Different Genetic Signatures of Small-Cell Lung Cancer Characterize Anti-GABAB R and Anti-Hu Paraneoplastic Neurological Syndromes.
Small-cell lung cancer (SCLC) is the malignancy most frequently associated with paraneoplastic neurological syndromes (PNS) and can trigger different antibody responses against intracellular (Hu) or neuronal surface (GABAB R) antigens. Our aim was to clarify whether the genomic and transcriptomic features of SCLC are different in patients with anti-GABAB R or anti-Hu PNS compared with SCLC without PNS. A total of 76 SCLC tumor samples were collected: 34 anti-Hu, 14 anti-GABAB R, and 28 SCLC without PNS. The study consisted of 4 steps: (1) pathological confirmation; (2) next generation sequencing using a panel of 98 genes, including those encoding the autoantibodies targets ELAVL1-4, GABBR1-2, and KCTD16; (3) genome-wide copy number variation (CNV); and (4) whole-transcriptome RNA sequencing. CNV analysis revealed that patients with anti-GABAB R PNS commonly have a gain in chromosome 5q, which contains KCTD16, whereas anti-Hu and control patients often harbor a loss. No significantly different number of mutations regarding any onconeural genes was observed. Conversely, the transcriptomic profile of SCLC was different, and the differentially expressed genes allowed effective clustering of the samples into 3 groups, reflecting the antibody-based classification, with an overexpression of KCTD16 specific to anti-GABAB R PNS. Pathway analysis revealed that tumors of patients with anti-GABAB R encephalitis were enriched in B-cell signatures, as opposed to those of patients with anti-Hu, in which T-cell- and interferon-γ-related signatures were overexpressed. SCLC genetic and transcriptomic features differentiate anti-GABAB R, anti-Hu, and non-PNS tumors. The role of KCTD16 appears to be pivotal in the tumor immune tolerance breakdown of anti-GABAB R PNS. ANN NEUROL 2023;94:1102-1115.


Agonist-receptor efficacy. II. Agonist trafficking of receptor signals.
There is evidence to suggest that receptors with seven transmembrane domains can exist in G protein-activating conformations. It is not known how many activated receptor forms exist for each receptor. Furthermore, if there are multiple forms, does the chemical structure of the agonist determine which form dominates, and therefore, which response pathway is activated? This latter scheme is referred to as agonist-receptor trafficking, and is discussed in this, the second of two articles by Terry Kenakin. One way to approach these questions is to study receptors that couple to more than one G protein and, in essence, to try to allow the G protein to indicate the receptor state.


Interferon production following NO2 exposure.
Studies were undertaken to assess the effects of nitrogen dioxide (NO2) on interferon (IFN) production in mice. Mice were exposed to either 5.0 ppm for 7 days or 25 ppm for 3 days followed by an i.p. injection with the IFN inducer, polyinosinic-polycytidilic acid (poly I:C). Sera and organ homogenates made from spleens and lungs were assayed for IFN. There were no significant differences in IFN levels between control and NO2 exposed mice. This was also true for isolated spleen cells from mice that were exposed in vitro to poly I:C. Under the conditions employed, it can be concluded that NO2 did not alter IFN production.


Synthesis and evaluation of new dinitrobenzamide mustards in human prostate cancer.
Tumor hypoxia has been widely explored over the years as a diagnostic and therapeutic marker. Herein, we have reported the design and synthesis of a series of dinitrobenzamide mustards (DNBM) based on the PR-104A hypoxia-selective prodrug. Specifically, we explored the impact of various leaving groups and the introduction of a carboxylic acid group on the biological performance of the DNBM constructs. Once in hand, the Log D values, cytotoxicity in PC-3 and DU-145 human prostate cancer cells lines and the hypoxia selectivities of the DNBM analogs were examined. Overall, the DNBM constructs were found to be tolerant to modifications with none of the explored modifications substantially degrading the cytotoxic potential of the constructs.


Effects of combinations of therapeutic agents on the proliferation of progenitor cells in chronic myeloid leukaemia.
Combination of STI571, a tyrosine kinase inhibitor, with other drugs may be beneficial in the treatment of chronic myeloid leukaemia (CML). We measured the effects of STI571, AG490, farnesyltransferase inhibitor (FTI), interferon alpha (IFN-alpha), cytosine arabinoside (Ara-C) and all-trans retinoic acid (ATRA), singly and in combination, on clonogenic leukaemic cell proliferation. STI571, IFN-alpha and ATRA each reduced proliferation by 50-60%; AG490, FTI and Ara-C had less effect. Comparing the observed and expected (i.e. additive) effects of drug combinations showed STI571 + FTI, STI571 + AG490 and IFN-alpha + ATRA were additive; STI571 + IFN-alpha, IFN-alpha + Ara-C and STI571 + AG490 + FTI were less than additive. Thus, STI571 + FTI, STI571 + AG490 and IFN-alpha + ATRA may be better combination therapies for CML than STI571 + IFN-alpha, IFN-alpha + Ara-C or STI571 + AG490 + FTI.


Dual n-back training improves functional connectivity of the right inferior frontal gyrus at rest.
Several studies have shown that the benefits of working memory (WM) training can be attributed to functional and structural neural changes in the underlying neural substrate. In the current study, we investigated whether the functional connectivity of the brain at rest in the default mode network (DMN) changes with WM training. We varied the complexity of the training intervention so, that half of the participants attended dual n-back training whereas the other half attended single n-back training. This way we could assess the effects of different training task parameters on possible connectivity changes. After 16 training sessions, the dual n-back training group showed improved performance accompanied by increased functional connectivity of the ventral DMN in the right inferior frontal gyrus, which correlated with improvements in WM. We also observed decreased functional connectivity in the left superior parietal cortex in this group. The single n-back training group did not show significant training-related changes. These results show that a demanding short-term WM training intervention can alter the default state of the brain.


A biochemical and pharmacological approach to the genesis of ulcer disease. I. A model study of ethanol-induced injury to gastric mucosa in rats.
Present concepts of acute ulceration in the gastric mucosa include the hypothesis that mucosal ischemia is an important initiating event. The evidence for this is based upon observations on tissue metabolism and determinations of gastric mucosal blood flow. Using the model of gastric mucosal injury in the rat with ethanol, we have found that mucosal injury could be detected at a time when tissue oxygenation as determined by biochemical, and pharmacological studies of ATP metabolism were not compatible with ischemia. We also found that drugs acting at different subcellular levels were able to both inhibit gastric acid secretion in 4 hour pylorus-ligated rats and gastric mucosal injury after ethanol. Certain drugs, such as histamine and pentagastrin, stimulated acid secretion but inhibited the injury to the mucosa by ethanol indicating that increased cellular activity could occur during the development of mucosal injury.


Dental practitioners' experiences on the usefulness of restorative materials in Finland 1992-1996.
To analyse general dentists' choice of restorative materials in Finland, where the use of amalgam has significantly decreased and the use of composites increased during the past 10 years. Postal survey in 1997 to a random sample of general dental practitioners mainly working with adult patients. Percentage distribution of dentists' opinions. The response rate was 82%. Tooth-coloured restorations were considered to be more time consuming, technically complicated and to have shorter life spans. Most dentists were not willing to return to the wide-scale use of amalgam restorations. The rapid changes in the restorative material selection have not resulted in serious problems in restorative therapy.


Cysts of serendipity.
Primary intradiaphragmatic cysts are diagnostically challenging lesions. Often serendipitously discovered on radiological examination, intradiaphragmatic cysts are uncommon and require surgical resection for accurate identification. Two children, aged 16 and 4 years, presented for surgical evaluation of what were believed to be asymptomatic cystic lesions of hepatic origin. Imaging studies of the 2 intradiaphragmatic cysts suggested lesions of extradiaphragmatic origins, and surgical excision was necessary for accurate diagnosis. The limitations of imaging studies in determining malignancy necessitate surgical intervention for lesions of the diaphragm and peridiaphragmatic structures.


The costs and benefits of primary total hip replacement. How likely are new prostheses to be cost-effective?
Many new hip prostheses are now available for use in total hip replacement. The majority remain untested relative to standard prostheses; however, many new prostheses are substantially more costly. We examine how much more effective new prostheses must be, in terms of reducing the need for revision operations, in order to justify this increased cost.


Green-fluorescent-protein-expressing mice as models for the study of axonal growth and regeneration in vitro.
The culture of hippocampal-entorhinal brain slices is a widely used model for studying neuronal differentiation, axon growth and pathfinding in vitro. The application of tracers (e.g. biocytin) is a well-established method for studying single or multiple neurons and their extensions in this model. For quantifying the growth of high numbers of axons after lesion, however, genetically expressed enhanced green fluorescent protein (EGFP) has proven particularly useful for labeling living axons in vivo and in vitro. Here, we introduce several EGFP-expressing mouse lines which improve the organotypic brain slice model. The questions addressed determine which mouse line to use: beta-actin-EGFP mice for labeling all cells and their extensions; Tau-EGFP mice for labeling the axoplasma; or Thy-1.2-EGFP mice for labeling the axonal membrane. Cocultures of EGFP-positive entorhinal cortex explants with EGFP-negative hippocampal explants allow the monitoring of fluorescent axons growing into the hippocampus in an easily quantifiable manner.


Short-term mortality risks among patients with non-metastatic bladder cancer.
Population-based analysis for the short-term non-bladder cancer related mortality among patients with non-metastatic bladder cancer is currently lacking. The objective of the current study was to assess and quantify cause of death after bladder cancer diagnosis. The custom Surveillance, Epidemiology, and End Results (SEER) dataset for standardized mortality ratios (SMRs) was utilized to identify 24,074 patients who were diagnosed with nonmetastatic (M0) bladder cancer from 2014 to 2015. SMRs for causes of death were calculated. Risk factors for bladder cancer-specific mortality, competing mortality, second-cancer mortality, and noncancer mortality were determined using either multivariable Cox or competing risk regression models. Among all the 4179 (17.4%) deaths occurred during the follow-up period, almost half of them (44.2%) were attributed to non-bladder cancer cause, including second non-bladder cancer (10%) and other non-cancer causes (34.2%). The most common noncancer causes of death were heart diseases followed by chronic obstructive pulmonary disease. Patients had a higher risk of death from second malignancies (SMR, 1.59; 95% CI, 1.47-1.74) compared with death from first malignancies in the US general population, and also had higher risks of death from heart diseases (SMR, 1.29; 95% CI, 1.18-1.40) and chronic obstructive pulmonary disease (SMR, 1.52; 95% CI, 1.29-1.79) compared with the US general population. Additionally, some risk factors for competing second malignancies or noncancer mortality were determined, such as age, gender, marital status and treatment modalities. Death from non-bladder cancer cause contributed to almost half of all deaths in bladder cancer survivors during the short-term follow-up period. These findings can inform medical management and assist clinicians in counseling those survivors regarding their short-term health risks.


Adenosine: setting the stage for plasticity.
It is widely accepted that Hebbian forms of plasticity mediate selective modifications in synaptic strength underlying information encoding in response to experience and circuit formation or refinement throughout development. Several complementary forms of homeostatic plasticity coordinate to keep Hebbian plasticity in check, frequently through the actions of conserved regulatory molecules. Recent evidence suggests that this may be the case for adenosine, which is ubiquitous in the brain and is released by both neurons and glial cells via constitutive and activity-dependent mechanisms. Through A1 and A2A receptor activation, adenosine modulates neuronal homeostasis and tunes the ability of synapses to undergo and/or sustain plasticity. Here, we review how adenosine equilibrates neuronal activity and sets the stage for synaptic plasticity.


Management of cutaneous malignant melanoma by dermatologists of the American Academy of Dermatology. I. Survey of biopsy practices of pigmented lesions suspected as melanoma.
The incidence of malignant melanoma (MM) has rapidly increased during the past five decades. Relatively little information is available on whether the role of the dermatologist has increased concomitantly in the surgical management of this cancer. Our purpose was to learn how members of the American Academy of Dermatology (AAD) treat patients with lesions highly suspected as being MM and how the management of these patients may have changed over the past decade. This, the first of a two-part series, concerns biopsies. The data for the study were collected by means of a questionnaire that was sent to all members of the AAD practicing in the United States (N = 7412). A total of 2991 valid questionnaires were returned, a response rate of 40%. The majority of respondents (89% in 1982; 90% in 1992) stated that they performed the biopsies of pigmented lesions suspected of being MMs. Excisional biopsy was the preferred technique (58% in 1982; 68% in 1992). The type of biopsy and who performed the initial biopsy of a suspected MM were associated with the following factors: (1) the number of years in practice, (2) the type of practice, and (3) whether the dermatologist subsequently performed the definitive surgery for the MM. Regional variations in biopsy practices were also noted. Most AAD dermatologists who responded to the questionnaire perform the biopsies of lesions highly suspected of being MM. During the last decade an increasing proportion of dermatologists are performing excisional biopsies rather than other types of biopsies for such lesions.


Enhancing effect of thoracotomy and/or laparotomy on the growth of ascitic tumor in rats.
To evaluate the effect of operative stress on a tumor growth, thoracotomy and/or laparotomy were performed 48 hours after the intraperitoneal inoculation of Sato lung cancer cells in Donryu rats. The survival time and the spread of the tumor were examined. Thoracotomy and laparothoracotomy reduced significantly the survival time of the inoculated rats as compared with the control but no significant difference was observed between the two test groups subjected to operative stress. No difference was observed in the spread of the tumor between the test groups and the control. These results indicated that the operative stress increased only the number of metastatic foci and did not change the characteristics of the tumor cells.


Monitoring neuronal calcium signalling using a new method for ratiometric confocal calcium imaging.
Ca2+ signalling influences many processes in the adult and developing nervous system like exocytosis, synaptic plasticity, and growth cone motility. Optical techniques in combination with fluorescent Ca2+ indicators are the most frequently used methods to measure Ca2+ signalling in cells. In the present study, a new method for ratiometric confocal Ca2+ imaging was developed, and the usefulness of the system was tested with two different neuronal preparations. Developing Manduca sexta antennal lobe neurons were loaded with the Ca2+-sensitive dye Fura Red-AM, and the ratio of fluorescence excited at 457 and 488nm was measured with a confocal laser scanning microscope. During pupal stages 4-12, the antennal lobe neuropil is restructured which includes the ingrowth of olfactory receptor axons, dendritic outgrowth of antennal lobe neurons, and synaptogenesis. In antennal lobe neurons, application of the AChR agonist carbachol induced Ca2+ oscillations the amplitude and frequency of which changed during stages 4-9, while at the end of synaptogenesis, at stages 11 and 12, only single Ca2+ transients were elicited. The Ca2+ oscillations were blocked by D-tubocurarine and Cd2+, indicating that they were due to Ca2+ influx through voltage-gated Ca2+ channels, activated by nAChR-mediated membrane depolarization. To test whether single action potentials can induce Ca2+ transients detectable by Fura Red, individual leech Retzius neurons were injected iontophoretically with the Ca2+ indicator, and the membrane potential was recorded during Ca2+ imaging. Single action potentials induced transient increases in the Fura Red ratio measured in the axon, while trains of action potentials elicited Ca2+ transients that could also be recorded in the cell body and the nucleus. The results show that Fura Red can be used as a ratiometric Ca2+ indicator for confocal imaging.


Regulation of hepatic insulin signaling and glucose homeostasis by sphingosine kinase 2.
Sphingolipid dysregulation is often associated with insulin resistance, while the enzymes controlling sphingolipid metabolism are emerging as therapeutic targets for improving insulin sensitivity. We report herein that sphingosine kinase 2 (SphK2), a key enzyme in sphingolipid catabolism, plays a critical role in the regulation of hepatic insulin signaling and glucose homeostasis both in vitro and in vivo. Hepatocyte-specific Sphk2 knockout mice exhibit pronounced insulin resistance and glucose intolerance. Likewise, SphK2-deficient hepatocytes are resistant to insulin-induced activation of the phosphoinositide 3-kinase (PI3K)-Akt-FoxO1 pathway and elevated hepatic glucose production. Mechanistically, SphK2 deficiency leads to the accumulation of sphingosine that, in turn, suppresses hepatic insulin signaling by inhibiting PI3K activation in hepatocytes. Either reexpressing functional SphK2 or pharmacologically inhibiting sphingosine production restores insulin sensitivity in SphK2-deficient hepatocytes. In conclusion, the current study provides both experimental findings and mechanistic data showing that SphK2 and sphingosine in the liver are critical regulators of insulin sensitivity and glucose homeostasis.


Impact of Carbon Dioxide on Cerebral Oxygenation and Vital Parameters in Stable Preterm and Term Infants Immediately after Birth.
Carbon dioxide (pCO2) induces changes in the tone of cerebral vessels. The aim of the present study was to evaluate the impact of pCO2 on cerebral regional tissue oxygen saturation (crSO2), cerebral fractional tissue oxygen extraction (cFTOE), and cerebral tissue oxygen extraction (cTOE), measured with near-infrared spectroscopy (NIRS), in preterm and term infants 15 min after birth. Post hoc analyses of secondary outcome parameters of prospective observational studies were performed. Stable preterm and term infants with cerebral NIRS monitoring (INVOS 5100C) until minute 15 after birth and a blood gas analysis, performed between minutes 14-18 after birth, were included. Heart rate (HR) and arterial oxygen saturation (SpO2) were recorded. pCO2 was correlated with crSO2, cFTOE, cTOE, SpO2, HR, and partial pressure of oxygen (pO2). Eleven preterm infants with a median (IQR) gestational age of 34.8 (32.7-36.1) weeks were analyzed. Mean ± SD pCO2 was 53.5 ± 4.2 mm Hg. At minute 15 after birth, crSO2 was 82.6 (74.3-91.3)%, cFTOE 0.15 ± 0.09, cTOE 14.6 ± 8.4%, SpO2 97.4 ± 2.1%, and HR 152 (136-167) bpm. pCO2 correlated negatively with crSO2 (p = 0.012) and positively with cFTOE (p = 0.035) and cTOE (p = 0.037). Eighty-four term infants with a gestational age of 39.0 (38.5-38.9) weeks were analyzed. pCO2 was 53.5 ± 6.3 mm Hg. At minute 15 after birth, crSO2 was 84.4 (80.8-85.1)%, cFTOE 0.14 ± 0.08, cTOE 13.6 ± 7.9%, SpO2 96.5 ± 2.6%, and HR 155 (153-163) bpm. pCO2 did only negatively correlate with pO2 (p = 0.034) in term infants. In preterm infants, higher pCO2 was associated with lower crSO2 and higher cFTOE/cTOE. In term infants, no associations were observed. The present findings suggest that the vasodilatative effect of pCO2 is less pronounced in preterm infants during immediate postnatal transition.


Interaction of purple membrane with solvents. I. Applicability of solubility parameter mapping.
We carried out spectral studies on the interaction between purple membrane fragments (isolated from Halobacterium halobium) and a series of different solvents, classified quantitatively according to their solubility parameters delta d, delta p, delta h. These represent the contribution of dispersion forces, polar forces, and hydrogen bonding, respectively, to the cohesive energy density of the solvent. Purple membrane fragments, kept in the dark, were suspended in each of the solvents as well as in binary mixtures of solvents, and the spectrum of the resulting suspension was recorded in the wavelength region 250-700 nm. The interaction of each solvent with the membrane fragments can be represented by a point on either a ternary diagram, where each of the three axes represents one of the solubility parameters, or a binary diagram, where one of the two axes is a combination of two of the solubility parameters (delta v = square root of delta d2 + delta p2 or delta a = square root of delta p2 + delta h2). In the former type of solvent map the contribution of each of the parameters is distinct but only their relative contributions are expressed. In the latter the absolute values of delta i are considered. In each of these modes of presentation an inner closed region is observed. The solvents inside its borders interact with bacteriorhodopsin with a resultant spectral change. Mixtures of solvents fit the maps according to their calculated delta values. Thus, a mixture of an apolar solvent with a highly polar solvent interacts with bacteriorhodopsin, even though each of these solvents alone does not.


Group B streptococcal leptomeningitis, ventriculitis, right cerebellitis, and cerebritis in an immunocompetent patient.
Group B streptococcal (GBS) meningitis is uncommon in non-puerperal adults outside of significant immunocompromise or structural abnormalities. We describe a relatively healthy 62-year-old man with GBS bacteremia, abnormal lumbar puncture, and MRI-confirmed leptomeningitis, ventriculitis, right cerebellitis, and cerebritis who presented without overt symptoms of meningitis. The suspected source of infection was a high-inoculum genitourinary infection in the setting of hydronephrosis and recent cystoscopy. We performed a literature review of previous cases and clusters of GBS meningitis. With increasing recognition of invasive GBS infection among adult patients, and in light of our patient's atypical presentation, we propose that an index of suspicion for GBS meningitis be maintained, even for patients who would traditionally have been considered at lower risk.


Risk factors for delayed gastric emptying after esophagectomy.
Delayed gastric emptying (DGE) is a common functional disorder after esophagectomy with gastric tube reconstruction. Little is known about risk factors that can predict this debilitating complication. Patients who underwent elective esophagectomy from 2008 to 2016 in a single center were retrospectively reviewed. Diagnosis of DGE was based on clinical, radiological, and endoscopic findings. Uni- and multivariate analyses were performed to identify patient-, tumor-, and procedure-related factors that increase the risk of DGE. One hundred eighty-two patients were included. Incidence of DGE was 39.0%. Overall, 27 (14.8%) needed an endoscopic intervention. Patients in the DGE group had a longer hospital stay (p < 0.01). No differences were found for the 30-day (p = 1.0) and hospital mortality (p = 1.0). On univariate analyses, a significant influence on DGE was demonstrated for pre-existing pulmonary comorbidity (p = 0.04), an anastomotic leak (p < 0.01), and postoperative pulmonary complications (pneumonia: p = 0.02, pleural empyema: p < 0.01, and adult respiratory distress syndrome: p = 0.03). Furthermore, there was a non-significant trend toward an increased risk for DGE for the following variable: female gender (p = 0.09) and longer operative time (p = 0.09). On multivariate analysis, only female gender (p = 0.03) and anastomotic leak (p = 0.01) were significantly associated with an increased risk for DGE. DGE is a frequent complication following esophagectomy that can successfully be managed with conservative or endoscopic measures. DGE did not increase mortality but was associated with increased morbidity and prolonged hospitalization. We identified risk factors that increase the incidence of DGE. However, this has to be confirmed in future studies with standardized definition of DGE.


Combinations of factors contribute to young driver crashes.
Motor-vehicle crashes are a leading cause of death in adolescence and young adults. A multitude of factors, including skill level, inexperience, and risk taking behaviors are associated with young drivers' crashes. This research investigated whether combinations of factors underlie crashes involving young drivers. A retrospective longitudinal study was conducted on population-wide one- and two-car crashes in Great Britain during years 2005-2012 per driver age (17-20, 21-29, 30-39, 40-49) and sex. Reporting officers provided their assessment of the factors contributing to crashes. Principal components analysis was conducted to identify combinations of factors underlying young drivers' crashes. Factor combinations, including challenging driving conditions, risk taking behaviors, and inexperience were implicated in young drivers' crashes. Combinations of factors reveal new insights into underlying causes of crashes involving young drivers. One combination revealed that slippery roads due to poor weather pose greater risk to young drivers who are inexperienced and likely to exceed the appropriate speed. The findings motivate new policy recommendations, such as educating young drivers about the importance of adjusting their speed to the road conditions.


TNF-α suppresses SHOX2 expression via NF-κB signaling pathway and promotes intervertebral disc degeneration and related pain in a rat model.
This study was conducted to verify the relative expression patterns of SHOX2 and its regulation by tumor necrosis factor alpha (TNF-α) during the development of intervertebral disc degeneration (IVDD). A rat disc-degeneration model was subjected to disc puncture (DP) and intradiscal injections with TNF-α to determine the roles of TNF-α and SHOX2 expression in IVDD in vivo. TNF-α and SHOX2 expression patterns in different degenerative rat nucleus pulposus (NP) tissues were measured by immunohistochemistry (IHC). The effects of TNF-α on IVDD were determined by magnetic resonance imaging (MRI) and pain development of wet-dog shakes (WDS) were blinded assessment by pain-behavior testing, respectively. Changes in TNF-α on SHOX2 expression were measured by Western blot analysis and real-time reverse transcription polymerase chain reaction (RT-PCR). The roles of nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) in TNF-α-mediated SHOX2 activation were studied using viral transfection, Western blot analysis, and real-time RT-PCR. In vivo, TNF-α accelerated the process of IVDD and suppressed SHOX2 expression; compared to the DP group, WDS was significantly increased in TNF-α intradiscal injection group at 2 to 6 weeks after puncture (P < .05); In NP cells, TNF-α negatively affected the IVDD-associated SHOX2 suppression. While TNF-α promotes IVDD through activation of both MAPK and NF-κB signaling, it seemed that only NF-κB signaling controlled the TNF-α-mediated SHOX2 suppression that is associated with IVDD. The results of this study indicated that TNF-α inhibits SHOX2 expression and has promoted effects on IVDD in the rat model, and these effects might be associated with through NF-κB signaling pathway and promotes IVDD and related pain in a rat model.


Antithrombic activity of some polysaccharide resins.
Crosslinked dextrans (Sephadex) bearing essentially carboxymethyl, benzylsulphonate and alpha-amino acid groups have been synthesized. The antithrombic activity of the resins may be the result of a cooperative effect between the functional groups. The binding of benzylsulphonate to carboxymethylated Sephadex endows these materials with activity. However the highest activity is obtained when the resins contain simultaneously benzylsulphonate, alpha-amino acid and carboxylic acid groups.


Multiple elements in the distal part of the 1.2 kb 5'-flanking region of the rat GnRH receptor gene regulate gonadotrope-specific expression conferred by proximal domain.
Several lines of evidence indicate that the number of GnRH receptors (GnRH-R) and therefore, gonadotrope responsiveness to GnRH, is highly dependent upon the level of GnRH-R mRNA. To explore this aspect of regulation, we have isolated a 3.3 kb fragment encompassing the promoter region of the rat GnRH-R gene. Primer extension and RNase protection assays allowed the identification of five major transcriptional start sites located within the 110 bp region upstream of the translation start codon. Transfection experiments using the CAT reporter gene demonstrated that the 1261 bp 5' flanking region is required to direct high efficient expression in the gonadotrope-derived alphaT3-1 cell line thus contrasting with mouse in which the only 500 bp proximal sequence appeared to be sufficient. Another difference between rat and mouse was apparent in the 183 bp region of the rat promoter which induced a 3-fold stimulation of thymidine kinase promoter activity in both alphaT3-1 and CHO cells. Subsequent deletion analysis of the region residing between -1261 and -519 revealed the presence of multiple regulatory domains that contributed to the cell-specific activity. However, despite this efficiency in the context of the wild-type promoter, they failed to induce the activity of the minimal thymidine kinase (TK) promoter in the absence of the proximal 600 bp promoter region. Accordingly, a composite TK promoter containing the entire 1.2 kb promoter induced a 10-fold increase in the activity of the TK promoter in alphaT3-1 cells. Taken together these data suggest that distal regulatory regions are critical and require cooperation with proximal specific-promoter elements for activating basal R-GnRH gene expression in gonadotrope cells.


Perioperative risk of noncardiac surgery associated with aortic stenosis.
The perioperative risk of noncardiac surgery in patients with aortic stenosis (AS) remains ill-defined, and the few studies published have reported conflicting results. A sample of patients from the National Hospital Discharge Survey database diagnosed with AS who underwent any noncardiac surgical procedure was searched. Patients who underwent any cardiac surgery were excluded. Patients with AS were matched by decile of age and surgical risk for twice as many controls. A discharge diagnosis of acute myocardial infarction (AMI) and death was used as the end points for analysis. From 1996 to 2002, 5,149 patients with a diagnosis of AS had undergone noncardiac surgery and were matched with 10,284 controls. The incidence of AMI was greater in patients with AS than in controls (3.86% vs 2.03%, p <0.001). After correcting for gender and the presence of coronary artery disease, hypertension, and diabetes mellitus in a multivariate logistic regression model, the presence of AS was associated with an increased likelihood of AMI (odds ratio 1.55, 95% confidence interval 1.27 to 1.90, p <0.001). There was no significantly increased risk for death in patients with AS versus controls. In the era of more intense perioperative medical management of patients who undergo noncardiac surgery, the presence of AS increases the risk for perioperative AMI but not overall mortality. The impact of the actual severity of AS on outcomes with noncardiac surgery needs further study.


The first national tuberculosis prevalence survey of Lao PDR (2010-2011).
The objective of the study was to measure the prevalence of bacteriologically confirmed pulmonary tuberculosis (TB) in Lao PDR in 2010-2011. A nationwide, multistage cluster-sampled cross-sectional survey was undertaken in 2010-2011. All consenting participants ≥15 years were screened for pulmonary TB with chest X-ray and symptom questionnaire. Two sputum specimens for bacteriological examination by microscopy and culture were collected from those who screened positive. Prevalence was estimated using multiple imputation and inverse probability weighting methods. Of 39 212 eligible participants from 50 clusters, 6290 participants provided at least one sputum sample for smear and culture. There were 237 bacteriologically confirmed pulmonary TB cases, 107 of which were smear-positive. Chest X-ray screening alone identified 230 (97.0%) cases compared with 118 (49.8%) by symptom screening alone. The estimated prevalence of smear-positive and bacteriologically confirmed TB in those ≥15 years was 278 per 100 000 (95%C.I. 199-356) and 595 per 100 000 (95%C.I. 457-733), respectively. Prevalence significantly increased with age and was higher in men than women. The prevalence of TB in Lao PDR is almost twice as high than previous estimates, with the greatest burden in the older population. Case detection efforts remain the primary goal of the national TB programme with case notifications being very low in comparison with the estimated number of prevalent cases. The survey observed major limitations with the diagnostic strategy of passive (symptom based) case finding that uses only direct smear microscopy for confirmation.


Oxygen vacancy mediated α-MoO3 bactericidal nanocatalyst in the dark: Surface structure dependent superoxide generation and antibacterial mechanisms.
Understanding bacteria inactivation mechanisms of nanomaterials on the surface molecular level is of prime importance for the development of antibacterial materials and their application in restraining the transmission of pathogenic microorganisms. This study prepared an oxygen vacancy-mediated bactericidal nanocatalyst α-MoO3 which exhibited excellent antibacterial activity against Escherichia coli and Staphylococcus aureus in the dark. By manipulating the surface structure of α-MoO3, the facile tuning of superoxide radical (•O2-) generation can be achieved, which was confirmed by electron paramagnetic resonance. •O2- disrupted bacterial membrane through attacking lipopolysaccharide (LPS) and phosphatidylethanolamine (PE). Intracellular reactive oxygen species (ROS) experiments confirm that oxidative stress induced by •O2- also played a vital role in bacterial inactivation, which might account for DNA damage verified by comet assays. The α-MoO3 with rich oxygen vacancies also exhibited good antibacterial efficiency (>99.00 %) toward airborne microbes under dark conditions, indicating its potential to impede the transmission of pathogenic microbes.


What constitutes optimal surgical revascularization? Answers from the Bypass Angioplasty Revascularization Investigation (BARI).
The study was done to derive the optimum definition of complete revascularization in coronary artery bypass surgery. "Complete revascularization" has been considered the goal of coronary artery bypass operations, but various definitions of completeness exist. We evaluated the Bypass Angioplasty Revascularization Investigation (BARI) surgical results in the seven years after operation. Different definitions of completeness of revascularization were retrospectively applied to the 1,507 patients in the combined randomized/registry group to derive the definition of complete operative revascularization with the best discrimination in long-term results between those with and without complete revascularization as defined. Four definitions were evaluated: 1) traditional complete revascularization with one graft to each major diseased artery system; 2) functional complete revascularization with one graft to all diseased major or primary segmental vessels; 3) number of distal anastomoses greater than, equal to or less than the number of diseased coronary segments; and 4) number of distal anastomoses to the major coronary systems equal to 1 or greater than 1. No independent survival advantage existed for traditional or functional complete revascularization as compared with incomplete revascularization. No survival advantage existed for any of the three arms of definition 3. For definition 4, seven-year death/myocardial infarction was highest (32.9%) when more than one anastomosis was constructed to any non-left anterior descending coronary artery (LAD) system (relative risk 1.37, p = 0.03). No increased risk was associated with constructing more than one anastomosis into the LAD system. The construction of more than one graft to any system other than the LAD appears to confer no long-term advantage, and may actually be deleterious.


Mixed anxiety-depression in a primary-care clinic.
To determine the prevalence and clinical significance of a mixed anxiety-depressive (MAD) syndrome in primary care, a two-stage sampling design was applied to 796 consecutive clinic attendees without known psychiatric illness. Among 78 systematically interviewed subjects, 10.3% (n = 8) had a depressive disorder alone, 12.8% (n = 10) had an anxiety disorder alone, 19.2% (n = 15) had a comorbid anxiety and depressive disorder and 12.8% (n = 10) had a combination of subsyndromal anxiety and depressive features that fulfilled either ICD-10 or our own operational criteria for MAD. Patients with MAD rated their disability as being comparable to that of patients with anxiety or depressive disorders. These findings lend support to the notion that there is a sizeable subgroup of patients in primary care who appear to be suffering from a psychiatric syndrome with an admixture of subsyndromal depressive and anxiety features. Questions about the temporal stability of MAD and preferred approaches to treatment have yet to be answered.


The relationship between cortical inhibition, antipsychotic treatment, and the symptoms of schizophrenia.
Cortical inhibition (CI) deficits assessed by transcranial magnetic stimulation paradigms, short-interval cortical inhibition (SICI), and cortical silent period (CSP) have been demonstrated in schizophrenia (SCZ) patients. Antipsychotic treatments can modify CI and improve clinical symptoms, suggesting a neurophysiological link between the two. Previous studies have demonstrated that clozapine is associated with prolongation in CSP, a gamma-hydroxybutyric acid (GABA)(B)-mediated phenomenon. Furthermore, SICI deficits were associated with psychotic symptom severity, suggesting alternation in GABA(A)-mediated neurotransmission. Such differential association patterns between clinical symptoms and CI deficits and their relationship to antipsychotic treatment thus might provide insights to the pathophysiology of schizophrenia. CI was assessed in 78 SCZ patients and 38 healthy subjects. Clinical symptoms were evaluated using the Positive and Negative Syndrome Scale (PANSS). Subjects were grouped according to antipsychotic medication status: unmedicated (n = 7), clozapine (n = 19), olanzapine/quetiapine (n = 32), and risperidone/typical antipsychotics (n = 20). Relative to control subjects, patients receiving clozapine had longer CSP and reduced SICI, whereas patients receiving other antipsychotics and unmedicated patients had shorter CSP. Across all subjects with SCZ, CSP was inversely associated with negative symptoms, and SICI was inversely associated with positive symptoms. These results confirm that unmedicated SCZ patients have CI deficits and that clozapine treatment is associated with potentiation of GABA(B)-inhibitory neurotransmission and reduced GABA(A) inhibitory neurotransmission. Also, the differential associations among SICI, CSP, and clinical symptom dimensions suggest that GABA(A)- and GABA(B)-mediated CI might have different roles in the pathophysiology of symptoms of schizophrenia.


Separation and characterization of bufadienolides in toad skin using two-dimensional normal-phase liquid chromatography×reversed-phase liquid chromatography coupled with mass spectrometry.
Bufadienolides possess various bioactivities especially antitumor. Due to the high structural diversity, the separation of bufadienolides often suffers from coelution problem on conventional RP columns. In this work, an off-line two-dimensional normal-phase liquid chromatography×reversed-phase liquid chromatography (2D-NPLC×RPLC) method was developed to separate and characterize bufadienolides in toad skin. Several RP and NP columns were evaluated with five reference bufadienlides. The XUnion C18 and XAmide columns exhibited superior chromatographic performances for bufadienlide separation, and were selected in RPLC and NPLC, respectively. RPLC was used in the second-dimension for the good compatibility with MS, while NPLC was adopted in the first-dimension. The orthogonality of the 2D-NPLC×RPLC system was investigated by the geometric approach using fifteen bufadienolide mixtures. The result was 49.6%, demonstrating reasonable orthogonality of this 2D-LC system. By combining the 2D-LC system with MS, 64 bufadienlides including 33 minor ones and 11 pairs of isomers in toad skin were identified. This off-line 2D-NPLC×RPLC allowed to solve the coelution problem of bufadienlides in one-dimension RPLC, and thus facilitated the identification significantly.


Cortical inhibition in Parkinson's disease: new insights from early, untreated patients.
Transcranial magnetic stimulation (TMS) has opened important perspectives on the pathophysiological bases and potential targets of treatment strategies for idiopathic Parkinson's disease (IPD). Studies have been mainly focusing on motor cortical inhibitory phenomena. However, differences in patients and methods caused several discrepancies, particularly on the so-called long-latency cortical inhibition (LICI). We wanted to challenge such controversies by studying early, drug-naïve patients, and by reproducing the original method that detected a pathologic LICI in IPD. We studied the motor potentials evoked in the first dorsal interosseous muscle on the more and the less parkinsonian side of the body in 18 asymmetrical untreated IPD patients in the early stages of their disease. We had 12 healthy controls. The TMS variables were the active motor threshold, the size of the motor-evoked potential, the cortical silent period and LICI. Average active motor threshold was similar in patients and controls, but its variability was significantly higher among patients (P<0.05). There was a trend for the cortical silent period to be shorter on the more affected side of the patients (P=0.1). Patients, especially on their more affected side, exhibited a late LICI peak, which was absent among controls (P<0.05). This effect was independent of the silent period duration. However, patients and controls having a short silent period also had a shorter LICI (P<0.05). Changes in LICI had a strong trend to correlate to the severity of the parkinsonian signs (P=0.1). Thus, the present study definitely reinforced several previous TMS findings in IPD as a feature of the "pure" disease pathophysiology. The pathologic enhancement of late LICI can act as a candidate physiological hallmark of IPD, to be tested in various diagnostic or therapeutic circumstances.


Chloridobis(dimethyl-glyoximato-κN,N')(ethyl pyridine-3-carboxyl-ate-κN)cobalt(III).
In the title compound, [Co(C(4)H(7)N(2)O(2))(2)Cl(C(8)H(9)NO(2))], which was prepared as a model complex of vitamin B(12), the Co(III) atom, which is linked to four N atoms of the pseudo-macrocyclic (dmgH)(2) ligand (dmgH is dimethyl-glyoximate) in the equatorial plane and one Cl(-) anion and one N atom of ethyl nicotinate in apical positions, displays an approximately octa-hedral coordination. The Co atom is 0.0187 (8) Å out of the mean plane of the four equatorial N atoms. The structure has an O⋯H⋯O bridge, which is very common in cobaloxime derivatives, with O⋯H distances of 1.24 (2) and 1.25 (2) Å.


A combination of amino-functionalized fibrous silica (KCC-1-NH2)/effectively and efficiently oxidized graphene oxide (EEGO) nanocomposite for dispersive solid-phase extraction, pre-concentration and fluorescence determination of total para-cresol in plasma samples of chronic kidney disease patients.
A novel amino-functionalized fibrous silica (KCC-1-NH2) and effectively and efficiently oxidized graphene oxide (EEGO) nanocomposite has been successfully synthesized. This nanocomposite was applied as a new sorbent in the dispersive solid-phase extraction (-SPE) to the preconcentration of total p-cresyl sulfate (pCS) in human plasma samples. The morphology and basic structure of the proposed nanocomposite were investigated through different techniques including field emission scanning electron microscopy (FESEM), energy dispersive X-ray (EDX), transmission electron microscopy (TEM), Fourier transform infrared (FTIR), and dynamic light scattering (DLS)/zeta potential techniques. The influence of different factors on the extraction efficiency, including the amount of sorbent, sample pH, extraction time, elution solvents and their volume, and desorption time were also investigated. The developed fluorescence-based method offers a linear dynamic range from 0.02 to 6 µg/mL with an acceptable correlation coefficient (R2 = 0.9982) and recovery (80%). The limit of quantification (LOQ) and limit of detection (LOD) were found to be 0.043 and 0.013 µg/mL, respectively. Plasma samples of five chronic kidney disease (CKD) patients were also analyzed and measured pCS concentrations were ranged from 16 to 41 µg/mL. The applicability of the method was successfully tested for the extraction and quantification of pCS from spiked and patients' plasma samples.


Improvement of anemia with erythropoietin and intravenous iron reduces sleep-related breathing disorders and improves daytime sleepiness in anemic patients with congestive heart failure.
Central sleep apnea (CSA) (with or without Cheyne-Stokes breathing) or obstructive sleep apnea (OSA) are common in congestive heart failure (CHF). Correction of anemia may improve CHF. We hypothesized that correction of anemia might also improve sleep-related breathing disorders (SRBDs) in CHF. Thirty-eight patients with CHF and anemia (hemoglobin level < 12 g/dL) were treated with erythropoietin and intravenous iron to a target hemoglobin level of 13 g/dL. Home sleep recordings were done before and after 3 months of treatment. Thirty-seven patients had SRBD (Apnea Hypopnea Index [AHI] of > or = 10). Hemoglobin level increased from 10.4 +/- 0.8 to 12.3 +/- 1.2 g/dL (P < .001). Total AHI values decreased from 35.9 +/- 12.2 to 24.9 +/- 12.2 (P < .001). The AHI of CSA, OSA and Cheyne-Stokes breathing decreased from 26.5 +/- 14.6 to 18.6 +/- 7.7, from 9.4 +/- 10.9 to 6.9 +/- 9.8, and from 13.1 +/- 16.4 to 9.0 +/- 12.2, respectively (all P < .05). Sleep minimal oxygen saturation (SaO2) increased from 62% +/- 12% to 71% +/- 11%; Epworth Sleepiness Scale score improved from 9.4 +/- 6.2 to 6.0 +/- 5.0 and New York Heart Association class improved from 2.9 +/- 0.4 to 1.7 +/- 0.7, all P < .001. Hemoglobin level improvement correlated with improvement in OSA+CSA, CSA, minimal SaO2, Epworth Sleepiness Scale score, and New York Heart Association class (all P < .001). Improvement of anemia in CHF is associated with a reduction in SRBD and an improvement in daytime sleepiness.


Predictive value of reduced pulmonary arterial elasticity in acute pulmonary embolism for right ventricular dysfunction.
Computed tomography pulmonary angiography (CTPA) yields indices, such as the right ventricular/left ventricular (RV/LV) ratio > 1.0, which are commonly used for risk stratification of patients with acute pulmonary embolism (APE). Although pulmonary artery elasticity (PAE) has been previously described, its relationship with right ventricular dysfunction (RVD) has not been explored. Here, we investigated whether PAE, measured using CTPA, is associated with RVD. Patients who underwent retrospective electrocardiogram-gated CTPA and had a definitive diagnosis of APE were included in the study. The subjects were classified into RVD and non-RVD groups according to the RVD on echocardiography. PAE, involving aortic distensibility (AD), aortic compliance (AC), and aortic stiffness (ASI), and right heart function indices were compared between the two groups, and their correlations were examined. Receiver operating characteristic (ROC) curves were generated to evaluate the specificity and sensitivity of the RVD prediction. Thirty-five patients with APE were enrolled in the study (RVD: 18, non-RVD: 17). The groups showed no significant differences in age, sex, number of patients receiving thrombolysis, and number of high-risk conditions (P > 0.05). Regarding PAE parameters, AD was significantly reduced in the RVD group compared to that in the non-RVD group (P < 0.05), whereas AC and ASI were not statistically different (P > 0.05). The ratio of the maximum cross-sectional area of PA and AA (PA/AAmax),the ratio of the minimum cross-sectional area of PA and AA(PA/AAmin), diameter of the coronary sinus, RV/LV diameter, RV/Lvarea, the ratio of the end-diastolic volume of right ventricular and left ventricular (RV/LVDV), the ratio of the end-systolic volume of right ventricular and left ventricular (RV/LVSV) were significantly greater in the RVD group than in the non-RVD group (P < 0.05). Correlation analysis of AD and right heart function parameters showed that AD was negatively correlated with PA/AAmax, PA/AAmin, RV/LV diameter, RV/LVDV, and PAE measured by ultrasound, with correlation coefficients ranging from - 0.336 to - 0.580 (P < 0.05). The ROC curves of AD and RV/LVdiameter to predict RVD had areas under the curve of 0.748 and 0.712, sensitivities of 82.35% and 70.59%, specificities of 66.67% and 72.22%, and cutoff values of 4.9433 and 1.1105, respectively. AD obtained by retrospective ECG-gated CTPA may be helpful in assessing RVD in patients with APE while accurately diagnosing APE. It contributes to timely diagnosis and treatment and improves the prognosis of patients with APE.


Penetration of prulifloxacin into sinus mucosa of patients undergoing paranasal sinus elective endoscopic surgery.
The aim of this study was to assess the concentration of ulifloxacin, the active metabolite of prulifloxacin, in sinuses mucosa and plasma of patients with chronic rhinosinusitis, requiring sinus elective endoscopic surgery. Thirty-nine patients (30 males, 9 females; age range 22-77 years) with chronic sinusitis were enrolled, 35 were treated with the investigational medication. Samples from four untreated patients were used to validate the analytical method, while four treated patients dropped out before surgery. One 600 mg prulifloxacin tablet once daily was administered for 5 days before surgery. The last dosing was scheduled from 2 to 12 hours from tissue and plasma sampling. In each patient, two samples of paranasal sinus mucosa (from ethmoid and turbinate, respectively) and one blood sample were collected. Concentrations of ulifloxacin in plasma and sinuses mucosa were measured using validated bioanalytical LC/MS/MS methods. Individual and mean ulifloxacin concentrations in tissues were always higher than the relevant plasma levels. The highest concentrations were observed between 2.5 and 4.5 hours after the last dosing in all districts. The mean tissue/plasma ratios were 2.5 and 3.0 for ethmoid and turbinate, respectively. Data expressed as Area Under the Curves (AUC±SD) showed that ulifloxacin concentrations in the ethmoid were slightly higher (18.68±6.48 μg/g*h) than in turbinate (15.00±2.89 μg/g*h), and definitely higher than in plasma (6.32±1.14 μg/ml*h). The AUC ratios between tissues and plasma were 3.0 for ethmoides and 2.4 for turbinates. One patient reported two treatment-related episodes of diarrhea, which spontaneously resolved after the drug suspension. Results from this study seem to suggest that prulifloxacin showed good distribution in sinus tissues, where it reaches concentrations significantly higher than in plasma. These findings strongly call for confirmatory clinical trials in patients with bacterial rhinosinusitis.


Associations of CYP2E1 rs2031920 and rs3813867 polymorphisms with colorectal cancer risk: a systemic review and meta-analysis.
Cytochrome P450 2E1 (CYP2E1) is a natural enzyme involved in the metabolic activation of many carcinogens, and the functional polymorphisms in the CYP2E1 gene might have impacts on colorectal cancer risk. Many studies were published to assess the associations of CYP2E1 rs2031920 and rs3813867 polymorphisms with colorectal cancer risk, but no consistent findings were reported. A systemic review and meta-analysis of eligible studies was performed to comprehensively assess the associations above. Odds ratios (ORs) with 95 % confidence interval (95 % CIs) were used to assess the strength of the associations. Seventeen studies from 15 publications with 17,082 individuals were finally included into this meta-analysis. Meta-analysis of the 13 studies on CYP2E1 rs2031920 polymorphism showed that there was a significant association between CYP2E1 rs2031920 polymorphism and colorectal cancer risk under two genetic models (c2 versus c1: OR = 1.19, 95 % CI 1.03-1.37, P = 0.022; c2c2/c2c1 versus c1c1: OR = 1.16, 95 % CI 1.00-1.35, P = 0.046). Meta-analysis of those four case-control studies on CYP2E1 rs3813867 polymorphism showed that there was no significant association between CYP2E1 rs3813867 polymorphism and colorectal cancer risk under all contrast models (c2 versus c1: OR = 0.96, 95 % CI 0.80-1.16, P = 0.672; c2c2 versus c1c1: OR = 1.26, 95 % CI 0.43-3.67, P = 0.672; c2c2/c1c2 versus c1c1: OR = 0.95, 95 % CI 0.78-1.16, P = 0.114; and c2c2 versus c1c2/c1c1: OR = 1.17, 95 % CI 0.41-3.36, P = 0.775). Therefore, the findings from this meta-analysis suggest that CYP2E1 rs2031920 polymorphism is associated with colorectal cancer risk, but CYP2E1 rs3813867 polymorphism is not associated with colorectal cancer risk. In addition, more well-designed studies with large sample size are needed to provide a more precise evaluation on the associations above.


Dolphin underwater bait-balling behaviors in relation to group and prey ball sizes.
We characterized dusky dolphin (Lagenorhynchus obscurus) feeding behaviors recorded on underwater video, and related behaviors to variation in prey ball sizes, dolphin group sizes, and study site (Argentina versus New Zealand, NZ). Herding behaviors most often involved dolphins swimming around the side or under prey balls, but dolphins in Argentina more often swam under prey balls (48% of passes) than did dolphins in NZ (34% of passes). This result may have been due to differences in group sizes between sites, since groups are larger in Argentina. Additionally, in NZ, group size was positively correlated with proportion of passes that occurred under prey balls (p<0.001). Prey-capture attempts most often involved capturing fish from the side of prey balls, but dolphins in Argentina more often swam through prey balls (8% of attempts) than did dolphins in NZ (4% of attempts). This result may have been due to differences in prey ball sizes between sites, since dolphins fed on larger prey balls in Argentina (>74m(2)) than in NZ (maximum 33m(2)). Additionally, in NZ, dolphins were more likely to swim through prey balls to capture fish when they fed on larger prey balls (p=0.025).


Are Opioid-Naive Patients With Acute Pancreatitis Given Opioid Prescriptions at Discharge?
Opioids are commonly used in the management of acute pancreatitis (AP). Inpatient opioid exposure is known to increase the risk of chronic opioid use after discharge. Prescription patterns for opioids at discharge for AP are unknown. Medical records of adult AP patients who presented to the emergency department from September 1, 2013, to August 31, 2016, were reviewed. Opioid prescription at discharge was defined as a prescription for opioids in a patient who was opioid naive at admission. Multivariable logistic regression was performed to identify predictors of opioid prescription at discharge. A total of 259 opioid-naive AP patients were identified. Of these, 108 (41.6%) of 259 were discharged with an opioid prescription and 61 (56.5%) of 108 had discharge pain scores of 3 or lower. Two hundred twenty-two (85.7%) received opioids during admission and 105 (47.3%) of 222 were discharged with an opioid prescription. On multivariable analysis, predictors of discharge opioid prescription included inpatient use of opioids, female sex, and discharge pain score greater than 3. In opioid-naive AP patients, 41.6% were discharged from the hospital with a new prescription for opioids, even though a significant proportion had pain scores of 3 or lower. Guidelines are needed for opioid prescriptions at discharge for AP.


Risperidone-Induced Tardive Akathisia: A Rare Antipsychotic Side Effect with Management Issues.
Akathisia is a movement disorder, a common extrapyramidal side effect that has been reported to occur primarily with antipsychotics and some neurological conditions. It is manifested by a subjective feeling of inner restlessness along with objective evidence of motoric restlessness. Tardive akathisia (TA) is rare, and there is very sparse literature available as regards to its phenomenology and management. We report a case of TA that occurred after 10 months of starting atypical antipsychotic, risperidone, and challenges faced in management.


Psychosocial work factors and sleep problems: findings from the French national SIP survey.
This study aimed at exploring the cross-sectional and prospective associations between psychosocial work factors and sleep problems. The study population consisted of a national representative sample of the French working population (SIP survey). The sample sizes were 7506 and 3555 for the cross-sectional and prospective analyses. Sleep problems were defined by either sleep disturbances or insufficient sleep duration at least several times a week. Psychosocial work factors included classical (job strain model factors) and emergent factors (recognition, insecurity, role/ethical conflict, emotional demands, work-life imbalance, etc.). Occupational factors related to working time/hours and physical work environment were also included as well as covariates related to factors outside work. Statistical analyses were performed using weighted Poisson regression analysis. In the cross-sectional analyses, psychological demands, low social support, low recognition, emotional demands, perception of danger, work-life imbalance and night work were found to be associated with sleep problems. In the prospective analyses, psychological demands and night work were predictive of sleep problems. Using a less conservative method, more factors were found to be associated with sleep problems. Dose-response associations were observed, showing that the more frequent the exposure to these factors, the higher the risk of sleep problems. No effect of repeated exposure was found on sleep problems. Classical and emergent psychosocial work factors were associated with sleep problems. More prospective studies and prevention policies may be needed.


A radioprotective effect of vitamin C observed in Chinese hamster ovary cells.
Vitamin C at high concentrations was found to inhibit the growth of CHO clone A cells in culture. It had a radioprotective effect, giving a maximum increase in cell survival of a factor of seven under the experimental conditions used. The protective effect was mainly but not exclusively attributable to an increase in the Do, the maximum increase observed being the order of 1.4.


Retracted: PM2.5 Exposure Induces Lung Injury and Fibrosis by Regulating Ferroptosis via TGF-β Signaling.
[This retracts the article DOI: 10.1155/2022/7098463.].


Opioids should not be used in migraine.
Opioids should not be used for the treatment of migraine. This brief review explores why not. Alternative acute and preventive agents should always be explored. Opioids do not work well clinically in migraine. No randomized controlled study shows pain-free results with opioids in the treatment of migraine. Saper and colleagues' 5-year study showed minimal effectiveness, with many contract violations, interfering with the therapeutic alliance. The physiologic consequences of opioid use are adverse, occur quickly, and can be permanent. Decreased gray matter, release of calcitonin gene-related peptide, dynorphin, and pro-inflammatory peptides, and activation of excitatory glutamate receptors are all associated with opioid exposure. Opioids are pro-nociceptive, prevent reversal of migraine central sensitization, and interfere with triptan effectiveness. Opioids precipitate bad clinical outcomes, especially transformation to daily headache. They cause disease progression, comorbidity, and excessive health care consumption. Use of opioids in migraine is pennywise and pound foolish.


Population growth of a gorgonian coral: equilibrium and non-equilibrium sensitivity to changes in life history variables.
A size dependent model of population growth of the Caribbean gorgonian Plexaura A is developed based on observed rates of survival, growth and colony fragmentation at a site in the San Blas Islands, Panama. Sensitivity and elasticity analyses indicate that the fate of large colonies has the greatest effect on population growth. Variables which directly affect the generation of large colonies have the next greatest effect on population growth. These variables include the recruitment of large fragments, and the survivorship of colonies in the next smaller size class. Sexual reproduction has an extremely limited ability to affect population growth. Vegetative reproduction has a greater potential effect on growth rates. Environmental conditions regularly change the matrix of transition probabilities which predicts population growth. This keeps the population from approaching its stable size class distribution. Deviations from the stable size class distribution alter sensitivity and elasticity and in this case have the effect of increasing the importance of survivorship of the smallest colonies. Nonequilibrium conditions alter sensitivity analyses and it is important to assess whether populations are at equilibrium and to determine the effects of such deviations on the sensitivity analysis.


Acetylation of oil palm empty fruit bunch fiber as an adsorbent for removal of crude oil.
Removal of oil spillage from the environment is a global concern. Various methods, including the use of fibers as sorbents, have been developed for oil spill control. Oil palm empty fruit bunch (OPEFB) fiber is a plant biomass that may be acetylated by acetic anhydride using N-bromosuccinimide (NBS) as a catalyst; here, the extent of acetylation may be calculated in terms of weight percent gain (WPG). The modified fiber was used to remove Tapis and Arabian crude oils. The optimum time, temperature, and catalyst concentration were 4 h, 120 °C, and 3 %, respectively, and these parameters could achieve an 11.49 % increase in WPG. The optimized parameters improved the adsorption capacity of OPEFB fibers for crude oil removal. The acetylated OPEFB fibers were characterized by using Fourier transform infrared spectroscopy and field emission scanning electron microscopy to observe the functional groups available and morphology. Kinetic and isotherm studies were conducted using different contact times and oil/water ratios. The rate of oil sorption onto the OPEFB fibers can be adequately described by the pseudo-second-order equation. Adsorption studies revealed that adsorption of crude oil on treated OPEFB fiber could be best described by the Langmuir isotherm model.


Using computers in nursing research.
The advent of the computer age has brought with it some powerful new ways of making nursing research a more efficient process. Michael Tait and Julie Slater report.


Preoperative versus intraoperative endoscopic sphincterotomy for management of common bile duct stones.
ERCP remains the prevailing method of treating CBDS; however, its ideal timing in respect to laparoscopic cholecystectomy (LC) is not defined. LC combined with intraoperative endoscopic sphincterotomy (IOES) was compared with preoperative endoscopic sphincterotomy (PES) followed by LC for management of preoperatively known cholecystocholedocholithiasis. Between June 2006 and September 2009, 198 patients diagnosed preoperatively by clinical assessment, liver chemistry, ultrasonography, and magnetic resonance cholangiopancreatography (MRCP) to have combined choledochocystolithiasis were eligible. They were randomly divided into two groups: PES/LC group (n = 100) and LC/IOES group (n = 98). The surgical times, surgical success rates, number of stone extractions, postoperative complications, retained common bile duct stones, and postoperative lengths of stay were compared prospectively. There were no statistically significant differences in surgical time, surgical success rate, CBD diameter, stone size, or stone number between the two groups. The success rate was 95.3% and 97.8% for PES/LC and LC/IOES, respectively. There were no significant difference in postoperative retained stones, surgical time, and complications, but the total hospital stay was significantly shorter in the LC/IOES group. PES/LC and LC/IOES are both good options for dealing with preoperatively diagnosed CBDS, but when there is enough experience and facilities, LC/IOES, as a single-stage treatment, would be preferable.


Peripheral vascular lesions in adults referred to MRI/MRA: Multivariable analysis of imaging features to help differentiate benign vascular anomalies from malignancies.
Symptomatic peripheral vascular lesions in adults are often clinically diagnosed as benign vascular anomalies and may receive MRI/MRA for pre-treatment vascular mapping. Malignant neoplasms are difficult to distinguish from benign vascular anomalies on MRI/MRA. This study was performed to determine if there are imaging signs that can distinguish malignancies from benign vascular anomalies in adults imaged with MRI/MRA. A radiology database was retrospectively searched for ISSVA classification terms in MRI/MRA reports from 1/1/2002-1/1/2019. Adult patients (n = 50, 52 corresponding lesions) with contrast-enhanced MRI/MRA, peripheral soft tissue based lesion (s), and available pathology or long-term (>1 year) imaging follow-up were included. MRI/MRA images were reviewed by 3 readers for the following lesional characteristics: morphology (marginal lobulation, internal septations, distinct soft tissue mass), peri-articular location, T2-weighted characteristics (hyperintensity, heterogeneity, perilesional edema, and adjacent triangular T2-peaks), bulk fat, hemorrhage, enhancement pattern (peripheral, diffuse, or absent), neovascularity, low-flow venous malformation type enhancement, arterial enhancement within 6 s, enhancement curve (progressive, plateau, or washout), measured size, and multifocality. The MRI/MRA features' associated sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated. To identify factors predictive of malignancy, a two-stage multivariable analysis was performed. 23% (12/52) of the lesions, corresponding to 22% (11/50) of the patients, were malignant neoplasms. No single imaging feature reliably predicted malignancy (PPV ≤ 60%). Absence of distinct soft tissue mass excluded malignancy (NPV 100%). Multivariate analysis derived a summary score based on the five strongest predictors of malignancy: adjacent T2 peaks, age ≥ 70 years, distinct soft tissue mass, lesion size ≥ 5 cm, and absence of septations. A score ≥ 3 resulted in sensitivity of 92% and specificity of 85%. Extremity MRI/MRA rarely differentiates malignant from benign soft-tissue vascular tumors in adults. However, MRI/MRA can suggest malignancy when patient age and multiple imaging features are considered. Periodic clinical follow-up after the planned endovascular or operative procedure should be performed to avoid missing a malignancy.


Demonstration of an in vivo generated sub-picomolar affinity fully human monoclonal antibody to interleukin-8.
The high specificity and affinity of monoclonal antibodies make them attractive as therapeutic agents. In general, the affinities of antibodies reported to be high affinity are in the high picomolar to low nanomolar range and have been affinity matured in vitro. It has been proposed that there is an in vivo affinity ceiling at 100 pM and that B cells producing antibodies with affinities for antigen above the estimated ceiling would have no selective advantage in antigen-induced affinity maturation during normal immune responses. Using a transgenic mouse producing fully human antibodies, we have routinely generated antibodies with sub-nanomolar affinities, have frequently rescued antibodies with less than 10 pM affinity, and now describe the existence of an in vivo generated anti-hIL-8 antibody with a sub-picomolar equilibrium dissociation constant. This confirms the prediction that antibodies with affinities beyond the proposed affinity ceiling can be generated in vivo. We also describe the technical challenges of determining such high affinities. To further understand the importance of affinity for therapy, we have constructed a mathematical model to predict the relationship between the affinity of an antibody and its in vivo potency using IL-8 as a model antigen.


Development and evaluation of a video program for presentation prior to elective cardiac surgery.
: The objective of the present study was to develop and evaluate the effects of a preparatory videotape on endocrine stress responses of patients prior to cardiac surgery and to analyze patient acceptance of this video for preoperative preparation. : 101 male patients prior to elective cardiac surgery were enrolled into the study. On the day before surgery, patients were assigned to one of the following groups: group 1 (n = 51) saw a video with realistic information about the upcoming perioperative procedure, and group 2 (n = 50) saw a video of the same length without surgery-related information. Venous blood was sampled before and 15 min after the video presentation. On the second postoperative day, patients filled in a questionnaire concerning their experiences of having preoperatively watched the video. : After viewing the video, blood levels of cortisol, adrenocorticotropic hormone (ACTH), beta-endorphin, prolactin, epinephrine and norepinephrine in patients of group 1 were not significantly different compared to values measured before the video presentation. In patients of group 2, blood levels of cortisol, ACTH, prolactin and norepinephrine were significantly lower after video presentation compared to values obtained before the video. Patients of group 1 (compared to group 2) were significantly more often of the opinion that the video had helped in the preparation for surgery, and that they would like to repeat this adjunct preoperative video preparation in another similar situation. : We conclude from our results that (i); cardiac surgical patients prefer preoperatively an adjunct surgery-related video preparation to a non-specific video presentation, and that (ii); preoperative preparation with realistic information about the upcoming medical procedure in patients undergoing cardiac surgery does not lead to an increase in endocrine stress hormone levels.


Are financial incentives cost-effective to support smoking cessation during pregnancy?
To investigate the cost-effectiveness of up to £400 worth of financial incentives for smoking cessation in pregnancy as an adjunct to routine health care. Cost-effectiveness analysis based on a Phase II randomized controlled trial (RCT) and a cost-utility analysis using a life-time Markov model. The RCT was undertaken in Glasgow, Scotland. The economic analysis was undertaken from the UK National Health Service (NHS) perspective. A total of 612 pregnant women randomized to receive usual cessation support plus or minus financial incentives of up to £400 vouchers (US $609), contingent upon smoking cessation. Comparison of usual support and incentive interventions in terms of cotinine-validated quitters, quality-adjusted life years (QALYs) and direct costs to the NHS. The incremental cost per quitter at 34-38 weeks pregnant was £1127 ($1716).This is similar to the standard look-up value derived from Stapleton & West's published ICER tables, £1390 per quitter, by looking up the Cessation in Pregnancy Incentives Trial (CIPT) incremental cost (£157) and incremental 6-month quit outcome (0.14). The life-time model resulted in an incremental cost of £17 [95% confidence interval (CI) = -£93, £107] and a gain of 0.04 QALYs (95% CI = -0.058, 0.145), giving an ICER of £482/QALY ($734/QALY). Probabilistic sensitivity analysis indicates uncertainty in these results, particularly regarding relapse after birth. The expected value of perfect information was £30 million (at a willingness to pay of £30 000/QALY), so given current uncertainty, additional research is potentially worthwhile. Financial incentives for smoking cessation in pregnancy are highly cost-effective, with an incremental cost per quality-adjusted life years of £482, which is well below recommended decision thresholds.


Corrigendum to: Qualitative analysis of post-consumer and post-industrial waste via near-infrared, visual and induction identification with experimental sensor-based sorting setup.
[This corrects the article DOI: 10.1016/j.mex.2022.101686.].


Sixth interim progress report of the British Institute of Radiology fractionation study of 3F/week versus 5F/week in radiotherapy of the laryngo-pharynx.
The results are reported of the multicentre BIR fractionation trial of 3F/week versus 5F/week in radiotherapy of the laryngo-pharynx. 687 patient records have been analysed with respect to survival rates, recurrence-free rates and laryngectomy-free rates. For the group as a whole these analyses show no difference between the two fractionation regimes. Analysis of the sub-group which had early disease confined to the vocal cords does, however, show a better recurrence-free and laryngectomy-free rate for those patients treated with 5F/week, though the survival rate for the two groups remains similar. Acute and late normal tissue reactions are reported for up to six years after treatment. It appears that treatment with 3F/week can be given safely to patients with advanced disease. The differences between the two treatment groups who had early disease of the vocal cords are discussed, but until more data become available in the future the problems raised cannot be resolved.


Brain connectivity under light sedation with midazolam and ketamine during task performance and the periodic experience of pain: Examining concordance between different approaches for seed-based connectivity analysis.
This work focused on functional connectivity changes under midazolam and ketamine sedation during performance of a memory task, with the periodic experience of pain. To maximize ability to compare to previous and future work, we performed secondary region of interest (ROI)-to-ROI functional connectivity analyses on these data, using two granularities of scale for ROIs. These findings are compared to the results of a previous seed-to-voxel analysis methodology, employed in the primary analysis. Healthy adult volunteers participated in this randomized crossover 3 T functional MRI study under no drug, followed by subanesthetic doses of midazolam or ketamine achieving minimal sedation. Periodic painful stimulation was delivered while subjects repeatedly performed a memory-encoding task. Atlas-based and network-level ROIs were used from within Conn Toolbox (ver 18). Timing of experimental task events was regressed from the data to assess drug-induced changes in background connectivity, using ROI-to-ROI methodology. Compared to saline, ROI-to-ROI connectivity changes under ketamine did not survive correction for multiple comparisons, thus data presented is from 16 subjects in a paired analysis between saline and midazolam. In both ROI-to-ROI analyses, the predominant direction of change was towards increased connectivity under midazolam, compared to saline. These connectivity increases occurred between functionally-distinct brain areas, with a posterior-predominant spatial distribution that included many long-range connectivity changes. During performance of an experimental task that involved periodic painful stimulation, compared to saline, low-dose midazolam was associated with robust increases in functional connectivity. This finding was concordant across different seed-based analyses for midazolam, but not ketamine. The neuroimaging drug trial from which this data was drawn was pre-registered (NCT-02515890) prior to enrollment of the first subject.


Gold nanoparticles conjugated with monosaccharide-modified peptide for lectin detection.
Gold nanoparticles (GNPs) conjugated with monosaccharide-modified peptides have been developed as optical probes for lectin detection. Mannose-modified peptides were designed and conjugated with GNPs. The GNPs with mannose-modified peptide showed remarkable red shift of absorption maximum due to the aggregation with concanavalin A (ConA), a mannose-binding lectin. The aggregation activity of glycopeptide-modified GNPs with ConA depended on the amino acid sequence around the mannose unit of glycopeptides.


Integrated proteomic and metabolomic profiling the global response of rat glioma model by temozolomide treatment.
Temozolomide (TMZ) is the first-line chemotherapeutic drug for glioblastoma treatment. It can induce O6-methylguanine DNA lesions, lead to prolonged G2-M arrest and ultimately cell death. However, the molecular response induced by TMZ has not been fully elucidated. In this study, by integrating quantitative proteomics and metabolomics, we identified protein and metabolite markers that correlate with TMZ treatment and discovered the protein-metabolite regulatory network. A total of 1782 proteins and 56 endogenous metabolites were significantly altered in the brain between sham and tumor groups, 38 metabolites markedly altered in plasma. After TMZ treatment, 251 proteins and 9 metabolites significantly changed in the brain, and 14 metabolites did in plasma. 35 proteins significantly altered by TMZ were further validated by parallel reaction monitoring (PRM) analysis. The multi-omics analysis revealed differential proteins and metabolites were involved in DNA replication, nucleotides degradation, cysteine biosynthesis, and other pathways. Adenosine, sarcosine and adenosine deaminase involved in multiple metabolic pathways may serve as potential biomarkers for TMZ treatment. This is the first report utilizing multi-omics analysis to investigate the global response of proteins and metabolites in glioma by TMZ treatment, and the data can provide a comprehensive insight to understand the mechanism of TMZ. SIGNIFICANCE: The study focused on integrating quantitative proteomics and endogenous metabolites profiling of the rat glioma brain in response to chemotherapeutic drug temozolomide treatment, which has not yet been reported. The results showed that the effect of temozolomide on glioma is significant, including DNA replication, nucleotides degradation, cysteine biosynthesis, and synaptogenesis signaling pathway. Our study can provide a comprehensive insight to screen potential targets and biomarkers of glioma as well as to elucidate the mechanism of temozolomide inhibiting tumor growth.


Enhanced Clinical Utility of Molecular Budding Signature as a Recurrence Risk Determinant in Stage II and III Colon Cancer Patients.
A molecular budding signature (MBS), which consists of seven tumor budding-related genes, was recently presented as a prominent prognostic indicator in colon cancer (CC) using microarray data acquired from frozen specimens. This study aimed to confirm the predictive power of MBS for recurrence risk based on formalin-fixed, paraffin-embedded (FFPE) materials. This research utilized the same microarray data from a prior multicenter study using FFPE whole tissue sections, which retrospectively reviewed 232 stage II CC patients without adjuvant chemotherapy and 302 stage III CC patients with adjuvant chemotherapy. All patients underwent upfront curative surgery without neoadjuvant therapy between 2009 and 2012. An MBS score was calculated using the mean of log2 [each signal] of seven genes (MSLN, SLC4A11, WNT11, SCEL, RUNX2, MGAT3, and FOXC1) as described before. The MBS-low group exhibited a better relapse-free survival (RFS) than the MBS-high group in stage II (P = 0.0077) and in stage III CC patients (P = 0.0003). Multivariate analyses revealed that the MBS score was an independent prognostic factor in both stage II (P = 0.0257) and stage III patients (P = 0.0022). Especially among T4, N2, or both (high-risk) stage III patients, the MBS-low group demonstrated markedly better RFS compared with the MBS-high group (P = 0.0013). This study confirmed the predictive power of the MBS for recurrence risk by employing FFPE materials in stage II/III CC patients.


Quantitative culture of Mycobacterium tuberculosis from clinical sputum specimens and dilution endpoint of its detection by the Amplicor PCR assay.
The minimum number of Mycobacterium tuberculosis CFU detectable in clinical sputum specimens by the Amplicor PCR test was estimated by performing the test on duplicate samples of quantitatively cultured serial dilutions of sputum. Positive PCR test results were obtained for all samples that contained 42 CFU of M. tuberculosis. The detection limits of the PCR assay for decontaminated (N-acetyl-L-cysteine [NALC]-NaOH) and nondecontaminated (NALC only) specimens were equivalent, even though the number of CFU cultured from decontaminated samples was only 11 to 20% of the number cultured from nondecontaminated samples. Thus, the 42 CFU that could be detected in nondecontaminated specimens by the Amplicor PCR test correspond to the approximately 8 CFU (0.20 x 42) that could be recovered in culture after decontamination with NALC-NaOH.


Effects of short and long-term indapamide treatments on urinary calcium excretion in patients with calcium oxalate dihydrate urinary stone disease: a pilot study.
The aim of this study was to determine the relative calcium-reducing effects of indapamide at 6 and 18 months using a dose of 1.5 mg/day. Twenty-two patients with idiopathic hypercalciuria and calcium oxalate dihydrate urinary stone disease (minimum one stone episode) were selected. Each patient began a therapy regime of 1.5 mg indapamide sustained release taken once a day in the evening. Under basal conditions and after 6 and 18 months of treatment, subjects submitted urine and blood samples for analysis. The primary aim of this study was to assess the effects on excretion and concentration of calcium in urine. For 2 h urine, there was a mean decrease in urinary calcium concentration of 47%, whereas urinary calcium concentrations decreased by 53% in 24 h urine (p < 0.05) at 6 months of treatment. Blood urate levels rose by 19% (p < 0.05). Treatment for 18 months resulted in significant reduction in urinary calcium levels, by approximately 48% (p < 0.05) in both 2 h and 24 h urine. A 21% increase in urate levels in the blood was observed (p < 0.05). The remaining parameters remained unaltered. Owing to the low effective dosage of indapamide (1.5 mg/day) and the lack of any severe side-effects, this drug would appear to be a good candidate for use in the control of hypercalciuria. As such, it could prove efficacious in the prevention of recurrent kidney stones that are often associated with this condition.


COVID-19 exposure risk level in daily activity in adapting to new habits in the pandemic period.
Analyze how the COVID-19 exposure risk level in daily activity in adapting to new habits. A cross-sectional online survey of the Indonesian adult population. Administered by an online questionnaire. A total of 497 samples, used a probabilistic sampling, collected between 20th and 24th June 2020. The sample lived in 108 districts across all 32 provinces in Indonesia. We found the distribution of COVID-19 exposure risk level in daily activities almost the same was 26.0% of participants had very high risk, 27.4% were high risk, 22.9% were moderate risk, and 23.7% were low risk. Male had activity risk level significantly lower than female (p-value 0.001). There are 14% of participants with a very high level of activity risk living in areas with uncontrolled virus transmission. The risk of COVID-19 transmission occurs through a variety of activities carried out daily. All public meeting places have to consider compliance with health protocol to prevent it.


Oxygen Nanocarrier for Combined Cancer Therapy: Oxygen-Boosted ATP-Responsive Chemotherapy with Amplified ROS Lethality.
Oxygen nanocarrier (A/D-ONC) with a polymeric core entrapping hemoglobin and a cationic lipid shell absorbing a DOX-intercalating DNA duplex is developed. After endocytosis oxygenated A/D-ONC donates O2 to cancer cells that acts therapeutically by: (1) increasing intracellular ATP content that promotes DOX release, thereby converting ATP to the trigger of detrimental chemotherapy; (2) by synchronously increasing the ROS amount to amplify the lethality to cancer cells.


Non-specific cell binding characteristics of para-magnetic polystyrene microspheres used for antibody-mediated cell selection.
The binding of cells to paramagnetic polystyrene microbeads in the absence of coupling antibodies was measured. Cells from normal bone marrow, from an acute lymphoblastic leukemia (ALL) cell line or from a neuroblastoma cell line, were labeled with the fluorochrome Hoechst 33342 and incubated with microbeads by rotation at 4 degrees C. Following this incubation, the microbeads with all attached cells were collected using an externally applied magnetic field and visualized by microscopic examination under ultraviolet illumination. The incubation variables included the protein content of the medium, and the period of rotation. Normal bone marrow was found to adhere sparingly to the microbeads; less than 1.0% of the total nucleated cell population was recovered with the beads, whereas greater than 5% of the ALL cells and greater than 30% of the neuroblastoma cells were found to bind non-specifically to the microspheres. Neither changes in the protein concentration of the medium or in the incubation period significantly altered the non-specific binding of the cell types examined. It is thus apparent that the use of these microspheres for positive selection of cells, such as the collection of hematopoietic stem cells for transplantation, would be compromised by a sizeable non-specific interaction. Modification of the surface of the microspheres to substantially reduce this interaction will be necessary before efforts at positive selection using the magnetic microspheres can be fruitful.


Inter- and Intra-individual Variations in Foveal Outer Nuclear Layer Thickness and Their Associations with Clinical Characteristics in a Healthy Chinese Population.
To evaluate foveal outer nuclear layer (ONL) thickness and the difference thereof between bilateral eyes and their possible associations with clinical characteristics in a healthy Chinese population. Normal subjects were enrolled. Generalized linear models were used to assess the associations of foveal ONL thickness with sex, age, and spherical equivalents (SEs) and the associations of the difference in foveal ONL thickness between bilateral eyes with sex, age, and difference in SEs between bilateral eyes. Totally, 304 subjects were included. The average foveal ONL thickness was 103.19 ± 14.25 (range 70-151) μm in the right eye and 103.90 ± 14.63 (range 69-155) μm in the left eye. The mean difference in foveal ONL thickness between right and left eyes was -0.71 ± 4.36 (range -13 to +12) μm. Men had slightly greater foveal ONL thickness values in both right and left eyes compared with women (both P < 0.05); however, some women had a thicker foveal ONL than that of men (85/198 vs. 46/106 in the right eye; 79/198 vs. 52/106in the left eye). Age and SEs were not associated with foveal ONL thickness in either eye (all P > 0.05). Sex, age, and difference in SEs between bilateral eyes were not associated with the difference in foveal ONL thickness between bilateral eyes (all P > 0.05). Foveal ONL thickness showed wide variation in a normal Chinese population but little difference between bilateral eyes. Both these parameters could not be adjusted by sex, age, SEs, or the SEs difference between bilateral eyes. Thus, in those diseases involving only one eye, the difference or ratio of foveal ONL thickness between the affected eye and normal fellow eye may reflect the actual degree of the disease, rather than the foveal ONL thickness in the affected eye alone.


An analysis of the role of collagenase and protease in the enzymatic dissociation of the rat pancreas for islet isolation.
Crude Clostridium histolyticum collagenase is widely used for the enzymatic degradation of pancreatic extracellular matrix in order to isolate the islets of Langerhans. The variable enzymatic composition of crude collagenases is a critical issue which contributes to the poor reproducibility of islet isolation procedures. In this study, the separate contributions of collagenase and protease to the islet isolation process were analysed by testing various combinations of purified collagenase and purified protease in rat pancreas dissociations under conditions which eliminated all other proteolytic activity. Under these conditions, complete tissue dissociation by purified collagenase required 99 +/- 10 min, whereas increasing amounts of protease progressively reduced this time to a minimum of 36 +/- 1 min. Histochemical analysis of the dissociation process showed that protease enhanced the degradation of all four major components of the extracellular matrix: collagen was degraded more completely, while proteoglycans, glycoproteins and elastin were degraded at a higher rate. Pancreas dissociation under the present, strictly controlled conditions resulted in a high yield of viable islets: 4.2-5.0 microliters islet tissue volume (3,300-3,800 islets) were isolated per g pancreas in the presence of a high or low protease concentration, respectively. Prolonged dissociation in the presence of protease resulted in a dramatic decrease in islet yield which correlated with the observation that the enzyme accelerated islet disintegration. It is concluded that the collagenase-induced dissociation of the extracellular matrix is facilitated by protease. Our study shows that high yields of viable islets can be obtained under controlled enzymatic conditions, provided that the exposure of islets to protease is limited.


Sequential method for fast neural population activity reconstruction in the cortex from incomplete noisy measurements.
During recent years there has been a growing interest in stochastic dynamic neural fields employed for modeling and predictions in biomedical and technical systems. In this paper, given some incomplete noisy data available from sensors, we propose and explore a state estimation method for fast restorations of membrane potential in the cortex based on such measurements and the Amari equation used for simulations of neural population activity in a stochastic setting. Our novel technique relies upon a Galerkin-type spectral approximation utilized within the conventional state-space approach. Translating a stochastic system into its state-space form creates a straightforward and fruitful way to the data-driven parameter estimation, filtering, prediction and smoothing. The present study is particularly focused on establishing a nonlinear stochastic Galerkin-spectral-approximation-induced system of large size, which is further estimated by the traditional extended Kalman filter (EKF). The efficiency of calculations is the main purpose of our research. That is why the fast filtering solution devised is based on processing the incoming data incrementally, that is, by processing measurements one at a time, rather than handling them as a unified high-dimensional vector. Such sequential filters suit well for dealing with large data sets as well as with real-time on-line computations. Also, their derivation and substantiation is of great interest in the context of neural network training because of large stochastic systems arisen there. In comparison to the batch filtering, our novel algorithm reduces the computational cost of membrane potential reconstructions in terms of the amount of grid nodes N accepted in the underlying spacial discretization, significantly. Apart from its computation efficiency, this sequential method is more robust to round-off errors committed within a computer-based finite precision arithmetics than the classical EKF because of the (N × N)-matrix inversion elimination from such membrane potential calculations. The superior performance of our technique is examined and confirmed in comparison to the batch one on two known scenarios in the dynamic neural field modeling.


[Synovectomy of the knee joint and postoperative exercise treatment in peridural anesthesia and analgesia].
The operative treatment of synovialitides of the knee-joint requires apart from an exact operative technique an effective postoperative therapy. The painless postoperative gymnastik treatment is an important factor to achieve a satisfactory result of therapy. The exercise of this "wounded articulation" by the "Frankfurter-mowing splint" needs sufficient analgesie for a long period which will be attained through our experience under continuous epidural anaesthesia and analgesia.


Response evaluation criteria in solid tumors response of the primary lesion in metastatic renal cell carcinomas treated with sunitinib: does the primary lesion have to be regarded as a target lesion?
We evaluated whether best overall response changes by designating primary renal lesions as either target or nontarget lesions and assessing response per Response Evaluation Criteria in Solid Tumors in mRCC patients treated with sunitinib. In addition, we evaluated whether discordance, if any, leads to a difference in predictive value of response in terms of time to progression (TTP) and overall survival (OS). Patients with mRCC with an intact primary tumor and at least 1 extrarenal measurable lesion were included in this study. The variation of the sum of diameters (ΔSOD) of target lesions and best overall response, assessed from all target lesions and from metastasis-only target lesions, was documented separately. There were 41 patients included. Median ΔSOD of the primary lesion and metastatic target lesion were -6.0% (range, -34.0% to 17.6%), and -18.0% (range, -100.0% to 120.0%), respectively. For metastasis-only target lesions, the best overall response of 2 patients (4.9%) changed from stable disease to partial response. When we categorized patients into responders and nonresponders, response determination using metastasis-only target lesions resulted in significantly better discrimination of time to progression (14.9 vs. 4.3 months, P = .001) and overall survival (18.5 vs. 9.6 months, P = .036) between 2 groups. Using all target lesions, both TTP (14.9 vs. 5.4 months, P = .056) and OS (18.0 vs. 10.6 months, P = .155) were not statistically significant. When treating nonnephrectomized mRCC patients, selecting metastasis-only lesions as target lesions might be better to determine response, which might be more representative of survival end point.


Community-based primary health care for older adults: a qualitative study of the perceptions of clients, caregivers and health care providers.
Older persons are often poorly served by existing models of community-based primary health care (CBPHC). We sought input from clients, informal caregivers, and health care providers on recommendations for system improvements. Focus group interviews were held with clients, informal caregivers, and health care providers in mid-sized urban and rural communities in Ontario. Data were analyzed using a combination of directed and emergent coding. Results were shared with participants during a series of feedback sessions. An extensive list of barriers, facilitators, and recommended health system improvements was generated. Barriers included poor system integration and limited access to services. Identified facilitators were person and family-focused care, self-management resources, and successful collaborative practice. Recommended system improvements included expanding and integrating care teams, supports for system navigation, and development of standardized information systems and care pathways. Older adults still experience frustrating obstacles when trying to access CBPHC. Identified barriers and facilitators of improved system integration aligned well with current literature and Wagner's Chronic Care Model. Additional work is needed to implement the recommended improvements and to discern their impact on patient and system outcomes.