Improving gastric cancer preclinical studies using diverse in vitro and in vivo model systems.
"Biomarker-driven targeted therapy," the practice of tailoring patients' treatment to the expression/activity levels of disease-specific genes/proteins, remains challenging. For example, while the anti-ERBB2 monoclonal antibody, trastuzumab, was first developed using well-characterized, diverse in vitro breast cancer models (and is now a standard adjuvant therapy for ERBB2-positive breast cancer patients), trastuzumab approval for ERBB2-positive gastric cancer was largely based on preclinical studies of a single cell line, NCI-N87. Ensuing clinical trials revealed only modest patient efficacy, and many ERBB2-positive gastric cancer (GC) patients failed to respond at all (i.e., were inherently recalcitrant), or succumbed to acquired resistance. To assess mechanisms underlying GC insensitivity to ERBB2 therapies, we established a diverse panel of GC cells, differing in ERBB2 expression levels, for comprehensive in vitro and in vivo characterization. For higher throughput assays of ERBB2 DNA and protein levels, we compared the concordance of various laboratory quantification methods, including those of in vitro and in vivo genetic anomalies (FISH and SISH) and xenograft protein expression (Western blot vs. IHC), of both cell and xenograft (tissue-sectioned) microarrays. The biomarker assessment methods strongly agreed, as did correlation between RNA and protein expression. However, although ERBB2 genomic anomalies showed good in vitro vs. in vivo correlation, we observed striking differences in protein expression between cultured cells and mouse xenografts (even within the same GC cell type). Via our unique pathway analysis, we delineated a signaling network, in addition to specific pathways/biological processes, emanating from the ERBB2 signaling cascade, as a potential useful target of clinical treatment. Integrated analysis of public data from gastric tumors revealed frequent (10 - 20 %) amplification of the genes NFKBIE, PTK2, and PIK3CA, each of which resides in an ERBB2-derived subpathway network. Our comprehensive bioinformatics analyses of highly heterogeneous cancer cells, combined with tumor "omics" profiles, can optimally characterize the expression patterns and activity of specific tumor biomarkers. Subsequent in vitro and in vivo validation, of specific disease biomarkers (using multiple methodologies), can improve prediction of patient stratification according to drug response or nonresponse.


Spectroscopic evaluation of manganese(II) complexes derived from semicarbazones and thiosemicarbazones.
Manganese(II) complexes having the general composition Mn(L)2X2 [where L=isopropyl methyl ketone semicarbazone (LLA), isopropyl methyl ketone thiosemicarbazone (LLB), 4-aminoacetophenone semicarbazone (LLC) and 4-aminoacetophenone thiosemicarbazone (LLD) and X=Cl-, 1/2SO(4)2-] have been synthesized. All the complexes were characterized by elemental analyses, molar conductance, magnetic moment susceptibility, EI-mass, 1H NMR, IR, EPR and electronic spectral studies. All the complexes show magnetic moments corresponding to five unpaired electrons. The possible geometries of the complexes were assigned on the basis of EPR, electronic and infrared spectral studies.


Pharmacokinetics and Pharmacodynamics of Recombinant Human Insulin-Like Growth Factor.
Recombinant human insulin-like growth factor (rhIGF-I) was evaluated in 18 healthy males to determine its effects on serum glucose, its relationship of total IGF levels to serum glucose response and dose proportionality when administered intravenously (IV) and subcutaneously (SQ). One group of six subjects received 60, 120, and 180 &mgr;g kg(minus sign1) IV over 8 h, 1 week apart, and three groups of four subjects received 60, 120, and 180 &mgr;g kg(minus sign1) IV over 8 h, and then 1 week later received 60, 120, and 90 &mgr;g kg(minus sign1) SQ of rhIGF-I, respectively. During each dosing period, placebo and then rhIGF-I was administered on two consecutive days. Intravenous and subcutaneous does of rhIGF-I demonstrated significant decreases in glucose levels as compared to placebo that did not correspond to peak total IGF levels. Sequential repeat administration of IV infusions of rhIGF-I in a single group of subjects demonstrated significant dose-dependent increases, whereas single administration of the doses in three groups of subjects failed to demonstrate dose dependency for either the IV or subcutaneous routes of administration. These findings suggest that saturation of the binding proteins and sites occurred at the lowest dose (60 &mgr;g kg(minus sign1)) evaluated.


DKK1 as a robust predictor for adjuvant platinum chemotherapy benefit in resectable pStage II-III gastric cancer.
Adjuvant chemotherapy (ACT) with 5-FU alone or 5-FU plus platinum after curative surgery improves the prognosis of pStage II-III gastric cancer (GC). However, only a subset of patients benefits from adjuvant platinum. To avoid the side effects of platinum, it is significant to accurately screen the patients who would benefit maximally with this treatment. The present study aimed to assess the value of DKK1 in predicting the benefit of adjuvant platinum chemotherapy in patients with pStage II -III GC. Platinum sensitivity-related genes were screened by bioinformatics. DKK1 expression in 380 GC specimens was detected by immunohistochemistry (IHC) staining, and the correlation with adjuvant platinum-specific benefits were analyzed. DKK1 was screened as the most significant platinum sensitivity-related gene. In patients with DKK1high GC, the estimated absolute 5-year overall survival (OS) benefits from adjuvant platinum for pStage II-III, II, IIIA, IIIB, and IIIC were 25.5%, 17.3%, 36.4%, 29.2% and 31.1%, respectively, and the estimated absolute 5-year disease-free survival (DFS) benefits in the corresponding stages were 27.4%, 17.5%, 36.7%, 29.7% and 31.5%, respectively. These benefits were significantly higher than those in the same TNM stage without adjusting for DKK1 status. The performance of DKK1 was independent of the TNM stage and other clinicopathological variables. Similar results were obtained in the TCGA and ACRG cohorts. Furthermore, nomograms were constructed to predict the survival benefits in DKK1 subgroups. The stratification strategy based on DKK1 status is more precise than the TNM staging system for the selection of pStage II-III GC patients suitable for platinum-containing ACT.


Drug discovery in Parkinson's disease-Update and developments in the use of cellular models.
Parkinson's disease (PD) is the second most common neurodegenerative disorder and is characterized by the degeneration of dopaminergic (DA) neurons within the substantia nigra. Dopamine replacement drugs remain the most effective PD treatment but only provide temporary symptomatic relief. New therapies are urgently needed, but the search for a disease-modifying treatment and a definitive understanding of the underlying mechanisms of PD has been limited by the lack of physiologically relevant models that recapitulate the disease phenotype. The use of immortalized cell lines as in vitro model systems for drug discovery has met with limited success, since efficacy and safety too often fail to translate successfully in human clinical trials. Drug discoverers are shifting their focus to more physiologically relevant cellular models, including primary neurons and stem cells. The recent discovery of induced pluripotent stem (iPS) cell technology presents an exciting opportunity to derive human DA neurons from patients with sporadic and familial forms of PD. We anticipate that these human DA models will recapitulate key features of the PD phenotype. In parallel, high-content screening platforms, which extract information on multiple cellular features within individual neurons, provide a network-based approach that can resolve temporal and spatial relationships underlying mechanisms of neurodegeneration and drug perturbations. These emerging technologies have the potential to establish highly predictive cellular models that could bring about a desperately needed revolution in PD drug discovery.


The validity of cerebrospinal fluid parameters for the diagnosis of tuberculous meningitis.
To assess the diagnostic validity of laboratory cerebrospinal fluid (CSF) parameters for discriminating between tuberculous meningitis (TBM) and other causes of meningeal syndrome in high tuberculosis incidence settings. From November 2009 to November 2011, we included patients with a clinical suspicion of meningitis attending two hospitals in Lima, Peru. Using a composite reference standard, we classified them as definite TBM, probable TBM, and non-TBM cases. We assessed the validity of four CSF parameters, in isolation and in different combinations, for diagnosing TBM: adenosine deaminase activity (ADA), protein level, glucose level, and lymphocytic pleocytosis. One hundred and fifty-seven patients were included; 59 had a final diagnosis of TBM (18 confirmed and 41 probable). ADA was the best performing parameter. It attained a specificity of 95%, a positive likelihood ratio of 10.7, and an area under the receiver operating characteristics curve of 82.1%, but had a low sensitivity (55%). None of the combinations of CSF parameters achieved a fair performance for 'ruling out' TBM. Finding CSF ADA greater than 6 U/l in patients with a meningeal syndrome strongly supports a diagnosis of TBM and permits the commencement of anti-tuberculous treatment.


Evaluation of a prospective radiation oncology departmental team review process using standardized simulation directives.
The primary objective of this study is to evaluate the utility and value of an institutional, multi-disciplinary radiation oncology team review process prior to radiotherapy (RT) simulation. Over a period of 3 months and through an iterative team-based process, a standardized simulation requisition directive (SSRD) was developed, piloted, modified, and subsequently implemented for all patients treated with external beam RT at a single tertiary care institution from January to December 2020. The SSRDs were reviewed at a daily multi-disciplinary radiation oncology team review conference; modifications consequential to the review were prospectively recorded in a quality database. 1500 consecutive SSRDs were prospectively reviewed for this study. 397 modifications on 290 (19.3%) SSRDs were recorded and parsed into 5 main categories and 18 subcategories. The most common modifications resulted from changes in immobilization device (n = 88, 22.2%), RT care path (n = 56, 14.1%), and arm positioning (n = 43, 10.8%). On univariate analysis, modifications were associated with RT intent, scan parameters, tumor site, and consultation type. An increased rate modifications was observed for patients had telemedicine consults (n = 101, 22.7%) compared to in-person consultations (n = 189, 17.9%) (p = 0.032). Using logistic regression analysis, there was also a statistically significant relationship between postoperative RT delivery and modification rates (OR: 2.913, 95% CI: 1.014-8.372) (p = 0.0126). Overall, only 14 patients (0.9%) needed re-simulation during the entire study period. Prospective multi-disciplinary radiation oncology team review prior to simulation identifies actionable change in approximately 19% of procedures, and results in an extremely low rate (<1%) of re-simulation. As departmental processes transition to virtual platforms, thorough attention is needed to identify patients at higher risk of simulation modifications.


Hippocampal mossy fiber distribution and long-term potentiation in two inbred mouse strains.
We studied long-term potentiation in the inbred mouse strains DBA/2 and C3H/He known to be different in both hippocampal mossy fiber distribution and several aspects of learning. Tetanic stimulation of mossy fibers resulted in a significantly stronger increase of the population spike amplitude in the CA3 pyramidal cell layer of C3H mice. This result suggests that the extent of the CA3 hippocampal mossy fiber projection correlates with synaptic efficacy in mice.


"Silver dust"--a tool to study growth interrelationships between bone, periosteum and muscle.
A cylinder of gelatin containing silver spongy granules was placed in and lay within the masseter muscle, the periosteum, and the mandible, and terminated in the medial pterygoid muscle of young (3 month-old) growing miniature pigs. On the basis of an animal sacrificed one week after placement of the cylinder, it was found that the suspending gelatin was removed by cellular activity. Nine months later the remaining animals were sacrificed. Periodic X-rays were taken during the course of the experiment. After sacrifice, the mandible and associated tissues were histologically examined. The results of this study suggest that the silver granules in the muscles maintained their location during growth; the silver granules in the mandible moved forward with mandibular growth. "Slippage" appeared to occur external to the fibrous layer of the periosteum; the site of movement was revealed by the trail of the silver granules. The described method should prove of value in studying the growth interrelationships between bone, periosteum, and muscle.


Pharmaceuticals, pesticides, personal care products and microplastics contamination assessment of Al-Hassa irrigation network (Saudi Arabia) and its shallow lakes.
This study assess the presence of pharmaceutical and personal care products (PPCPs) and pesticides in different environmental compartments and microplastics in water of a characteristic lagoon wetland in Saudi Arabia to establish the transport, accumulation and fate of these pollutants in a water-stressed area under high anthropogenic pressure. In water, diazinon (up to 1016 ng L-1), caffeine (up to 20,663 ng L-1), diclofenac (up to 1390 ng L-1) and paracetamol (up to 3069 ng L-1) were at the highest concentrations. The substances with the highest frequency of detection were carbendazim, atorvastatin, caffeine, etoricoxib, lorazepam, metformin, ofloxacin, paracetamol, salicylic acid and tramadol. Considerably less pesticides and PPCPs at concentrations ranging from 0.01 to 126 ng g-1 dry weight (d.w.) were detected in the other matrices (sediment ≫ soil > plants). The concentration of microplastics in water ranged from 0.7 to 7.8 items/L in the Al-Asfar lake and from 1.1 to 9.0 items/L in the Al-Hubail lake. Risk assessment [using hazards quotients (HQ)] was used to highlight pesticides and PPCPs of major ecological concern that should be closely monitored to avoid adverse effects.


Acceptability of measures aimed at preventing mother-to-child transmission of HIV among pregnant women.
To assess the acceptability of measures aimed at preventing mother-to-child transmission of HIV among counseled and yet-to-be-counseled antenatal women in a federal medical center in Nigeria. A valid and reliable questionnaire was interviewer administered to newly booking antenatal women who were yet to be counseled about HIV/AIDS and women on an antenatal follow-up visit who had already been counseled about HIV/AIDS. A total of 108 newly booked women and 116 women on follow-up visit responded to the questionnaire. The proportion of the counseled women who accepted HIV screening (98%) was significantly higher than the proportion of the yet-to-be-counseled women who would want to be screened (88%). Also, the proportions of the counseled women who accepted HIV screening so as to benefit from interventions like prevention of mother-to-child transmission, antiretroviral therapy and prevention of transmission to partner were significantly higher than the proportions among the yet-to-be-counseled women. The majority of the women in the study would accept antiretroviral drugs and avoidance of breastfeeding to prevent mother-to-child transmission, while only 29 (14%) respondents would accept cesarean section to prevent mother-to-child transmission. There was no statistically significant difference in the proportion of the counseled women (15%) who would accept cesarean section to prevent mother to child transmission when compared to the proportion among the yet-to-be-counseled women (11%). Antenatal HIV screening is acceptable to most pregnant women attending our hospital, and while many would accept antiretroviral drugs and avoidance of breastfeeding to prevent mother-to-child transmission of HIV, there is low acceptability of elective cesarean section.


Interaction of Graphene Nanoparticles and Lipid Membranes Displaying Different Liquid Orderings: A Molecular Dynamics Study.
Understanding the effects of graphene-based nanomaterials on lipid membranes is fundamental to determine their environmental impact and the efficiency of their biomedical use. By means of molecular dynamics simulations of simple model lipid bilayers, we analyze in detail the different interaction modes. We have studied bilayers consisting of lipid species (including cholesterol) which display different internal liquid orderings. Nanometric graphene layers can be transiently adsorbed onto the lipid membrane and/or inserted in its hydrophobic region. Once inserted, graphene nanometric flakes display a diffusive dynamics in the membrane plane, they adopt diverse orientations depending on their size and oxidation degree, and they show a particular aversion to be placed close to cholesterol molecules in the membrane. Addition of graphene to phase-segregated ternary membranes is also investigated in the context of the lipid raft model for the lipid organization of biological membranes. Our simulation results show that graphene layers can be inserted indistinctly in the ordered and disordered regions. Once inserted, nanometric flakes migrate to disordered and cholesterol-poor lipid phases.


Increased antibodies against unfolded viral antigens in the elderly after influenza vaccination.
Our studies aimed to measure the quality of antibody response to influenza vaccines in the elderly. The frequency of significant rise in hemagglutination inhibition (HAI) titer in the elderly is low and although annual vaccination reduces morbidity and mortality, better correlates of vaccine efficacy in the elderly are needed. We measured the amount and avidity of serum antibodies against native H3N2 influenza glycoproteins or denatured virus (unfoldons) in pre- and post-vaccinated sera of 36 elderly subjects. Eighty percent of subjects had high pre-immunization antibody levels and only 13% showed >or=2fold increase after vaccination, but 33% showed >or=2fold increase in avidity. With increasing dosage there was a significant increase in avidity against unfoldons with 50% of subjects showing >or=2fold increase at the highest dose. Elderly subjects given subunit vaccine showed higher reactivity with unfoldons (78% of native) than younger subjects studied earlier who were given inactivated whole virus vaccine (19% of native). The clear inverse relationship between pre-immunization antibody levels and antibody increase after vaccination implies that a major reason for the low frequency of antibody responses in elderly subjects is simply because they have high pre-immunization antibody levels. Only low reactivity was observed with earlier viruses. The increased proportion and avidity of antibodies against unfoldons is of concern, as these are not protective, and vaccine developers need to be aware of the role of age or vaccine formulation in inducing anti-unfoldon antibodies.


The RAMANITA method for non-destructive and in situ semi-quantitative chemical analysis of mineral solid-solutions by multidimensional calibration of Raman wavenumber shifts.
The "RAMANITA" method, for semi-quantitative chemical analysis of mineral solid-solutions by multidimensional calibration of Raman wavenumber shifts and mathematical calculation by simultaneous equations, is published here in detail in English for the first time. It was conceived by the present writer 20 years ago for binary and ternary pyroxene and garnet systems. The mathematical description was set out in 1989, but in an abstract in an obscure French special publication. Detailed "step-by-step" calibration of two garnet ternaries, followed by their linking, in the early 1990s provided a hexary garnet database. Much later, using this garnet database, which forms part of his personal database called RAMANITA, the present writer began to develop the method by improving the terminology, automating the calculations, discussing problems and experimenting with different real chemical problems in archaeometry. Although this RAMANITA method has been very briefly mentioned in two recent books, the necessary full mathematical explanation is given only here. The method will find application in any study which requires obtaining a non-destructive semi-quantitative chemical analysis from mineral solid solutions that cannot be analysed by any destructive analytical method, in particular for archaeological, geological or extraterrestrial research projects, e.g. Recently some other workers have begun deducing chemical compositions from Raman wavenumber shifts in multivariate chemical space, but the philosophical approach is quite different.


Predominant expression and activity of vacuolar H(+)-ATPases in the mixed segment of the wood-feeding termite Nasutitermes takasagoensis.
The mixed segment is a unique part of the gut present only in the most apical lineage of termites and consists of a complex of overlapping mesenteric and proctodeal epithelia. In spite of its unique structure, the physiological functions of the mixed segment have been poorly studied. We performed transcriptome analysis to identify functional enzymes acting in the mixed segment of the wood-feeding higher termite Nasutitermes takasagoensis. We sequenced the transcripts (4563 isotigs) of the mixed segment and compared them with those of the midgut (4813 isotigs) and the first proctodeal segment (3629 isotigs). We found that vacuolar H(+)-ATPase (V-ATPase) subunits were predominant in the mixed segment, which was confirmed by RT-qPCR analysis. The V-ATPase activity in these three tissues was in a good agreement with the expression patterns, suggesting that V-ATPase is a prevalent enzyme in the mixed segment of the termites. The results confirmed the proposed role of the mixed segment as a transporting epithelium.


Effect of monolithic CAD-CAM ceramic thickness on resin cement polymerization: An in-vitro study.
To evaluate the effect of different thicknesses of CAD-CAM ceramic sections on the polymerization of two different resin cements. Three CAD-CAM all-ceramic restorative materials were sectioned with four different thicknesses. A total of 240 resin cement specimens were prepared from light cured and dual cure resin cements and absorption peaks were recorded. 10 samples of each resin cement were examined before and after polymerization and served as the control group. Data were analyzed using one-way ANOVA, independent t- and Tukey HSD tests (P< 0.05). Control group showed the highest DOC values while samples cured under Vita Enamic section with a thickness of 2 mm presented the lowest values (P< 0.05). Polymerization performed under sections of 0.5 and 1 mm thicknesses provided statistically higher values. Dual cured resin cement samples showed higher DOC values compared to light cured resin cement samples. IPS Empress CAD sections with 0.5 and 1 mm thickness exhibited statistically higher values than other ceramics of the same thickness for light cured resin cement samples. A significant difference was observed between IPS Empress CAD and Vita Enamic while comparing ceramic sections of the same thickness (P< 0.05). There was no difference for sections of 1.5 and 2 mm (P>> 0.05). Thickness of the restorative material for an indirect restoration is a key element to determine the type of resin cement.


Pilot testing fentanyl test strip distribution in an emergency department setting: Experiences, lessons learned, and suggestions from staff.
Fentanyl test strips (FTSs) are increasingly used to address fentanyl contamination of the illicit drug supply by testing a drug for the presence of fentanyl, allowing people who use drugs (PWUD) to engage in overdose prevention. While emergency departments (EDs) have implemented various harm reduction strategies for PWUD, to date distribution of FTSs in EDs is limited and not evaluated. Thus, we sought to explore ED staff experiences distributing FTSs. Twenty-one staff serving different roles (e.g., physician, nurse, technician, social worker, certified recovery specialist) within two urban EDs in a major metropolitan area were enrolled in a pilot study to distribute FTS to patients who use drugs. Participants were interviewed about their experience at 3 weeks and again at 3 months. Interviews were recorded, transcribed verbatim, and coded using a conventional content analysis approach. All participants endorsed the utility of FTS distribution in the ED. Across 42 interviews, participants discussed evolving strategies to approach patients about FTS, primarily favorable patient reactions to FTSs, improved dynamics between participants and patients, mixed intervention support from other staff, and named challenges of FTS distribution and recommendations to make FTS distribution in the ED widespread. Recommendations included medical records prompts to offer FTS, offering via different types of staff, and offering FTS during triage. Implementing FTS distribution may improve patient rapport while providing patients with tools to avoid a fentanyl overdose. Participants generally reported positive experiences distributing FTSs within the ED but the barriers they identified limited opportunities to make distribution more integrated into their workflow. EDs considering this intervention should train staff on FTSs and how to identify and train patients and explore mechanisms to routinize distribution in the ED environment.


Pressure distribution in the pial arterial system of rats based on morphometric data and mathematical models.
The objective of the present work was a theoretical evaluation of pial arterial pressures in normotensive rats and spontaneously hypertensive rats based on the geometry and topography of the pial arterial system as well as on various topological models of the vascular trees. Pial branches of the middle cerebral artery in the diameter range of 30-320 microns were selectively visualized by corrosion compound, and the diameter and length of vascular segments were measured. The vessels were classified into branching orders by the methods of Horsfield and Strahler. The steady-state pressure distribution in the pial arterial system was calculated assuming that the flow at the bifurcations was partitioned in proportion to a given power of the diameters of the daughter branches (diameter exponent). The maximum number of vascular segments along the longest branch varied between 16 and 33. The mean branching ratio was 4.14 +/- 0.23 (SD). The mean diameter of vessels classified into Strahler orders 1-5 were: 50 +/- 12, 71 +/- 19, 106 +/- 22, 168 +/- 22, and 191 +/- 7 microns, respectively. The calculated pressure drop in the pial trees of normotensive rats was approximately twice as large in proximal orders 3 and 4 than in distal orders 1 and 2. The mean pressure in arteries of order 1 ranged from 54.4 to 58.4 mm Hg in the normotensive rat (input pressure: 83 mm Hg), and from 77.2 to 89.0 mm Hg in the spontaneously hypertensive rat (input pressure: 110 mm Hg). The coefficient of variation of terminal pressures in vessels of order 1 increased linearly with the mean pressure drop in the system. The coefficient of variation in terminal pressure had a minimum as a function of the diameter exponent in case of each pial tree. At its minimum, it was higher in all spontaneously hypertensive rats (10.1-22.9%) than in any normotensive rats (6.0-8.5%). The corresponding diameter exponents were in most cases lower in the spontaneously hypertensive rat (1.3-2.5) than in the normotensive rat (2.5-3.0). Topologically consistent models of the pial arterial network predicted significantly less variation in intravascular pressures than was obtained by direct calculations. More idealized models suggested the dependence of coefficient of variation in terminal pressure on the total number of vascular segments contained by the tree. All models predicted the existence of the minimum of coefficient of variation in terminal pressure in function of the diameter exponent.(ABSTRACT TRUNCATED AT 400 WORDS)


Inhaled amiloride and tobramycin solutions fail to eradicate Burkholderia dolosa in patients with cystic fibrosis.
Burkholderia dolosa can result in chronic airway infection and rapid decline in lung function in patients with cystic fibrosis (CF). Amiloride has antibacterial properties that may be synergistic with aminoglycosides against other species belonging to the Burkholderia cepacia complex (Bcc). We attempted to eradicate B. dolosa using a combination of nebulized tobramycin and nebulized amiloride in infected CF patients. A 6-month, open-label trial of continuous inhaled amiloride, delivered via nebulization four times daily, and continuous inhaled tobramycin (TIS or TOBI®) nebulized twice daily, was offered to all CF patients at our institution who are chronically infected with B. dolosa. Twenty two of 27 patients with B. dolosa were eligible and twelve elected to participate. Eradication of B. dolosa was not noted in any study subject. While patients tolerated treatment with no adverse effects, there was also no apparent impact on other secondary outcome measures. Concurrent, continuous inhalation of amiloride and tobramycin for 6 months was not effective for the eradication of chronic B. dolosa airway infection in CF patients.


Effects of an intensive lifestyle intervention on the underlying mechanisms of improved glycaemic control in individuals with type 2 diabetes: a secondary analysis of a randomised clinical trial.
The aim was to investigate whether an intensive lifestyle intervention, with high volumes of exercise, improves beta cell function and to explore the role of low-grade inflammation and body weight. This was a randomised, assessor-blinded, controlled trial. Ninety-eight individuals with type 2 diabetes (duration <10 years), BMI of 25-40 kg/m2, no use of insulin and taking fewer than three glucose-lowering medications were randomised (2:1) to either the standard care plus intensive lifestyle group or the standard care alone group. Standard care consisted of individual guidance on disease management, lifestyle advice and blinded regulation of medication following a pre-specified algorithm. The intensive lifestyle intervention consisted of aerobic exercise sessions that took place 5-6 times per week, combined with resistance exercise sessions 2-3 times per week, with a concomitant dietary intervention aiming for a BMI of 25 kg/m2. In this secondary analysis beta cell function was assessed from the 2 h OGTT-derived disposition index, which is defined as the product of the Matsuda and the insulinogenic indices. At baseline, individuals were 54.8 years (SD 8.9), 47% women, type 2 diabetes duration 5 years (IQR 3-8) and HbA1c was 49.3 mmol/mol (SD 9.2); 6.7% (SD 0.8). The intensive lifestyle group showed 40% greater improvement in the disposition index compared with the standard care group (ratio of geometric mean change [RGM] 1.40 [95% CI 1.01, 1.94]) from baseline to 12 months' follow-up. Plasma concentration of IL-1 receptor antagonist (IL-1ra) decreased 30% more in the intensive lifestyle group compared with the standard care group (RGM 0.70 [95% CI 0.58, 0.85]). Statistical single mediation analysis estimated that the intervention effect on the change in IL-1ra and the change in body weight explained to a similar extent (59%) the variance in the intervention effect on the disposition index. Our findings show that incorporating an intensive lifestyle intervention, with high volumes of exercise, in individuals with type 2 diabetes has the potential to improve beta cell function, associated with a decrease in low-grade inflammation and/or body weight. ClinicalTrials.gov NCT02417012 Graphical abstract.


Diffuse large B-cell lymphoma mimicking advanced basal cell carcinoma.
Primary cutaneous B-cell lymphomas (PCBCLs) are made up of a heterogenous group of B-cell lymphoproliferative diseases confined to the skin at the time of diagnosis with no evidence of extracutaneous involvement. With early diagnosis and adequate treatment, PCBCLs as a group has excellent prognosis, with about a 95% survival rate at five years. We report a case of diffuse large B-cell lymphoma (DLBCL) in a 52-year-old woman presenting as a fungating skin ulcer mimicking advanced basal cell carcinoma. Review of available literature showed most studies of PCBCLs being done on Europeans with no universally acceptable system of classification. Clinical findings, diagnostic evaluations and treatment outcomes of PCBCLs are discussed with emphasis on comparison of European Organization for Research and Treatment of Cancer (EORTC) and the World Health Organization (WHO) Classification of Neoplasms of the Hematopoietic and Lymphoid Tissue classification systems.


Tension-free vaginal tape evaluated using patient self-reports and urodynamic testing--a two-year follow-up.
Urinary incontinence entails both reduced quality of life for many women and considerable public expense. Compared with other methods aimed at alleviating incontinence, tension-free vaginal tape (TVT) is minimally invasive, can be performed under local anaesthesia and results in less morbidity and shorter hospitalization. The present study was carried out to evaluate early and late complications and as a 2-year follow-up after surgery. In 1996-98, 75 women underwent TVT sling plasty; mean time for surgery was 39 min and for hospitalization 24 h. The procedure caused bladder perforation in 3 women, but this was detected by cystoscopy and immediately corrected. Postoperative retention occurred in 9 patients but was transient. After surgery 80% were cured, 9% showed improvement and 11% were failures. Two women exhibited vaginal erosion, and one of these had previously undergone radiation therapy. One sling caused obstruction and had to be cut. Improvements included less impact on social and physical activities and mental status and significant reduction of voiding frequency, leakage episodes and pad use. The TVT technique seems to provide results comparable with those obtained with Burch colposuspension, but it entails less risk of obstruction than previous slings techniques because it causes no compression of the urethra. TVT is effective in women with genuine stress incontinence due to urethral hypermobility and in elderly women with sphincter incompetence, although the outcome is better in the former.


Weighing the risks and benefits of vaccination.
The following summarizes this author's current thoughts regarding veterinary vaccines and their safety: 1. Every licensed animal vaccine is probably effective, but also produces some adverse effects. 2. Prelicensing studies of vaccines are not specifically designed to detect adverse vaccine reactions. 3. An improved system of national postmarketing surveillance is required to identify most adverse vaccine reactions that occur at low and moderate frequency. 4. Even a good postmarketing surveillance system is unlikely, however, to detect delayed adverse vaccine reactions, and the longer the delay the less likely they will be associated with vaccination. 5. Analytic epidemiologic (field) studies are the best way to link vaccination with delayed adverse reactions, but these are often hindered by incomplete vaccination histories in medical records in veterinary practice and by a lack of veterinarians in industry trained in epidemiologic methods. 6. Each licensed veterinary vaccine should be subjected to a quantitative risk assessment, and these should be updated on a regular basis as new information becomes available. 7. Risk assessment should be used to identify gaps in information regarding the safety and efficacy of vaccines, and appropriate epidemiologic studies conducted to fill these gaps that contribute to the uncertainty in risk estimates. 8. Risk assessment is an analytical process that is firmly based on scientific considerations, but it also requires judgments to be made when the available information is incomplete. These judgments inevitably draw on both scientific and policy considerations. 9. Representatives from industry, government, veterinary medicine, and the animal-owning public should be involved in risk management, that is, deciding between policy options. The controversy regarding vaccine risks is intensifying to the point that some animal owners have stopped vaccinating their animals. They offer as justification the belief that current vaccines are "just too dangerous." Some owners report that since they completely stopped vaccinating their animals, they have been healthy. What they fail to realize is that a high percentage of animal owners are responsible and do vaccinate their animals, thus providing "herd immunity" protection to the unvaccinated animals whom they contact. The solution to the vaccine controversy is not to abandon vaccination as an effective means of disease prevention and control, but rather to encourage vaccine research to answer important questions regarding safety and to identify the biological basis for adverse reactions. Key questions to be answered include these: What components of vaccines are responsible for adverse reactions? What is the genetic basis for susceptibility to adverse health effects in animals? How can susceptible individuals be identified? Do multivalent vaccines cause a higher rate of adverse reactions than monovalent vaccines? Is administration of multiple doses of monovalent vaccines really any safer than administering a single multivalent vaccine? These and other vaccine-related questions deserve our attention as veterinarians so we can fulfill our veterinary oath to relieve animal suffering and "above all else, do no harm."


Lifespan trajectory of myelin integrity and maximum motor speed.
Myelination of the human brain results in roughly quadratic trajectories of myelin content and integrity, reaching a maximum in mid-life and then declining in older age. This trajectory is most evident in vulnerable later myelinating association regions such as frontal lobes and may be the biological substrate for similar trajectories of cognitive processing speed. Speed of movement, such as maximal finger tapping speed (FTS), requires high-frequency action potential (AP) bursts and is associated with myelin integrity. We tested the hypothesis that the age-related trajectory of FTS is related to brain myelin integrity. A sensitive in vivo MRI biomarker of myelin integrity (calculated transverse relaxation rates (R(2))) of frontal lobe white matter (FLwm) was measured in a sample of very healthy males (N=72) between 23 and 80 years of age. To assess specificity, R(2) of a contrasting early-myelinating region (splenium of the corpus callosum) was also measured. FLwm R(2) and FTS measures were significantly correlated (r=.45, p<.0001) with no association noted in the early-myelinating region (splenium). Both FLwm R(2) and FTS had significantly quadratic lifespan trajectories that were virtually indistinguishable and both reached a peak at 39 years of age and declined with an accelerating trajectory thereafter. The results suggest that in this very healthy male sample, maximum motor speed requiring high-frequency AP burst may depend on brain myelin integrity. To the extent that the FLwm changes assessed by R(2) contribute to an age-related reduction in AP burst frequency, it is possible that other brain functions dependent on AP bursts may also be affected. Non-invasive measures of myelin integrity together with testing of basic measures of processing speed may aid in developing and targeting anti-aging treatments to mitigate age-related functional declines.


Analysis of maternal and perinatal determinants of allergic sensitization in childhood.
Non-communicable diseases, such as allergies, are influenced by both genetic and epigenetic factors. Perinatal determinants conceivably modify the epigenetic makeup of the developing fetal immune system preventing or predisposing the development of allergies. The aim of this study therefore was to identify independent perinatal factors associated with allergic sensitization in childhood. In a single center retrospective case-cohort study electronic obstetric medical records and available skin prick testing results of children were analyzed. For the analysis 286 skin prick test positive (sensitized) children [median (IQR): 3.47 (1.70-7.34) years] were compared with data from all remaining live births in the obstetric cohort (n = 66,583). Sensitized children more frequently had a mother born in Asia (19.1% vs. 10.2%; P < 10-6). Applying backward elimination logistic regression, seven out of 23 initially entered perinatal factors remained in the model. High maternal age (> 35 years; OR: 1.912; P < 0.001), male offspring sex (OR: 1.423; P < 0.01) and assisted conception (OR: 1.771; P < 0.05) increased the risk for allergic sensitization. In contrast, maternal smoking (OR: 0.469; P < 0.005), increasing parity (OR: 0.881; P < 0.05), maternal pre-pregnancy overweight (OR: 0.742; P < 0.005) and preterm birth (OR: 0.484; P < 0.05) decreased the risk for allergic sensitization. In addition to supporting previous findings, this study is first to report an increased risk of allergic sensitization after assisted conception. Beyond this finding's potential implementation in preventative strategies, exploration of this association could further pathophysiological understanding of allergic disease.


Can remittances contribute to financing climate actions in developing countries? Evidence from analyses of households' climate hazard exposure and adaptation actors in SE Nigeria.
Migrant remittances are potentially significant sources of funding for climate change adaptation and resilience building in developing countries. However, very little is understood about the linkages between climate actions and remittances at the household level. It is not clear how remittances can affect households' responses to climate change. This paper presents evidence from analyses of the associations between remittances to households, their climate hazard exposure, and adaptation actors. It uses concurrent data on international remittances receipts, three climate change related hazards (flooding, intense and irregular rainfall), and main adaptation actors (self/family, community, government, and NGOs) from over 600 households in South Eastern Nigeria. The results showed that household incidence of remittances is low (15%) while exposure to climate hazards is higher (flooding: 41.2%, intense rainfall: 47.1%, irregular rainfall: 29.9%). Nominal (contingency coefficient) associations between remittances and household climate hazard exposure and remittances and household adaptation actors were mostly moderate and insignificant. Therefore, households that received remittances and those that did not were not significantly different in terms of their exposure to climate hazard and main actors in climate adaptation. Self/families were the main actors in household climate actions. Governments and NGO actors were less prominent. The results suggest that unregulated remittances have limited impact on household climate hazard exposure and adaptive actions. However, there are indications that the contribution of remittances to financing climate adaptation may be enhanced by addressing issues with cost of remitting and remittee understanding of climate change to increase remittances volumes, incidence, and use.


Diagnostic accuracy of solid phase HLA antibody assays for prediction of crossmatch strength.
Solid phase antibody assays are increasingly used to provide quantitative measures of donor-specific HLA antibodies for assessment of pretransplant risk, although cell-based crossmatches continue to serve as gold standards for determination of donor HLA antibody strength. This study determined the ability of HLA antibody solid phase assays to predict the strength of cell-based flow cytometric (FC) and complement-dependent cytotoxicity (CDC) crossmatches. Eighty-two recipient/donors pairs were analyzed using receiver operating characteristic (ROC) curve analyses to determine the accuracy of donor-specific median fluorescence intensity values (Σ MFI) from single antigen bead assays for predicting strong FC and CDC crossmatches. Diagnostic sensitivity and specificity of optimal Σ MFI values were highest for predicting strong T cell FCs. Σ MFI values showed good sensitivity for predicting positive direct and AHG-augmented CDC crossmatches (91% and 94%, respectively), but with lower specificity (67% each). Specificity and sensitivity for predicting positive B cell CDC crossmatches were 73% and 84%. Σ MFI values derived from single antigen bead assays can predict strong flow and positive CDC crossmatches, but with tradeoffs between sensitivity and specificity. The results support the use of solid phase assays for quantitative virtual crossmatching and as a replacement for cell-based crossmatching.


Crystallization of recombinant green mamba ρ-Da1a toxin during a lyophilization procedure and its structure determination.
ρ-Da1a toxin from eastern green mamba (Dendroaspis angusticeps) venom is a polypeptide of 65 amino acids with a strong affinity for the G-protein-coupled α(1A)-adrenoceptor. This neurotoxin has been crystallized from resolubilized lyophilized powder, but the best crystals grew spontaneously during lyophilization. The crystals belonged to the trigonal space group P3(1)21, with unit-cell parameters a = b = 37.37, c = 66.05 Å, and diffracted to 1.95 Å resolution. The structure solved by molecular replacement showed strong similarities to green mamba muscarinic toxins.


Minimally invasive bipolar fractional radiofrequency treatment upregulates anti-senescence pathways.
The sirtuin gene family has been implicated in various anti-senescence pathways. Its connection, if any, with the skin wound healing response has yet to be elucidated. The goal of our study was to better understand the effects of FRF treatment on the sirtuin anti-senescence pathway in skin. Human abdominal skin was treated with FRF, and then harvested at 0, 2, 14, and 28 days post-treatment to assess for temporal changes in gene expression levels. Decreased levels of SIRT1, 3, 5, and 7 were observed immediately post-FRF treatment. By Day 2, SIRT1, 6, and 7 expressions increased 50-100%. SIRT6 and 7 expression continued to increase through Day 28. Expression levels of apoptosis genes FoxO3 and p53 decreased, while Bax levels increased by Day 28. Our results raise the possibility that sirtuin activity may be used as an accurate corollary to clinical improvement in skin quality.


Recent progress in epigenetics of obesity.
Nowadays, obesity is one of the largest public health problems worldwide. In the last few decades, there has been a marked increase in the obesity epidemic and its related comorbidities. Worldwide, more than 2.2 billion people (33%) are affected by overweight or obesity (712 million, 10%) and its associated metabolic complications. Although a high heritability of obesity has been estimated, the genetic variants conducted from genetic association studies only partially explain the variation of body mass index. This has led to a growing interest in understanding the potential role of epigenetics as a key regulator of gene-environment interactions on the development of obesity and its associated complications. Rapid advances in epigenetic research methods and reduced costs of epigenome-wide association studies have led to a great expansion of population-based studies. The field of epigenetics and metabolic diseases such as obesity has advanced rapidly in a short period of time. The main epigenetic mechanisms include DNA methylation, histone modifications, microRNA (miRNA)-mediated regulation and so on. DNA methylation is the most investigated epigenetic mechanism. Preliminary evidence from animal and human studies supports the effect of epigenetics on obesity. Studies of epigenome-wide association studies and genome-wide histone modifications from different biological specimens such as blood samples (newborn, children, adolescent, youth, woman, man, twin, race, and meta-analysis), adipose tissues, skeletal muscle cells, placenta, and saliva have reported the differential expression status of multiple genes before and after obesity interventions and have identified multiple candidate genes and biological markers. These findings may improve the understanding of the complex etiology of obesity and its related comorbidities, and help to predict an individual's risk of obesity at a young age and open possibilities for introducing targeted prevention and treatment strategies.


Automatic coronary artery segmentation and diagnosis of stenosis by deep learning based on computed tomographic coronary angiography.
Coronary computed tomography angiography (CCTA) has rapidly developed in the coronary artery disease (CAD) field. However, manual coronary artery tree segmentation and reconstruction are time-consuming and tedious. Deep learning algorithms have been successfully developed for medical image analysis to process extensive data. Thus, we aimed to develop a deep learning tool for automatic coronary artery reconstruction and an automated CAD diagnosis model based on a large, single-centre retrospective CCTA cohort. Automatic CAD diagnosis consists of two subtasks. One is a segmentation task, which aims to extract the region of interest (ROI) from original images with U-Net. The second task is an identification task, which we implemented using 3DNet. The coronary artery tree images and clinical parameters were input into 3DNet, and the CAD diagnosis result was output. We built a coronary artery segmentation model based on CCTA images with the corresponding labelling. The segmentation model had a mean Dice value of 0.771 ± 0.021. Based on this model, we built an automated diagnosis model (classification model) for CAD. The average accuracy and area under the receiver operating characteristic curve (AUC) were 0.750 ± 0.056 and 0.737, respectively. Herein, using a deep learning algorithm, we realized the rapid classification and diagnosis of CAD from CCTA images in two steps. Our deep learning model can automatically segment the coronary artery quickly and accurately and can deliver a diagnosis of ≥ 50% coronary artery stenosis. Artificial intelligence methods such as deep learning have the potential to elevate the efficiency in CCTA image analysis considerably. • The deep learning model rapidly achieved a high Dice value (0.771 ± 0.0210) in the autosegmentation of coronary arteries using CCTA images. • Based on the segmentation model, we built a CAD autoclassifier with the 3DNet algorithm, which achieved a good diagnostic performance (AUC) of 0.737. • The deep neural network could be used in the image postprocessing of coronary computed tomography angiography to achieve a quick and accurate diagnosis of CAD.


Surgical correction of pectus excavatum.
It has been observed that some patients who had correction of funnel chest deformity by methods which failed to provide fixed elevation of the involved sternal segment developed progressive sagging in later years in spite of looking good at the operating table. This has led to the adoption of a new technique of double sternal support. This procedure has resulted in 35 of 37 children (94%) being classified as excellent or satisfactory. This double support was initially established in 1959 by overlapping the upper transsected sternum while maintaining elevation of the lower end with a soft tissue sling of perichondrium and intercostal muscle. Beginning in 1961, a rigid bridge of rib or stainless steel bar was substituted at the lower end of the sternum. This has provided better support and the current preference of using the steel bar has been validated in this group of patients. The few disappointments were related to removal of the bar earlier than desired, failure to excise all the protruding sternal cartilage stumps or rib graft tips and inability to cover the lateral sternal edges with pectoral muscles. If possible, the steel bar should not be removed before 12 mo. When these pitfalls were avoided, the results were almost uniformly excellent. The wisdom of excising all depressed cartilaginous segments, as advocated by Ravitch in 1949, has been substantiated. A submammary transverse incision has provided an excellent cosmetic appearance. The morbidity has been low and the mortality zero. In spite of the absence of objective evidence of cardiopulmonary dysfunction, there seems to be an almost uniform improvement in appearance and in patient activity following successful correction of the funnel chest. The latter may be as much a psychological response as a physiologic one. The low morbidity, satisfactory long term results, and general improvement in the patient's body image and outlook on life indicate the need to offer correction of the severe pectus excavatum deformity to low risk children.


Noncoding RNAs in subchondral bone osteoclast function and their therapeutic potential for osteoarthritis.
Osteoclasts are the only cells that perform bone resorption. Noncoding RNAs (ncRNAs) are crucial epigenetic regulators of osteoclast biological behaviors ranging from osteoclast differentiation to bone resorption. The main ncRNAs, including miRNAs, circRNAs, and lncRNAs, compose an intricate network that influences gene transcription processes related to osteoclast biological activity. Accumulating evidence suggests that abnormal osteoclast activity leads to the disturbance of subchondral bone remodeling, thus initiating osteoarthritis (OA), a prevalent joint disease characterized mainly by cartilage degradation and subchondral bone remodeling imbalance. In this review, we delineate three types of ncRNAs and discuss their related complex molecular signaling pathways associated with osteoclast function during bone resorption. We specifically focused on the involvement of noncoding RNAs in subchondral bone remodeling, which participate in the degradation of the osteochondral unit during OA progression. We also discussed exosomes as ncRNA carriers during the bone remodeling process. A better understanding of the roles of ncRNAs in osteoclast biological behaviors will contribute to the treatment of bone resorption-related skeletal diseases such as OA.


Corrigendum: Individual, Sociodemographic, and Environmental Factors Related to Physical Activity During the Spring 2020 COVID-19 Lockdown.
[This corrects the article DOI: 10.3389/fpsyg.2021.643109.].


Crystals containing a single subunit type of Panulirus interruptus haemocyanin.
Crystals have been grown of the 94K subunit of Panulirus interruptus haemocyanin. The best crystals were obtained by the "two-layer liquid diffusion technique" with ammonium sulphate solutions as precipitating agent. The crystals have space group P6(3)22 with cell dimensions a = b = 195.6 A and c = 158.0 A. The diffraction pattern extends to a resolution of approximately 3.0 A resolution. The unit cell may contain two hexameric molecules with 32 symmetry, i.e. one subunit per asymmetric unit.


Positron emission tomography in the management of non-small cell lung cancer.
In the past 10 years, FDG-PET has become an important imaging modality in NSCLC. Its indication in the assessment of lung nodules and staging is based on large prospective experience, further supported by some meta-analyses. This evidence has important consequences for patient management, which recently was proved in a randomized trial that showed a reduction in the number of futile thoracotomies by preoperative PET. The use of FDG-PET could become more widespread when commercial isotope distributors are able to deliver FDG so that an on-site cyclotron is no longer a prerequisite. FDG has a half-life of 110 minutes, so a practical distribution radius of 200 km should be feasible. Current indications for PET in the staging of newly diagnosed NSCLC are mainly the patients who are considered to be candidates for radical treatment. The technique does not have a clinical indication in other patients--for example, when metastatic lymph nodes are detected at clinical examination, when a simple ultrasound study already points to diffuse hepatic metastases, or in cases of poor performance status. PET also has prognostic value; it can be used for the evaluation of response or restaging after radiotherapy or chemotherapy and for early detection of relapse. The combination of CT and PET improves radiotherapy planning and it is to be expected that combined CT-PET-guided planning devices will further refine three-dimensional conformal radiotherapy. Finally, a whole new field of application of PET in molecular biology using new radiopharmaceutics is in development. FDG, with its possibility to study tumor glucose metabolism, has paved the way for PET in clinical oncology. It is hoped that PET examinations with new molecular tracers will allow ever better specificity and become sufficiently reliable and manageable to evaluate receptors, transport proteins, and intracellular enzymes so that very early response monitoring during chemotherapy or radiotherapy, evaluation of novel molecular-targeted lung cancer therapies, or even gene therapy becomes possible. New tracers that have showed their promise in early clinical studies include 18F-fluorothymidine (a proliferation marker that might give better specificity in the assessment of solitary pulmonary nodules or better accuracy in the evaluation of early response), (99m)Tc-Annexin V (Apomate; an apoptosis-imaging agent that could be correlated with overall and progression-free survival in phase I data), or 18F-fluoromisonidazole (which can be used to quantify regional hypoxia in human tumors with PET).


Treatment of flaring of the costal arch after the minimally invasive pectus excavatum repair (Nuss procedure) in children.
Flaring of the costal arch may be part of the pectus excavatum deformity. This aspect will in rare cases be even worsen after the Nuss repair. This remaining deformity can be treated with a minimal subperichondral partial resection of the costal arch cartilage. In 5 patients, this additional technique regained good to excellent results.


Cigarette smoke decreases the rate constant for the association of elastase with alpha 1-proteinase inhibitor by a non-oxidative mechanism.
This paper describes a non-oxidative impairment of the biological function of alpha 1-proteinase inhibitor by cigarette smoke. Aqueous solutions of cigarette smoke are able to decrease the rate constant kass for the inhibition of porcine pancreatic elastase by human plasma alpha 1-proteinase inhibitor. The value of kass decreases linearly with the concentration of smoke (from 2.2 X 10(5) M-1 s-1 to 0.6 X 10(5) M-1 s-1). This effect is not due to an oxidation of the inhibitor. When pancreatic elastase is reacted with elastin in the presence of alpha 1-proteinase inhibitor and cigarette smoke solution, elastolysis occurs at a rate nearly identical to that observed in the absence of inhibitor. This effect is due to a smoke-induced decrease in kass. These observations may serve as a model of biological regulation of proteolysis via a change in the rate constant for a proteinase-proteinase inhibitor association. The influence of cigarette smoke on the inhibition of human neutrophil elastase by alpha 1-proteinase inhibitor could not be studied in detail because the enzyme precipitates in the presence of concentrated smoke solution.


Progression of type 1 diabetes from the prediabetic stage is controlled by interferon-α signaling.
Blockade of IFN-α but not IFN-β signaling using either an antibody or a selective S1PR1 agonist, CYM-5442, prevented type 1 diabetes (T1D) in the mouse Rip-LCMV T1D model. First, treatment with antibody or CYM-5442 limited the migration of autoimmune "antiself" T cells to the external boundaries around the islets and prevented their entry into the islets so they could not be positioned to engage, kill, and thus remove insulin-producing β cells. Second, CYM-5442 induced an exhaustion signature in antiself T cells by up-regulating the negative immune regulator receptor genes Pdcd1, Lag3, Ctla4, Tigit, and Btla, thereby limiting their killing ability. By such means, insulin production was preserved and glucose regulation maintained, and a mechanism for S1PR1 immunomodulation described.


[Three-phalangeal thumbs].
Many teratogenic mechanisms converge to create a three-phalangeal thumb: duplication, fusion and deletion. Fine observation of the position of growth centres and of associated hand malformations suggests that the intermediate delta phalanx of the three-phalangeal thumb results of the fusion of a three-phalanx ray with a two-phalanx thumb. The ulnar or radial side of the deviation is determined by the radial or ulnar position of this three-phalangeal ray fusing with the thumb. An opposable three-phalangeal thumb ulnarly deviated with a radial intermediate delta phalanx is the result of the fusion of a duplicated Wassel VII type thumb composed by a radial three-phalangeal ray and an ulnar two-phalangeal ray. In split hands, the three-phalangeal thumb is most often radially deviated because it presumably results from the fusion of a radial two phalanx thumb with the index, deleted in this fusion. The aligned opposable three-phalangeal thumb is quite uncommon and is probably the result of a fusion of two Wassel VII-type duplicated three-phalangeal rays. Conversely, the five-fingered hand or non-opposable three-phalangeal thumb, usually has no deviation and could result of a thumb deletion associated to an index duplication. This understanding of three-phalangeal thumbs makes usual classifications obsolete, but explains the various pathologic associations found in literature and in our own series. Treatment varies with age and takes in account all fundamental aspects of this congenital hand anomaly: the extraphalanx, the clinodactyly due to a delta phalanx, the thumb duplication or the absence of opposable thumb.


Transcripts of three mitochondrial genes in the RNA of sea urchin eggs and embryos.
cDNA clones representing mitochondrial 16 S rRNA, and mRNAs for cytochrome oxidase I and an unidentified reading frame were used to measure the prevalence and stability of these transcripts in gastrula stage embryos. The 16 S rRNA is the most prevalent embryo poly(A) RNA, and is synthesized about four times more rapidly than is the mRNA for cytochrome oxidase. The relative prevalence of the two mRNAs is largely determined by their turnover rates.


Serum fibroblast growth factor 23 for early detection of acute kidney injury in critical illness.
Serum fibroblast growth factor 23 (FGF23) is associated with acute kidney injury (AKI) and mortality in patients with critical illnesses. However, the accurate predictive performance of FGF23 on AKI remains inconclusive. Meta-analysis was performed using data sources including PubMed, Web of Science, EMBASE, and Cochrane (until June 1, 2021). Cohort or observational studies including patients with AKI and serum FGF23 level as the index test were included. The primary outcome was the AKI detective accuracy. This study has been registered in PROSPERO (CRD42021249930). Eleven studies with 1946 patients in seven countries were included. Across all settings, the sensitivity and specificity for serum FGF23 levels to predict AKI were 82% (95% CI, 66-91%) and 77% (95% CI, 67-85%), respectively. The diagnostic odds ratio of FGF23 was 15.51 (95% CI, 4.89-49.19), with the pooled positive likelihood ratio of 3.62 (95% CI, 2.25-5.83) and a negative likelihood ratio of 0.23 (95% CI, 0.11-0.50). The area under the receiver operating characteristic curve to detect AKI was 0.86 (95% CI, 0.82-0.88). C-terminal FGF23 had a better performance than intact FGF23. Plasma FGF23 is a valuable biomarker for incident AKI in critically ill patients. Comparisons of FGF23 with other biomarkers in AKI still need more studies to prove.


Differences between brain and rectal temperatures during routine critical care of patients with severe traumatic brain injury.
Theoretical models suggest that small differences only exist between brain and body temperature in health. Once the brain is injured, brain temperature is generally regarded to rise above body temperature. However, since reports of the magnitude of the temperature gradient between brain and body vary, it is still not clear whether conventional body temperature monitoring accurately predicts brain temperature at all times. In this prospective, descriptive study, 20 adults with severe primary brain trauma were studied during their stay in the neurointensive care unit. Brain temperature ranged from 33.4 to 39.9 degrees C. Comparisons between paired brain and rectal temperature measurements revealed no evidence of a systematic difference [mean difference -0.04 degrees C (range -0.13 to 0.05 degrees C, 95% CI), p = 0.39]. Contrary to popular belief, brain temperature did not exceed systemic temperature in this relatively homogeneous patient series. The mean values masked inconsistent and unpredictable individual brain-rectal temperature differences (range 1.8 to -2.9 degrees C) and reversal of the brain-body temperature gradient occurred in some patients. Brain temperature could not be predicted from body temperature at all times.


Persistence of low drug treatment coverage for injection drug users in large US metropolitan areas.
Injection drug users (IDUs) are at high risk for HIV, hepatitis, overdose and other harms. Greater drug treatment availability has been shown to reduce these harms among IDUs. Yet, little is known about changes in drug treatment availability for IDUs in the U.S. This paper investigates change in drug treatment coverage for IDUs in 90 metropolitan statistical areas (MSAs) during 1993-2002. We define treatment coverage as the percent of IDUs who are in treatment. The number of IDUs in drug treatment is calculated from treatment entry data and treatment census data acquired from the Substance Abuse and Mental Health Service Administration, divided by our estimated number of IDUs in each MSA. Treatment coverage was low in 1993 (mean 6.7%; median 6.0%) and only increased to a mean of 8.3% and median of 8.0% coverage in 2002. Although some MSAs experienced increases in treatment coverage over time, overall levels of coverage were low. The persistence of low drug treatment coverage for IDUs represents a failure by the U.S. health care system to prevent avoidable harms and unnecessary deaths in this population. Policy makers should expand drug treatment for IDUs to reduce blood-borne infections and community harms associated with untreated injection drug use.


Induction and activation of antiviral enzyme 2',5'-oligoadenylate synthetase by in vitro transcribed insulin mRNA and other cellular RNAs.
Double-stranded RNA (dsRNA) can induce antiviral enzyme 2',5'-oligoadenylate synthetase (2'5'AS) expression and activate latent 2'5'AS. Our previous data have shown pancreatic β cells are sensitive to dsRNA-induced 2'5'AS expression, and constitutive high basal 2'5'AS expression is associated with susceptibility to developing type 1 diabetes (T1D), a disease due to pancreatic β cell loss. Here we report that in vitro transcribed human insulin mRNA induces the activation of human OAS gene promoter sequences, and specifically and dose-dependently induces 2'5'AS expression in murine pancreatic βTC3 cells. Over-expression of dsRNA receptor retinoic acid-inducible gene-1 enhances insulin mRNA-induced 2'5'AS expression. In vitro transcribed insulin and other mRNAs, as well as total cellular RNAs, activate latent 2'5'AS in vitro with activation ability likely associated with the sequence and length of individual mRNAs or the sample source of total cellular RNA. Insulin mRNA does not show any specificity to activate 2'5'AS, but total cellular RNA from βTC3 cells has high activation ability. Constitutive 2'5'AS expression in βTC3 cells leads to cell proliferation inhibition and apoptosis. Our study suggests the possibility of cellular RNA-regulated 2'5'AS expression and activation, and the potential risk of high insulin gene transcription in pancreatic β cells, and may help explain genetic predisposition to T1D associated with INS VNTR class I alleles.


Interaction of palliative care and primary care.
Primary care physicians are often the first medical providers patients seek out, and are in an excellent position to provide primary palliative care. Primary palliative care encompasses basic skills including basic evaluation and management of symptoms and discussions about goals of care and advance care planning. Specialty palliative care consultation complements primary care by assisting with complex psychosocial-spiritual patient and family situations. This article reviews primary palliative care skill sets and criteria for when to consider referring patients to specialty palliative care and hospice services.


Elastic properties of relaxed, activated, and rigor muscle fibers measured with microsecond resolution.
Tension responses due to small and rapid length changes (completed within 40 microseconds) were obtained from skinned single-fiber segments (4- to 7-mm length) of the iliofibularis muscle of the frog incubated in relaxing, rigor, and activating solution. The fibers were skinned by freeze-drying. The first 500 microseconds of the responses for all three conditions could be described with a linear model, in which the fiber is regarded as a rod composed of infinitesimally small identical segments, containing an undamped elastic element, two damped elastic elements and a mass in series. An additional damped elastic element was needed to describe tension responses of activated fibers up to the first 5 ms. Consequently phase 1 and phase 2 of activated fibers can be described with four apparent elastic constants and three time constants. The results indicate that fully activated fibers and fibers in rigor have similar elastic properties within the first 500 microseconds of tension responses. This points either to an equal number of attached cross-bridges in rigor and activated fibers or to a different number of attached cross-bridges in rigor and activated fibers and nonlinear characteristics in rigor cross-bridges. Mass-shift measurements obtained from equatorial x-ray diffraction patterns support the latter possibility.


Readmission after pancreatic resection: causes, costs and cost-effectiveness analysis of high versus low quality hospitals using the Nationwide Readmission Database.
Objectives were to determine the causes of readmission and assess the cost-effectiveness of high (HQ) and low quality (LQ) hospitals in performing pancreatic resection, by using readmission rates as the measure of quality. We identified 53,572 pancreatic resection cases from National Readmission Database from 2010 through 2014. Hospitals were risk adjusted and ranked based on readmission. Top 20% HQ hospitals having the lowest readmission rates were compared to the bottom 20% LQ hospitals with the highest readmission rates. The 90-day readmission rate was 27.2% (HQ: 25.7%, LQ: 30.9%, p < 0.001). Compared to LQ, HQ hospitals had lower mortality (2.1% vs 10.2%, p < 0.001) and major complication (10.5% vs 53%, p < 0.001). Major complication during index operation was a major predictor of readmission (RR: 1.6, 95% CI: 1.6-1.7, p < 0.001). The optimal cut point of hospital volume associated with low mortality was 70 or more cases/year. Per year of survival benefit at HQ hospitals, the costs were lower by $9,293 with cost-savings of $6.98 million/year. HQ hospitals were cost-effective at performing pancreatic resection and achieved substantial cost-savings by avoiding major complications during index operation and having lower rates of readmissions. Hospital readmission rate is a strong marker of quality of care.


Computational signatures of inequity aversion in children across seven societies.
[Correction Notice: An Erratum for this article was reported online in Journal of Experimental Psychology: General on Aug 10 2023 (see record 2023-96713-001). In the original article, there were affiliation errors for the first and 14th authors. The affiliations for Dorsa Amir are Department of Psychology, University of California, Berkeley; and Department of Psychology, Boston College. The affiliation for Katherine McAuliffe is Department of Psychology, Boston College. All versions of this article have been corrected.] Inequity aversion is an important factor in fairness behavior. Previous work suggests that children show more cross-cultural variation in their willingness to reject allocations that would give them more rewards than their partner-advantageous inequity-as opposed to allocations that would give them less than their partner-disadvantageous inequity. However, as past work has relied solely on children's decisions to accept or reject these offers, the algorithms underlying this pattern of variation remain unclear. Here, we explore the computational signatures of inequity aversion by applying a computational model of decision-making to data from children (N = 807) who played the Inequity Game across seven societies. Specifically, we used drift-diffusion models to formally distinguish evaluative processing (i.e., the computation of the subjective value of accepting or rejecting inequity) from alternative factors such as decision speed and response strategies. Our results suggest that variation in the development of inequity aversion across societies is best accounted for by variation in the drift rate-the direction and strength of the evaluative preference. Our findings underscore the utility of looking beyond decision data to better understand behavioral diversity. (PsycInfo Database Record (c) 2023 APA, all rights reserved).


Cluster formation in a symmetrical network: a dynamical system for the description of the suppression among non-immune T lymphocytes and its application to the effects of immunization.
A mathematical model has been developed for the description of the suppressive regulation between polyclonally activated normal and immune T cells. The model assumes reversible cell-cell interactions to interpret results from limiting dilution experiments performed to determine the frequencies of precursor cells for antigen-specific T effector lymphocytes and to analyse mechanisms regulating the maturation of precursor into effector T cells. In particular, the model deals with the changes induced in the T lymphocytes population following immunization with antigens. In these limiting dilution experiments, T cells are placed in cultures at varying cell numbers with all other essential culture constituents kept in excess. After polyclonal activation of the T cells in culture they are supplied with growth and maturation factors so that they form daughter clones of functionally active T effector cells. The typical result observed was that effector T cells develop in cultures at low cell input but that this development is totally suppressed at high cell numbers. This result suggested that, at high cell numbers, the effector T cells are exposed to a sufficient number of other T cells of appropriate specificity to permit suppressive interactions. Whereas this is the case for non-immune T cells, T cells after immunization develop into effector cells both at high as well as at low cell concentrations, though with efficiencies less than proportional to their number of precursors. Our mathematical model is made up of a set of first order autonomous ordinary differential equations in many variables permitting the calculations of numbers of free cells and of cells engaged in cellular clusters of varying sizes. Free cells can develop into effector cells whereas cells engaged in clusters cannot. We calculate the consequences of several reasonable hypotheses concerning the effects of immunization. We consider the possibility that immunization modifies the growth behavior of the antigen-specific cells to permit an increased or accelerated clonal expansion in culture. Alternatively, we consider the possibility that immunization changes the interaction strength between cells specific for the immunizing antigen and other cells. Thirdly, we have connected both behaviors by calculating the case of an inverse relationship between growth rates and intensities of interaction between cells. Our model has been inspired by the symmetrical network model and can be interpreted in this framework. It proposes that immune regulation is a consequence of idiotype-anti-idiotype interactions.(ABSTRACT TRUNCATED AT 400 WORDS)


Primary afferent terminals in the nucleus of the solitary tract of the frog: an electron microscopic study.
In the frog solitarius nucleus, primary afferent terminals of the facial and glossopharyngeal-vagal nerves were identified with cobalt labelling and electron microscopy. The labelled terminals were grouped in two main categories, one with small (1-2 micron) and pale terminals, and another with large (3-5 micron) and dark terminals. The small terminals greatly outnumbered the large ones. In addition many terminals intermediate in size and staining reactions were found. All kinds of labelled boutons contained medium-size clear synaptic vesicles, among which dense-core vesicles of the smaller type frequently occurred. The labelled primary afferent terminals established axo-dendritic contacts of the asymmetric type. Close to these contact sites they were themselves very frequently contacted by a profile interpreted as presynaptic in relation to them. Such profiles contained spherical, pleomorphic (including dense-core) or flattened vesicles; a fourth kind was interpreted as presynaptic dendrites. It is concluded that viscerosensory fibres, as opposed to somatosensory fibres, predominantly generate small and lightly stained terminals. It is likely that the effect of synaptic transmission at the solitarius tract terminals is modulated in a very versatile manner by the various presynaptic profiles converging on these terminals.


Certain background factors exhibit an association with an increased risk for pancreatic calcification among Japanese male alcoholics.
This was a cross-sectional study conducted from April 2003 through March 2004 to investigate the background factors related to pancreatic calcification (PC) in male Japanese alcoholics. Helical computed tomography examination revealed PC in 44 of 263 alcoholics, and this group was further divisible into 3 subgroups: "scant" (n = 24), "moderate" (n = 6), and "extensive" PC subgroups (n = 14). The extensive subgroup was associated with larger daily ethanol consumption (P = 0.05) and high-alcohol beverages, such as whisky (P = 0.02). The moderate subgroup was associated with a longer duration of habitual drinking (P = 0.04), whereas the scant PC group was associated with never having smoked (P = 0.05) and with low-alcohol beverages, such as beer (P = 0.09). None of the 40 subjects with inactive mitochondrial aldehyde dehydrogenase (ALDH2*2 allele) exhibited PC (P = 0.004). Heterozygous alcohol dehydrogenase 2 genotype (ADH2*1/2*2) exhibited an association with the scant subgroup (P = 0.02). The TG12 repeats in the cystic fibrosis transmembrane conductance regulator (CFTR) gene tended to have a weak association with PC. Drinking behavior, smoking status, and genetic backgrounds are associated with PC and are likely to increase the risk for alcoholic chronic pancreatitis.


Expression in Escherichia coli of active human alcohol dehydrogenase lacking N-terminal acetylation.
Human alcohol dehydrogenase (ADH, beta beta isozyme of class I) was expressed in Escherichia coli, purified to homogeneity, and characterized regarding N-terminal processing. The expression system was obtained by ligation of a cDNA fragment corresponding to the beta-subunit of human liver alcohol dehydrogenase into the vector pKK 223-3 containing the tac promoter. The enzyme, detected by Western-blot analysis and ethanol oxidizing activity, constituted up to 3% of the total amount of protein. Recombinant ADH was separated from E. coli ADH by ion-exchange chromatography and the isolated enzyme was essentially pure as judged by SDS-polyacrylamide gel electrophoresis and sequence analysis. The N-terminal sequence was identical to that of the authentic beta-subunit except that the N-terminus was non-acetylated, indicating a correct removal of the initiator methionine, but lack of further processing.


Hepatitis C virus infection in mouse hepatoma cells co-expressing human CD81 and Sip-L.
Although human CD81 has been shown to be essential for hepatitis C virus (HCV) infection, non-hepatic cells or transgenic animals expressing human CD81 alone did not support HCV replication. Co-expression of other cofactors was thus necessary for HCV replication. Previously, a hepatic factor named Sip-L was found to support HCV replication in an otherwise non-permissive cell line. To understand the species specificity of hepatic factors required for HCV replication, mouse hepatoma cells co-expressing human CD81 and Sip-L (Hepa1-6-CD81-Sip-L cells) were subjected for HCV infection assay. It was discovered that Hepa1-6-CD81-Sip-L cells were permissive for HCV infection and replication. An animal model was thus established by subcutaneous injection of the permissive cells into nude mice to generate tumors. Viral passages could be achieved in these animals. The antiviral effects of interferon and sodium stibogluconate administrated as a single agent or in combination were demonstrated in this animal model.


Evaluation of acquired acid resistance of enamel surrounding orthodontic brackets irradiated by laser and fluoride application.
Demineralization of enamel around orthodontic brackets is a clinical problem which can lead to some esthetic concerns like white spot lesions. The aim of this in vitro study was to evaluate the effect of the Er, Cr:YSGG laser and fluoride application on the acid resistance of enamel adjacent to orthodontic brackets. A total of 60 healthy, permanent, human premolars were selected and bonded with brackets, then they were randomly assigned to four groups (n = 15): topical APF gel (1.23% F, pH 3.5, for 4 min); Er,Cr:YSGG laser (P:0.25 W, E:12.5 mJ, RR:20 Hz, PD:140 μs, 11% air, without water, for 10 s); fluoride + laser group (F + L), and control group (C). All specimens were demineralized for 10 days in a 0.2 M acetate buffer solution, and the calcium content were subsequently determined with atomic absorption spectrometry. There were significant differences between the calcium content of F + L and F group in comparison to control group. The least concentration of calcium was seen in F + L group, and the most value was observed in C group. Combination of Er, Cr:YSGG laser with fluoride and fluoride alone decreased enamel solubility significantly more than laser alone. In addition, combination of laser and fluoride leads to less consumption of fluoride amount. And patients can use it at the beginning of treatment instead of daily use of fluoride. So we suggest using it in preventing enamel demineralization around orthodontic brackets.


Delphinidin-3-O-glucoside in vitro suppresses NF-κB and changes the secretome of mesenchymal stem cells affecting macrophage activation.
Anthocyanins are polyphenols that are promising chemopreventive agents. They stand out for their anti-inflammatory properties, with specific modulatory actions on the immune system. Additionally, regarding the immune system, a group of cells identified as mesenchymal stem cells (MSCs) have been attracting attention, mainly because of their capacity to migrate to sites of inflammation and produce potent immunomodulatory effects. Considering the ability of these cells to act on the immune system, as well as the properties of anthocyanins, especially delphinidin, in modulating the immune system, the aim of this study was to investigate the effects of delphinidin in influencing some immunoregulatory properties of MSCs. MSCs were cultivated in the presence of delphinidin 3-O-β-d-glycoside and cell viability, the cell cycle and the production of soluble factors (interleukin [IL]-1β, IL-6, IL-10, transforming growth factor [TGF]-β, prostaglandin E2 [PGE2] and nitric oxide [NO]) were evaluated, as was the expression of the transcription factors nuclear factor (NF)-κB and STAT3. Additionally, the effects of conditioned media from MSCs on macrophage activation were assessed. Delphinidin at 50 µM does not affect cell viability. In association with lipopolysaccharide, delphinidin was able to induce MSC proliferation. Additionally, delphinidin modulated the MSC immune response, showing increased levels of anti-inflammatory cytokines such as IL-10 and TGF-β as well as lower expression of NF-κB. Furthermore, conditioned media from MSCs inhibited macrophage metabolism, reducing the production of IL-1β, IL-12, and TNF-α and increasing IL-10. Overall, this work showed that delphinidin can modify the immunomodulatory properties of MSCs, increasing the IL-10 production by macrophages.


Qiliqiangxin affects L type ca(2+) current in the normal and hypertrophied rat heart.
Qiliqiangxin capsule is newly developed Chinese patent drug and proved to be effective and safe for the treatment of patients with chronic heart failure. We compared the effects of different dose Qiliqiangxin on L type Ca(2+) current (I(Ca-L)) between normal and hypertrophied myocytes. A total of 40 healthy Sprague-Dawley rats were used in the study. The rats were randomly divided into two groups (control group and hypertrophy group). Cardiac hypertrophy was induced by pressure overload produced by partial ligation of the abdominal aorta. The control group was the sham-operated group. After 1 month, cardiac ventricular myocytes were isolated from the hearts of rats. Ventricular myocytes were exposed to 10 and 50 μmol/L Qiliqiangxin, and whole cell patch-clamp technique was used to study the effects of Qiliqiangxin on I(Ca-L). The current densities of I(Ca-L) were similar in control group (-12.70 ± 0.53 pA/pF, n = 12) and in hypertrophy group (-12.39 ± 0.62 pA/pF, n = 10). They were not statistically significant. 10 and 50 μmol/L Qiliqiangxin can decrease I(Ca-L) peak current 48.6%±16.8% and 59.0%±4.4% in control group. However, the peak current was only reduced 16.73%±8.03% by 50 μmol/L Qiliqiangxin in hypertrophied myocytes. The inhibited action of Qiliqiangxin on I(Ca-L) of hypertrophy group was lower than in control group. Qiliqiangxin affected L-type Ca(2+) channel and blocked I(Ca-L), as well as affected cardiac function finally. Qiliqiangxin has diphasic action that is either class IV antiarrhythmic agent or the agent of effect cardiac function.


Atmospheric Deposition of Metals in TSP of Guiyang, PR China.
Total concentrations and speciation of metals had been studied in TSP of Guiyang from April 2006 and January 2007, PR China. The average concentration ranged from 14.48 ng m(-3) for Cd to 1,161.45 ng m(-3) for Zn. The concentrations of Cd, Cr, Pb and Zn were significantly higher during winter than those at other seasons. The environmentally mobile fractions of Cd and Zn were the highest in the three stages. The highest proportion of Pb was the fraction that bound to carbonate and oxide. Cr and Cu were clearly restricted to the fraction that bound to silicate and organic matter.


Motion-onset visual-evoked potentials as a function of retinal eccentricity in man.
Visual-evoked potentials were elicited by the motion-onset of a black-and-white square-wave grating of 2.4 cycles/deg that drifted from right to left at a velocity of 3 deg/s. The center of the 2 x 2 deg stimulus field was binocularly viewed either foveally or at eccentricities of 6, 12, or 20 deg in the lower visual field along the vertical meridian. Peak-to-peak amplitudes P1-N2 and N2-P2 were found to decrease non-linearly as a function of eccentricity. The VEP-amplitudes were standardized by setting each foveal value to 100%, and a relative measure was derived for peripheral values given by the ratio of the peripheral to the foveal values. The decrease of the relative VEP-values with eccentricity was significantly smaller than that of the relative cortical magnification factor of striate cortex in man, whereas it agreed fairly well with that of the relative point-image size of the area MT in Macaque monkey. In this respect, the motion-onset VEP is distinct from the pattern-reversal VEP, the amplitude of which decreases much more rapidly with retinal eccentricity; hence, it may involve different generating structures of the brain.


Sterility Cultures Following Pancreatectomy with Islet Autotransplantation in the Pediatric Population: Do They Matter?
Pancreatectomy with islet autotransplantation (IAT) is a treatment option for children with debilitating chronic pancreatitis. Sterility cultures from preservation solutions are often positive, yet their impact has not been well studied in children. A retrospective review of all patients who underwent IAT from 2015 to 2018 at a single institution was performed. Sterility culture data were obtained from both the pancreas transport and islet transplant media. All patients received prophylactic perioperative meropenem and vancomycin for 72 h per our protocol. If cultures resulted positive, antibiotics were extended for a total of 7 days. Primary outcomes were postoperative fever and 30-day infectious complications. Forty-one patients underwent IAT during the study period. Seventeen (41.5 %) patients had negative cultures of both the transport and transplant media, while 24 (58.5 %) patients had a positive culture from either sample. Of these patients, 13 (31.7 %) were positive in both, 10 (24.4 %) were positive in only the transport media, and 1 (2.4 %) was positive in only the transplant media. Patients with positive transplant media were similar with regard to age, gender, etiology, and disease duration compared to those with negative transplant media (all p > 0.05), but the positive group was more likely to have a pancreatic stent in place at the time of surgery (38.5 % vs. 4.2 %, p = 0.01). The overall postoperative infectious complication rate was 31.2 % (n = 13). No difference was detected between the transplant positive and negative culture groups in postoperative fever or 30-day infectious complications (p > 0.05 for each). An existing pancreatic stent at the time of pancreatectomy with IAT is a risk factor for positive sterility cultures. However, positive islet transplant media culture was not associated with increased risk of post-IAT infection or morbidity in the setting of an empiric antibiotic protocol. Future work is necessary to study the optimal perioperative antibiotic regimen in pediatric IAT.


Androgens increase excitement in brain organoid research.
Despite the surrounding controversy, quantitative sex-based differences exist in the human brain. In a recent issue of Nature, Kelava et al. shed light on the mechanisms underlying increased brain volume and neuron density in males, while highlighting the importance of human PSC-derived organoids for studying human development.


Conjunction of tumor cells with lymphocytes: implications for tumor invasion and metastasis.
Our previous studies have led to a novel hypothesis that tumor metastasis is triggered by aberrant lymphocyte infiltration that disrupts intercellular junctions and surface adhesion molecules and causes dissociation of tumor cells from the primary tumor core, allowing lymphocytes to conjoin with dissociated tumor cells and physically 'drag' them to different tissue sites. Our hypothesis is supported by morphological and immunohistochemical data from multiple types of human cancer. This hypothesis challenges the traditional belief that the physical conjunction between tumor cells and lymphocytes would lead to degeneration of the tumor cells. To validate our hypothesis, H&E and immunostained sections were examined under high magnification to identify potential signs of degeneration-related changes. Our study revealed that >60% of isolated tumor cells overlying focal capsule disruptions, or within the stroma and vascular structures, were physically conjoined with lymphocytes to form tumor cell-lymphocyte chimeras (TLCs). Approximately 90% of the tumor cell partners of TLCs were morphologically indistinguishable from their counterparts within the tumor core. In addition, one third of the tumor cells of TLCs expressed high levels of cell proliferation specific proteins, or were undergoing mitosis. Our study also revealed that a subset of dilated lymphatic ducts or blood vessels at the site of focal capsule disruptions harbored variable numbers of tumor cells, and the wall of these structures was in direct physical continuity with the myoepithelial cell layer. Our study suggests that the onset of tumor metastasis may occur in two forms: (1) lymphocyte-mediated shuttling that allows lymphocytes to physically 'drag' tumor cells to different sites, and (2) tumor progenitor-mediated angiogenesis that allows tumor cells to directly enter the vascular structures.


Allele frequencies and other forensic parameters of the HID-Ion AmpliSeq™ Identity Panel markers in Basques using the Ion Torrent PGM™ platform.
The HID-Ion AmpliSeq™ Identity Panel amplifies 90 autosomal SNPs and 34 Y- SNPs with massively parallel sequencing (MPS) using the Ion Torrent PGM™ platform. In the present study, 105 Basques were analyzed to assess this panel. All loci were in Hardy-Weinberg equilibrium and no association between them was detected. Forensic parameters were calculated as 5.74×10-36 for combined match probability and 99.99998% for combined power of exclusion. In conclusion, the HID Identity panel and the use of this new MPS technology are very promising tools for paternity testing and human identification in routine casework in the forensic field.


Acute coronary artery injury in dogs following administration of CI-1034, an endothelin A receptor antagonist.
The objective of this study was to characterize acute coronary artery injury evoked by the endothelin A receptor (ETAR) antagonist, CI-1034. Male dogs (n = 5) were intravenously administered CI-1034 at 120 mg/kg for 4 d. Control animals (n = 3) received vehicle. Macroscopically, drug-related hemorrhage was observed in the right coronary groove and atrium. Histologically, drugrelated coronary changes were characterized as medial hemorrhage and necrosis, with mixed inflammatory-cell infiltrates in the adventitia and media. Immunohistochemistry staining indicated increased expression of inducible nitric oxide synthase (iNOS), cleaved caspase-3, and S100A8/A9 (within in monocytes and neutrophils) proteins in coronary arteries of CI-1034-treated animals. However, there were similar expression levels of endothelial nitric oxide synthase (eNOS) among control and CI-1034-treated animals. Significant drug-related nitric oxide (NO) accumulation occurred on days 1 through 4 in serum. Increased interleukin (IL)-6 and fibrinogen in plasma and serum amyloid A (SAA) occurred on days 2 through 5 in CI-1034-treated animals. Increased levels of NO accumulation in serum; increased IL-6 and fibrinogen levels in plasma; increased SAA levels; and increased expressions of iNOS, cleaved caspase-3, and S100A8/A9 complex appear to be characteristic of CI-1034-induced acute vascular injury in dogs.


Stimulation of quiescent 3T3 cells by phosphatidic acid-containing liposomes.
Liposomes containing phosphatidic acid were capable of stimulating DNA synthesis in quiescent Swiss 3T3 cells while liposomes composed of other phospholipids were not. These results show that liposomes, which are usually employed to deliver non-lipid molecules into cells, can themselves have profound effects on cell growth. The possible mechanism of phosphatidic acid-mediated cell stimulation and its relation to other growth factors are discussed.


Effects of nerve stimulation on enzyme secretion from the in vitro rat pancreas and 3H-release after preincubation with catecholamines.
In the presence of the cholinergic antagonist atropine, electrical field stimulation (FS) (5-20 Hz) caused a marked, reversible increase in the amylase output from superfused rat pancreatic segments. Adrenaline and noradrenaline evoked dose-dependent increases in amylase output which were similar to those produced by FS. The FS- and catecholamine-evoked amylase secretions were abolished by the beta-adrenergic antagonist propranolol. The FS-evoked secretion could be abolished by either the removal of external Ca2+ or the application of tetrodotoxin (TTX, 2 X 10(-6) M). FS also resulted in a reversible increase in the fractional efflux of tritium (3H) from rat pancreatic tissues preincubated with either 3H-noradrenaline or 3H-adrenaline. The effects of FS (5-20 Hz) on 3H efflux were abolished by TTX (2 X 10(-6) M). TTX had no effect on the enhancement of 3H efflux caused by elevation of external potassium concentration (high K+, 75 mM). Removal of superfusate Ca2+ completely abolished both the FS- and high K+-induced increases in 3H efflux. These observations suggest that intrinsic nerve stimulation (i.e. FS) results in the Ca2+-dependent release of sympathetic neurotransmitter, noradrenaline, which has a direct secretory action on the rat pancreas. Furthermore, the findings suggest that adrenaline can be taken up by nervous elements. This raises the possibility that uptake and re-release of circulating adrenaline might contribute to the control of rat pancreatic enzyme secretion by the adrenergic nervous system.


The biology of peritonitis and implications for treatment.
Peritonitis continues to be one of the major infectious problems confronting surgeons. Despite the many advances in antimicrobial agents and supportive care, mortality from diffuse suppurative peritonitis remains unacceptably high. The authors review the anatomy and defense capabilities of the peritoneal cavity and then focus on the polymicrobial nature of peritonitis and how, through microbial interactions with host defenses, there is either resolution or persistent infection. They also consider possible infection-potentiating agents in the peritoneal cavity and experimental modes of therapy.