Role of aerosil dispersion on the activated kinetics of the LC1-xSilx system.
This study explores the role of aerosil dispersion on activated phase transitions of bulk octylcyanobiphenyl (8CB) liquid crystals by performing heating rate-dependent experiments. Differential scanning calorimetry (DSC) was used at various heating ramp rates in order to probe the activated phase dynamics of the system. The system, LC1-xSilx, was prepared by mixing aerosil nanoparticles (7 nm in diameter) in the bulk 8CB by the solvent dispersion method (SDM). LC represents bulk 8CB, and Sil represents aerosil nanoparticles with concentration x in percent. The concentration of the aerosil nanoparticles (x) varied from 0 to 0.2 g/cm3 in the bulk 8CB. Well-defined, endothermic peaks were found on a heating scan at melting and at the smectic-A to nematic (SmA-N) and nematic to isotropic (N-I) transitions. These peaks show a temperature shift and a change in their shapes and sizes in the presence of aerosil nanoparticles. In addition, an exothermic peak also appeared before the melting peak during the heating scan in the presence of aerosil nanoparticles. All transitions shifted significantly with different heating ramp rates, following an Arrhenius behavior, showing activated kinetics. The presence of aerosil nanoparticles caused a significant increase in the enthalpy and a decrease in the activation energy compared to the results found in bulk 8CB. This behavior can be explained by aerosil dispersion in the LC1-xSilx, inducing a disorder in the bulk 8CB. Infrared (IR) spectroscopy shows a shift to higher frequency for the broad peak at 1082 cm-1, corresponding to an Si-O bond as the density of the aerosil increases, and can be explained in terms of surface and molecular interactions between aerosil nanoparticles and 8CB liquid crystal molecules.


Cholecystokinin-2 Receptor Targeting with Radiolabeled Peptides: Current Status and Future Directions.
A wide variety of radiolabeled peptide analogs for specific targeting of cholecystokinin- 2 receptors (CCK2R) has been developed in the last decades. Peptide probes based on the natural ligands Minigastrin (MG) and Cholecystokinin (CCK) have a high potential for molecular imaging and targeted radiotherapy of different human tumors, such as Medullary Thyroid Carcinoma (MTC) and Small Cell Lung Cancer (SCLC). MG analogs with high persistent uptake in CCK2R expressing tumors have been preferably used for the development of radiolabeled peptide analogs. The clinical translation of CCK2R targeting has been prevented due to high kidney uptake or low metabolic stability of the different radiopeptides developed. Great efforts in radiopharmaceutical development have been undertaken to overcome these limitations. Various modifications in the linear peptide sequence of MG have been introduced mainly with the aim to reduce kidney retention. Furthermore, improved tumor uptake could be obtained by in situ stabilization of the radiopeptide against enzymatic degradation through coinjection of peptidase inhibitors. Recent developments focusing on the stabilization of the Cterminal receptor binding sequence (Trp-Met-Asp-Phe-NH2) have led to new radiolabeled MG analogs with highly improved tumor uptake and tumor-to-kidney ratio. In this review, all the different aspects in the radiopharmaceutical development of CCK2R targeting peptide probes are covered, giving also an overview on the clinical investigations performed so far. The recent development of radiolabeled MG analogs, which are highly stabilized against enzymatic degradation in vivo, promises to have a high impact on the clinical management of patients with CCK2R expressing tumors in the near future.


Immunotherapy as part of a multidisciplinary approach to melanoma treatment.
We have made tremendous advances in the earlier diagnosis and treatment of melanoma. Indeed, the early recognition and surgical management of thin primary cutaneous melanoma of less than 1.00 mm in Breslow's thickness has resulted in a >97% cure rate. For stage III and IV disease, our current treatment options are poor, with response rates well below 20% and only rare long-term responders noted. This is most clearly highlighted in a recent review by Rosenberg et al. who examined the role of immunotherapy in the treatment of patients with stage IV melanoma over a nine-year period. Overall, 96% of all patients had metastatic melanoma, utilizing a wide array of vaccine strategies including synthetic peptides, naked DNA, dendritic cells (DC) and recombinant viruses in patients with various advanced malignancies. They found that the overall objective response rate, utilizing conventional oncologic criteria for clinical tumor response, was only 2.6%. By combining the results of the Surgery Branch with the latter trials above, a total of 1,306 vaccine treatments have been given for an overall objective response rate of 3.3%. Such dismal results compel us to take a critical look at our current approach to tumor immunology and immunotherapy, with the intention of improving our current understanding of the complex interactions that occur within the tumor microenvironment. This in turn will provide us with new insight and direction as we design the next generation of vaccines for patients with advanced cancer and in particular melanoma.


REM sleep and memory.
Memory consolidation, a process which stabilizes recently acquired information into long-term storage, is thought to be optimized during sleep. Although recent evidence indicates that non-rapid-eye movement sleep (NREMs) is directly involved in memory consolidation, the role of rapid-eye movement sleep (REMs) in this process has remained controversial due to the extreme difficulty in experimentally isolating neural activity during REMs. Using a combination of electrophysiological recording and optogenetic techniques, recent work demonstrated for the first time that neural activity occurring specifically during REMs is required for spatial and contextual memory consolidation. Identifying the underlying mechanisms behind these observations, precisely how they translate to humans, and clarifying the extent of REMs' role in other modalities of memory are important challenges of future research with implications for human health.


Therapeutic applications of melatonin and related compounds.
Increasing knowledge of the pharmacological effects of melatonin has suggested various possible therapeutic applications for the hormone. Because, as a natural substance, melatonin cannot be patented, melatonin-related compounds have been synthesized by industrial groups. The scope of such compounds is also to specifically target the recently discovered melatonin receptor subtypes. The sleep-inducing properties of melatonin are disputed, but are distinct from those of benzodiazepines. The observed effects on sleep latency or sleep efficiency, which remain to be confirmed, could be accounted for by the effects of melatonin on core body temperature and on circadian rhythms. There is also an urgent need for safety data, both in animals and in humans, particularly when long-term use is envisaged.


Endovascular treatment of splenic artery aneurysms.
To assess the feasibility and effectiveness of endovascular treatment of splenic artery aneurysms (SAAs). Between May 2000 and June 2003 we treated 11 true SAAs in 9 patients (7 females and 2 males; mean age 58 years), 8 saccular and 3 fusiform, 4 located at the middle tract of the splenic artery, 5 at the distal tract and 2 intra-parenchymal. The diagnosis was performed with colour-Doppler ultrasound and/or CT-angiography; 7 patients were symptomless, 1 had left hypochondriac pain, and 1 had acute abdomen caused by a ruptured SAA. Four SAAs were treated by microcoil embolization of the aneurysmal sac with preservation of splenic artery patency; in 2 cases this was associated with transcatheter injection of N-butyl-2-cyanoacrylate. Four cases were treated by endovascular ligature, with sectoral spleen ischaemia. One ruptured SAA received emergency treatment with splenic artery cyanoacrylate embolization. Two intra-parenchymal SAAs were excluded, one by cyanoacrylate embolization of the afferent artery and the other by transcatheter thrombin injection in the aneurysmal sac. Technical success was observed in all cases (in 10/11 at the end of the procedure; in 1/11 at CT performed 3 days after the procedure). The follow-up (mean 18 months; range 6-36) was performed by colour-Doppler ultrasound and/or CT-angiography 3, 6 and 12 months after the procedure and subsequently once a year; the complete exclusion of the aneurysms was confirmed in 11/11 cases. The complications were: 4 cases of mild left pleuritis; fever and left hypochondriac pain 1 day after the procedure (in the same 4 patients and in one other case); 5 cases of sectoral spleen ischaemia and 1 case of diffuse spleen infarction with partial revascularization by collateral vessels. No alteration of the levels of pancreatic enzymes was found; a transitory increase in platelet count occurred only in the patient with diffuse spleen infarction. Using different techniques, endovascular treatment is feasible in nearly all SAAs. It ensures good immediate and long term results, and no doubt presents some advantages in comparison to surgical treatment, as it is less invasive and allows the preservation of splenic function.


Anaphylactic reactions to biological drugs.
This review summarizes the current knowledge of the pathogenic mechanisms of biologics-induced anaphylaxis, and the diagnostic and prophylactic strategies in the management of potentially reactive patients, to improve the safety profile of biologics. The recent knowledge on the topic highlights the involvement of both effector and regulatory mechanisms in the immune response to biological agents. In addition, the impact of biological's immunogenicity on hypersensitivity reactions has been confirmed in a wider number of studies, defining some details about the kinetics of antidrug antibodies development, specifically immunoglobulin G (IgG) and immunoglobulin E (IgE). Biological agents may induce anaphylaxis, mainly through the induction of antidrug antibodies. Biologics-related infusion reactions are often clinically consistent with type I hypersensitivity, but IgG antidrug antibodies may also be involved. The immune response toward biologicals is orchestrated by both effector and regulatory T cells. In addition, nonantibody-dependent mechanisms may occur. Among clinicians persists today again a low awareness, not only of the possibility to understand the immunological mechanisms behind anaphylaxis to biologicals but also the opportunity to apply potential strategies for the management of reactive patients aimed to guarantee a safe retreatment.


Role of potassium in vasopressin-induced production of cyclic AMP in rat renal papillary collecting tubule cells in culture.
The effect of potassium (K)-free medium on the stimulation of cyclic AMP (cAMP) production by arginine vasopressin (AVP) and forskolin was examined in rat renal papillary collecting tubule cells in culture. All experiments were performed in the presence of 3-isobutyl-l-methylxanthine (0.5 mmol/l). Cellular cAMP levels in response to 1 nmol and 0.1 mumol AVP/1 were 430.9 +/- 42.1 (S.E.M.) and 501.8 +/- 43.6 fmol/micrograms protein per 10 min respectively; these levels were significantly (P less than 0.01) higher than those in the vehicle-treated group (126.6 +/- 23.3 fmol/micrograms protein per 10 min). The cellular cAMP response to 1 nmol AVP/1 was significantly attenuated after 24 and 72 h of exposure of cells to K-free medium, cellular concentrations of cAMP being 280.2 +/- 37.1 and 233.0 +/- 9.6 fmol/microgram protein per 10 min respectively. The response of cAMP to AVP remained unchanged when the cells were preincubated with K-free medium for 1 h. Similarly, forskolin (20 nmol/l)-stimulated cellular cAMP production was also significantly impaired after 24 or 72 h of exposure of cells to K-free medium. When the cells preincubated in K-free medium were again exposed for 1 h to K-replete medium containing 5 mmol KC1/1, cellular cAMP production in response to AVP or forskolin recovered totally. Cellular protein and ATP content and cellular viability were not altered by exposure of cells to K-free medium for 24 h, and thus the impaired cAMP response to AVP or forskolin in the K-depleted cells was independent of altered cellular viability and source of ATP.(ABSTRACT TRUNCATED AT 250 WORDS)


DDX17 nucleocytoplasmic shuttling promotes acquired gefitinib resistance in non-small cell lung cancer cells via activation of β-catenin.
Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are effective for non-small cell lung cancer (NSCLC) patients with EGFR mutations, almost all these patients will eventually develop acquired resistance to EGFR-TKI. However, the molecular mechanisms responsible for gefitinib resistance remain still not fully understood. Here, we report that elevated DDX17 levels are observed in gefitinib-resistant NSCLC cells than gefitinib-sensitive cells. Upregulation of DDX17 enhances the gefitinib resistance, whereas DDX17-silenced cells partially restore gefitinib sensitivity. Mechanistically, we demonstrate that DDX17 disassociates the E-cadherin/β-catenin complex, resulting in β-catenin nuclear translocation and subsequently augmenting the transcription of β-catenin target genes. Moreover, we identify two nuclear localization signal (NLS) and four nuclear export signal (NES) sequences mediated DDX17 nucleocytoplasmic shuttling via an exportin/importin-dependent pathways. Interruption of dynamic nucleocytoplasmic shuttling of DDX17 impairs DDX17-mediating the activation of β-catenin and acquired resistance in NSCLC cells. In conclusion, our findings reveal a novel and important mechanism by which DDX17 contributes to acquired gefitinib resistance through exportin/importin-dependent cytoplasmic shuttling and followed by activation of β-catenin, and DDX17 inhibition may be a promising strategy to overcome acquired resistance of gefitinib in NSCLC patients.


Evaluation of the Analgesic Effect of Combination Therapy on Chronic Plantar Pain Through the Myofascial Trigger Points Approach.
Closely related pathologic disorders sometimes manifest with the same symptoms, making for a complex differential diagnosis. This is the situation in plantar fasciitis (PF) and myofascial pain syndrome (MPS) with myofascial trigger points (MTPs) in the sole of the foot. This research assessed the analgesic effect on plantar pain of combination therapy with interferential current stimulation therapy (ICST), treating MTPs in the great toe adductor muscle and the short flexor muscles of the toes in patients whose diagnosis was compatible with PF or MPS. This study included 22 feet of 17 patients with a diagnosis compatible with PF or MPS with MTP. Participants received combination therapy with ICST for 15 sessions, and the decrease in pain was measured with an algometer and the visual analog scale. Both measurements were taken before and after every fifth session. The pressure pain threshold (PPT) results obtained with the Student t test and the pain intensity perception (PIP) results obtained with the Wilcoxon signed rank test were analyzed by comparing the measurements taken before the treatment and after the fifth, tenth, and 15th sessions. The decrease in PIP was significant after the fifth, tenth, and 15th sessions ( P < .001). The increase in PPT was also significant after the fifth ( P = .010), tenth ( P = .023), and 15th ( P = .001) sessions ( P < .05). The suggested combination therapy of ultrasound with ICST is clinically significant for reducing plantar pain after 15 treatment sessions, with a 6.5-point reduction in mean PIP and a 4.6-point increase in PPT.


The paraventricular nucleus modulates thyroidal motilin release and rat gastric motility.
Motilin, an important endocrine regulator of gastrointestinal motility, was once considered to be produced in the gastrointestinal tract and brain. In recent years, however, motilin has been found in the human thyroid, as well as in that of the guinea pig. The physiological function and central modulation of thyroidal motilin remain poorly understood. To determine the functional role of thyroidal motilin, we observed the concentration of motilin in the plasma and also gastric motility before and after thyroidectomy. Our studies show that both the concentration of plasma motilin and gastric motility were decreased after thyroidectomy. To explore modulation-related nuclei, a c-Fos immune response experiment was carried out. The PVN of the hypothalamus was the main area of reactivity after thyroidectomy. Subsequently, we studied the effects of electrical excitation and PVN lesions on gastric motility and the expression of motilin in the thyroid and plasma. Excitation of the PVN was shown to prompt gastric motility that was partly prevented by the motilin receptor antagonist, GM-109. The effects of PVN excitation on gastric contraction were significantly reduced in thyroidectomised rats. In addition, the expression of motilin in the thyroid was significantly increased after PVN excitation and decreased after PVN lesions. The changes in the concentration of motilin in plasma induced by PVN stimulation were positively correlated with changes of gastric motility. In our in vitro study, the motilin secreted from TT cells (a parafollicular cell line originating from human thyroid medullary carcinoma) gradually increased on day 6 of culture, and motilin and calcitonin (CT) were co-expressed in TT cells. These results demonstrate that motilin from the thyroid could be secreted into the peripheral plasma and affect gastric motility and that PVN was a central nucleus for modulating gastric motility and motilin expression in the thyroid.


Knowledge deficit, attitude and behavior scales association to objective measures of sun exposure and sunburn in a Danish population based sample.
The objective of this study was to develop new scales measuring knowledge and attitude about UVR and sun related behavior, and to examine their association to sun related behavior objectively measured by personal dosimetry. During May-August 2013, 664 Danes wore a personal electronic UV-dosimeter for one week that measured their UVR exposure. Afterwards, they answered a questionnaire on sun-related items. We applied descriptive analysis, linear and logistic regression analysis to evaluate the associations between the questionnaire scales and objective UVR measures. Perceiving protection as routine and important were positively correlated with protective behavior. Knowledge deficit of UV and risk of melanoma, perceived benefits and importance of protection behavior was also correlated with use of protection. 'Knowledge deficit of UV and risk of melanoma and Perceived barrier towards sun avoidance between 12 and 15' were both associated with increased risk of sunburn. Attitude towards tan was associated to both outdoor time and exposure as well as use of protection, but not to sunburn. The results regarding Knowledge deficit of UV and risk of melanoma associated to UVR exposure and Perceived barrier towards sun avoidance between 12 and 15 emphasize the importance of awareness of melanoma risk and the priority of the skin cancer prevention advice. Shifting activities to outside the suns peak-hours could be an approach for structural and campaign preventive measures. Knowledge of items predicting exposure to UVR, use of protection and sunburn are important for planning of preventive interventions and melanoma research.


[Evaluation of an advisory program in antibiotic therapy].
Increases in microbial resistance and pharmaceutical costs have prompted an interest in antibiotic control programs (ACP). Nevertheless, there is controversy on the optimal ACP design and implementation. An ACP based on the infectious diseases' specialist recommendations was evaluated. Interventional study of two hospital departments (medical and surgical). Antibiotic costs, mortality rate, readmissions following an infectious disease, and incidence of MRSA and Clostridium difficile between the intervention period and the same period in the previous year were compared. An anonymous survey among health care workers in both departments was conducted. One-hundred and one antimicrobial therapy courses administered to 80 patients were evaluated. A total of 77 recommendations were issued, which consisted of therapy discontinuation (39%), switch to oral antibiotics (31%), decrease in the antimicrobial spectrum (24%) or enhancing the antimicrobial spectrum (6%). Eighty-five percent of the recommendations were accepted. The antimicrobial use remained stabilized, but the oral administration increased from 12.5 to 18.6 DDD/100 patient-days and parenteral use decreased from 25.9 to 22.3 DDD/100 patient-days. Antimicrobial costs decreased by 19.4% (901,794 pesetas). No changes, either in the mortality rate or in readmission rate due to infectious diseases was observed. In contrast, a decrease in the incidence of both MRSA (3.7% to 0.8%; p < 0.05) and Clostridium difficile (1.2% to 0%; p = 0.05) was observed. All health care workers that responded to the survey thought that ACP should be extended to the rest of the hospital. Our ACP, based on the advice of an infectious diseases specialist, was very well accepted and allows for a decrease in antibiotic costs by simplified therapy. The ACP did not cause a negative impact on patients' outcomes and would probably help reducing the incidence of some nosocomial pathogens.


The effects of chronic prenatal exposure to nicotine on the behavior of guinea pigs (Cavia porcellus).
Three groups of 15 offspring from guinea pig dams were injected twice daily throughout gestation with one of three doses (0.5, 1.5 or 2.5 mg/kg) of nicotine-hydrogen tartrate. These offspring and 15 saline-exposed offspring were tested on several behavioral measures. Offspring of nicotine-treated dams had significantly lower rates of spontaneous alternation as neonates. The 1.5 and 2.5 mg/kg nicotine-exposed offspring also alternated less at puberty than control offspring and would not enter an unfamiliar stimulus alley that a majority of controls entered. Nicotine offspring, as adults, performed significantly poorer than their controls on errors and trials to criterion on a discrimination and reversal task. Prenatal nicotine treatment resulted in performance deficits on both learned and innate behavioral measures throughout development and adulthood.


Method validation, dissipation and residue status of fluopicolide and fosetyl-aluminium in citrus using a rapid extraction method coupled with ultra-performance liquid chromatography-tandem mass spectrometry.
The dissipation and residue status of a combination of fluopicolide and fosetyl-aluminium (fosetyl-Al) in citrus were evaluated in an experimental field. An efficient and sensitive liquid chromatography-tandem mass spectrometry, with rapid extraction, was carried out according to the SANTE guidelines. During the method validation, the recovery was within the range of 106.1-117.5, 94.4-115 and 85.4-109.5%, for fluopicolide, its metabolite 2,6-dichlorobenzamide and fosetyl-Al, respectively, with a relative standard deviation (RSD) of 0.3-10.6%. As a result, accuracy and precision at the spiking concentrations of 0.01, 0.05 and 0.10 mg/kg in citrus were within the acceptable range of 70-120% with an RSD of 20%. The amount of the deposits of fluopicolide, 2,6-dichlorobenzamide and fosetyl-Al was less than the limit of quantification (LOQ) at 0.01 mg/kg at 0 day, adhering to the application in standard [1.77 + 2.66 g of active ingredient (a.i.)/L] and double (3.54 + 5.32 g a.i./L) doses. The present study proposes that the utilisation of fluopicolide and fosetyl-Al in citrus and the soil may not pose a health or environmental hazard provided that good agricultural practices are followed.


Unscheduled return visits with and without admission post emergency department discharge.
Monitoring unscheduled return visits to the Emergency Department (ED) is useful to identify medical errors. To investigate the differences between unscheduled return visit admissions (URVA) and unscheduled return visit no admissions (URVNA) after ED discharge. From January 1, 2008 to March 31, 2008, URVA and URVNA patients who returned within 3 days after ED discharge were enrolled in the study. We compared the clinical characteristics, underlying diseases, ED crowding indicators, staff experience at the patient's first visit, and several other risk factors. We used multivariate logistic regression to evaluate differences between the two groups and to identify predictors of admission from unscheduled return visits. The unscheduled return visit rate was 3.1%. Of the 413 patients included, 147 patients (36%) were admitted, and had a mortality rate of 4.1%. The most common reason for the return visit was an illness-based factor (47.9%). Compared to URVNA patients, unscheduled return visit admissions had higher prevalence rates for old age, non-ambulatory status, high-grade triage, and underlying diseases (e.g., malignancy, diabetes mellitus, hypertension, coronary artery disease, heart failure, and chronic obstructive pulmonary disease). The independent predictors for URVA were: age≥65 years (adjusted odds ratio [OR] 2.2, 95% confidence interval [CI] 1.4-3.5); high-grade triage (adjusted OR 2.1, 95% CI 1.3-3.2); and doctor-based factors (adjusted OR 3.5, 95% CI 2.0-6.1). More advanced staff experience (p=0.490) and ED crowding were not significant predictors (p=0.498 for whole-day number of patients, p=0.095 for whole-shift number of patients). Old age, high-grade triage, and doctor-based factors were found to be significant predictors for URVA, whereas advanced staff experience and ED crowding were not.


Glucosylceramide: a marker for multiple-drug resistant cancers.
Multiple-drug resistance (MDR) is a major reason for chemotherapy failure. Herein we describe glucosylceramide, a new marker for MDR. Cellular lipids were analyzed in three human MDR cancer cell lines and their drug-sensitive counterparts. Analysis of glucosylceramide was also performed in six melanoma specimens and one breast tumor specimen obtained from patients who had undergone chemotherapy. Glucosylceramide, analyzed by mass and by cellular utilization of radiolabeled precursor ([3Hpalmitic acid), was isolated by lipid extraction techniques and resolved from other components by thin-layer chromatography. Glucosylceramide was present consistently in all MDR cell lines and was absent, or present only at very low levels, in the corresponding drug-sensitive cells. Examination of human tumor specimens documented presence of the marker in all patients who had failed chemotherapy, and absence of the marker in each of the patients with known clinical response to chemotherapy. The response to chemotherapy was followed for a median of 8 months in melanoma patients and for 22 months in the breast cancer patient. These findings suggest that glucosylceramide may hold clinical significance for the early identification of drug-resistant tumors.


The influence of cancer on endocrine, immune, and behavioral stress responses.
Tumors perturb various physiological systems beyond their local microenvironment, including the immune, nervous, and metabolic systems. Given the involvement of these systems in physiological stress responses, the goal of this review is to compile evidence regarding whether or not cancer alters acute stress responses. Here, we focus on stress responses that are endocrine, immune, or behavioral. This question is clinically relevant as cancer patients are exposed to many stressors throughout diagnosis and treatment, and then later as survivors. Alterations in their stress responses may specifically affect how they respond to advice, treatments, and surgery under duress. To determine whether tumors alone alter stress responses, the relevant literature using rodent cancer models is first reviewed. Next, the more complicated clinical literature in cancer patients is integrated into the discussion. Based on the results of this analysis, goals for future basic and clinical research are proposed. This work aims to advance our understanding of the most effective methods for treating cancer patients and supporting their long-term survival.


An unusual combination of an anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA) and a right coronary artery system with two separate ostia from the aorta in an adult.
We describe a patient with an infrequent combination of variants in both the right and the left coronary arterial ostia, namely a combination of two separate right coronary artery (RCA) ostia from the aorta, and an anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA). To our knowledge, such a combination has not been previously reported. Based on published statistics for individual variants, such a combination is expected to occur approximately once for every 500,000 to one million live births. ALCAPA and dual RCA anatomy was characterized in our patient by echocardiography, conventional angiography, and multidetector computed tomography before and after Takeuchi repair.


Does Vancomycin Powder Decrease Surgical Site Infections in Growing Spine Surgery?: A Preliminary Study.
Vancomycin powder has been demonstrated to be safe in children, and yet there are no data on its use to reduce surgical site infections (SSIs) in surgery for early-onset scoliosis. We performed a retrospective study of our patients treated for early-onset scoliosis in the period of 2010 to 2016. In 2010, we updated our standardized perioperative growing spine care path. The only later change was the gradual introduction of intrawound vancomycin powder. Procedures were categorized into either the control group (without vancomycin powder) or the experimental group (with vancomycin powder), with otherwise identical perioperative management. Initial insertion, revision, and lengthening procedures and final fusions were included. We compared the rate of postoperative SSIs per procedure between the groups. Thirty-six patients who underwent 191 procedures met the inclusion criteria. The clinical and radiographic data were essentially the same between the groups. During the study period, 14 (39%) of the 36 patients developed ≥1 deep SSI. Only 2 patients had multiple acute infections. There were 87 procedures with 12 infections in the control group (SSI rate of 13.8% per procedure), while there were 104 procedures with 5 infections in the vancomycin group (4.8% per procedure). The difference in the SSI rate per procedure was significant (p = 0.038). The number of individual procedures needed to be performed using vancomycin to prevent an SSI was 10.9. The use of vancomycin powder in growing spine surgery for early-onset scoliosis is associated with a significant decreased risk of SSI. It appears to be effective even when previous surgeries have been performed without its use. Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.


Incorporating Oxygen Atoms in a SnS2 Atomic Layer to Simultaneously Stabilize Atomic Hydrogen and Accelerate the Generation of Hydroxyl Radicals for Water Decontamination.
Photoelectrocatalysis (PEC) is an efficient way to address various pollutants. Surface-adsorbed atomic hydrogen (H*) and hydroxyl radicals (•OH) play a key role in the PEC process. However, the instability of H* and low production of •OH considerably limit the PEC efficiency. In this study, we noted that incorporating oxygen atoms could regulate the behavior of H* by creating a locally favorable electron-rich state of S atoms in the SnS2 catalyst. The finely modulated H* led to a 12-fold decrease in the overpotential of H2O2 generation (H*-OOH*-H2O2-•OH) by decreasing the activation energy barrier of OOH* (rate-determining step). Considering density functional theory calculations, an H*-•OH redox pair suitable for a wide pH range (3-11) was successfully constructed based on the photocathode. The optimal SnS1.85O0.15 AL@TNA photocathode exhibited a ∼90% reduction in Cr(VI) in 10 min and ∼70% TOC removal of 4-nitrophenol, nearly 2- and 3-fold higher than that without oxygen incorporation. Electron spin resonance spectrometry and radical quenching experiments verified that H* and the derived •OH via 1-electron and 3-electron reduction were the main active species. Operando Raman spectroscopy confirmed that the stable SnO2 phase helped constantly activate the production of H* and •OH.


Heritable aspects of biological motion perception and its covariation with autistic traits.
The ability to detect biological motion (BM) and decipher the meaning therein is essential to human survival and social interaction. However, at the individual level, we are not equally equipped with this ability. In particular, impaired BM perception and abnormal neural responses to BM have been observed in autism spectrum disorder (ASD), a highly heritable neurodevelopmental disorder characterized by devastating social deficits. Here, we examined the underlying sources of individual differences in two abilities fundamental to BM perception (i.e., the abilities to process local kinematic and global configurational information of BM) and explored whether BM perception shares a common genetic origin with autistic traits. Using the classical twin method, we found reliable genetic influences on BM perception and revealed a clear dissociation between its two components-whereas genes account for about 50% of the individual variation in local BM processing, global BM processing is largely shaped by environment. Critically, participants' sensitivity to local BM cues was negatively correlated with their autistic traits through the dimension of social communication, with the covariation largely mediated by shared genetic effects. These findings demonstrate that the ability to process BM, especially with regard to its inherent kinetics, is heritable. They also advance our understanding of the sources of the linkage between autistic symptoms and BM perception deficits, opening up the possibility of treating the ability to process local BM information as a distinct hallmark of social cognition.


Trapping and apoptosis of novel subsets of memory T lymphocytes expressing CCR6 in the spleen of HIV-infected patients.
CCR6, a homeostatic chemokine receptor, is shown here to characterize subsets of both central and effector memory T cells that secrete high levels of IL-2 and TNF-alpha in response to polyclonal and antigen-specific stimulation. CCR6(+) T lymphocytes disappeared dramatically from the peripheral blood of HIV-infected patients as HIV disease progressed. The capacity of CD4(+)CCR6(+) to secrete multiple cytokines remained intact among HIV-infected long-term nonprogressors but was partially lost from subjects with standard disease progression. CCR6(+) T lymphocytes, regardless of their CCR7 expression, accumulated in the spleen of HIV-infected patients, where they died by apoptosis. Assessment of CCR6 expression allowed us to describe novel memory T-cell subpopulations capable of high cytokine production and provided evidence of a pathologic CCR6-dependent pathway of memory T-cell homing that may participate in the loss of memory response against infections.


[Diabetes mellitus and fibrinolysis (experience with an in vitro clot lysis test)].
After a concise review on fibrinolysis in diabetes mellitus, special attention is given to the observations suggesting impaired fibrinolysis in non-insulin dependent diabetes mellitus and in hyperinsulinaemia. This fibrinolytic defect, based mainly upon indirect data, may contribute to the development of macroangiopathy. The results discussed here, gained by a simple in vitro clot lysis assay revealed decreased fibrinolytic properties in some of the non-insulin dependent diabetic patients, however the mean value did not differ significantly from the control. The potential profibrinolytic effect of different antidiabetic treatment profibrinolytic effect of different antidiabetic treatment modalities also received attention. The clinical significance of the apparent alteration of fibrinolysis in diabetes mellitus should be evaluated appropriately as a part of a complex disturbance of haemostatic balance in diabetes mellitus. Further studies and improved fibrinolytic methods seems to be required to ascertain a causal relationship between altered fibrinolysis and diabetic vascular complications.


Comparative bioavailability study of two tablet formulations of cimetidine.
A two-way crossover bioavailability study of two commercial cimetidine formulations was performed on 24 healthy male volunteers. Drug was administered after an overnight fast and plasma samples were withdrawn periodically for 12 h. Urine was collected throughout the study period. Results indicated that the two formulations were bioequivalent since no statistically significant difference in means was detected for any of the parameters studied. Extensive interpatient variation in cimetidine blood concentration was observed during both treatments.


Developmental modulation of protein synthetic patterns by the human malarial parasite Plasmodium falciparum.
Under conditions of in vitro culture, Plasmodium falciparum incorporated amino acids into particulate (membrane) and soluble proteins in a pattern which changed sequentially and which was dependent upon the stage of parasite maturation. Synchronized cultures pulse labeled with a mixture of 15 14C-labeled amino acids or [14C]histidine alone displayed stage-related patterns of polypeptide biosynthesis. Certain plasmodial proteins were associated with both particulate (membrane) and soluble fractions, whereas others appeared to be specific to a given fraction. Proteolysis of intact infected cells with pronase under conditions which removed 97 +/- 2.2% of the endogenous red cell acetylcholinesterase activity did not cause the apparent removal of any radiolabeled proteins; this suggests the absence of externally exposed, parasite-synthesized proteins in the infected red cell membrane. Such a result was consistent whether the radiolabel was [14C]histidine or the 14C-labeled amino acid mixture. These results indicate that specific modulation of parasite biosynthetic patterns occurs during the asexual reproductive cycle and is probably one mechanism whereby parasite differentiation occurs. Despite the formation of surface excrescences on infected red cells containing mature parasites, results of surface digestion experiments failed to demonstrate the presence of surface-exposed plasmodial proteins.


Targeted Therapies in Adult B-Cell Malignancies.
B-lymphocytes are programmed for the production of immunoglobulin (Ig) after antigen presentation, in the context of T-lymphocyte control within lymphoid organs. During this differentiation/activation process, B-lymphocytes exhibit different restricted or common surface markers, activation of cellular pathways that regulate cell cycle, metabolism, proteasome activity, and protein synthesis. All molecules involved in these different cellular mechanisms are potent therapeutic targets. Nowadays, due to the progress of the biology, more and more targeted drugs are identified, a situation that is correlated with an extended field of the targeted therapy. The full knowledge of the cellular machinery and cell-cell communication allows making the best choice to treat patients, in the context of personalized medicine. Also, focus should not be restricted to the immediate effects observed as clinical endpoints, that is, response rate, survival markers with conventional statistical methods, but it should consider the prediction of different clinical consequences due to other collateral drug targets, based on new methodologies. This means that new reflection and new bioclinical follow-up have to be monitored, particularly with the new drugs used with success in B-cell malignancies. This review discussed the principal aspects of such evident bioclinical progress.


Militarinone A induces differentiation in PC12 cells via MAP and Akt kinase signal transduction pathways.
The fungal metabolite militarinone A (MILI A) promotes neurite outgrowth in PC12 cells. This study was conducted to investigate the signaling pathways involved in the cellular differentiation processes induced by the compound, with a focus on cascades implicated with nerve growth factor (NGF)-mediated neuritogenesis. MILI A possessed pronounced amphiphilic properties. The compound rapidly accumulated in the cell membrane and was slowly released into the cytoplasma. In primed PC12 cells, an early activation of protein kinase B (Akt), representing a downstream target of phosphoinositol 3 (PI3) kinase, and a delayed phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2), and of transcription factor cAMP responsive element binding protein (CREB) was found. The NGF-dependent activation of c-Jun amino terminal kinase (SAPK/JNK1) was potentiated. Morphological differentiation of cells and the phosphorylation of specific signal molecules were blocked by the MAP kinase (MEK1) inhibitor PD098059, the PI3-kinase (PI3K) inhibitor wortmannin and the adenylyl cyclase inhibitor 9-cyclopentyladenine.


Stroke mortality in Andalusia (Spain) from 1975 to 1999: effect of age, birth cohort and period of death.
The aim of this study was to analyze stroke mortality rates in Andalusia during the period from 1975 to 1999 by studying age, cohort and period effects. Deaths due to stroke along with the corresponding population figures were divided into 11 age groups and five 5-year periods. From this, age-specific mortality rates for 15 birth cohorts were then computed. These were plotted and fitted to Poisson regression models to assess age, period and cohort effects. An exponential age effect was present for both sexes regardless of cohort or period. The rates of stroke mortality decreased significantly among both sexes in Andalusia during the study period, although in recent years, this declining trend has started to slow down, primarily in males. Age- and period-adjusted stroke mortality was greater for earlier cohorts and lower for generations born at the beginning of the 20th century.


Families of homicide victims: psychiatric responses and help-seeking.
The number of homicides in the UK is increasing: 850 homicides were recorded in England and Wales last year, but little is known about their impact on surviving family members. This study describes their psychological and social effects. Relatives seeking help from Victim Support were surveyed about their experiences, responses and help-seeking and asked to complete a number of psychological measures. Victim Support workers provided additional information. High levels of post-traumatic stress symptomatology and generalized distress were identified, as well as an increase in prescribed psychotropic medication. Other effects included increases in anger and irritability, cigarette consumption and loss of employment. However, few family members had been referred for professional treatment.


Self sampling as part of screening for sexually transmitted diseases in clinic attenders. A preliminary study.
Self sampling of the secretions of the female genital tract for microbiological investigations for Neisseria gonorrhoeae, Chlamydia trachomatis and Trichomonas vaginalis was assessed in female attenders of the genitourinary medicine clinic in Coventry and Warwickshire Hospital. The purpose of the study was to evaluate the possibility of offering this method of investigation to workers in the sex industry, who are reluctant to attend GUM Clinics. This Pilot Study aimed at assessing the feasibility and acceptability of self sampling of the secretions of the lower genital tract by female patients and its reliability in the detection of sexually transmitted infections. The analysis of the data from 75 participants, indicated that 7 infections were detected on patient sampling as compared to 11 on samples taken by a physician. Self sampling may prove a valuable alternative for the sex industry workers who are reluctant to attend GUM clinics.


VDT work, oculomotor strain, and subjective complaints: an experimental and clinical study.
Two studies, one experimental and one clinical, are presented. Study I examines the effect of three hours of continuous VDT work (text-editing) on a set of optometric and health-related variables in an experimental design with two matched groups, one experimental (n = 18) and one control group (n = 19). Doing the same keyboard activities for 3 h as the experimental group, the control group was looking out of a window instead of at the display while working (distance viewing). There were significant group differences in work related effects on the eyes' ciliary and extraocular muscles and on subjective symptoms, indicating that not only visual symptoms but also muscle pain in the head, neck, and upper back regions may result from near-point induced oculomotor strain. Study II shows the health effect of optical corrections on symptomatic VDT workers (n = 14). There is a significant pre-post reduction in symptoms, indicating that visual anomalies contribute to work-related symptoms. The results of both studies are discussed in a visual ecological perspective.


Selection of patients with stage B prostate cancer for radical prostatectomy.
There are several areas of concern in dealing with clinical stage B disease. First, understaging is common. Second, recognition of extension into the seminal vesicles is important. Third, the patient's predicted life expectancy must be taken into account. Moreover, even clinically localized prostate cancer may have metastasized, and the need for surgical staging by lymph node dissection has been a significant factor in the authors' preference for radical retropubic rather than radical perineal prostatectomy. Neither of the two serum markers in clinical use is an absolute predictor of stage. Analysis of tumor ploidy may prove useful, and transrectal ultrasound warrants further study. In the elderly patient, the urologist certainly may elect to monitor the tumor without definitely deciding on operative versus conservative treatment.


Long-term control of diabetes mellitus and periodontitis.
The purpose of this study was to evaluate the association between long-term control of diabetes mellitus (DM) and periodontitis. A total of 75 diabetics (Type I or II) aged 20-70 years with long-term records of their diabetic control were selected for the study. The following periodontal variables were recorded in a randomized half-mouth examination: plaque, calculus (+/-), probing depth (pd) and attachment loss (al). The mean of glycosylated hemoglobin measurements (HbAlc) over the past 2-5 years was used to indicate the long-term control of DM. The study participants were divided into well-, moderately- and poorly-controlled diabetics. An increase in the prevalence, severity and extent of periodontitis with poorer control of diabetes was observed. The extent of calculus also increased with poorer control. In a multiple regression analysis, calculus and long-term control of diabetes were significant variables when pd > or = 4 mm was used as the dependent variable. Age was a significant predictor for al > or = 3 mm but not for pd > or = 4 mm. Sex, duration and type of DM were not significant variables in the regression models. Less than 2% of sites with no calculus demonstrated pd > or = 4 mm. When calculus was present, the frequency of pd > or = 4 mm increased from 6% in the well-controlled diabetics to 16% in the poorly-controlled ones. We conclude that periodontitis in diabetics is associated with long-term metabolic control and presence of calculus.(ABSTRACT TRUNCATED AT 250 WORDS)


Recent Advances in Cell Electrospining of Natural and Synthetic Nanofibers for Regenerative Medicine.
The progression of nanotechnology provides opportunities to manipulate synthetic and natural materials to mimic the natural structure for tissue engineering applications. The electrospinning technique applies electrostatic principle to fabricate electrospun nanofibers. Nanofiber scaffolds are precisely similar to the native extracellular matrix (ECM) and support cell proliferation, adhesion, tendency to preserve their phenotypic shape and directed growth according to the nanofiber direction. This study reviewed both the natural and synthetic type of nanofibers and described the different properties used to trigger certain process in the tissue development. Also, the potential applications of electrospun scaffolds for regenerative medicine were summarized.


KIRKIA ACUMINATA OLIV.: A REVIEW OF ITS ETHNOBOTANY AND PHARMACOLOGY.
Local communities in sub-Saharan Africa have a long history of medicinal plant usage. Like in other parts of the developing world, rural and urban communities are still dependent on herbal medicines for primary health care, and the use of herbal medicines is still an integral part of their daily life and socio-cultural life style. The objective of this paper is to summarise information on the ethnobotany and pharmacology of Kirkia acuminata Oliv. throughout its distributional range. The information documented in this article is derived from books, theses, scientific journals and reports obtained from library collections, Scopus, Pubmed, MEDLINE, ISI Web of Science, Google Scholar and Science Direct. Kirkia acuminata is the most known and widely distributed Kirkia species in the genus and is one of the most popular and promising plant resources due to its several beneficial uses. Kirkia acuminata is used to treat abdominal pains, backache, cholera, constipation, cough, diarrhea, dysentery, snake bites, toothache and wounds. Other applications include its use as charcoal; hedge, ornamental or shade; stock feed, timber and source of water during drought periods. Preliminary phytochemical assessment of roots and stem bark of K. acuminata showed presence of lignans, neo-lignans, nor-carotinoids and other compounds. The extracts of K. acuminata exhibited antibacterial and antimycobacterial activities. These phytochemical compounds may be responsible for the medicinal uses and biological activities demonstrated by K. acuminata. Detailed research is required aimed at exploring mode of action of bioactive compounds of Kirkia acuminata that are responsible for the documented pharmacological effects. Kirkia acuminata is an important plant species that has potential to contribute to the primary health care and livelihood improvement of local communities in the geographical areas where it is indigenous and found in abundance.


A bi-functional siRNA construct induces RNA interference and also primes PCR amplification for its own quantification.
RNA interference (RNAi) is a process of post-transcriptional gene silencing initiated by double-stranded RNAs, including short interfering RNA (siRNA). Silencing is sequence-specific and RNAi has rapidly become central to the study of gene function. RNAi also carries promise for selective silencing of viral and endogenous genes causal for disease. To detect the very low levels of siRNA effective for RNAi we modified the 3' end of the sense strand of siRNA with a nuclease-resistant DNA hairpin. We show that the modified siRNA-DNA construct (termed 'crook' siRNA) functions as a primer for the PCR and describe a novel, yet simple PCR protocol for its quantification (amolar levels/cell). When transfected into mammalian cells, crook siRNA induces selective mRNA knock-down equivalent to its unmodified siRNA counterpart. This new bifunctional siRNA construct will enable future in vivo studies on the uptake, distribution and pharmacokinetics of siRNA, and is particularly important for the development of siRNA-based therapeutics. More generally, PCR-based detection of siRNA carries wide-ranging applications for RNAi reverse genetics.


Adherence to hypothermia guidelines: a French multicenter study of fullterm neonates.
The objective of this study was to describe the French practice of hypothermia treatment (HT) in full-term newborns with hypoxic-ischemic encephalopathy (HIE) and to analyze the deviations from the guidelines of the French Society of Neonatology. From May 2010 to March 2012 we recorded all cases of HIE treated by HT in a French national database. The population was divided into three groups, "optimal HT" (OHT), "late HT" (LHT) and "non-indicated" HT (NIHT), according to the guidelines. Of the 311 newborns registered in the database and having HT, 65% were classified in the OHT group, 22% and 13% in the LHT and NIHT groups respectively. The severity of asphyxia and HIE were comparable between newborns with OHT and LHT, apart from EEG. HT was initiated at a mean time of 12 hours of life in the LHT group. An acute obstetrical event was more likely to be identified among newborns with LHT (46%), compared to OHT (34%) and NIHT (22%). There was a gradation in the rate of complications from the NIHT group (29%) to the LHT (38%) group and the OHT group (52%). Despite an insignificant difference in the rates of death or abnormal neurological examination at discharge, nearly 60% of newborns in the OHT group had an MRI showing abnormalities, compared to 44% and 49% in the LHT and NIHT groups respectively. The conduct of the HT for HIE newborns is not consistent with French guidelines for 35% of newborns, 22% being explained by an excessive delay in the start of HT, 13% by the lack of adherence to the clinical indications. This first report illustrates the difficulties in implementing guidelines for HT and should argue for an optimization of perinatal care for HIE.


Highly Regio- and Stereoselective Synthesis of Bioactive Oligosaccharides Using 1,2-O-Ethylidene-α-d-gluco- and -β-d-Mannopyranose as the Acceptors and Acetobromosugars as the Donors via Ortho Ester Intermediates.
This paper presents a new, and effective method for highly regio- and stereoselective synthesis of oligosaccharides with 1,2-trans linkages using 1,2-O-ethylidenated gluco- and mannopyranose as the acceptors and simple acetobromosugars as the glycosyl donors through ortho ester formation-rearrangement strategy. Biologically important 3,6-branched oligosaccharides such as the phytoalexin elicitor hexasaccharide and ConA-binding 3,6-branched mannotriose were synthesized readily in high yields by the new method.


Intermittent growth attenuation: is this a sign of craniopharyngioma?
We present two young children eventually diagnosed with large craniopharyngiomas, who had a normal growth velocity for several years following an initial short period of growth attenuation. These cases suggest the need for a low threshold to undertake hormonal evaluation of patients who present with a past history of growth attenuation.


Natural sound archives: past, present and future.
Recordings of wild animals were first made in the Palearctic in 1900, in the Nearctic in 1929, in Antarctica in 1934, in Asia in 1937, and in the Neotropics in the 1940s. However, systematic collecting did not begin until the 1950s. Collections of animal sound recordings serve many uses in education, entertainment, science and nature conservation. In recent years, technological developments have transformed the ways in which sounds can be sampled, stored and accessed. Now the largest collections between them hold altogether around 0.5 million recordings with their associated data. The functioning of a major archive will be described with reference to the British Library Sound Archive. Preserving large collections for the long term is a primary concern in the digital age. While digitization and digital preservation has many advantages over analogue methods, the rate of technology change and lack of standardization are a serious problem for the world's major audio archives. Another challenge is to make collections more easily and widely accessible via electronic networks. On-line catalogues and access to the actual sounds via the internet are already available for some collections. Case studies describing the establishment and functioning of sound libraries in Mexico, Colombia and Brazil are given in individually authored sections in an Appendix.


[Distinguishing of scar tissue from recurrent tumor after therapy of tumors of the female pelvis].
Patients treated for gynecological malignancies are followed up at short intervals during the first 3 years after treatment. Locoregional recurrence in the pelvis is often not detectable by palpation. Thus, efficient and sensitive follow-up of patients treated for gynecologic malignancies requires the use of imaging techniques. Computed tomography is well suited for the primary diagnoses of locoregional recurrences and lymph-node metastases after radical surgery. In addition to detailed anatomical information, magnetic resonance imaging (MRI) permits tissue characterization on the basis of signal intensity and thus differentiation between fibrosis and recurrence. After primary radiotherapy for cervical cancer, MRI follow-up can assess tumor response to treatment. Prognostic evaluation of the success or failure of treatment requires knowledge of the signal characteristics and volume of the primary tumor and of the interval since primary treatment. In our experience, conventional spin-echo sequences with heavy T2-weighting are best for distinguishing between fibrosis and recurrence.


Evidence of porcine epidemic diarrhea virus (PEDV) shedding in semen from infected specific pathogen-free boars.
In 2013, PED emerged for the first time in the United States (US). The porcine epidemic diarrhea virus (PEDV) spread quickly throughout North America. Infection with PEDV causes watery diarrhea and up to 100% mortality in piglets, particularly for highly pathogenic non-InDel strains circulating in the US. PEDV is mainly transmitted by the fecal-oral route. Transmission via the venereal route has been suspected but not previously investigated. The aim of the study was to determine if PEDV could be detected in semen from infected specific pathogen-free (SPF) boars inoculated with a PEDV US non-InDel strain suggesting venereal transmission may occur. Two boars orally inoculated with PEDV showed clinical signs and virus shedding in feces. Transient presence of the PEDV genome was detected by RT-qPCR in the seminal (5.06 × 102 to 2.44 × 103 genomic copies/mL) and sperm-rich fraction of semen (5.64 × 102 to 3.40 × 104 genomic copies/mL) and a longer duration of viral shedding was observed in the sperm-rich fraction. The evidence of PEDV shedding in semen raises new questions in term of disease spread within the pig population with the use of potentially contaminated semen.


Comparison of mammography, ultrasound, and MRI in size assessment of ductal carcinoma in situ with histopathologic correlation.
Background The ability to accurately assess tumor size in ductal carcinoma in situ (DCIS) is an important clinical issue when selecting the appropriate treatment plan. Purpose To compare the accuracy of using mammography, ultrasound (US), and magnetic resonance imaging (MRI) to assess DCIS tumor size based on imaging and histopathological findings. Material and Methods Fifty-six patients with DCIS were included. Mammography, US, and MRI were reviewed, and the accuracy of the measured tumor sizes were compared with the imaging and histopathological parameters. Results If visible, tumor measurements demonstrated high reliability with the pathologically determined size, with the best results obtained using US ( k = 0.851) followed by mammography ( k = 0.815) and MRI ( k = 0.738). Tumor size assessment was significantly more accurate when the lesion was shown as a mass on US ( P = 0.003) or MRI ( P < 0.001) with minimal and mild background parenchymal enhancement ( P = 0.016) on MRI. When mammography was used to assess tumor size, the tumors with positive estrogen receptor status and luminal A subtype demonstrated a significantly more accurate tumor size. Conclusion The combination of US and MRI, in addition to mammography, has an important role in assessing the exact tumor extent of DCIS.


Peripheral nonresponsiveness to orally administered soluble protein antigens.
The presentation of soluble model food antigens to the intestinal immune system typically induces antigen-specific systemic nonresponsiveness. Yet, the gut-associated lymphoid tissue (GALT) must launch an effective attack against potentially invasive pathogens even as it avoids mounting a response to innocuous food antigens. Although the mechanism by which the GALT is able to recognize and respond to these different forms of antigen is not clear, recent studies have shown that, initially, both tolerogenic and immunogenic forms of orally administered antigen elicit transient T-cell activation and proliferation. The unique microenvironment of the GALT plays a central role in determining whether functional T-cell anergy or adaptive immunity is the ultimate response. Administration of model food proteins with adjuvants (microbial products that activate the innate immune system) induces a productive immune response to this normally tolerogenic form of antigen. Recent work from our laboratory has shown that an ongoing enteric infection can itself act as an adjuvant and prime for a response to an orally administered soluble protein antigen.


Physicochemical and structural properties of lunasin revealed by spectroscopic, chromatographic and molecular dynamics approaches.
Lunasin is a 43-amino acid peptide from seeds and grains with bioavailability in humans and potent chemotherapeutic action against several cancer cell lines. Here, we investigate new information about the physicochemical and structural properties of lunasin using circular dichroism (CD), fluorescence spectroscopy, electrospray ionization-ion mobility spectrometry-mass spectrometry (ESI-IMS-MS), size exclusion chromatography (SEC), molecular dynamics (MD), and bioinformatics. CD analysis and disorder prediction obtained by PONDR indicate that lunasin has a mostly unordered structure. Double wavelength [θ]222nm x [θ]200nm plot data suggests that lunasin is an intrinsically disordered peptide (IDP) in a pre-molten globule-like (PMG-like) state, while CD spectrum deconvolution and MD simulation indicate small β-strand content. The presence of residual structure was supported by loss of CD signal at 222 nm after treatment with urea and by increasing fluorescence emission upon bis-ANS binding. Lunasin also demonstrated stability to heating up to the temperature of 100 °C, as verified by CD. MD and CD analyses in the presence of TFE and MoRFpred prediction indicated the helix propensity of lunasin. ESI-IMS-MS data revealed that lunasin shows a propensity to form disulfide bonds at the conditions used. MD data also indicated that disulfide bond formation affects the adopted structure, showing a possible role of aspartyl-end in structure stabilization and compaction. In conclusion, our data support a characterization of lunasin as a peptide with an intrinsic disorder in a PMG-like state and reveal new aspects about its structural stability and plasticity, as well as the effects of disulfide bond formation and electrostatic attractions.


Catalytic generation of α-CF3 enolate: direct catalytic asymmetric Mannich-type reaction of α-CF3 amide.
The introduction of the CF3 unit is a common strategy for modifying pharmacokinetic properties and slowing metabolic degradation in medicinal chemistry. A catalytic and enantioselective addition of α-CF3 enolates allows for expeditious access to functionalized chiral building blocks with CF3-containing stereogenicity. To date, α-CF3 enolates have been a less explored class of nucleophiles because of rapid defluorination. The present study reveals that a designed α-CF3 amide enables a direct asymmetric Mannich-type reaction in a cooperative catalytic system.


The Impact of the Derotational Mobilization of Manual Therapy According to Kaltenborn-Evjenth on the Angle of Trunk Rotation in Patients with Adolescent Idiopathic Scoliosis--Pilot Study, Direct Observation.
The use of manual therapy in the treatment of scoliosis has been controversial. Scientific reports do not clearly indicate its effectiveness or harmfulness. The aim of this study was to determine the effectiveness of passive and active derotation techniques of manual therapy according to Kaltenborn-Evjent on the reduction of the angle of trunk rotation in patients with idiopathic scoliosis. The study enrolled 33 female patients from the Department of Rehabilitation who were diagnosed with adolescent idiopathic scoliosis. The patients were divided into two groups according to the curve location (SRS classification). Group A consisted of 17 women, aged 14.±2.4 years, with single-curve scoliosis in the thoracolumbar segment and group B was composed of 16 women, aged 15±2.24 years, with double-curve scoliosis in the thoracic and lumbar segments. In both groups, the angle of trunk rotation, the magnitude of thoracic kyphosis and lumbar lordosis were measured twice, before and after each session of derotation techniques. Both groups demonstrated a positive impact of active and passive derotation techniques on the angle of trunk inclination. The greatest difference was observed after a session of active derotation in the patients with lumbar scoliosis. The angle of trunk rotation decreased on average by 4.5°±1.14°. No correlations were found between the curve angle values and the degree of thoracic derotation after the application of these techniques. Derotational mobilization techniques may be a valuable complement to scoliosis treatment methods as they increase their effectiveness.


Exploring super-Gaussianity toward robust information-theoretical time delay estimation.
Time delay estimation (TDE) is a fundamental component of speaker localization and tracking algorithms. Most of the existing systems are based on the generalized cross-correlation method assuming gaussianity of the source. It has been shown that the distribution of speech, captured with far-field microphones, is highly varying, depending on the noise and reverberation conditions. Thus the performance of TDE is expected to fluctuate depending on the underlying assumption for the speech distribution, being also subject to multi-path reflections and competitive background noise. This paper investigates the effect upon TDE when modeling the source signal with different speech-based distributions. An information theoretical TDE method indirectly encapsulating higher order statistics (HOS) formed the basis of this work. The underlying assumption of Gaussian distributed source has been replaced by that of generalized Gaussian distribution that allows evaluating the problem under a larger set of speech-shaped distributions, ranging from Gaussian to Laplacian and Gamma. Closed forms of the univariate and multivariate entropy expressions of the generalized Gaussian distribution are derived to evaluate the TDE. The results indicate that TDE based on the specific criterion is independent of the underlying assumption for the distribution of the source, for the same covariance matrix.


Differences in trends in discharge location in a cohort of hospitalized patients with cancer and non-cancer diagnoses receiving specialist palliative care: A retrospective cohort study.
Patients with and without cancer are frequently hospitalized, and have specialist palliative care needs. In-hospital mortality can serve as a quality indicator of acute care. Trends in acute care outcomes have not previously been evaluated in patients with confirmed specialist palliative care needs or between diagnostic groups. To compare trends in discharge location between hospitalized patients with and without cancer who received specialist palliative care. Retrospective cohort study. Association between diagnosis (cancer, non-cancer) and in-hospital mortality was assessed using multivariable logistic regression, controlling for demographic, clinical, and admission-specific information. Patients who received specialist palliative care at an academic tertiary hospital in Toronto, Canada from 2013 to 2019. The cohort comprised 6846 patients, 5024 with and 1822 without cancer. A higher proportion of patients without cancer had a Palliative Performance Scale score <30%, anticipated prognosis of <1 month, and were referred for end-of-life care (all p < 0.001). The adjusted odds of dying in hospital was 1.24-times higher among patients without cancer (95% CI: 1.05-1.46; p = 0.011). Though the proportion of patients without cancer who died in hospital decreased by 8.4% from 2013 to 2019, this proportion (41.2%) remained substantially higher compared to patients with cancer (14.0%) in 2019. Hospitalized patients without cancer were referred to specialist palliative care at a lower functional status, a poorer anticipated prognosis, and more likely for end-of-life care; and were more likely to die in hospital. Future studies are required to determine whether a proportion of hospital deaths in patients without cancer represent goal-discordant end-of-life care.


Posterior cervical fusion in chidren.
Six cases of posterior cervical fusion with rib grafts in children are reported. Four of the children had sustained cervical spine injuries in accidents, and two had congenital absence of the odontoid. Three-level fusions (C1-3) were done in four children, and four-level fusions (C1-4) in two. One child died of unrelated causes 3 months after the operation. The other five children have been followed for 5 to 13 years. All are doing well and each has a remarkably supple, stable neck and no neurological deficit.


Synthesis and protective effects of novel salidroside analogues on glucose and serum depletion induced apoptosis in PC12 cells.
Salidroside is a natural product isolated from Rhodiola rosea L. which possesses a wide range of biological activities, especially neuroprotective effects in the treatment of ischemic stroke. In an attempt to improve its neuroprotective effects, a series of novel salidroside analogues were synthesized and their neuroprotective activities were evaluated against the glucose and serum depletion-induced cell death in differentiated PC12 cells. Most target compounds displayed protective effects on the cell viability, especially for compound 6, which had a great potency superior to salidroside. MTT assay and Hoechst 33342 staining collectively showed that pretreatment with 6 attenuated cell viability loss and reduced apoptotic death in cultured PC12 cells with glucose and serum depletion. And its neuroprotective effects might be associated with the increase of the apoptosis-related protein Bcl-2/Bax expression ratio, and also with the inhibition of caspase-3 activation. Therefore, our new findings may provide potentially important information for further development of salidroside analogues and lay the basis for further studies on the cerebral ischemic stroke and neurodegenerative diseases for human clinical treatment.


Increase in peripheral benzodiazepine receptors on monocytes in fibromyalgia.
The aim of this study is to evaluate the expression of Peripheral Benzodiazepine Receptors (PBRs) on leukocytes in patients affected by primary fibromyalgia and to argue their possible role in pain perception and in modulation of immunologic process. The expression of PBRs has been evaluated by flow cytometry on monocytes, on lymphocytes and on granulocytes in twenty patients with primary fibromyalgia, with indirect immunofluorescence methods. Upregulation of leukocyte PBRs expression has been demonstrated in fibromyalgia. A statistically significant difference has been documented only in monocytes. The monocyte PBRs expression was 26.74 +/- 14.84 MIF in fibromyalgia versus 17.45 +/- 8.54 MIF in controls (P < 0.023). Upregulation of PBRs expression, although not statistically significant, was also observed in lymphocytes and granulocytes. The monocyte PBRs overincrease in fibromyalgia may be due to abnormalities in the regulation of pain or to inflammation. It might perhaps explicate the possible mechanisms of therapeutic response to benzodiazepine in fibromyalgia.


A phase II study of Tg4010 (Mva-Muc1-Il2) in association with chemotherapy in patients with stage III/IV Non-small cell lung cancer.
TG4010 is a recombinant viral vector expressing both the tumor-associated antigen MUC1 and Interleukine-2. This vector is based on the modified virus of Ankara, a significantly attenuated strain of vaccinia virus. TG4010 has been designed to induce or amplify a cellular immune response directed against tumor cells expressing MUC1. A multicenter, randomized phase II study has explored two schedules of the combination of TG4010 with first line chemotherapy in patients with stage IIIB/IV non-small cell lung cancer. In Arm 1, TG4010 was combined upfront with cisplatin (100 mg/m day 1) and vinorelbine (25 mg/m day 1 and day 8). In Arm 2, patients were treated with TG4010 monotherapy until disease progression, followed by TG4010 plus the same chemotherapy as in Arm1. Response rate was evaluated according to RECIST. Median time to progression and median overall survival were calculated according to the Kaplan-Meier method. Sixty-five patients were enrolled, 44 in Arm 1 and 21 in Arm 2, in accordance with the two stage Simon design of the statistical plan. In Arm 1, partial response was observed in 13 patients out of 37 evaluable patients (29.5% of the intent to treat population, 35.1% of the evaluable patients). In Arm 2, two patients experienced stable disease for more than 6 months with TG4010 alone (up to 211 days), in the subsequent combination with chemotherapy, one complete and one partial response were observed out of 14 evaluable patients. Arm 2 did not meet the criteria for moving forward to second stage. The median time to progression was 4.8 months for Arm 1. The median overall survival was 12.7 months for Arm 1 and 14.9 for Arm 2. One year survival rate was 53% for Arm 1 and 60% for Arm 2. TG4010 was well tolerated, mild to moderate injection site reactions, flu-like symptoms, and fatigue being the most frequent adverse reactions. A MUC1-specific cellular immune response was observed in lymphocyte samples from all responding patients evaluable for immunology. The combination of TG4010 with standard chemotherapy in advanced non-small cell lung cancer is feasible and shows encouraging results. A randomized study evaluating the addition of TG4010 to first line chemotherapy in this population is in progress.


Endothelial and Autonomic Functions in Patients with Migraine.
It has been shown that patients with migraine have endothelial dysfunction. Migraine patients with aura, especially, have more clinical manifestations of autonomic nervous system dysfunction. We aimed to evaluate the endothelial and autonomic functions in migraine patients during both migraine headache attack and headache-free periods. This was a cross-sectional, randomized study. A total of 130 participants (67 male and 63 female patients, minimum age = 19 years, maximum age = 71 years, mean age = 38.8 ± 12.2 years) were enrolled into the study. For the statistical evaluation of data, we classified the participants of the study as follows: group 1: headache (+) aura (+); group 2: headache (+) aura (-); group 3: headache (-) aura (+); group 4: headache (-) aura (-). Noninvasive evaluation of endothelial function was performed by flow-mediated dilation (FMD) and pulse wave analysis methods. Heart rate variability measurements were used for noninvasive evaluation of autonomic functions. Group 1 had a higher FMD ratio than the control group, group 3, or group 4 (P < 0.001, P < 0.001, and P = 0.003, respectively). Group 4 had lower FMD ratio levels than the other migraine groups and or the control group (P < 0.001). Group 3 had the highest high-frequency (HF) power levels among all migraine groups (P < 0.001). Group 2 had higher low-frequency/HF ratio values than other migraineurs (P < 0.001). We concluded that endothelial dysfunction and headache are closely related. Additionally, higher parasympathetic tonus might be associated with the presence of aura.


Postpartum home visits by maternity nursing students.
Fewer babies are being born; hospital postpartum days are being shortened; and many families are choosing home births: These facts have prompted nursing educators to seek maternity experiences for students outside the hospital setting. At the university where the student-visit program was implemented, faculty appreciated the need for follow-up home care and focused on more than the experiences in prenatal clinics and the acute-care setting. Rather than turning the family over to another community service or colleague when indicated, second and third home visits are being considered. These additional visits would assure a greater opportunity for primary prevention in the care of the total family. Hospital management and home-care maternity nurses have found that postpartum visits have decreased the need for parents to return to the emergency room or the hospital. Problems have been anticipated or assessed and nursing intervention provided on the home visit. This service gradually is becoming available to more families, with both physical and psychosocial needs being considered. It is hoped that it soon will be provided to all families. Postpartum families, nurses, and nursing students benefit from follow-up postpartum visits in the home. The families are assisted in their parenting roles and nurses gain satisfaction in providing continuity of care.


Sex determination using nonmetric characteristics of the mandible in Koreans.
The mandible is the largest and hardest facial bone and retains its shape better than other bones in the forensic and physical anthropologic field. The mandible can be used to distinguish among ethnic groups and between sexes. We examined the morphological characteristics of the mandibles of 102 Koreans of either sex. Of 13 nonmetric items of the mandible, the characteristic that best allowed the sexes to be distinguished was the contour of the lower border of the mandible: rocker-shaped mandibles predominated in males (68.1%), whereas most females (84.6%) exhibited a straight mandible. In addition, the mental region was shaped differently between the sexes: the shape of the chin in most males was generally bilobate or square (91.7%), whereas the chin in females was either square (45.5%) or pointed (54.5%). In this study, the positive predict values of male and female were 92.5% and 73.7%, respectively. Therefore, the nonmetric method used to analyze the mandible in this study can be used for sex discrimination.


Using Genomic Sequencing to Improve Management in Melanoma.
Rapidly advancing genomic sequencing technologies are changing all areas of cancer, from diagnosis to surveillance, and prognostication to treatment. The role of genomic testing in melanoma is expanding, and multiple genomically based tests are available, including somatic tumor sequencing for actionable genetic alterations and tumor mutational burden, prognostic gene expression profiling from tumor tissue, and germline genetic testing from blood. The available testing options have varying levels of supporting data, from robust to preliminary. Here we summarize the available genomic and genetic tests for melanoma, and the level of evidence supporting each of these. We also discuss the current impact of genomic sequencing on the management of melanoma, as well as roles it may play in the near future.


The interaction of lac repressor headpiece with its operator: an NMR view.
Analysis of nuclear Overhauser enhancements in two-dimensional NMR spectra of the complex of lac repressor headpiece with a 14 base pair lac operator fragment shows that the second helix of the headpiece binds in the major groove of DNA, as has been suggested. The orientation of this helix is approximately 180 degrees different from the proposed models and from that found in the X-ray structure of the 434 repressor-operator complex. The model of the lac headpiece-operator complex provides a good explanation for a large amount of biochemical, genetic and physical data.


Low temperature plasma diagnostics with tunable synchrotron vacuum ultraviolet photoionization mass spectrometry.
Plasma-based technology is of great importance for a range of industrial applications. However, due to the complexity of gas-phase and surface chemical reactions, the underlying plasma chemistry is still poorly understood, leading to a growing demand for experimental setups on plasma diagnostics. In this paper, we report an apparatus that combines tunable synchrotron vacuum ultraviolet (VUV) photoionization with molecular-beam mass spectrometry for detecting ionic and neutral species formed in the processes of plasma discharge. The products including reactive intermediates such as enols can be identified unambiguously with the measurements of photoionization mass spectrometry (PIMS) and photoionization efficiency spectra. The tunable VUV PIMS has been proven as an ideal and sensitive tool for a comprehensive understanding of plasma chemistry.


Reprint of: environmental information for military planning.
A study was conducted to consider the implications of presenting Environmental Information (EI; information on current environmental features including weather, topography and visibility maps) for military planning to the growing audience of non-technical users; to provide guidance for ensuring usability and for development of a suitable EI interface, and to produce an EI concept interface mock-up to demonstrate initial design ideas. Knowledge was elicited from current EI users and providers regarding anticipated use of EI by non-specialists. This was combined with human factors and cognition expertise to produce guidance for data usability and development of an EI interface. A simple mock-up of an EI concept interface was developed. Recommendations for further development were made including application of the guidance derived, identification of a user test-bed and development of business processes.


High performance liquid chromatography preparation of the molecular species of GM1 and GD1a gangliosides with homogeneous long chain base composition.
A semi-preparative, analytical high performance liquid chromatographic (HPLC) procedure is described for the isolation of molecular species of GM1 and GD1a gangliosides containing a single long chain base, C18 or C20 sphingosine, C18 or C20 sphinganine, each in its natural erythro or unnatural threo form. The threo forms were obtained from 2,3-dichloro-5,6-dicyanobenzoquinone/NaBH4 -treated gangliosides. The ganglioside molecular species separated by HPLC were analyzed for carbohydrate, fatty acid, and long chain base composition. In particular, long chain bases were submitted to gas-liquid chromatographic-mass spectrometric analyses as their trimethylsilyl (TMS) or N-acetyl-TMS derivatives, and chain length, presence or absence of C4-C5 double bond, and C-3 steric configuration were ascertained. The final preparations of individual molecular species of GM1 and GD1a gangliosides were more than 99% homogeneous in their saccharide moiety, contained a single long chain base (homogeneity higher than 99%), and had a fatty acid composition primarily of stearic acid (92 to 97%). All the individual molecular species of GM1 and GD1a gangliosides were also prepared in radioactive form by selective tritiation at C-3 of the long chain base. Their specific radioactivity ranged from 1.3 to 1.45 Ci/mmol. The availability of these molecular species of gangliosides is expected to facilitate studies aimed at ascertaining the role played by the hydrophobic portion in the functional behavior of gangliosides.


Modelling spinal circuitry involved in locomotor pattern generation: insights from deletions during fictive locomotion.
The mammalian spinal cord contains a locomotor central pattern generator (CPG) that can produce alternating rhythmic activity of flexor and extensor motoneurones in the absence of rhythmic input and proprioceptive feedback. During such fictive locomotor activity in decerebrate cats, spontaneous omissions of activity occur simultaneously in multiple agonist motoneurone pools for a number of cycles. During these 'deletions', antagonist motoneurone pools usually become tonically active but may also continue to be rhythmic. The rhythmic activity that re-emerges following a deletion is often not phase shifted. This suggests that some neuronal mechanism can maintain the locomotor period when motoneurone activity fails. To account for these observations, a simplified computational model of the spinal circuitry has been developed in which the locomotor CPG consists of two levels: a half-centre rhythm generator (RG) and a pattern formation (PF) network, with reciprocal inhibitory interactions between antagonist neural populations at each level. The model represents a network of interacting neural populations with single interneurones and motoneurones described in the Hodgkin-Huxley style. The model reproduces the range of locomotor periods and phase durations observed during real locomotion in adult cats and permits independent control of the level of motoneurone activity and of step cycle timing. By altering the excitability of neural populations within the PF network, the model can reproduce deletions in which motoneurone activity fails but the phase of locomotor oscillations is maintained. The model also suggests criteria for the functional identification of spinal interneurones involved in the mammalian locomotor pattern generation.


The effect of maternal undernutrition before muscle differentiation on the muscle fiber development of the newborn lamb.
There is a need to improve the lean tissue content of ruminant animals destined for meat production. Muscle fiber number is set during fetal development. The effect of undernutrition of pregnant ewes on subsequent muscle fiber characteristics of their offspring was investigated. The trial involved 32 pregnant ewes carrying twins. The ewes were allocated randomly to one of four groups: three different treatment groups (n = 8) and a control group (n = 8). The diet of the treatment groups was dropped to 50% of their daily requirement to support the ewe and allow for conceptus growth for varying periods before being returned to 100% of their daily requirement until term. Group d 30-70 ewes were fed 100% of their daily requirement until d 30, the diet was then decreased to 50% until d 70; it was then returned to 100% of their daily requirement until term. Group d 55-95 ewes were similarly restricted from d 55 through 95, and Group d 85-115 ewes were restricted from d 85 through 115. The control group was fed 100% of their daily requirement to support the ewe and allow for conceptus growth throughout gestation. After parturition, the lactating ewes were fed a normal commercial diet. On d 14 (after parturition), the lambs were slaughtered and the LM, semitendinosus (ST), and vastus lateralis (VL) were dissected and snap frozen. The immunochemical determination of myosin heavy-chain slow (MHC-slow) and myosin heavy-chain fast (MHC-fast) proteins was measured by immunoprobing of Western blots. The number of fast and slow fibers and the diameter of these fibers also were measured in each muscle sample by histochemical techniques. Decreased maternal nutrition before fiber formation (d 30 through 70) was observed to change the muscle characteristics of the newborn lambs. These lambs had significantly fewer fast fibers (P < 0.001) and significantly more slow fibers (P < 0.001) in both the LM and VL compared with the other groups. Maternal nutrient restriction at the other periods had no effect on the number of muscle fibers in the newborn lambs; however, a decrease (LM, P < 0.05; VL, P < 0.01; ST, P = 0.08) in muscle weight was observed in the lambs born to the ewes restricted between d 85 and 115 of gestation compared with the other groups. This study has shown that decreased maternal diet before muscle fiber formation will alter the muscle fiber development in the fetus.


Testicular tumor in an aviator.
Testicular tumor is an uncommon cancer mainly affecting males between 20 and 54 yr of age. In the United States, approximately 2 to 3 new testicular cancer cases per 100,000 males occur each year. Testicular cancer is disqualifying for all classes of Federal Aviation Administration medical certificates, and consideration must be deferred to the FAA for Special Issuance (waiver) consideration. This article presents a case report of testicular cancer in an airline pilot, a brief discussion of testicular cancer, and the aeromedical implications of the diagnosis.


Independent losses of function in a polyphenol oxidase in rice: differentiation in grain discoloration between subspecies and the role of positive selection under domestication.
Asian rice (Oryza sativa) cultivars originated from wild rice and can be divided into two subspecies by several criteria, one of which is the phenol reaction (PHR) phenotype. Grains of indica cultivars turn brown in a phenol solution that accelerates a similar process that occurs during prolonged storage. By contrast, the grains of japonica do not discolor. This distinction may reflect the divergent domestication of these two subspecies. The PHR is controlled by a single gene, Phr1; here, we report the cloning of Phr1, which encodes a polyphenol oxidase. The Phr1 gene is indeed responsible for the PHR phenotype, as transformation with a functional Phr1 can complement a PHR negative cultivar. Phr1 is defective in all japonica lines but functional in nearly all indica and wild strains. Phylogenetic analysis showed that the defects in Phr1 arose independently three times. The multiple recent origins and rapid spread of phr1 in japonica suggest the action of positive selection, which is further supported by several population genetic tests. This case may hence represent an example of artificial selection driving the differentiation among domesticated varieties.


KRT17High/CXCL8+ tumor cells display both classical and basal features and regulate myeloid infiltration in the pancreatic cancer microenvironment.
Pancreatic ductal adenocarcinoma (PDAC) is generally divided in two subtypes, classical and basal. Recently, single cell RNA sequencing has uncovered the co-existence of basal and classical cancer cells, as well as intermediary cancer cells, in individual tumors. The latter remains poorly understood; here, we sought to characterize them using a multimodal approach. We performed subtyping on a single cell RNA sequencing dataset containing 18 human PDAC samples to identify multiple intermediary subtypes. We generated patient-derived PDAC organoids for functional studies. We compared single cell profiling of matched blood and tumor samples to measure changes in the local and systemic immune microenvironment. We then leveraged longitudinally patient-matched blood to follow individual patients over the course of chemotherapy. We identified a cluster of KRT17-high intermediary cancer cells that uniquely express high levels of CXCL8 and other cytokines. The proportion of KRT17High/CXCL8+ cells in patient tumors correlated with intra-tumoral myeloid abundance, and, interestingly, high pro-tumor peripheral blood granulocytes, implicating local and systemic roles. Patient-derived organoids maintained KRT17High/CXCL8+cells and induced myeloid cell migration in an CXCL8-dependent manner. In our longitudinal studies, plasma CXCL8 decreased following chemotherapy in responsive patients, while CXCL8 persistence portended worse prognosis. Through single cell analysis of PDAC samples we identified KRT17High/CXCL8+ cancer cells as an intermediary subtype, marked by a unique cytokine profile and capable of influencing myeloid cells in the tumor microenvironment and systemically. The abundance of this cell population should be considered for patient stratification in precision immunotherapy.


Metabolism of the aryl hydrocarbon receptor agonist 3,3',4,4'-tetrachlorobiphenyl by the marine fish scup (Stenotomus chrysops) in vivo and in vitro.
The metabolism of the polychlorinated biphenyl congener 3,3',4,4'-tetrachlorobiphenyl (TCB) was examined in vitro and in vivo in the marine fish scup (Stenotomus chrysops). Untreated scup liver microsomes catalyzed metabolism of TCB with an estimated KM of 0.7 microM, at a rate < or = 0.13 pmol/min/mg. Metabolism was NADPH-dependent and inhibited by cytochrome c and CO, indicating cytochrome P450 (CYP) involvement. alpha-Naphthoflavone strongly inhibited microsomal TCB metabolism, and treatment of fish with CYP1A inducers increased the rates by approximately 2-fold, suggesting involvement of CYP1A. Scup were injected intraperitoneally with 0.1 or 5 mg TCB/kg and sampled on days 1-16 after treatment (after 3 days without food at each sampling). Concentrations of unmetabolized TCB in liver peaked on day 5 in low dose fish and on day 12 in high dose fish. In both groups the TCB content in the liver had declined 60% or more by day 16, suggesting depuration or redistribution from the liver. GC and MS revealed TCB and TCB metabolites in bile within 24 hr of treatment. The concentrations of TCB and metabolites in bile peaked at the same time that TCB concentrations peaked in the liver. The major metabolites were 5-hydroxy-3,3'4,4'-TCB (5-OH-TCB) and 4-hydroxy-3,3',5,4'-TCB (4-OH-TCB); 2-hydroxy-3,3',4,4'-TCB and 6-hydroxy-3,3',4,4'-TCB were minor metabolites. Animals given the high dose had much less 5-OH-TCB and much more parent TCB in bile than did fish given the low dose. Amounts of 4-OH-TCB in bile did not differ between doses. The reduced excretion of 5-OH-TCB coincided with a suppression of CYP1A in fish given the high dose, that did not occur in low dose fish, consistent with an involvement of CYP1A in TCB metabolism and particularly in formation of 5-OH-TCB. This study provides the first direct demonstration of 3,3',4,4'-TCB metabolism by fish. Data also indicate that these fish are able to eliminate TCB both as parent compound and as metabolites, despite a very slow rate of metabolism in vitro.


Unpacking cognitive emotion regulation in eating disorder psychopathology: The differential relationships between rumination, thought suppression, and eating disorder symptoms among men and women.
While previous literature suggests that emotion dysregulation is a salient factor contributing to the onset and maintenance of eating disorders (EDs), less is known about how maladaptive, cognitively oriented regulation strategies such as rumination and thought suppression may be uniquely related to ED symptoms in men and women. The present study sought to examine the independent associations of ruminative brooding and thought suppression with ED symptoms, after controlling for negative affect intensity, and assess whether these associations differ by gender. Participants were 263 undergraduates who completed a series of questionnaires, including measures of ED symptoms (Eating Disorder Diagnostic Scale), ruminative brooding (Ruminative Response Scale), and thought suppression (White Bear Suppression Inventory). Generalized linear models examined main effects of ruminative brooding and thought suppression and their interactions with gender on ED symptoms, controlling for negative affect intensity. Higher ruminative brooding was associated with higher binge eating among women. Thought suppression was associated with higher vomiting and fasting frequency in both genders, with a stronger association between suppression and fasting in men compared to women. Together results demonstrate the unique contributions of cognitive perseveration and avoidance in ED symptomatology; specifically, ruminative brooding may be a salient factor contributing to binge eating in women, while high levels of thought suppression among males may contribute to fasting. Findings highlight the potential importance of examining and differentially targeting specific facets of cognitive emotion regulation in men and women engaging in ED behaviors.


Arylaminoethyl amides as novel non-covalent cathepsin K inhibitors.
A series of N(alpha)-benzyloxycarbonyl- and N(alpha)-acyl-L-leucine(2-phenylaminoethyl)amide derivatives were prepared and evaluated for their inhibitory activity against rabbit and human cysteine proteases cathepsins K, L, and S. These data indicate that N(alpha)-acyl-alpha-amino acid-(arylaminoethyl)amides represent a new class of selective non-covalent inhibitors of cathepsin K. Compounds 4b, 4e, and 4g exhibit high potency toward rabbit and human cathepsin K (IC(50) < 0.006 microM) and are characterized by an excellent selectivity profile vs human cathepsins L and S.


Clinical Recommendations for the use of Neurotropic B vitamins (B1, B6, and B12) for the Management of Peripheral Neuropathy: Consensus from a Multidisciplinary Expert Panel.
Peripheral neuropathy (PN) is an insidious disease that is often asymptomatic during the early stages but which can have a significant impact on quality of life at later stages when nerve damage occurs. There is currently no guidance on the use of neurotropic B vitamins (B1, B6, and B12) for the management of asymptomatic and symptomatic PN. To provide guidance to primary care physicians on an integrated approach to managing PN with neurotropic B vitamins (B1, B6, and B12). A multidisciplinary panel of eight experts participated in an iterative quasi-anonymous Delphi survey consisting of two rounds of questions and a virtual meeting. A literature review formed the basis of the survey questions. The first round included multiple select, qualitative, and Likert Scale questions; the subsequent round consisted of 2-point scale (agree or disagree) questions that sought to develop consensus-based statements refined from the first round and recommendations derived from discussions during the virtual expert panel meeting. Clinical recommendations for the use of neurotropic B vitamins (B1, B6, and B12) have been developed for the prevention of PN progression or to delay onset in patients at high risk of developing PN. Recommendations have also been provided for the assessment of PN etiology and considerations for the use of loading dose (high dose) and maintenance dose (lower dose) of these neurotropic B vitamins (B1, B6, and B12). These clinical recommendations provide an initial step towards formulating comprehensive guidelines for the early and long-term management of PN with neurotropic B vitamins (B1, B6, and B12) and move beyond addressing only neuropathic pain associated with the late stages of PN.