change in Abnormal Involuntary Movement Scale: -3.20, P<0.001) and quality of life were significantly improved in patients treated with olanzapine. However, some patients experienced significant weight gain (3.60+/-4.50 kg, P<0.001) with olanzapine treatment, relative to baseline. This study shows that switching to olanzapine may be effective in improving symptoms, may be well-tolerated and may improve the quality of life in Asian patients who are only partially responsive to treatment with conventional antipsychotics. The pragmatic design and naturalistic setting of this large study make the findings relevant for treating patients from some Asian countries in routine clinical practice.


Mitochondrial Translation Initiation Factor 3: Structure, Functions, Interactions, and Implication in Human Health and Disease.
Mitochondria are essential organelles of eukaryotic cell that provide its respiratory function by means of the electron transfer chain. Expression of mitochondrial genes is organized in a bacterial-like manner; however multiple evolutionary differences are observed between the two systems, including translation initiation machinery. This review is dedicated to the mitochondrial translation initiation factor 3 (IF3mt), which plays a key role in the protein synthesis in mitochondria. Involvement of IF3mt in human health and disease is discussed.


Epstein-Barr virus infection in liver transplantation patients: correlation of histopathology and semiquantitative Epstein-Barr virus-DNA recovery using polymerase chain reaction.
Epstein-Barr virus (EBV) infection may complicate orthotopic liver transplantation, and can lead to hepatitis with subsequent graft failure and to benign and malignant lymphoproliferative disorders. Early diagnosis allows for prevention or treatment of complications. Histopathologic features of EBV infection in the liver vary and may be difficult to recognize. To delineate the morphologic features that allow for recognition we studied 61 biopsy specimens from 37 patients, correlating the results of EBV-DNA demonstration after polymerase chain reaction with histopathology of formalin-fixed, hematoxylin-eosin-stained liver biopsy specimens. DNA was extracted from fresh liver biopsy samples, and polymerase chain reaction was carried out with EBV primers (capsid protein gp220) using standard techniques and 25-cycle amplification. Epstein-Barr virus-related sequences after polymerase chain reaction were detected by DNA blot assay. Histopathologic features were classified into three categories on the basis of the semiobjective determination of the number and distribution of immunoblasts and other immature lymphocytes in portal tracts and sinusoids: highly suggestive (three biopsy specimens), indeterminant (one biopsy specimen), and negative (57 biopsy specimens). Only the three highly suggestive biopsy specimens had high levels of EBV-DNA. We conclude that the histopathologic features of EBV infection after orthotopic liver transplantation can be relied on to establish the diagnosis.


Diffuse mesangial sclerosis: association with unreported congenital anomalies and placental enlargement.
A case of diffuse mesangial sclerosis (DMS) associated with a number of undescribed congenital anomalies is reported. The occurrence of additional anomalies, especially ocular anomalies, is a common finding in DMS. However, neither megalocornea, Dandy-Walker malformation, postaxial hexadactyly, rocker-bottom feet, nor atrial septal defect, as observed in our patient, has been reported previously in association with DMS. This case might be considered an atypical manifestation of the Galloway-Mowat syndrome. In contrast to most cases of DMS, the patient revealed intrauterine proteinuria as the placenta was enlarged to 31% of birth weight. This case demonstrates that the large placenta, >25% of birth weight, is not only pathognomonic of the congenital nephrotic syndrome of the Finnish type but can also occur in DMS.


Quantitative PCR overestimation of DNA in samples contaminated with tin.
Metals can pose challenges while conducting forensic DNA analysis. The presence of metal ions in evidence-related DNA extracts can degrade DNA or inhibit PCR as applied to DNA quantification (real-time PCR or qPCR) and/or STR amplification, leading to low success in STR profiling. Different metal ions were spiked into 0.2 and 0.5 ng of human genomic DNA in an "inhibition study" and the impact was evaluated by qPCR using the Quantifiler™ Trio DNA Quantification Kit (Thermo Fisher Scientific) and an in-house SYBR Green assay. This study reports on a contradictory finding specific to tin (Sn) ions, which caused at least a 38,000-fold overestimation of DNA concentration when utilizing Quantifiler Trio. This was explained by the raw and multicomponent spectral plots, which indicated that Sn suppresses the Quantifiler Trio passive reference dye (Mustang Purple™, MP) at ion concentrations above 0.1 mM. This effect was not observed when DNA was quantified using SYBR Green with ROX™ as the passive reference, nor when DNA was extracted and purified prior to Quantifiler Trio. The results show that metal contaminants can interfere with qPCR-based DNA quantification in unexpected ways and may be assay dependent. The results also highlight the importance of qPCR as a quality check to determine steps for sample cleanup prior to STR amplification that may be similarly impacted by metal ions. Forensic workflows should recognize the risk of inaccurate DNA quantification of samples that are collected from substrates containing tin.


Phospholipase C-beta 1 is a GTPase-activating protein for Gq/11, its physiologic regulator.
Purified M1 muscarinic cholinergic receptor and Gq/11 were coreconstituted in lipid vesicles. Addition of purified phospholipase C-beta 1 (PLC-beta 1) further stimulated the receptor-promoted steady-state GTPase activity of Gq/11 up to 20-fold. Stimulation depended upon receptor-mediated GTP-GDP exchange. Addition of PLC-beta 1 caused a rapid burst of hydrolysis of Gq/11-bound GTP that was at least 50-fold faster than in its absence. Thus, PLC-beta 1 stimulates hydrolysis of Gq/11-bound GTP and acts as a GTPase-activating protein (GAP) for its physiologic regulator, Gq/11. GTPase-stimulating activity was specific both for PLC-beta 1 and Gq/11. Such GAP activity by an effector coupled to a trimeric G protein can reconcile slow GTP hydrolysis by pure G proteins in vitro with fast physiologic deactivation of G protein-mediated signaling.


Coil Embolization with Subsequent Subacute Flow Diversion Before Hospital Discharge as a Treatment Paradigm for Ruptured Aneurysms.
Subtotal coil embolization followed by subsequent flow diversion is often pursued for treatment of acutely ruptured aneurysms. Owing to the need for anti-platelet therapy, the optimal time of safely pursuing flow diversion treatment has not been fully elucidated. In this study, we aim to demonstrate the safety and feasibility of staged treatment of acutely ruptured aneurysms with early coil embolization followed by flow diversion prior to discharge. A retrospective study to evaluate clinical outcomes of patients who presented with aneurysmal subarachnoid hemorrhage and underwent coil embolization followed by subacute flow diversion treatment during the same hospitalization. A total of 18 patients are included in our case series. Eight patients presented with Hunt-Hess (H-H) grade 2 bleed, 6 patients with H-H grade 3, and 2 patients each with H-H grade 4 and H-H grade 1. Eight patients required placement of an external ventricular drain on admission. After initial coil embolization, 12 achieved Raymond-Roy grade 2 occlusion, and 6 attained grade 3a/b occlusion. The mean duration between coil embolization and subsequent flow diversion was 9.83 days (range: 1-30). There were no instances of re-hemorrhage between initial coil embolization and subsequent flow diversion treatment. Sixteen patients had a minimum of 6-month follow-up, of which 15 were found to have complete occlusion, and 1 required subsequent clipping. Subtotal coil embolization followed by definitive treatment using flow diversion during the same hospitalization is feasible and achieves excellent aneurysm occlusion rates while avoiding dual anti-platelet therapy during the initial hemorrhage period.


Medical and legal aspects of the Munchausen by proxy perpetrator.
The Munchausen by Proxy syndrome is described, and illuminated by case histories. A plea is put forward for the adoption into Israeli law of the doctrine of diminished responsibility, as perpetrators of crimes who suffer from the MbP syndrome are treated by the law as if they had no psychiatric disability.


Diagnosis of genetic amyloidosis through the analysis of transthyretin gene mutation using high-resolution melting.
Transthyretin amyloidosis can be either the wild-type (ATTR-wt) or the hereditary form (ATTR-m) with autosomal dominant inheritance. ATTR seems to be an underdiagnosed disease, despite now being recognized as one of the most frequent causes of heart failure (HF) with preserved ejection fraction. The confirmation of diagnosis includes a genetic analysis as a critical step to distinguish between ATTR-wt and hereditary amyloidosis. The present study aimed to evaluate the potential application of High-Resolution Melting (HRM) analysis for identifying gene mutations in patients with suspected ATTR-m. We have adapted and validated the use of HRM for TTR mutations. We, therefore, sequenced the TTR gene and used HRM in a group of 134 patients suspected of suffering from amyloidosis. Seven patients were diagnosed with mutations in the TTR gene (p.Glu74Gln, heterozygous p.Val142Ile, and homozygous p.Val142Ile). HRM is capable of clearly detecting these TTR mutations, including the heterozygous and homozygous variants. The results show a 100% correlation between the HRM study and TTR sequencing. These results support future studies of applying HRM analysis as a diagnostic approach for ATTR-m, mainly for epidemiological studies.


The intrinsic cybernetics of large complex systems and how droughts turn into floods.
The cyber-physical nature of engineering systems requires the smooth integration of decision making across soft and hard infrastructure. This need is common to any systems where decision making considers multiple complex systems such as the climate, the natural and built environment, and the dynamics of large organisations. As an example, in the Anthropocene, acute droughts and floods cannot only be imputed to more extreme variations of the climate patterns, but also to the alteration of the habitable environment and of the resources that support it, hence to their governance and management. In this discussion paper we present arguments about the extent to which the natural environment is modified to support urbanisation. We expose the cyber-physical nature of large infrastructure systems taking as an example the events of the 2011 Brisbane flood and the operations of the damming system of the river Brisbane. Using literature resources and data, we show how flood defence devices had to provide for a population of almost 2 million people, while being engineered when the population was less than one million, with increase in water withdrawal mainly due to residential utilities. We show how the cyber-physical aspects of the problem materialised in moth-long delays in the governance and management structure and made the flood event transcend the boundary of a purely climatic or engineering incident. Looking beyond the Brisbane example, our conclusions point at overcoming the discontinuity between operation, management and political layers when operating on cyber-physical systems such as freshwater networks.


Anchorage-independent growth of normal human mesothelial cells: a sensitive bioassay for EGF which discloses the absence of this factor in fetal calf serum.
This laboratory recently reported that normal human mesothelial cells require epidermal growth factor (EGF) and hydrocortisone (HC), in addition to fetal calf serum and a complex defined medium component, in order to grow optimally in surface culture. We report here that this normal cell type also forms large colonies at high efficiency in semi-solid medium, but exhibits more stringent serum and EGF requirements for anchorage-independent than for surface growth. Mesothelial cells are unable to divide at all in semi-solid medium without added EGF or with less than 2% serum, whereas they grow slowly but progressively in surface culture under such conditions. In semi-solid medium containing 20% serum and HC, mesothelial cells are stimulated to divide by the addition of as little as 30 pg/ml purified EGF. Human urine or male mouse plasma could substitute for purified EGF, yielding growth commensurate with the levels of EGF in these biological fluids previously measured by others using radioreceptor and radioimmune assays. Thus growth of mesothelial cells in semi-solid medium can serve as a highly sensitive assay of EGF biological activity which is unaffected by the presence of serum proteins. In addition, our results demonstrate that fetal calf serum does not provide mitogenic levels of EGF to cultured cells, raising the question of the identity of plasma and serum mitogens.


Influence of radiotherapy treatment concept on the outcome of patients with localized ependymomas.
To assess the outcome of 57 patients with localized ependymomas treated with radiotherapy (RT). Fifty-seven patients with localized ependymomas were treated with RT. Histology was myxopapillary ependymoma (n = 4), ependymoma (n = 23), and anaplastic ependymoma (n = 30). In 16 patients, irradiation of the craniospinal axis (CSI) was performed with a median dose of 20 Gy. Forty-one patients were treated with local RT, with a local dose of 45 Gy to the posterior fossa, including a boost to the tumor bed of 9 Gy. In 19 patients, the tumor bed was irradiated with a median dose of 54 Gy. Overall survival after primary diagnosis was 83% and 71% at 3 and 5 years. Five-year overall survival was 80% in low-grade and 79% in high-grade tumors. Survival from RT was 79% at 3 and 64% at 5 years. We could not show a significant difference in overall survival between CSI and local RT only. Freedom of local failure was 67% at 5 years in patients treated with CSI and 60% at 5 years after local RT. A rate of 83% for distant failure-free survival could be observed in the CSI group as opposed to 93% in the group receiving local RT only. Local RT in patients with localized tumors is equieffective to CSI. The radiation oncologist must keep in mind that patients with localized ependymomas benefit from local doses > or =45 Gy.


Mitochondrial regulation of oxygen sensing.
Maintenance of oxygen homoeostasis is required for the survival of higher organisms. The transcription factor hypoxia inducible factor (HIF) has a crucial role in oxygen homoeostasis by integrating the decrease in oxygen levels to increase hypoxic gene expression. How cells sense decrease in oxygen levels to elicit an increase in HIF dependent gene expression is not fully understood. In this review, we discuss the role of mitochondria as oxygen sensors regulating HIF.


Food composition databases for effective quality nutritional care.
The main aim of this study was to validate a nutrient-estimation method applied using OPEN, a Slovenian platform for clinical nutrition. As the most desirable validation is a direct comparison of the calculated values with the values obtained from a chemical analysis of the same food, we performed a chemical analysis and a calculation for a representative set of daily meals (n=20) and compared the data. The secondary aim was to evaluate the usability of the OPEN for dietary assessment. We used a Student's t test to observe any differences between the analysed and calculated nutrient-content data, considering the 0.01 significance level. No statistically significant differences were observed in the mean contents of energy, total dietary fibre, water, macro-nutrients, and selected essential minerals: Ca, Fe, Mg, Zn, Na, P, Cu and I. We notice statistically significant difference in the mean calculated and analytical values of selenium. We noticed remarkable, but not statistically significant, difference in the mean values of iodine (-11%). The present study also indicates that the OPEN is a useful and cost-effective tool for both dieticians and patients.


A computational study of aortic reconstruction in single ventricle patients.
Patients with hypoplastic left heart syndrome (HLHS) are born with an underdeveloped left heart. They typically receive a sequence of surgeries that result in a single ventricle physiology called the Fontan circulation. While these patients usually survive into early adulthood, they are at risk for medical complications, partially due to their lower than normal cardiac output, which leads to insufficient cerebral and gut perfusion. While clinical imaging data can provide detailed insight into cardiovascular function within the imaged region, it is difficult to use these data for assessing deficiencies in the rest of the body and for deriving blood pressure dynamics. Data from patients used in this paper include three-dimensional, magnetic resonance angiograms (MRA), time-resolved phase contrast cardiac magnetic resonance images (4D-MRI) and sphygmomanometer blood pressure measurements. The 4D-MRI images provide detailed insight into velocity and flow in vessels within the imaged region, but they cannot predict flow in the rest of the body, nor do they provide values of blood pressure. To remedy these limitations, this study combines the MRA, 4D-MRI, and pressure data with 1D fluid dynamics models to predict hemodynamics in the major systemic arteries, including the cerebral and gut vasculature. A specific focus is placed on studying the impact of aortic reconstruction occurring during the first surgery that results in abnormal vessel morphology. To study these effects, we compare simulations for an HLHS patient with simulations for a matched control patient that has double outlet right ventricle (DORV) physiology with a native aorta. Our results show that the HLHS patient has hypertensive pressures in the brain as well as reduced flow to the gut. Wave intensity analysis suggests that the HLHS patient has irregular circulatory function during light upright exercise conditions and that predicted wall shear stresses are lower than normal, suggesting the HLHS patient may have hypertension.


Corrigendum: Diffusion-Weighted Magnetic Resonance Imaging for Breast Cancer Screening in High-Risk Women: Design and Imaging Protocol of a Prospective Multicenter Study in Korea.
This corrects the article on p. 218 in vol. 24, PMID: 33913277.


Randomized, placebo-controlled study of the efficacy of a calcium phosphate containing paste on dentin hypersensitivity.
Hypersensitivity of non-carious cervical lesions (DH) is a frequently encountered disease. This randomized, controlled, single-blind crossover study evaluated the effectiveness of a calcium phosphate containing desensitizer paste (TAP) on DH in comparison to water as placebo (PLA). In this clinical trial 35 patients were randomly assigned to the test and the negative control group. Using a 10cm long VAS (visual analog scale) patients should respond with DH score >6 on one tooth in each of two quadrants for allocation. Pain stimuli were a 2-seconds air blast (AB) and probe scratching (PS) of the exposed dentin. VAS scores were determined pre-operatively (PRE), immediately after treatment (POST), at 1 week, 1, 3 and finally after 6 months. Both TAP and PLA applications decreased DH significantly at POST and throughout the 6-months recalls (p<0.001). Pain reductions upon AB stimulation of TAP treated teeth, assessed at POST and 6 months were 35 and 55%, upon PS stimuli 21 and 54%, respectively. PLA treated lesions responded to AB at POST and after 6 months with 20 and 36% pain reduction, to PS with 11 and 30% pain reduction, respectively. Differences between TAP and PLA pain scores were statistically significant at all recalls (p<0.05). TAP paste reduced DH successfully during this 6-months trial. The calcium phosphate crystallites included in the paste and the presumed hydroxyapatite precipitates upon exposure to saliva were hypothetically able to occlude open dentinal tubules, at least to some extent. TAP is considered a biocompatible desensitizer paste.


Changes of bacterial community structure,monosaccharide composition and CO2 exchange along the successional stages of biological soil crusts.
Biological soil crusts (BSCs) are a dominant ecological landscape of drylands, which have a significant impact on global biogeochemical flux. However, it is unclear how bacterial community and physiological characteristics vary along the BSCs successional stages. In this study, bacterial community composition, physiological characteristics, and monosaccharide composition of extracellular polysaccharides (EPSs) were compared among different successional stages. Our findings demonstrated that besides the dominant bacterial species, the bacterial communities also showed considerable differences between these two stages. Cyanobacteria were keystone taxa in the early stage, while heterotrophic bacteria (Proteobacteria, Actinobacteria and Acidobacteria) were keystone taxa in the later stages. According to the results of CO2 exchange, cyanobacterial crusts accumulated net carbon faster than moss crusts, while moss crusts had a significantly higher respiration rate. The monosaccharide analysis indicated that the EPSs components also varied depending on BSCs' successional stages. Specifically, the contents of rhamnose and arabinose were higher in the cyanobacterial crusts than other types of crusts, while the contents of fucose, xylose, mannose and glucose were the highest in cyanobacterial-lichen crusts, and galactose content was highest in the moss crusts. Altogether, our results stress the heterogeneous variation of BSCs along with succession, and this work offered a fresh viewpoint for a deeper comprehension of the interactions between the monosaccharide components of EPS and the networks of bacterial communities in BSCs.


Retrospective assessment of the association between noise exposure and nonfatal and fatal injury rates among miners in the United States from 1983 to 2014.
Mining is a significant economic force in the United States but has historically had among the highest nonfatal injury rates across all industries. Several factors, including workplace hazards and psychosocial stressors, may increase injury and fatality risk. Mining is one of the noisiest industries; however, the association between injury risk and noise exposure has not been evaluated in this industry. In this ecological study, we assessed the association between noise exposure and nonfatal and fatal occupational injury rates among miners. Federal US mining accident, injury, and illness data sets from 1983 to 2014 were combined with federal quarterly mining employment and production reports to quantify annual industry rates of nonfatal injuries and fatalities. An existing job-exposure matrix for occupational noise was used to estimate annual industry time-weighted average (TWA, dBA) exposures. Negative binomial models were used to assess relationships between noise, hearing conservation program (HCP) regulation changes in 2000, year, and mine type with incidence rates of injuries and fatalities. Noise, HCP regulation changes, and mine type were each independently associated with nonfatal injuries and fatalities. In multivariate analysis, each doubling (5 dB increase) of TWA was associated with 1.08 (95% confidence interval: 1.05, 1.11) and 1.48 (1.23, 1.78) times higher rate of nonfatal injuries and fatalities, respectively. HCP regulation changes were associated with 0.61 (0.54, 0.70) and 0.49 (0.34, 0.71) times lower nonfatal injury and fatality rates, respectively. Noise may be a significant independent risk factor for injuries and fatalities in mining.


A systematic review on the role of biomarkers in liquid biopsies and saliva samples in the monitoring of salivary gland cancer.
Salivary gland cancer is a rare disease, and approximately 20% of tumors in the salivary glands are malignant. Reliable biomarkers may have a role in monitoring salivary gland cancer. To review the current literature on the role of biomarkers in liquid biopsies and saliva samples in the monitoring of salivary gland cancer. This study systematically reviewed the literature on studies detecting salivary gland cancer by biomarkers in liquid biopsies and saliva samples by systematically searching PubMed and Embase between 1 January 2013 and 7 March 2023. Five studies covering 64 malignant cases of salivary gland cancer were included, which considered inflammatory biomarkers or markers of genetic material in either blood or saliva. In saliva, there were demonstrated elevations of CA-19-9 in malignant cases, and elevations of miRNA in malignant and benign cases. In blood, there were demonstrated elevations of IL-33 in malignant and benign cases, elevations of ctDNA in malignant cases, and elevations of CTC in malignant cases. The studies indicate that there is potential in the detection method. The studies detecting genetic material by liquid biopsies showed the most promising results. At present, there is still progression to be made before the method can be implemented for diagnostic use.


Reduced blood loss and operation time in lumbar posterolateral fusion using a bipolar sealer.
A bipolar sealer using Transcollation® technology, a combination of radiofrequency energy and saline, can provide hemostasis at 100 °C, which is lower than that used in standard electrocautery. Previous studies of joint arthroplasty have shown that use of the bipolar sealer reduces blood loss and tissue damage during the operation. However, it is unknown whether a bipolar sealer reduces blood loss and tissue damage in lumbar posterolateral fusion (PLF) surgery. The purpose of this study was to analyze the efficacy of this device in limiting blood loss during exposure of the lumbar spine in the treatment of PLF and postoperative pain. Fifty patients who underwent PLF were prospectively enrolled between October 2011 and March 2013. Twenty-five patients were randomized to the bipolar sealer group (BS group) and 25 patients to the standard electrocautery group (control group). Operative time and blood loss during exposure of posterior bony elements including the transverse process for PLF, visual analog scale (VAS) to quantify postoperative pain, and the interval from the surgery to hospital discharge were compared. Operative time and blood loss expressed per level of exposure were significantly lower in the BS group than in the control group. There was a tendency toward a lower VAS at postoperative week 1 in the BS group. The duration of hospitalization was 15 and 26 days in the BS and control groups, respectively. A large randomized control trial adjusted for the number of fusion levels and body mass index is required to confirm the novelty value of this new bipolar sealers.


Synthesis, Spectroscopic Study and Radical Scavenging Activity of Kaempferol Derivatives: Enhanced Water Solubility and Antioxidant Activity.
Kaempferol (Kae) is a natural flavonoid with potent antioxidant activity, but its therapeutic use is limited by its low aqueous solubility. Here, a series of Kae derivatives were synthesized to improve Kae dissolution property in water and antioxidant activity. These compounds included sulfonated Kae (Kae-SO₃), gallium (Ga) complexes with Kae (Kae-Ga) and Kae-SO₃ (Kae-SO₃-Ga). The compound structures were characterized by high-resolution mass spectrometry (HRMS), nuclear magnetic resonance (NMR) spectroscopy, ultraviolet-visible (UV-Vis) spectroscopy, Fourier transform infrared (FT-IR) spectroscopy and thermal methods (TG/DSC). The results showed that a sulfonic group (-SO₃) was successfully tethered on the C3' of Kae to form Kae-SO₃. And in the metal complexation, 4-CO and 3-OH of the ligand participated in the coordination with Ga(III). The metal-to-ligand ratio 1:2 was suggested for both complexes. Interestingly, Kae-SO₃-Ga was obviously superior to other compounds in terms of overcoming the poor water-solubility of free Kae, and the solubility of Kae-SO₃-Ga was about 300-fold higher than that of Kae-Ga. Furthermore, the evaluation of antioxidant activities in vitro was carried out for Kae derivatives by using α,α-diphenyl-β-picrylhydrazyl (DPPH) and 2,2'-azino-bis(3-ethylbenzo-thiazoline-6-sulfonic acid) diammonium salt (ABTS) free radical scavenging. The results showed that Kae-SO₃-Ga was also optimal for scavenging free radicals in a dose-dependent manner. These data demonstrate that sulfonate kaempferol-gallium complex has a promising future as a potential antioxidant and as a potential therapeutic agent for further biomedical studies.


Presence of NOD2 mutations is not associated with hepatic or systemic hemodynamic abnormalities of cirrhosis.
Patients with cirrhosis who carry NOD2 mutations are susceptible to bacterial infections. The aim was to evaluate the association of NOD2 mutations with hepatic and systemic hemodynamics in cirrhosis. This is a secondary analysis of a prospectively collected database in the context of the screening for the INCA trial (EudraCT 2013-001626-26). This cross-sectional study compared hemodynamic findings according to NOD2 status in 215 patients. Patients were genotyped for NOD2 variants (p.N289S, p.R702W, p.G908R, c.3020insC, rs72796367). Hepatic hemodynamic study and right heart catheterization were performed. Patients had a median age of 59 (IQR 53-66) years, and 144 (67%) were men. Most patients (64%) were Child-Pugh stage B. Sixty-six patients (31%) carried a NOD2 mutation, which was slightly more common among Child-Pugh stage C (p = 0.05), without differences in MELD [wild-type: 13 (10-16); NOD2 variants 13 (10-18)]. No differences in hepatic and systemic hemodynamics were observed according to NOD2 status. If excluding patients on prophylactic or therapeutic antibiotics, again no association between hepatic or systemic hemodynamics and NOD2 status could be observed. NOD2 mutations are not associated with hepatic or systemic hemodynamic abnormalities in patients with decompensated cirrhosis, suggesting that other mechanisms leading to bacterial translocation predominate.


Comparison of two methods of high-molecular-weight DNA isolation from human leucocytes.
Among the different methods for isolation of high-molecular-weight DNA from leucocytes, two of them were retained as being the most interesting and were compared. This choice was based on three criteria: the quality of the DNA obtained (high-molecular-weight DNA, RNA, and protein free), the efficiency of the method (in terms of the yield of DNA obtained), and the ease and length of the method. The first method described was chosen as a reference (100% efficiency); in comparison, the second one had a 70% efficiency, but was shorter and easier to handle.


Floral Induction Systems for the Study of Arabidopsis Flower Development.
Assessing the molecular changes that occur over the course of flower development is hampered by difficulties in isolating sufficient amounts of floral tissue at specific developmental stages. This is especially problematic when investigating molecular events at early stages of Arabidopsis flower development, as floral buds are minute and are initiated sequentially so that a single flower on an inflorescence is at a given developmental stage. Moreover, young floral buds are hidden by older flowers, which presents an additional challenge for dissection. To circumvent these issues, floral induction systems that allow the simultaneous induction of a large number of flowers on the inflorescence of a single plant were developed. To allow the plant community to avail of the full benefits of these systems, we address some common problems that can be encountered when growing these plants and collecting floral buds for analysis.


Natural cell-mediated cytotoxicity against syngeneic rat chondrocytes originating from different types of cartilage.
Natural anti-chondrocyte cytotoxicity of normal rat splenocytes, peritoneal cells and thymocytes was tested by means of 51Cr-release assay. Chondrocytes derived from epiphyseal, costal, nasal, and auricular cartilages were used as target cells. In some experiments, erythroleukaemic K-562 cells, known as typical natural killer cell targets, were also used. All types of chondrocytes were lysed equally well by splenocytes. Peritoneal cells exerted a low cytotoxic effect, whilst very low, almost negligible, cytotoxicity was noted with thymocytes. Negative selection with antibodies and complement showed that spleen-derived anti-chondrocyte effector cells are endowed with surface ganglioside asialo-GM1. A similar result was obtained in parallel experiments with K-562 cells. Moreover, 'cold' target experiments demonstrated that the release of 51Cr from the labelled chondrocytes could be inhibited by addition of unlabelled chondrocytes and K-562 cells.


Analytical problems in the quantification of elements in water bodies.
The main aspects of element analysis in natural waters are briefly surveyed. Particular attention is devoted to sampling, pretreatment and storage problems, as well as pitfalls, followed by a detailed discussion on the most flexible and powerful routine analytical techniques. A number of examples are also given to illustrate the major sectors of investigation presently being explored. Future trends and needs are finally outlined.


Bromide intoxication in the elderly.
Four patients with dysfunction of the central nervous system secondary to bromide intoxication are reported. Three of them were referred because of symptoms of "senility," which appeared to preclude further independent living. After diagnosis and treatment of the bromism, they were able to continue living at home. The development of bromide toxicity with relatively low serum bromide levels in the elderly is discussed. The importance of a home visit to establish the diagnosis of drug-induced cognitive dysfunction is emphasized.


Role of XPD in cellular functions: To TFIIH and beyond.
XPD, as part of the TFIIH complex, has classically been linked to the damage verification step of nucleotide excision repair (NER). However, recent data indicate that XPD, due to its iron-sulfur center interacts with the iron sulfur cluster assembly proteins, and may interact with other proteins in the cell to mediate a diverse set of biological functions including cell cycle regulation, mitosis, and mitochondrial function. In this perspective, after first reviewing the function and some of the key disease causing variants that affect XPD's interaction with TFIIH and the CDK-activating kinase complex (CAK), we investigate these intriguing cellular roles of XPD and highlight important unanswered questions that provide a fertile ground for further scientific exploration.


Neurorrhaphy, nerve grafting, and neurotization: a functional comparison of nerve reconstruction techniques.
This study examines the efficacy of three methods of peripheral nerve reconstruction: neurorrhaphy, nerve grafting, and neurotization. The extensor digitorum longus (EDL) neuromuscular unit of 63 New Zealand rabbits was used as the experimental model. Neuromuscular function was examined after 2, 4, and 6-month recovery periods. Variable recovery was seen after 2 months of recovery. At 6 months postoperatively, nerve grafting and neurorrhaphy were not statistically different from the unoperated control neuromuscular units. Neurotization grafting demonstrated a recovery of function of no greater than 50% at 6 months.


Crystal structures of a type-1 ribosome inactivating protein from Momordica balsamina in the bound and unbound states.
The ribosome inactivating proteins (RIPs) of type 1 are plant toxins that eliminate adenine base selectively from the single stranded loop of rRNA. We report six crystal structures, type 1 RIP from Momordica balsamina (A), three in complexed states with ribose (B), guanine (C) and adenine (D) and two structures of MbRIP-1 when crystallized with adenosine triphosphate (ATP) (E) and 2'-deoxyadenosine triphosphate (2'-dATP) (F). These were determined at 1.67Å, 1.60Å, 2.20Å, 1.70Å, 2.07Å and 1.90Å resolutions respectively. The structures contained, (A) unbound protein molecule, (B) one protein molecule and one ribose sugar, (C) one protein molecule and one guanine base, (D) one protein molecule and one adenine base, (E) one protein molecule and one ATP-product adenine molecule and (F) one protein molecule and one 2'-dATP-product adenine molecule. Three distinct conformations of the side chain of Tyr70 were observed with (i) χ(1)=-66°and χ(2)=165° in structures (A) and (B); (ii) χ(1)=-95° and χ(2)=70° in structures (C), (D) and (E); and (iii) χ(1)=-163° and χ(2)=87° in structure (F). The conformation of Tyr70 in (F) corresponds to the structure of a conformational intermediate. This is the first structure which demonstrates that the slow conversion of DNA substrates by RIPs can be trapped during crystallization.


The impact of the embryo banking on the cumulative live birth rate in women with poor ovarian response according to the Bologna criteria.
To evaluate the impact of embryo banking on the cumulative live birth rate (CLBR) and the time to live birth (TTLB) in poor ovarian responders (POR) according to the Bologna criteria. A total of 276 infertile women undergoing IVF with POR were included in this retrospective study. They were divided into two groups with (n = 121) or without (n = 155) embryo banking at the discretion of the attending physicians. A total of 656 and 405 stimulation cycles were started in the two groups respectively during the 24 month follow-up. The biochemical pregnancy, clinical pregnancy, ongoing pregnancy, and live birth rate per transfer were comparable between two groups (p > 0.05). The CLBR was significantly lower in the banking group than in the non-banking group (31.4% (38/121) and 43.2% (67/151), p < 0.05). TTLB was significantly longer in the banking group (20.5 months vs. 16.0 months, p < 0.001). In the Kaplan-Meier analysis, the cumulative incidence of live birth was significantly lower in the banking group compared with the non-banking group (Log rank test, chi-square = 21.958, p < 0.001). Embryo banking in women undergoing IVF with POR based on the Bologna criteria reduces CLBR and lengthens TTLB when compared with no embryo banking.


Classification of left-side hepatolithiasis for laparoscopic middle hepatic vein-guided anatomical hemihepatectomy combined with transhepatic duct lithotomy.
Laparoscopic middle hepatic vein-guided anatomical hemihepatectomy combined with transhepatic duct lithotomy (MATL) is an approach that can substantially improve stone clearance rates while reducing the rate of postoperative biliary fistula formation, residual stone rates, and rates of recurrence. In this study, we classified left-side hepatolithiasis cases into four subtypes based upon the diseased stone-containing bile duct, the middle hepatic vein, and the right hepatic duct. We then investigated the risk associated with different subtypes and evaluated the safety and efficacy of the MATL procedure. In total, 372 patients who underwent left hemihepatectomy for left intrahepatic bile duct stones were enrolled. Based on the distribution of the stones, the cases could be divided into four types. The risk of surgical treatment was compared for the four types and the safety, short-term efficacy, and long-term efficacy of the MATL procedure in the four types of left intrahepatic bile duct stones were studied. Type II was found to be the most likely to cause intraoperative bleeding while type III was likely to cause biliary tract damage and type IV was associated with the highest stone recurrence rate. The MATL procedure did not increase the risk of surgery and was found to reduce the rate of bile leakage, residual stones, and stone recurrence. Left-side hepatolithiasis-associated risk classification is feasible and may represent a viable means of improving the safety and feasibility of the MATL procedure.


Lobectomy for early-stage lung carcinoma: a cost analysis of full thoracoscopy versus posterolateral thoracotomy.
Major pulmonary resections for early-stage non-small-cell lung cancer (NSCLC) are increasingly being performed by thoracoscopy, but there are economic concerns related to the use of many disposable items and increased operative time. We evaluated and compared the costs of thoracoscopic lobectomy versus open lobectomy. Data from all patients who underwent lobectomy for clinical stage I NSCLC from January 1, 2007, to December 31, 2009 were reviewed. Two hundred eighty-seven major pulmonary resections (269 lobectomies and 18 anatomic segmentectomies) for NSCLC were performed: 98 cases via a totally endoscopic approach (TS) and 189 via a classical posterolateral thoracotomy (PLT). Direct medical costs [hospital stay, intensive care unit (ICU) stay, disposables, theatre time, laboratory, and radiology costs] were evaluated. Patient demographics were similar in both groups. The two groups did not differ in histology, pathologic stage, or type of lobectomy. There were no differences in postoperative complications or readmissions during the 30-day postoperative period; however, patients in the TS group had significantly fewer chest tube days and shorter hospital length of stay (p < 0.001). Theatre costs were significantly higher in the TS group [<euro>2,861 ± 458 vs. <euro>2,260 ± 399 (p < 0.001)]. Mean cost for disposables for TS was <euro>1,800 ± 560.46 vs. <euro>901 ± 328 for PLT (p < 0.001). Thoracoscopic upper-right lobectomy and anatomic segmentectomy were more expensive than other thoracoscopic lobectomies. Mean costs for hospital stay, laboratory, and radiological services for TS were less than for PLT (p < 0.001), although mean ICU stay was similar in both groups. Finally, overall costs were significantly greater for the PLT group (<euro>14,145.57 ± 7,117.84) than for the TS group (<euro>11,934.13 ± 6,690.25) (p < 0.001). Thoracoscopic lobectomy was less expensive than open lobectomy for patients with early-stage NSCLC. Although thoracoscopic lobectomy has a higher initial cost, overall cost is less expensive due to a shorter hospital stay.


Using turbidity for designing water networks.
Some methods to design water networks with minimum fresh water consumption are based on the selection of a key contaminant. In most of these "single contaminant methods", a maximum allowable concentration of contaminants must be established in water demands and water sources. Turbidity is not a contaminant concentration but is a property that represents the "sum" of other contaminants, with the advantage that it can be cheaper and easily measured than biological oxygen demand, chemical oxygen demand, suspended solids, dissolved solids, among others. The objective of this paper is to demonstrate that turbidity can be used directly in the design of water networks just like any other contaminant concentration. A mathematical demonstration is presented and in order to validate the mathematical results, the design of a water network for a guava fudge production process is performed. The material recovery pinch diagram and nearest neighbors algorithm were used for the design of the water network. Nevertheless, this water network could be designed using other single contaminant methodologies. The maximum error between the expected and the real turbidity values in the water network was 3.3%. These results corroborate the usefulness of turbidity in the design of water networks.


Elements to increase translation in pyrethroid epidemiology research: A review.
Pyrethroid insecticides have been the subject of numerous epidemiology studies in the past two decades. We examined the pyrethroids epidemiology literature published between 2016 and 2021. Our objective with this exercise was to inform interested readers regarding information on methodological elements that strengthen a study's use for translation (i.e., use in risk assessment) and to describe aspects of future research methods that could improve utility for decision-making. We focused on the following elements: (i) study design that provided evidence that pyrethroid exposure preceded the outcome, (ii) evidence that the method used for exposure characterization was reliable and sufficiently accurate for the intended purpose, and (iii) use of a robust approach for outcome ascertainment. For each of the 74 studies identified via the literature search, we categorized the methodological elements as Acceptable or Supplemental. A study with three Acceptable elements was considered Relevant for risk assessment purposes. Based on our evaluative approach, 18 (24%) of the 74 publications were considered to be Relevant. These publications were categorized as Acceptable for all three elements assessed: confirmed exposure (N = 24), confirmed outcome (N = 64), exposure preceded the outcome (N = 44). Three of these studies were birth cohorts. There were 15 Relevant publications of adults which included 10 Agricultural Health Study cohort publications of self-reported permethrin. Overall, the majority of the reviewed studies used methods that did not permit a determination that pyrethroid exposure preceded the outcome, and/or did not utilize robust methods for exposure assessment and outcome ascertainment. There is an opportunity for investigators and research sponsors to build on the studies reviewed here and to incorporate more translational approaches to studying exposure/outcome associations related to pesticides and other chemicals.


A purification and some properties of two proteases from papaya latex.
Two proteases, one of which is papaya peptidase A and the other a previously unknown enzyme in papaya latex have been purified to homogeneity in a simple two stage process. Both are markedly less reactive than papain or chymopapain. Each has a molecular weight of 24,000, N-terminal sequences commencing Leu-Pro-Glu, and contains no carbohydrate. Their amino acid compositions differ for several residues. The essential -SH groups of the enzymes examined appear to be 'masked' in the native state.


A computational model of direct brain excitation induced by electroconvulsive therapy: comparison among three conventional electrode placements.
Electroconvulsive therapy (ECT) is a highly effective treatment for severe depressive disorder. Efficacy and cognitive outcomes have been shown to depend on variations in electrode placement and other stimulus parameters, presumably because of differences in the pattern of neuronal activation. This latter effect, however, is poorly understood. In this study, we present an anatomically accurate human head computational model to stimulate neuronal excitation during ECT, to better understand the effects of varying electrode placement and stimulus parameters. Electric field and current density throughout the head, as well as direct neural activation within the brain, were computed using the finite element method. Regions representing passive volume conductors (skin, skull, cerebrospinal fluid) were extracellularly coupled to an excitable neural continuum region representing the brain. The skull was modeled with anistropic electrical conductivity. Simulation results indicated that direct activation of the brain occurred immediately beneath the electrodes on the scalp, consistent with existing imaging studies. In addition, we found that the brainstem was also activated using a right unilateral electrode configuration. Simulation also demonstrated that a reduction in stimulus amplitude or pulse width led to a reduction in the spatial extent of brain activation. The novel model described in this study was able to simulate direct excitation of the brain during ECT, was useful in characterizing differences in neuronal activation as electrode placement, pulse width, and amplitude were altered, and is proposed as a tool for further exploring the effects of variations in ECT stimulation approaches. Results from the simulations assist in understanding recently described clinical phenomena, in particular, the reduction in cognitive side effects with ultrabrief pulse width stimulation, and greater effects of the ECT stimulus on cardiovascular function with unilateral electrode placement.


Long-term outcome and its predictors among patients with ST-segment elevation myocardial infarction complicated by shock: insights from the GUSTO-I trial.
This study sought to assess long-term outcome and determine its predictors among 30-day survivors of cardiogenic shock. Patients with cardiogenic shock have high in-hospital and 30-day mortality, but there are little data about those who survive beyond 30 days. We analyzed baseline, in-hospital, and survival data from patients in the U.S. with ST-segment elevation myocardial infarction (STEMI) and cardiogenic shock enrolled in the GUSTO (Global Utilization of Streptokinase and Tissue-Type Plasminogen Activator for Occluded Coronary Arteries)-I trial and compared them with patients in the same trial who did not have shock. Of 22,883 patients enrolled in the U.S., shock occurred in 1,891 (8.3%); 953 (50.4%) survived 30 days and 527 (27.8%) survived 11 years. Of 20,992 U.S. patients without shock, 20,360 (96.9%) survived 30 days and 14,131 (67.3%) survived 11 years. After the first year, 2% to 4% of patients died each year regardless of whether they had cardiogenic shock. Using Cox proportional hazards models, we were able to predict long-term mortality in all U.S. GUSTO-I 30-day survivors from their baseline demographics and in-hospital complications. The strongest predictors were diabetes mellitus, cardiogenic shock, hypertension, previous myocardial infarction, current smoking, anterior infarct, higher Killip class, higher heart rate, and older age; patients >75 years were at highest risk. Percutaneous revascularization during the index hospitalization was associated with a reduced risk of death. Among patients with cardiogenic shock who survive 30 days after STEMI, annual mortality rates of 2% to 4% approximate those of patients without shock.


Robotic D2 Lymph Node Dissection During Distal Subtotal Gastrectomy for Gastric Cancer: Toward Procedural Standardization.
This study was undertaken to outline, in detail, the procedures for robotic D2 lymph node dissection during distal gastrectomy for middle- or lower-third gastric cancer, and to present data that may suggest the safety and feasibility of robotic D2 lymph node dissection.1 (-) 4 METHODS: From July 2005 to December 2009, a total of 316 robotic gastrectomies were performed at the Severance Hospital, Yonsei University Health System, Seoul, Korea. Of these, 95 distal subtotal gastrectomies with D2 lymph node dissection with partial omentectomy for gastric cancer were robotically performed. The operative procedures for robotic distal subtotal gastrectomy using the da Vinci (®) Si system are demonstrated in a step-by-step manner, with technical tips for each step, in the video clip. Short- and long-term follow-up results are also presented. The mean age of patients was 53.3 years (range 26-80) and the average body mass index was 23.2 kg/m(2) (range 16.9-33.3). All surgeries were successfully performed without open or laparoscopy conversion. The overall mean operation time was 215.7 min (range 131-296 min, and the mean estimated blood loss was 56.1 mL (range 4-396). No immediate postoperative mortality was observed, and 11 patients (11.6 %) experienced a complication after surgery. The operation-related complications consisted of six wound complications, one intra-abdominal fluid collection and abscess, one anastomosis leakage, one anastomosis stenosis, one intraluminal bleeding, and one postoperative pancreatitis. The TNM stages according to the 7th American Joint Committee on Cancer (AJCC) classifications were distributed as follows: 58 stage Ia, 13 stage Ib, four stage IIa, four stage IIb, six stage IIIa, six stage IIIb, and four stage IIIc cases. No microscopic tumor involvement of the resection line was noted. A mean of 41.8 lymph nodes (range 11-89) was retrieved. Less than 15 lymph nodes were retrieved in two patients and less than 25 lymph nodes were harvested in 4 of 95 patients. The mean follow-up period was 60.5 months (range 5-97 months, median 59.5 months), with the last follow-up date being 31 December 2014. The overall survival was 92.8 % and relapse-free survival was 91.8 %. Our large case series demonstrates the feasibility and safety of robotic D2 lymph node dissection during distal subtotal gastrectomy. The adoption of robotic surgery could improve the quality of surgery and facilitate D2 lymph node dissection for gastric cancer.


A gene hunting we will go!
Two general approaches toward the identification of new genes which may contribute to specific developmental, physiologic, or pathologic processes can be pursued: (1) a strategy of positional cloning or reverse genetics and linkage analysis in which affected individuals or families are studied to identify defective genes, and (2) an immediately focused approach which uses available partial information about a gene to screen cDNA libraries toward the isolation and characterization of the complete gene. The general principles that form the basis of how these two strategies aid the gene hunter in the pursuit of new genes is discussed. The modern day urologist should become familiar with these techniques and the promise they hold for the future diagnosis and treatment of urologic diseases.


Neurobiology, Functions, and Relevance of Excitatory Amino Acid Transporters (EAATs) to Treatment of Refractory Epilepsy.
Epilepsy is one of the most prevalent and devastating neurological disorders characterized by episodes of unusual sensations, loss of awareness, and reoccurring seizures. The frequency and intensity of epileptic fits can vary to a great degree, with almost a third of all cases resistant to available therapies. At present, there is a major unmet need for effective and specific therapeutic intervention. Impairments of the exquisite balance between excitatory and inhibitory synaptic processes in the brain are considered key in the onset and pathophysiology of the disease. As the primary excitatory neurotransmitter in the central nervous system, glutamate has been implicated in the process, with the glutamatergic system holding center stage in the pathobiology as well as in developing disease-modifying therapies. Emerging data pinpoint impairments of glutamate clearance as one of the key causative factors in drug-resistant disease forms. Reinstatement of glutamate homeostasis using pharmacological and genetic modulation of glutamate clearance is therefore considered to be of major translational relevance. In this article, we review the neurobiological and clinical evidence suggesting complex aberrations in the activity and functions of excitatory amino acid transporters (EAATs) in epilepsy, with knock-on effects on glutamate homeostasis as a leading cause for the development of refractory forms. We consider the emerging data on pharmacological and genetic manipulations of EAATs, with reference to seizures and glutamate dyshomeostasis, and review their fundamental and translational relevance. We discuss the most recent advances in the EAATs research in human and animal models, along with numerous questions that remain open for debate and critical appraisal. Contrary to the widely held view on EAATs as a promising therapeutic target for management of refractory epilepsy as well as other neurological and psychiatric conditions related to glutamatergic hyperactivity and glutamate-induced cytotoxicity, we stress that the true relevance of EAAT2 as a target for medical intervention remains to be fully appreciated and verified. Despite decades of research, the emerging properties and functional characteristics of glutamate transporters and their relationship with neurophysiological and behavioral correlates of epilepsy challenge the current perception of this disease and fit unambiguously in neither EAATs functional deficit nor in reversal models. We stress the pressing need for new approaches and models for research and restoration of the physiological activity of glutamate transporters and synaptic transmission to achieve much needed therapeutic effects. The complex mechanism of EAATs regulation by multiple factors, including changes in the electrochemical environment and ionic gradients related to epileptic hyperactivity, impose major therapeutic challenges. As a final note, we consider the evolving views and present a cautious perspective on the key areas of future progress in the field towards better management and treatment of refractory disease forms.


Life expectancy after total hip arthroplasty.
A total of 3,807 patients undergoing total hip arthroplasty (THA) between the years 1970 to 1995 were evaluated for mortality. Patient age groups were designated in 10-year intervals as follows: age <40; 41-50; 51-60; 61-70; 71-80; age >80. The life expectancy estimate of the patients with THA was calculated by the Kaplan-Meier method, and that of the normal population was obtained from standard life-tables. Statistical significance was evaluated using 95% confidence limits. A significant difference in life expectancy was found in patient age groups >60 (61-70, 71-80, >80) demonstrating significantly higher survival rates among THA patients when compared with the normal population.


Environmental and toenail metals concentrations in copper mining and non mining communities in Zambia.
Copper mining contributes to increased concentrations of metals in the environment, thereby increasing the risk of metals exposure to populations living in and around mining areas. This study investigated environmental and toenail metals concentrations of non-occupational human exposure to metals in 39 copper-mining town residents and 47 non-mining town residents in Zambia. Elevated environmental concentrations were found in samples collected from the mining town residents. Toenail concentrations of cobalt (GM 1.39 mg/kg), copper (GM 132 mg/kg), lead (21.41 mg/kg) selenium (GM 0.38 mg/kg) and zinc (GM 113 mg/kg) were significantly higher in the mining area and these metals have previously been associated with copper mining. Residence in the mining area, drinking water, dust and soil metals concentrations were the most important contributors to toenail metals concentrations. Further work is required to establish the specific pathways of exposure and the health risks of elevated metals concentrations in the copper mining area.


Effects of eugenol on respiratory burst generation in newborn rat brainstem-spinal cord preparations.
Eugenol is contained in several plants including clove and is used as an analgesic drug. In the peripheral and central nervous systems, this compound modulates neuronal activity through action on voltage-gated ionic channels and/or transient receptor potential channels. However, it is unknown whether eugenol exerts any effects on the respiratory center neurons in the medulla. We examined the effects of eugenol on respiratory rhythm generation in the brainstem-spinal cord preparation from newborn rat (P0-P3). The preparations were superfused by artificial cerebrospinal fluid at 25-26 °C, and inspiratory C4 ventral root activity was monitored. Membrane potentials of respiratory neurons were recorded in the parafacial region of the rostral ventrolateral medulla. Bath application of eugenol (0.5-1 mM) decreased respiratory rhythm accompanied by strong inhibition of the burst activity of pre-inspiratory neurons. After washout, respiratory rhythm partly recovered, but the inspiratory burst duration was extremely shortened, and this continued for more than 60 min after washout. The shortening of C4 inspiratory burst by eugenol was not reversed by capsazepine (TRPV1 antagonist) or HC-030031 (TRPA1 antagonist), whereas the depression was partially blocked by GABAA antagonist bicuculline and glycine antagonist strychnine or GABAB antagonist phaclofen. A spike train of action potentials in respiratory neurons induced by depolarizing current pulse was depressed by application of eugenol. Eugenol decreased the negative slope conductance of pre-inspiratory neurons, suggesting blockade of persistent Na+ current. These results suggest that changes in both membrane excitability and synaptic connections are involved in the shortening of respiratory neuron bursts by eugenol.


Child abuse. Perspectives on treatment and research.
This article provides an historical survey of child abuse. Incidence and prevalence, etiology, diagnosis and clinical features, treatment, and the importance of prevention are detailed.


Fabrication of an ultra-sensitive electrochemical DNA biosensor based on CT-DNA/NiFe2O4NPs/Au/CPE for detecting rizatriptan benzoate.
A novel and first electrochemical biosensor based on Deoxyribonucleic acid (DNA) as a biological component to measure an antimigraine drug, rizatriptan benzoate (RZB) for patients under treatment in biological samples was developed. A carbon paste electrode (CPE) was modified by calf thymus (CT) double-stranded (ds)-DNA, nickel ferrite magnetic nanoparticles (NiFe2O4NPs), and gold nanoparticles (AuNPs). The morphology of the CT-DNA/NiFe2O4NPs/AuNPs/CPE was characterized by Field emission scanning electron microscope (FESEM). The presence of NiFe2O4NPs and AuNPs was confirmed by energy-dispersive X-ray spectroscopy (EDS) image of the NiFe2O4NPs/AuNPs/CPE surface. Electrochemical impedance spectroscopy (EIS) and cyclic voltammetry (CV) were used to determine the structure and electrochemical characteristics of the CT-DNA/NiFe2O4NPs/AuNPs/CPE. Differential pulse voltammetry (DPV) was used to investigate the electrochemical behavior of RZB. Chronoamperometry (CA) was applied to study the effect of CT-DNA immobilization time on the peak oxidation current of RZB accumulated on the surface of the CT-DNA/NiFe2O4NPs/AuNPs/CPE. The results showed that, under optimum conditions, the prepared electrode responded linearly to RZB concentrations between 0.01 and 2.0 μM, with a 0.0033 μM detection limit (LOD) and 0.01 μM limit of quantification (LOQ). The parameters influencing the biosensor performance (temperature, CT-DNA immobilization time, and RZB/CT-DNA accumulation time) were optimized. DPV showed the displacement of the peak potential towards positive values and the reduction of its current, indicating that the drug could intercalate between the guanine base pairs of CT-DNA. Our biosensor was successfully applied for RZB measurement in human urine, blood serum, plasma samples, and tablets. The presented biosensor was fast response, sensitive, selective, cost-effective, and easy-to-use for RZB determination in pharmaceutical formulations and biological samples.


Histamine-sensitive adenylate cyclase of human gastric mucosa.
The adenylate cyclase system of human fundic gastric mucosa was found to respond to histamine, prostaglandin E 2 and the non-hormonal activators NaF and 5'-guanylyl-imidodiphosphate (GMP(PNP)). Half maximal stimulation of enzyme activity was observed at a histamine concentration of 50 micrometer. Maximal stimulation (about 25%) occurred at a histamine concentration of 1 mM. The stimulatory effect of histamine was competitively inhibited by cimetidine. The stimulatory effect of prostaglandin E 2 was found to be dose-dependent over a concentration range from 0.1 micrometer to 1 mM exerting maximal effects at 0.3 mM. NaF and GMP(PNP) by inducing an about 3.5-fold increase of enzyme activity were more potent in stimulating the human enzyme system than histamine and prostaglandin E 2. Maximal stimulatory doses of prostaglandin E 2 and histamine had an additive effect on the adenylate cyclase activity from fundic gastric mucosa. This implies that histamine acts on an individual adenylate cyclase system. Our results are suggestive for the existence of an adenylate cyclase system in human gastric mucosa coupled to histamine H 2-receptor sites.


Role of community health outreach program "living for health" in improving access to federally qualified health centers in Miami-dade county, Florida: a cross-sectional study.
Care of the underserved remains one of the most compelling challenges to American healthcare. Federally Qualified Health Centers (FQHCs) address uninsurance and underinsurance by providing primary and preventive care to vulnerable populations with fees charged based on ability to pay. Our goal is to study the effectiveness of FQHCs system in engaging patients and the barriers to utilization, which have not been well defined. Retrospective analysis was performed on data from "Living for Health" (L4H) program participants from 2008 to 2012. Univariate and multivariate logistic regression analysis were performed to determine factors associated with FQHC utilization. Among 9453 subjects screened, 1889 were referred to a FQHC, but only 201(11%) actually sought treatment. Public insurance, non-Hispanic ethnicity, and hypertension were associated with higher rates of FQHC utilization. Inability to afford costs, cultural factors and inflexible appointment times were the most common reasons for FQHC underutilization. The current status of FQHC utilization is sub-optimal. Community outreach programs like L4H can improve the access and utilization of FQHCs.


Serotonin (5-HT) induces IPSPs in pyramidal layer cells of rat piriform cortex: evidence for the involvement of a 5-HT2-activated interneuron.
In a slice preparation of rat piriform cortex, both intracellular and extracellular techniques were used to examine the pharmacological and electrophysiological actions of serotonin (5-HT). Bath application of 5-HT resulted in either depolarization (57%), hyperpolarization (34%) or no change (9%) in membrane potential of cells in the pyramidal cell layer (layer II) of piriform cortex. Additionally, when KCl-containing electrodes were used, 5-HT induced an increase in depolarizing synaptic potentials in 41% of these cells. It was concluded that these potentials were reverse inhibitory post-synaptic potentials (IPSPs) because they were blocked by bicuculline and tetrodotoxin. The induction of IPSPs by 5-HT was blocked by the 5-HT2-selective antagonist ritanserin. By recording extracellularly in the presence of 5-HT, a group of 5-HT-activated, putative interneurons was found at the border of layers II and III of piriform cortex, 5-HT but not norepinephrine activation was blocked by ritanserin. The actions of 5-HT were mimicked by the 5-HT2 agonist alpha-methyl-5-HT; the 5-HT2 partial agonist, 2,5-dimethoxy-4-methyl-amphetamine had a small agonist action of its own and blunted the effect of 5-HT. Activation of a larger group of putative interneurons by the more universal excitant N-methyl-D-aspartate showed that the 5-HT-activated interneurons represented 23% of the interneurons located on the border between layers II and III. We conclude that 5-HT induces IPSPs in layer II pyramidal cells by activating a subpopulation of interneurons at the border of layers II and III of piriform cortex.


Dissecting the role of Engrailed in adult dopaminergic neurons--Insights into Parkinson disease pathogenesis.
The homeoprotein Engrailed (Engrailed-1/Engrailed-2, collectively En1/2) is not only a survival factor for mesencephalic dopaminergic (mDA) neurons during development, but continues to exert neuroprotective and physiological functions in adult mDA neurons. Loss of one En1 allele in the mouse leads to progressive demise of mDA neurons in the ventral midbrain starting from 6 weeks of age. These mice also develop Parkinson disease-like motor and non-motor symptoms. The characterization of En1 heterozygous mice have revealed striking parallels to central mechanisms of Parkinson disease pathogenesis, mainly related to mitochondrial dysfunction and retrograde degeneration. Thanks to the ability of homeoproteins to transduce cells, En1/2 proteins have also been used to protect mDA neurons in various experimental models of Parkinson disease. This neuroprotection is partly linked to the ability of En1/2 to regulate the translation of certain nuclear-encoded mitochondrial mRNAs for complex I subunits. Other transcription factors that govern mDA neuron development (e.g. Foxa1/2, Lmx1a/b, Nurr1, Otx2, Pitx3) also continue to function for the survival and maintenance of mDA neurons in the adult and act through partially overlapping but also diverse mechanisms.


Zeroing in on zoster: A tale of many disorders produced by one virus.
While herpes zoster infection has been recognized since antiquity, chickenpox (varicella) was confused with smallpox until the 1800s, when both illnesses became better understood. In the 20th century, varicella zoster virus (VZV) was shown to cause varicella upon primary (first-time) infection and herpes zoster (shingles) after reactivation of latent VZV. Scientific progress over the past 50 years has rapidly advanced the understanding and prevention of disease produced by VZV. Combined imaging and virological studies continue to reveal the protean neurological, ocular and visceral disorders produced by VZV.


Ex vivo occupancy by tamsulosin of alpha1-adrenoceptors in rat tissues in relation to the plasma concentration.
At 0.5-12 h after oral administration of tamsulosin (2.3 micromol/kg) in rats, there was a significant decrease in specific [3H]prazosin binding in the prostate as compared to the control value. The greater decrease occurred in the submaxillary gland. The effect of tamsulosin was mainly due to a marked reduction of [3H]prazosin binding sites (Bmax) rather than to an increase in the dissociation constant (Kd). In contrast, there was only a slight decrease or no change in the [3H]prazosin binding in the spleen, heart, and cerebral cortex of tamsulosin-administered rats at 0.5-12 h. Oral administration of terazosin (21.7 micromol/kg) significantly increased Kd values for [3H]prazosin binding with little effect on Bmax values in the rat prostate at 3 and 6 h. The greater increases in Kd values were observed in the submaxillary gland, spleen and heart at 0.5-12 h. Terazosin had a slight effect on Kd values for the cerebral cortical [3H]prazosin binding. Tamsulosin was absorbed rapidly after oral administration at a dose of 2.3 micromol/kg in rats, and at 6 h, plasma concentration decreased markedly to approximately one-twentieth of the 0.5 h peak level. alpha1-Adrenoceptor occupancy was estimated as a percentage of decrease in Bmax values for [3H]prazosin binding in tissues of tamsulosin-treated rats compared with control rats. The alpha1-adrenoceptor occupancy by tamsulosin in the prostate and submaxillary gland occurred rapidly in parallel with the rise in plasma concentration of tamsulosin, and lasted for over 12 h despite the marked decrease in plasma concentration. Consequently, it is suggested that tamsulosin produces more selective and sustained occupancy in vivo of alpha1-adrenoceptors in the submaxillary gland and prostate of rats than in other tissues.


Molecular MRI of hematopoietic stem-progenitor cells: in vivo monitoring of gene therapy and atherosclerosis.
A characteristic feature of atherosclerotic cardiovascular disease is the diffuse involvement of arteries across the entire human body and the presence of multiple, simultaneous lesions. The diffuse nature of this disease creates a unique challenge for early diagnosis and effective treatment. We believe that recent progress in the field of molecular MRI has opened new avenues towards solving the problem. A new technology has been developed that uses molecular MRI to monitor the migration and homing of hematopoietic stem-progenitor cells to injured arteries and atherosclerosis. In this Review, we introduce several novel technical developments in the field of molecular MRI of atherosclerosis, including advanced techniques for magnetic labeling of stem-progenitor cells and molecular MRI of hematopoietic bone marrow cells migrating to injured arteries and homing to atherosclerotic plaques. In addition, we examine molecular MRI of vascular gene therapy mediated by stem-progenitor cells. These new techniques provide the basis for the further development of in vivo MRI techniques to monitor stem-cell-mediated vascular gene therapy for multiple and diffuse atherosclerotic cardiovascular lesions.


Celecoxib impairs primary human myoblast proliferation and differentiation independent of cyclooxygenase 2 inhibition.
The use of non-steroidal anti-inflammatory drugs (NSAIDs) for treatment of musculoskeletal injuries is commonplace in the general, athletic, and military populations. While NSAIDs have been studied in a variety of tissues, the effects of NSAIDs on skeletal muscle have not been fully defined. To address this, we investigated the degree to which the cyclooxygenase (COX)-2-selective NSAID celecoxib affects muscle cell proliferation, differentiation, anabolic signaling, and mitochondrial function in primary human skeletal myoblasts and myotubes. Primary muscle cells were treated with celecoxib or NS-398 (a pharmacological inhibitor of COX-2) as a control. Celecoxib administration significantly reduced myoblast proliferation, viability, fusion, and myotube area in a dose-dependent manner, whereas NS-398 had no effect on any of these outcomes. Celecoxib treatment was also associated with reduced phosphorylation of ribosomal protein S6 in myoblasts, and reduced phosphorylation of AKT, p70S6K, S6, and ERK in myotubes. In contrast, NS-398 did not alter phosphorylation of these molecules in myoblasts or myotubes. In myoblasts, celecoxib significantly reduced mitochondrial membrane potential and respiration, as evidenced by the decreased citric acid cycle (CAC) intermediates cis-aconitic acid, alpha-keto-glutarate acid, succinate acid, and malic acid. Similar results were observed in myotubes, although celecoxib also reduced pyruvic acid, citric acid, and fumaric acid. NS-398 did not affect CAC intermediates in myoblasts or myotubes. Together, these data reveal that celecoxib inhibits proliferation, differentiation, intracellular signaling, and mitochondrial function in primary human myoblasts and myotubes independent of its function as a COX-2 inhibitor.


Mutational status of EGFR and KIT in thymoma and thymic carcinoma.
This study was conducted to evaluate the prevalence of EGFR and KIT mutations in thymomas and thymic carcinomas as a means of exploring the potential for molecularly targeted therapy with tyrosine kinase inhibitors. Genomic DNA was isolated from 41 paraffin-embedded tumor samples obtained from 24 thymomas and 17 thymic carcinomas. EGFR exons 18, 19, and 21, and KIT exons 9, 11, 13, and 17, were analyzed for mutations by PCR and direct sequencing. Protein expression of EGFR and KIT was evaluated immunohistochemically. EGFR mutations were detected in 2 of 20 thymomas, but not in any of the thymic carcinomas. All of the EGFR mutations detected were missense mutations (L858R and G863D) in exon 21. EGFR protein was expressed in 71% of the thymomas and 53% of the thymic carcinomas. The mutational analysis of KIT revealed only a missense mutation (L576P) in exon 11 of one thymic carcinoma. KIT protein was expressed in 88% of the thymic carcinomas and 0% of the thymomas. The results of this study indicate that EGFR and KIT mutations in thymomas and thymic carcinomas are rare, but that many of the tumors express EGFR or KIT protein.


Getting published: reflections of a collaborative writing group.
Writing for publication, in the nursing profession, is considered essential for the development of the profession and individual career advancement. In education there is also the increasing pressure to produce University research output. To develop a collaborative writing group to develop and write articles relating to our teaching practice. The idea of forming a writing group was discussed at a module team meeting where five academics expressed an interest. The process of forming the group involved an initial meeting to discuss and agree to the aims, interests, expertise and areas of responsibility for each member. Regular meetings are held and each member takes on responsibility for an aspect of work towards completing the articles. Three articles and one editorial have been published and another is under peer review. We have endeavoured to develop and maintain a theme, this being supporting nursing students' development with an emphasis on an aspect of their decision making skills. Also, importantly, we have created a supportive environment and friendships. The demands made upon the nurse educator to be clinically, educationally and research active can be difficult to meet. Collaborative writing groups may be one way to fulfil the scholarly activity element.


Neural activity associated with stress-induced cocaine craving: a functional magnetic resonance imaging study.
Stress is known to increase cocaine craving and relapse risk in cocaine dependence. Identifying neural activity associated with stress and stress-induced cocaine craving is important in understanding the neurobiology of cocaine craving and relapse. Blood oxygenation level dependent (BOLD) signal changes were assessed in a functional magnetic resonance imaging (fMRI) session with healthy controls and treatment-engaged, abstinent, cocaine-dependent individuals (patients) as they participated in brief guided imagery and recall of three personal stress and three personal neutral situations. During stress, patients showed significantly less BOLD activation than controls in specific frontal and para-limbic regions, such as the anterior cingulate (AC) region, left hippocampal/parahippocampal region, right fusiform gyrus, and the right postcentral gyrus. On the other hand, patients had increased activity in the caudate and dorsal striatum region during stress, activation that was significantly associated with stress-induced cocaine craving ratings. Patients failed to activate AC and related circuits during stress, regions associated with control, and regulation of emotion and distress states. Instead, they exhibited greater craving-related activation in the dorsal striatum, a region related to reward pathways and part of the obsessive-compulsive circuitry. Such functional alterations in stress processing may underlie the stress-related vulnerability to cocaine relapse often observed in cocaine-dependent individuals in early recovery.


Cleavage specificity of cucumisin, a serine protease, with synthetic substrates.
The substrate specificity of a plant serine protease, cucumisin (EC 188.8.131.52), was studied by the use of synthetic oligopeptides and peptidyl-pNA substrates. Since P1'-Ser, Ala, and Gly substrates were hydrolyzed rapidly, cucumisin appears to prefer a small side chain at the P1' position of the oligopeptide substrate. The k(cat)/Km for the hydrolysis of P1-Leu, Ala, Phe, and Glu substrates demonstrated that they were preferentially cleaved over P1-Lys, diaminopropionic acid (Dap), Gly, Val, and Pro substrates. From the digestion of peptidyl-pNAs, the specificity of the protease was determined to be broad, but the preferential cleavage sites were hydrophobic amino acid residues at the P1 position.


Aberrant expression of signaling-related proteins 14-3-3 gamma and RACK1 in fetal Down syndrome brain (trisomy 21).
Although Down Syndrome (DS, trisomy 21) is the most frequent isolated cause of mental retardation, information on brain protein expression and in particular protein expression of signaling-related proteins is limited. Impaired signaling in DS involving different signaling systems has been proposed and the availability of fetal brain along with recent proteome technologies unambiguously identifying individual brain proteins made us study individual signaling factors in the brain. We studied fetal brain cortex of controls (n = 7) and DS (n = 9) from early second trimester of gestation by two-dimensional gel electrophoresis with subsequent matrix-assisted laser/desorption ionization (MALDI) identification followed by quantification with specific software. Four 14-3-3 protein isoforms, mitogen-activated protein kinase 1, receptor for activited kinase 1 (RACK1), constitutive photomorphogenesis (COP9) complex subunit 4 and cAMP-dependent protein kinase type II have been identified. Quantification showed that protein 14-3-3 gamma (means +/- standard deviation of controls: 10.18+/-2.30 and of DS 4.20+/-1.19) and two spots assigned to RACK1 (controls spot 1: 4.15+/-2.45 and DS 1.95+/-0.93; controls spot 2: 5.08+/-2.4 vs. DS: 2.56+/-1.19) were significantly decreased in DS cortex. Reduced 14-3-3 gamma may represent impaired neuronal differentiation, synaptic plasticity and impaired signaling by PKC and Raf while decreased RACK1 (anchoring protein receptor for activated C-kinase) may reflect or generate deranged beta-II- protein kinease C (PKC) function with the putative biological meaning of aberrant migration and neuritic outgrowth in DS early in life.


Paraproteinemic neuropathies.
The term paraproteinemic neuropathy refers to a heterogeneous group of neuropathies, which share the common feature of a homogeneous immunoglobulin in the serum. The presence of a monoclonal gammopathy indicates an underlying clonal B-cell expansion, which may appear in the context of a lymphoproliferative disorder. If a neoplastic origin of the gammopathy is identified, the treatment should be targeted to the neoplasm. In most patients, however, the monoclonal gammopathy is not associated with malignant haematological disorders, and is defined as monoclonal gammopathy of undetermined significance.


E-cadherin expression in papillary transitional cell carcinoma of the urinary bladder.
E-cadherin (E-CD), a cell adhesion molecule that plays a diverse role in cell-cell and cell-matrix interaction, has recently been associated with tumor invasion and metastasis. We evaluated the E-CD expression in 55 cases of urinary bladder papillary transitional cell carcinoma using a double-linked immunoalkaline phosphatase procedure on formalin-fixed, paraffin-embedded specimens quantified as percentage positive staining area with the Roche RPW image analyzer (Roche Image Analysis Systems, Elon College, NC). The 10 grade I tumors stained intensely for E-CD (66%) and showed enhanced staining compared with normal transitional epithelium. The 20 grade II lesions stained moderately at 45%, and the 25 grade III lesions showed weak expression of E-CD with a 33% positive stain. This loss of expression for high-grade versus low-grade tumors was statistically significant (P < .02). There was a similar decrease in E-CD expression for high-stage versus low-stage specimens with 30 stage 0 and stage A cases having an average of 51% positive stain and 25 stage B, C, and D cases having an average stain of 33%. This difference was also statistically significant (P < .001). We conclude that loss of expression of E-CD in high-grade, high-stage urinary bladder transitional cell carcinoma is associated with significant bladder wall invasion, indicates potential for metastasis, and may be of clinical value in the assessment of prognosis and planning of therapy for patients with bladder tumors.


Optics (communication arising): mechanism for 'superluminal' tunnelling.
In their discussion of a mechanism that I proposed to explain the apparent superluminal (that is, faster than light) tunnelling of light pulses observed in photonic barrier experiments, Büttiker and Washburn used an old 'reshaping' argument that is at variance with my model and is not supported by the bulk of the experimental tunnelling evidence. The mechanism I proposed agrees with experiment and resolves a long-standing paradox - namely, the lack of dependence of tunnelling time on barrier length for thick barriers (the Hartman effect).


The threonine-sensitive homoserine dehydrogenase and aspartokinase activities of Escherichia coli K12. Specific inactivation of the homoserine dehydrogenase activity by the affinity label, 2-amino-4-oxo-5-chloropentanoic acid.
2-Amino-4-oxo-5-chloropentanoic acid inactivates specifically the homoserine dehydrogenase activity of the bifunctional enzyme, aspartokinase I--homoserine dehydrogenase I. The aspartokinase activity remains essentially untouched and retains its threonine sensitivity. The inactivation of the dehydrogenase requires the covalent binding of one equivalent of the analogue per subunit. Alkylation does not affect the tetrameric state of the protein. The alkylating agent, a substrate analogue, meets the qualitative and quantitative requirements of an affinity label.


Extent of intravital contraction of arterial and venous thrombi and pulmonary emboli.
Blood clots and thrombi undergo platelet-driven contraction/retraction followed by structural rearrangements. We have established quantitative relationships between the composition of blood clots and extent of contraction to determine intravital contraction of thrombi and emboli based on their content. The composition of human blood clots and thrombi was quantified using histology and scanning electron microscopy. Contracting blood clots were segregated into the gradually shrinking outer layer that contains a fibrin-platelet mesh and the expanding inner portion with compacted red blood cells (RBCs). At 10% contraction, biconcave RBCs were partially compressed into polyhedral RBCs, which became dominant at 20% contraction and higher. The polyhedral/biconcave RBC ratio and the extent of contraction displayed an exponential relationship, which was used to determine the extent of intravital contraction of ex vivo thrombi, ranging from 30% to 50%. In venous thrombi, the extent of contraction decreased gradually from the older (head) to the younger (body, tail) parts. In pulmonary emboli, the extent of contraction was significantly lower than in the venous head but was similar to the body and tail, suggesting that the emboli originate from the younger portion(s) of venous thrombi. The extent of contraction in arterial cerebral thrombi was significantly higher than in the younger parts of venous thrombi (body, tail) and pulmonary emboli but was indistinguishable from the older part (head). A novel tool, named the "contraction ruler," has been developed to use the composition of ex vivo thrombi to assess the extent of their intravital contraction, which contributes to the pathophysiology of thromboembolism.


Comparison of the anesthetic efficacy of the conventional inferior alveolar, Gow-Gates, and Vazirani-Akinosi techniques.
The purpose of this prospective, randomized study was to compare the degree of pulpal anesthesia obtained with the conventional inferior alveolar, the Gow-Gates, and the Vazirani-Akinosi techniques in vital, asymptomatic teeth. With a crossover design, 40 subjects received all 3 techniques in a random manner by using 3.6 mL of 2% lidocaine with 1:100,000 epinephrine at 3 separate appointments. An electric pulp tester was used to test for anesthesia in 3-minute cycles for 60 minutes of the first molars, first premolars, and lateral incisors. Anesthesia was considered successful when 2 consecutive 80 readings were obtained within 15 minutes, and the 80 reading was continuously sustained through the 60th minute. The ranges of successful anesthesia were as follows: inferior alveolar technique, 25%-62%; Gow-Gates technique, 16%-44%; and for the Vazirani-Akinosi technique, 13%-50%. There was no significant difference (P > .05) in success among the 3 techniques. However, the Gow-Gates and Vazirani-Akinosi techniques resulted in a statistically slower onset of pulpal anesthesia than the inferior alveolar nerve block. We concluded that in vital, asymptomatic teeth and for the subjects who achieved lip numbness, the conventional inferior alveolar nerve block is similar to the Gow-Gates and Vazirani-Akinosi techniques regarding anesthetic success but has a faster onset of pulpal anesthesia.


Danowhetaksa gen. nov. with two species from the early Eocene lst Formation from Denmark, the first Palearctic Whetwhetaksidae (Odonata: Cephalozygoptera).
We propose Danowhetaksa n. gen. (Odonata: Whetwhetaksidae) with two new species: D. birgitteae n. gen. et sp. and D. rusti n. gen. et sp. from the earliest Ypresian Stolleklint clay of the lst Formation in northwestern Denmark. Whetwhetaksidae has previously been known only from the Ypresian Okanagan Highlands of far-western North America, the new records are, therefore, the first from the Palearctic Region.


Vibrio parahaemolyticus serovar O3:K6 gastroenteritis in northeast Brazil.
To examine the virulence factors and the genetic relationship isolates of the serogroup O3 of Vibrio parahaemolyticus in outbreaks of diarrhoea in the northeast region of Brazil. Eighteen samples of the O3:K6 and O3:KUT serotypes of V. parahaemolyticus were analysed by multiplex polymerase chain reaction (m-PCR) for detection of the tl, tdh and trh genes, by random-amplified polymorphic DNA (RAPD) using two primers, and by amplification of the rDNA 16S-23S region. The gene tl was amplified in all the samples, tdh in 16 while trh in none; amplification of rDNA 16S-23S generated only one profile; each RAPD primer produced two amplification patterns allowing grouping two tdh(-) Kanagawa-negative isolates. V. parahaemolyticus with characteristics of the pandemic clone appears to be widely disseminated in the studied region. Because of the genetic uniformity of the isolates, elucidation of outbreaks or tracking the source of contamination by the present molecular techniques seems useless. Detection of V. parahaemolyticus with virulence potential of pandemic clone from two outbreaks and from several isolated gastroenteritis cases points out the need for inclusion of this micro-organism in the Brazilian routine monitoring of the diarrhoeas for elucidation of their aetiology.