What to do with targeted IL-2.
A common strategy in immunotherapy of cancer is the induction of an increased immunogenicity of syngeneic malignancies. A novel approach to achieve this goal is the targeting of cytokines into the tumor microenvironment with antibody-cytokine fusion proteins, called immunocytokines. This report summarizes therapeutic efficacy and immune mechanisms involved in targeting IL-2 to syngeneic tumors and describes their extended use as a synergistic treatment modality for cancer vaccines and antiangiogenesis. Treatment of established melanoma and colon carcinoma metastases with IL-2 immunocytokines resulted in eradication of disease, followed by a vaccination effect protecting mice from lethal challenges with wild-type tumor cells. In a syngeneic neuroblastoma model, targeted IL-2 elicited effective antitumor responses mediated by NK cells in the absence of a T-cell memory. Interestingly, targeted IL-2 was effective in amplification of memory immune responses previously induced by cancer vaccines. Furthermore, a synergistic effect achieved by combining targeted IL-2-immunotherapy with an antiangiogenic inhibitor of integrin alpha(v)beta(3) extends the potential of this immunotherapeutic strategy in combination with antiangiogenesis as demonstrated in three syngeneic tumor models. Based on these findings, targeted IL-2 may provide an effective tool for the adjuvant treatment of cancer either applied as a single strategy or in combination with cancer vaccines and antiangiogenic strategies.


Data quality of Glasgow Coma Scale and Systolic Blood Pressure in scientific studies involving physician-staffed emergency medical services: Systematic review.
Emergency physicians on-scene provide highly specialized care to severely sick or injured patients. High-quality research relies on the quality of data, but no commonly accepted definition of EMS data quality exits. Glasgow Coma Score (GCS) and Systolic Blood Pressure (SBP) are core physiological variables, but little is known about the quality of these data when reported in p-EMS research. This systematic review aims to describe the quality of pre-hospital reporting of GCS and SBP data in studies where emergency physicians are present on-scene. A systematic literature search was performed using CINAHL, Cochrane, Embase, Medline, Norart, Scopus, SweMed + and Web of Science, in accordance with the PRISMA guidelines. Reported data on accuracy of reporting, completeness and capture were extracted to describe the quality of documentation of GCS and SBP. External and internal validity assessment was performed by extracting a set of predefined variables. We included 137 articles describing data collection for GCS, SBP or both. Most studies (81%) were conducted in Europe and 59% of studies reported trauma cases. Reporting of GCS and SBP data were not uniform and may be improved to enable comparisons. Of the predefined external and internal validity data items, 26%-45% of data were possible to extract from the included papers. Reporting of GCS and SBP is variable in scientific papers. We recommend standardized reporting to enable comparisons of p-EMS.


Nonsurgical management of postoperative cicatricial lower lid ectropion.
Two patients with postoperative cicatricial lower lid ectropion were managed by having the patient massage the lower lid in an upward direction over a methyl-methacrylate scleral ring. The ectropion was corrected. Such nonsurgical management may be attempted as an alternate initial therapy for the patient who refuses or should not immediately undergo additional surgery.


The NAD(P)H dehydrogenase in barley thylakoids is photoactivatable and uses NADPH as well as NADH
An improved light-dependent assay was used to characterize the NAD(P)H dehydrogenase (NDH) in thylakoids of barley (Hordeum vulgare L.). The enzyme was sensitive to rotenone, confirming the involvement of a complex I-type enzyme. NADPH and NADH were equally good substrates for the dehydrogenase. Maximum rates of activity were 10 to 19 &mgr;mol electrons mg-1 chlorophyll h-1, corresponding to about 3% of linear electron-transport rates, or to about 40% of ferredoxin-dependent cyclic electron-transport rates. The NDH was activated by light treatment. After photoactivation, a subsequent light-independent period of about 1 h was required for maximum activation. The NDH could also be activated by incubation of the thylakoids in low-ionic-strength buffer. The kinetics, substrate specificity, and inhibitor profiles were essentially the same for both induction strategies. The possible involvement of ferredoxin:NADP+ oxidoreductase (FNR) in the NDH activity could be excluded based on the lack of preference for NADPH over NADH. Furthermore, thenoyltrifluoroacetone inhibited the diaphorase activity of FNR but not the NDH activity. These results also lead to the conclusion that direct reduction of plastoquinone by FNR is negligible.


Awake surgery for nonlanguage mapping.
During the past decade, numerous reports have supported the contribution of awake mapping in surgical removal of brain lesions in eloquent areas, with a significant increase of the extent of resection while minimizing the risk of permanent deficit--and even improving quality of life. Most of these awake procedures were performed in patients with lesions in language areas, to avoid postoperative aphasia. Surprisingly, mapping of nonlanguage functions received less attention, despite the possible consequences of deficits other than aphasia on daily life. Visuospatial and cognitive deficits are reported after brain surgery, because of more objective and extensive neuropsychological assessments. This review provides new insights into the indications of awake craniotomies for nonlanguage mapping in surgery for lesions in areas not related to language processing.


Fatty Acids Dietary Supplements Exert Anti-Inflammatory Action and Limit Ganglion Cell Degeneration in the Retina of the EAE Mouse Model of Multiple Sclerosis.
Optic neuritis is an acute inflammatory demyelinating disorder of the optic nerve (ON) and is an initial symptom of multiple sclerosis (MS). Optic neuritis is characterized by ON degeneration and retinal ganglion cell (RGC) loss that contributes to permanent visual disability and lacks a reliable treatment. Here, we used the experimental autoimmune encephalomyelitis (EAE) mouse model of MS, a well-established model also for optic neuritis. In this model, C57BL6 mice, intraperitoneally injected with a fragment of the myelin oligodendrocyte glycoprotein (MOG), were found to develop inflammation, Müller cell gliosis, and infiltration of macrophages with increased production of oncomodulin (OCM), a calcium binding protein that acts as an atypical trophic factor for neurons enabling RGC axon regeneration. Immunolabeling of retinal whole mounts with a Brn3a antibody demonstrated drastic RGC loss. Dietary supplementation with Neuro-FAG (nFAG®), a balanced mixture of fatty acids (FAs), counteracted inflammatory and gliotic processes in the retina. In contrast, infiltration of macrophages and their production of OCM remained at elevated levels thus eventually preserving OCM trophic activity. In addition, the diet supplement with nFAG exerted a neuroprotective effect preventing MOG-induced RGC death. In conclusion, these data suggest that the balanced mixture of FAs may represent a useful form of diet supplementation to limit inflammatory events and death of RGCs associated to optic neuritis. This would occur without affecting macrophage infiltration and the release of OCM thus favoring the maintenance of OCM neuroprotective role.


[Oral ketoconazole therapy of a case of pulmonary histoplasmosis].
A 46-year-old man with recurrent pulmonary histoplasmosis was given oral treatment with ketoconazole (a new imidazole derivative related to miconazole) in a dose of 400 mg/day for 3 months, followed by 200 mg daily for 6 months. The clinical and microbiological signs disappeared and the chest X-ray cleared. The drug was well tolerated without clinical or biological side-effects. The pharmacology of ketoconazole, its indications and the results of treatment of other deep mycoses are discussed. Unlike amphotericin B, ketoconazole can be administered orally without noticeable toxicity and appears to have approximately the same fungicidal activity.


[The lumbar ligamentum flavum. Anatomic characteristics with reference to microdiscotomy].
One important step in lumbar discotomy is the safe penetration and exact partial removal of the Lig. flavum. This is a crucial prerequisite for the selective and gentle removal of prolapsed and sequestrated intervertebral disc tissue. Extensive lancing of the Lig. flavum should be avoided, to minimize intraoperative and postoperative complications, such as injuries to the nerves and the Dura mater, instabilities, bleeding and scarring. As there has up to now been insufficient information on the anatomy of the Lig. flavum especially regarding microdiscotomy, an analysis of the Ligg. flava L2/L3 to L5/S1, guided by this aim, was carried out on 36 corpses kept in formaline (16 f, 20 m; 52-78 y). Preparations showed the lumbar Ligg. flava to be embodied in the Foramina interarcualia in a characteristic configuration. There also proved to be defined insertion areas on the laminae of the vertebral arches, which must be taken into consideration during the operative exposure. The Lig. flavum rises from the cranial vertebral arch from the ventral surface of the lamina (6.8 mm) whilst the insertion area on the caudal lamina covers the dorsal and the ventral surface. The extent at the ventral surface is 2.2 mm in average. Taking the insertion proportions into account we would suggest the Lig. flavum to be divided as follows: Pars interspinalis, which clearly differs from the Lig. interspinale (and from the M. interspinalis), and which houses venous anastomoses in its dorsal, ridge-shaped extension. Pars interlaminaris, which starts at the laminae and constitutes the target area for flavotomy in its lateral section, and Pars capsularis, which merges into the capsular structures of the facets. In all levels examined, there proved to be dorso-ventrally a typical change in the direction of the course of the fibres in the Pars interlaminaris. Whilst the direction of the fibres dorsally is oriented cranio-medially to caudo-laterally at an angle between 15 degrees and 30 degrees to the median line, the ventral fibres of the Lig. flavum are strictly aligned cranio-caudally. The changes in the directions of the fibres are continuous with the fibres being very closely intertwined, without there being any spatium at all. The texture of the Lig. flavum is, therefore, a mirror image of that of the autochthonuous muscular system of the back, even if the overlapping angle area is considerably smaller. The different segment levels show a segment-specific thickness profile. The analysis has provided anatomic information about the Ligg. flava L2/L3 to L5/S1. These data represent important prerequisites for a selective, gentle and safe intraoperative procedure for discotomy.


Angiotensin II affects basal, pulsatile, and glucose-stimulated insulin secretion in humans.
Angiotensin II (Ang II) modulates the tissue response to insulin (insulin sensitivity), but the effect of Ang II on the secretion of insulin has not been investigated thus far. Nineteen healthy volunteers (17 male; mean age, 26+/-1 years) were studied. In a double-blind, randomized, placebo-controlled study, seven volunteers were allocated on three occasions in random order after an overnight fast to three interventions: (1) solvent (placebo) infusion; (2) infusion of 1.0 ng Ang II x kg(-1) x min(-1) (subpressor dose); and (3) infusion of 5.0 ng Ang II x kg(-1) x min(-1) (pressor dose). Frequent blood samples (each minute) were obtained for estimation of plasma insulin concentrations over a period of 120 minutes to assess basal and pulsatile insulin secretion. In an ancillary study, plasma glucose and insulin levels were measured after an oral glucose tolerance test while solvent (placebo) or Ang II was infused in 12 fasting healthy volunteers. Plasma insulin concentrations were measured immunoenzymatically (enzyme-linked immunosorbent assay). Insulin secretion pulses were analyzed with the deconvolution technique, and the regularity of insulin secretion was analyzed with the approximate entropy technique. Plasma insulin half-life was assessed using the hyperinsulinemic euglycemic clamp method. The pressor dose of Ang II reduced total, basal, and pulsatile insulin secretion, and this effect was highly significant (P<.01). The subpressor dose tended to suppress insulin secretion. The burst frequency (number of peaks) and the regularity of insulin secretion were not affected by administration of Ang II. After the oral glucose load, the insulinemic response was significantly lower and plasma glucose concentrations were significantly higher with infusion of Ang II compared with placebo. Ang II affects both the basal (nonpulsatile) and the pulsatile component of spontaneous insulin secretion and the glucose-stimulated insulin secretion in humans. This observation is of potential interest with respect to the interaction of Ang II and insulin, eg, in the genesis of hyperinsulinemia and hypertension.


Cancer-related disparities and opportunities for intervention in Northern Plains American Indian communities.
We examined behavioral trends associated with cancer risk and cancer screening use from 1997 through 2006 among American Indians/Alaska Natives (AI/ANs) in the Northern Plains region (North Dakota, South Dakota, Nebraska, and Iowa) of the United States. We also examined disparities between that population and non-Hispanic white (NHW) people in the Northern Plains and AI/ANs in other regions. We analyzed Behavioral Risk Factor Surveillance System data from the Centers for Disease Control and Prevention for 1997-2000 and 2003-2006. We used age-adjusted Wald Chi-square tests to test the difference between these two periods for AI/ANs and the difference between AI/ANs and NHW people during 2003-2006. There was no statistically significant improvement among AI/ANs in the Northern Plains region for behaviors associated with cancer risk or cancer screening use, and there was a significant increase in the obesity rate. The prevalence of binge drinking, obesity, and smoking among AI/ANs in the Northern Plains was significantly higher than among NHW people in the same region and among AI/AN populations in other regions. Although the percentage of cancer screening use was similar for all three groups, the use of sigmoidoscopy/colonoscopy was significantly lower among the Northern Plains AI/ANs than among NHW people. These results indicate a need for increased efforts to close the gaps in cancer health disparities between AI/ANs and the general population. Future efforts should focus not only on individual-level changes, but also on system-level changes to build infrastructure to promote healthy living and to increase access to cancer screening.


[Diagnostic benefits of adrenocortical scintigraphy in hepatic adrenal rest tumor].
An 81-year-old female was referred to our hospital for the examination of an S7 liver tumor. The tumor was suspected to be a hepatic adrenal rest tumor (HART) based on ultrasonography, dynamic CT, Gd-EOB-DTPA-enhanced MRI, and CT during abdominal angiography. After various hormonal tests, the tumor was confirmed as hormonally non-functional. The diagnosis of HART was confirmed based on (131)I-adosterol accumulation in the tumor by adrenocortical scintigraphy. The resected tumor was histologically compatible with HART, and it may have been able to produce cortisol based on the immunohistochemical findings of various adrenocortical hormone metabolic enzymes. Adrenocortical scintigraphy may thus be useful in diagnosing HART.


Sex differences in the causes and natural history of heart failure.
Heart failure is a clinical syndrome of increasing prevalence in the United States, with significant morbidity and mortality. Although men have a higher annual mortality rate, more women than men die from heart failure each year. Optimal disease management is critical in limiting the impact of heart failure on life quality, quantity, and health care expenditures. Women have a unique risk-factor profile and different clinical manifestations of heart failure than men. Understanding inherent sex differences in heart failure epidemiology, pathophysiology, and natural history is imperative in determining whether the optimal therapy for this prevalent and important syndrome is affected by sex.


Relationship between Sequential Organ Failure Assessment (SOFA) and intra-abdominal pressure in intensive care unit.
Patients in the intensive care unit are at risk of developing intra-abdominal hypertension and abdominal compartment syndrome. To describe the relation between Sequential Organ Failure Assessment (SOFA) vs. intra-abdominal pressure and the relation between SOFA and risk factors for intra-abdominal hypertension. In accordance with the recommendations of the World Society of the Abdominal Compartment Syndrome, the present study measured the intra-abdominal pressure of patients 24 h and 48 h after admission to the unit and calculated the SOFA after 24 h and 48 h. Data was collected over two-month period. No correlation was found between SOFA and intra-abdominal pressure. Seventy percent of the patients were men and the mean age was 44 years, 10% had been referred from general surgery (with a mean intra-abdominal pressure of 11) and 65% from neurosurgery (with a mean intra-abdominal of 6.7). Only three (7.5%) presented with intra-abdominal hypertension. The highest SOFA was 15 and the most frequent kind of organ failure was neurological, with a frequency of 77%. There was a strong correlation between the SOFA after 24 h and 48 h and peak respiratory pressure (ρ=0.43/p=0.01; ρ=0.39/p=0.02). No correlation was found between SOFA and intra-abdominal pressure in the patients covered by the present study. However, it is possible in patients undergoing abdominal surgery or those with abdominal sepsis. Não houve correlação entre o SOFA e a pressão intra-abdominal nos pacientes aqui estudados; contudo, sinalizou ser possível em pacientes com operação abdominal ou naqueles com sepse abdominal.


Decorin Reduces Intraocular Pressure and Retinal Ganglion Cell Loss in Rodents Through Fibrolysis of the Scarred Trabecular Meshwork.
To investigate whether Decorin, a matrikine that regulates extracellular matrix (ECM) deposition, can reverse established trabecular meshwork (TM) fibrosis, lower IOP, and reduce progressive retinal ganglion cell (RGC) death in a novel rodent model of TM fibrosis. Adult rats had intracameral (IC) injections of human recombinant (hr) TGF-β over 30 days (30 d; to induce TM fibrosis, raise IOP, and initiate RGC death by 17 d) or PBS (controls) and visually evoked potentials (VEP) were measured at 30 d to evaluate resultant visual pathway dysfunction. In some animals TGF-β injections were stopped at 17 d when TM fibrosis and IOP were consistently raised and either hrDecorin or PBS IC injections were administered between 21 d and 30 d. Intraocular pressure was measured biweekly and eyes were processed for immunohistochemical analysis of ECM deposition to assess TM fibrosis and levels of matrix metalloproteinases (MMP) and tissue inhibitors of matrix metalloproteinases (TIMP) to assess fibrolysis. The effect of hrDecorin treatment on RGC survival was also assessed. Transforming growth factor-β injections caused sustained increases in ECM deposition in the TM and raised IOP by 17 d, responses that were associated with 42% RGC loss and a significant decrease in VEP amplitude measured at 30 d. Decorin treatment from 17 d reduced TGF-β-induced TM fibrosis, increased levels of MMP2 and MMP9 and lowered TIMP2 levels, and lowered IOP, preventing progressive RGC loss. Human recombinant Decorin reversed established TM fibrosis and lowered IOP, thereby rescuing RGC from progressive death. These data provide evidence for the candidacy of hrDecorin as a treatment for open-angle glaucoma.


[Present-day situation with regard to the transplantation of the small intestine].
At the time of writing, seven transplantations of intestine in man have been carried out, three of these being in children. All the patients eventually died. The longest survival time was 75 days. The animal experiments on the various problems of small-intestine transplantation, tolerance of ischemia, preservation of transplants, section of lymph vessels and nerves and the problem of rejection are summarized with reference to the literature and the Author's own investigations. Transplantation of the small intestine is only justified if all the other possibilities have been exhausted. The Author attempted to lay down provisional guidelines on the indications for transplantation of the intestine. With the necessarily strict indications, the patients coming into question are likely to be rare and must be concentrated in a small number of specielized centers.


CAR T Cells Redirected to CD44v6 Control Tumor Growth in Lung and Ovary Adenocarcinoma Bearing Mice.
The main challenge of adoptive therapy with Chimeric Antigen Receptor modified T cells (CAR T) is the application to the field of solid tumors, where the identification of a proper antigen has emerged as one of the major drawbacks to CAR T cell treatment success. CD44 is a glycoprotein involved in cell-cell and cell-matrix interactions. The isoform containing the variant domain 6 of CD44 gene (CD44v6) has been implicated in tumorigenesis, tumor cell invasion and metastasis and represents an attractive target for CAR T cell therapies. Targeting CD44v6 antigen has been shown to control tumor growth in acute myeloid leukemia and multiple myeloma mouse models. While CAR T approach for the treatment of B cell malignancies has shown great success, response rates among patients with solid cancer are less favorable. The purpose of our study was to test the efficacy of CD44v6.CAR T cells, produced in compliance with Good Manufacturing Practice (GMP), in adenocarcinoma tumor models. We generated a bicistronic retroviral vector containing the CD44v6 CAR and the HSV-TK Mut2 suicide gene to enhance the safety of the proposed CAR T cell therapy. CD44v6 transduced CAR T cells were homogeneously positive for ΔLNGFR selection marker, were enriched in T central memory (TCM) and T memory stem cells (TSCM) and displayed a highly activated phenotype. In vitro assays revealed antigen-specific activation and cytotoxicity of human CD44v6.CAR T cells against CD44v6 expressing tumor cell lines. When infused in immunodeficient tumor bearing mice, human CD44v6.CAR T cells were able to reach, infiltrate and proliferate at tumor sites, finally resulting in tumor growth control. Next, we checked if cells produced in compliance with GMP grade standards retained the same antitumor activity of those produced with research grade materials and protocols. Noteworthy, no differences in the potency of the CAR T obtained with the two manufacturing processes were observed. In conclusion, our preclinical results suggest that CD44v6.CAR T based adoptive therapy could be a promising strategy in solid cancer treatment.


Clinical significance of nonpalpable prostate cancer with favorable biopsy features in Japanese men.
To assess the clinical significance of nonpalpable localized prostate cancers with relatively favorable six sextant biopsy features in Japanese men. 136 nonpalpable prostate cancers of which biopsy features confined to (1) a Gleason score of 6 or less, (2) one or two positive cores per six sextant cores, and (3) 50% or less involvement of any positive core were collected. The Gleason score, tumor extension, and cancer volume were compared with preoperative serum PSA and PSA density for the patients who underwent radical prostatectomy. PSA doubling time was measured for the patients who were treated expectantly. Treatments chosen for 136 patients with favorable biopsy features were radical prostatectomy alone for 48 and with preoperative androgen deprivation for 30, radiation to the prostate for 12, androgen deprivation therapy for 21, and watchful waiting for 25. Of 48 patients who underwent radical prostatectomy without androgen deprivation therapy, 25% had nonorgan-confined cancers. Seven cancers (14.6%) were Gleason score of 7, but no cancers were 8 or greater. Among 42 prostatectomy specimens for which cancer volume was measured, 22 (52.4%) had cancer volume >0.5 cm(3). Pretreatment serum PSA levels were correlated neither with the Gleason score, tumor extension nor cancer volume. There was only one nonorgan-confined cancer in the 23 cancers for which PSA density was <0.2 ng/ml/g. The ability of PSA density to predict cancer volume <0. 5 cm(3) was 0.61 using a cut-off of 0.2 ng/ml/g. Of the 25 patients treated expectantly, the PSA doubling time was less than 2 years for 3 patients, while it was stable or fluctuated for 13. Tumor extension can be predicted based on PSA density in nonpalpable prostate cancer with favorable biopsy features, but predictability of cancer volume based on PSA or PSA density is not satisfactorily high. New parameters or biomarkers that complement needle biopsy findings are needed to predict clinical significance of T1c prostate cancer with favorable biopsy features.


Minimum internal diameter of the greater saphenous vein is an important determinant of successful femorodistal bypass grafting that is independent of the quality of the runoff.
The greater saphenous vein is assessed as part of the workup for femorodistal bypass surgery in our unit. The aim of this study was to determine whether the minimum internal diameter (MID) of the vein predicted graft patency and limb salvage in femorodistal bypass surgery, independently of the quality of the runoff. A consecutive series of 67 infrainguinal vein bypass grafts were performed on 62 patients with critical lower limb ischemia. All were followed for at least 1 year. The MID of the greater saphenous vein was calculated from preoperative saphenograms, and all of the arteriograms were scored for their runoff using an ad hoc method approved by the Society for Vascular Surgery. The cumulative patency of all vein grafts at 3 years was 59 +/- 7% (SE), and the limb salvage was 85 +/- 5%. All femoropopliteal bypass grafts were patent at 3 years if the MID of the vein was greater than 3.0 mm. The crural bypass patency was 66 +/- 12% for an MID greater than 3.0 mm and only 27 +/- 12% for an MID less than 3.0 mm. Every extra point on the runoff score increased the hazard of bypass failure by 16% (95% CI 1.0-34; p < .05). Vein diameter and runoff score were independent of one another (r2 = -.106). The MID of the greater saphenous vein is a major determinant of outcome in infrainguinal vein bypass surgery independent of the arterial runoff.


A Qualitative Study of Perspectives of Older Adults on Deintensifying Diabetes Medications.
While many older adults with type 2 diabetes have tight glycemic control beyond guideline-recommended targets, deintensifying (stopping or dose-reducing) diabetes medications rarely occurs. To explore the perspectives of older adults with type 2 diabetes around deintensifying diabetes medications. This qualitative study used individual semi-structured interviews, which included three clinical scenarios where deintensification may be indicated. Twenty-four adults aged ≥65 years with medication-treated type 2 diabetes and hemoglobin A1c <7.5% were included (to thematic saturation) using a maximal variation sampling strategy for diabetes treatment and physician specialty. Interviews were independently coded by two investigators and analyzed using a grounded theory approach. We identified major themes and subthemes and coded responses to the clinical scenarios as positive (in favor of deintensification), negative, or ambiguous. Participants' mean age was 74 years, half were women, and 58% used a sulfonylurea or insulin. The first of four major themes was fear of losing control of diabetes, which participants weighed against the benefits of taking less medication (Theme 2). Few participants viewed glycemic control below target as a reason for deintensification and a majority would restart the medication if their home glucose increased. Some participants were anchored to their current diabetes treatment (Theme 3) driven by unrealistic views of medication benefits. A trusting patient-provider relationship (Theme 4) was a positive influence. In clinical scenarios, 8%, 4%, and 75% of participants viewed deintensification positively in the setting of poor health, limited life expectancy, and high hypoglycemia risk, respectively. Optimizing deintensification requires patient education that describes both individualized glycemic targets and how they will change over the lifespan. Deintensification is an opportunity for shared decision-making, but providers must understand patients' beliefs about their medications and address misconceptions. Hypoglycemia prevention may be a helpful framing for discussing deintensification.


Cytotoxic platinum(II) complexes derived from saccharinate and phosphine ligands: synthesis, structures, DNA cleavage, and oxidative stress-induced apoptosis.
A series of the structurally related platinum(II) saccharinate (sac) complexes with alkylphenylphosphines, namely cis-[Pt(sac)2(PPh2Me)2]·DMSO (1), cis-[Pt(sac)2(PPhMe2)2] (2), cis-[Pt(sac)2(PPh2Et)2] (3), and cis-[Pt(sac)2(PPhEt2)2]·2DMSO (4), were synthesized and fully characterized; their structures were determined by X-ray crystallography. All the complexes were investigated for their anticancer potentials on three human cancer cells including A549 (lung), MCF-7 (breast), and HCT116 (colon) in addition to a noncancerous human bronchial epithelial cells (BEAS-2B). Specifically, 1 and 3 showed significant cytotoxic effects against MCF-7 and HCT116 cell lines in comparison to cisplatin, and were considered as the most potent ones in the series. The cytotoxic complexes were found to cleave DNA efficiently. In addition, the binding interactions of the complexes with DNA were confirmed by enzyme inhibition and molecular docking studies. Complexes 1 and 3 were capable of inducing apoptosis and arrested the cell cycle at the DNA synthesis (S) phase in MCF-7 cells. Furthermore, 1 and 3 caused the excessive generation of reactive oxygen species (ROS), leading to mitochondrial dysfunction and double-strand DNA breaks.


Significance and limits of cerebrospinal fluid beta-2-microglobulin measurement in course of acute lymphoblastic leukemia.
Cerebrospinal fluid beta-2-microglobulin (CSF-beta 2m) was measured longitudinally in 48 patients affected by acute lymphoblastic leukemia (ALL). Thirteen developed a central nervous system (CNS) involvement during the course of the disease; although moderately higher mean CSF-beta 2m levels were found in these subjects, no significant statistical differences were observed in comparison with patients without this complication and compared with the control group. No correlations were found between beta 2m and other biochemical parameters in CSF. Furthermore, CSF-beta 2m levels appeared to be influenced by previous combined chemoradiotherapeutic treatment for CNS prophylaxis, presence of meningeal non-neoplastic infiltrates, patients' ages, amount of CSF blasts, and their immunological phenotype. In particular, only clearly B-committed leukemic cells, when tested, showed a strong surface expression of beta 2m, as demonstrated by immunocytochemical detection of this protein on cell membrane. However, in specific cases, CSF beta 2m measurement and CSF/serum beta 2m ratio were helpful in diagnosing and monitoring isolated CNS disease. Such findings suggest that CSF-beta 2m assay may be a useful tool in the management of CNS involvement in the course of ALL in only selected patients, as several factors can modify the outcome.


Exocomets size distribution in the [Formula: see text] Pictoris planetary system.
The star [Formula: see text] Pictoris harbors a young planetary system of about 20 million years old, which is characterized by the presence of a gaseous and dusty debris disk, at least two massive planets and many minor bodies. For more than thirty years, exocomets transiting the star have been detected using spectroscopy, probing the gaseous part of the cometary comas and tails. The detection of the dusty component of the tails can be performed through photometric observations of the transits. Since 2018, the Transiting Exoplanet Survey Satellite has observed [Formula: see text] Pic for a total of 156 days. Here we report an analysis of the TESS photometric data set with the identification of a total of 30 transits of exocomets. Our statistical analysis shows that the number of transiting exocomet events (N) as a function of the absorption depth (AD) in the light curve follows a power law in the form [Formula: see text], where [Formula: see text]. This distribution of absorption depth leads to a differential comet size distribution proportional to [Formula: see text], where [Formula: see text], showing a striking similarity to the size distribution of comets in the Solar system and the distribution of a collisionally relaxed population ([Formula: see text]).


Triceps to biceps transfer to restore elbow flexion in three patients with brachial plexus palsy.
Between April 1994 and April 1998, triceps to biceps transfers were done for three men with post-traumatic lesions of the brachial plexus and consequent loss of elbow flexion. Their mean age at the time of their accidents was 33 years (range 19-41) and at the time of muscle transfer 40 years (28-46), with a mean observation period of 21 months (12-31). The transfer resulted in active elbow flexion in all patients with a mean of 113 degrees (90 degrees-130 degrees) and a degree of strength 4-5 (contraction against resistance) with no remaining deficit of passive extension. Two patients were satisfied with the result of the operation and the other was content. No complications were noted. The transfer of the triceps muscle to the tendon of the biceps muscle on loss of elbow flexion resulted in adequate movement and degree of strength. The triceps to biceps transfer involves operating close to the elbow joint and minimal complications, is cosmetically satisfactory, and is particularly suitable for co-contraction of triceps and biceps.


The Jahn-Teller effect in CH(3)CN(+) (X(2)E) and CD(3)CN(+) (X(2)E) studied by zero kinetic energy photoelectron spectroscopy.
The Jahn-Teller effect in CH(3)CN(+) (X(2)E) and CD(3)CN(+) (X(2)E) has been found experimentally by zero kinetic energy (ZEKE) photoelectron spectroscopy using coherent extreme ultraviolet (XUV) radiation. The vibronic bands of CH(3)CN(+) (X(2)E) and CD(3)CN(+) (X(2)E) at about 4500 cm(-1) above the ground states have been recorded. The spectra consist mainly of the Jahn-Teller active C-C[triple bond]N bending (v(8)), the CN stretching (v(2)), the CH(3) (CD(3)) deforming (v(6)), and the C-C stretching (v(4)) vibronic excitations. The Jahn-Teller active vibronic bands (v(8)) have been assigned with a harmonic model including linear and quadratic Jahn-Teller coupling terms, taking into account only the single mode vibronic excitation. The ionization potentials of CH(3)CN and CD(3)CN have also been determined, and their values are 12.2040(+/-0.001) and 12.2286(+/-0.001) eV, respectively.


Toll-like receptor 2 polymorphisms and nontuberculous mycobacterial lung diseases.
To investigate the occurrence of the Toll-like receptor 2 (TLR2) polymorphisms in patients with pulmonary disease caused by nontuberculous mycobacteria (NTM), TLR2 Arg677Trp and Arg753Gln polymorphisms were examined. TLR2 polymorphisms do not appear to be responsible for host susceptibility to NTM lung disease, at least in the Korean population.


The utility of thrombophilia testing in patients with newly diagnosed portal vein thrombosis.
: Thrombophilia testing is frequently performed in both seemingly provoked and unprovoked portal vein thrombosis (PVT), yet the clinical implications of these expensive laboratory tests are unknown. We investigated the frequency of clinical management changes in patients with newly diagnosed PVT. This is a retrospective analysis of adult patients with a newly diagnosed PVT at a single institution. The primary outcome is change in clinical management, defined as documented change in choice, dose, or duration of anticoagulation, future thromboprophylaxis, or counseling of asymptomatic family members. Five-hundred and forty-four patients with PVT were identified, 438 (80.5%) of whom had an identifiable pretesting provoking factor, most commonly cirrhosis (39.2%). Two-hundred ninety-one patients (53.5%) had at least one hypercoagulable laboratory test performed. The most frequently positive test was PAI-1 polymorphism, followed by elevated homocysteine and MTHFR mutational analysis. However, the only test that was frequently positive and consistently altered management was JAK2 mutational analysis (15.3%). Factor V Leiden was commonly positive but rarely changed clinical decision-making (1.5%), as was flow cytometric testing for paroxysmal nocturnal hemoglobinuria (0.8%), and antiphospholipid antibodies (0.7%). Patients with cirrhosis rarely had thrombophilia testing results that were clinically significant. A rough cost estimate was dramatically reduced from $231 000 to $76 000 if only clinically meaningful tests were employed in the hypercoagulable work-up. These results highlight the need for focused thrombophilia testing in patients with PVT.


[Effectiveness of Pharmaceutical Intervention While Administering 5-Aminolevulinic Acid Hydrochloride through a Collaboration of Physicians and Pharmacists].
5-aminolevulinic acid hydrochloride is a highly effective drug in reducing tumor residuals in transurethral resection of the bladder tumors; however, hypotension is a serious side effect that causes clinical problems. To avoid serious side effects, a pharmacist, in consultation with a physician, decided to discontinue the antihypertensive medication, and the effect of this pharmaceutical intervention was examined retrospectively. This study included patients who received 5-aminolevulinic acid hydrochloride at Gifu Municipal Hospital and were instructed to continue receiving their usual antihypertensive medication on the day of surgery. The control group comprised 17 patients before the pharmaceutical intervention, and the intervention group comprised 18 patients after the pharmaceutical intervention. The difference in systolic blood pressure before and after 5-aminolevulinic acid hydrochloride administration was -19.4±22.5 mmHg in the control group and -2.8±16.0 mmHg in the intervention group. The intervention group showed a significantly lower decrease in blood pressure(p=0.019). Intervention to avoid hypotension through the collaboration between physicians and pharmacists may be effective in improving the safety of 5-aminolevulinic acid hydrochloride.


The CB(1) cannabinoid receptor of astrocytes is coupled to sphingomyelin hydrolysis through the adaptor protein fan.
Cannabinoids exert most of their effects through the CB(1) receptor. This G protein-coupled receptor signals inhibition of adenylyl cyclase, modulation of ion channels, and stimulation of mitogen- and stress-activated protein kinases. In this article, we report that Delta(9)-tetrahydrocannabinol (THC), the major active component of marijuana, induces sphingomyelin hydrolysis in primary astrocytes but not in other cells expressing the CB(1) receptor, such as primary neurons, U373 MG astrocytoma cells, and Chinese hamster ovary cells transfected with the CB(1) receptor cDNA. THC-evoked sphingomyelin breakdown in astrocytes was also exerted by the endogenous cannabinoid anandamide and the synthetic cannabinoid HU-210 and was prevented by the selective CB(1) antagonist SR141716. By contrast, the effect of THC was not blocked by pertussis toxin, pointing to a lack of involvement of G(i/o) proteins. A role for the adaptor protein FAN in CB(1) receptor-coupled sphingomyelin breakdown is supported by two observations: 1) coimmunoprecipitation experiments show that the binding of FAN to the CB(1) receptor is enhanced by THC and prevented by SR141716; 2) cells expressing a dominant-negative form of FAN are refractory to THC-induced sphingomyelin breakdown. This is the first report showing that a G-protein-coupled receptor induces sphingomyelin hydrolysis through FAN and that the CB(1) cannabinoid receptor may signal independently of G(i/o) proteins.


The functional-cognitive framework as a tool for accelerating progress in cognitive neuroscience: On the benefits of bridging rather than reducing levels of analyses.
The subject matter of neuroscience research is complex, and synthesising the wealth of data from this research to better understand mental processes is challenging. A useful strategy, therefore, may be to distinguish explicitly between the causal effects of the environment on behaviour (i.e. functional analyses) and the mental processes that mediate these effects (i.e. cognitive analyses). In this article, we describe how the functional-cognitive (F-C) framework can accelerate cognitive neuroscience and also advance a functional treatment of brain activity. We first highlight that cognitive neuroscience can particularly benefit from the F-C approach by providing an alternative to the problematic practice of reducing cognitive constructs to behavioural and/or neural proxies. Next, we outline how functional (behaviour-environment) relations can serve as a bridge between cognitive and neural processes by restoring mental constructs to their original role as heuristic tools. Finally, we give some examples of how both cognitive neuroscience and traditional functional approaches can mutually benefit from the F-C framework.


Memory complaints in patients with normal cognition are associated with smaller hippocampal volumes.
We aimed to investigate volumetry of the medial temporal lobe in patients with subjective memory complaints without any cognitive impairment. This study included 20 patients with subjective memory complaints and normal cognitive function and 28 controls without memory complaints. Volumes of the hippocampus and parahippocampal gyrus (PHG) were measured using coronal T1-weighted MR images. Cognitive functions were assessed using the Cambridge Cognitive Examination. Depressive symptoms were assessed using the Geriatric Depression Scale. Differences between groups were analysed using t-tests. Patients with subjective memory complaints had a higher education and more depressive symptoms than controls ( p < 0.01). Moreover, they had smaller left hippocampal volumes than controls ( p < 0.01). There were no differences between groups in the volume of the right hippocampus or PHG. There was a moderate association between the volume of left hippocampus and left PHG and memory-score (r = 0.32, p = 0.03; r = 0.34, p = 0.02). We concluded that memory complaints in patients without any cognitive impairment were associated with smaller left hippocampal volumes and more depressive symptoms. These preliminary results suggest that memory complaints may reflect minimal brain deficits associated with impending dementia, depression or a combination of both disorders.


Na⁺/K⁺-ATPase β2-subunit (AMOG) expression abrogates invasion of glioblastoma-derived brain tumor-initiating cells.
Mechanisms of glioma invasion remain to be fully elucidated. Glioma cells within glioblastoma multiforme (GBM) range from well-differentiated tumor cells to less-differentiated brain tumor-initiating cells (BTICs). The β2-subunit of Na(+)/K(+)-ATPase, called the adhesion molecule on glia (AMOG), is highly expressed in normal glia but is thought to be universally downregulated in GBM. To test our hypothesis that expression of AMOG is heterogeneous in GBM and confers a less invasive phenotype, we compared it between BTICs and differentiated cells from patient-matched GBM and then tested GBM invasion in vitro after AMOG overexpression. Immunohistochemistry, immunoblotting, and real-time PCR were used to characterize AMOG protein and mRNA expression in tumor samples, BTICs, and differentiated cells. Matrigel invasion assay, scratch assay, and direct cell counting were used for testing in vitro invasion, migration, and proliferation, respectively. While AMOG expression is heterogeneous in astrocytomas of grades II-IV, it is lost in most GBM. BTICs express higher levels of AMOG mRNA and protein compared with patient-matched differentiated tumor cells. Overexpression of AMOG decreased GBM cell and BTIC invasion without affecting migration or proliferation. Knockdown of AMOG expression in normal human astrocytes increased invasion. AMOG expression inhibits GBM invasion. Its downregulation increases invasion in glial cells and may also represent an important step in BTIC differentiation. These data provide compelling evidence implicating the role of AMOG in glioma invasion and provide impetus for further investigation.


Intestinal epithelial cells in inflammatory bowel diseases.
The pathogenesis of inflammatory bowel diseases (IBDs) seems to involve a primary defect in one or more of the elements responsible for the maintenance of intestinal homeostasis and oral tolerance. The most important element is represented by the intestinal barrier, a complex system formed mostly by intestinal epithelial cells (IECs). IECs have an active role in producing mucus and regulating its composition; they provide a physical barrier capable of controlling antigen traffic through the intestinal mucosa. At the same time, they are able to play the role of non-professional antigen presenting cells, by processing and presenting antigens directly to the cells of the intestinal immune system. On the other hand, immune cells regulate epithelial growth and differentiation, producing a continuous bi-directional cross-talk within the barrier. Several alterations of the barrier function have been identified in IBD, starting from mucus features up to its components, from epithelial junctions up to the Toll-like receptors, and altered immune responses. It remains to be understood whether these defects are primary causes of epithelial damage or secondary effects. We review the possible role of the epithelial barrier and particularly describe the role of IECs in the pathogenesis of IBD.


Effect of a performance improvement CME activity on management of patients with diabetes.
Primary care in the United States faces unprecedented challenges from an aging population and the accompanying prevalence of chronic disease. In response, continuing medical education (CME) initiatives have begun to adopt the principles of performance improvement (PI) into their design, although currently there is a dearth of evidence from national initiatives supporting the effectiveness of this methodology. The specific aim of this study was to demonstrate the value of a national PI-CME activity to improve the performance of physicians treating patients with diabetes. We analyzed data from the American Academy of Family Physicians' METRIC® PI-CME activity in a cohort of family physician learners. The study utilized the 3-stage design standard approved for PI-CME. Baseline and follow-up performance data across a range of clinical and systems-based measures were compared in aggregate. Data were assessed for 509 learners who completed the activity. Statistically significant changes occurred both for self-assessment of a range of practice aspects and for diabetes care measures. Learners recognized that the organization of their practices had improved, and mechanisms were in place for better staff feedback, as well as aspects of patient self-management. Based on the clinical data obtained from 11 538 patient charts, 6 out of 8 diabetes measures were significantly improved. The activity appears to have had a positive, measurable impact on the medical practice of learners and suggests that, when appropriately designed and executed, PI-CME on a national scale can be a useful vehicle to influence performance change in physicians and to inform future CME activities.


Moderate Changes in the Circadian System of Alzheimer's Disease Patients Detected in Their Home Environment.
Alzheimer's disease (AD) is a neurodegenerative disease often accompanied with disruption of sleep-wake cycle. The sleep-wake cycle is controlled by mechanisms involving internal timekeeping (circadian) regulation. The aim of our present pilot study was to assess the circadian system in patients with mild form of AD in their home environment. In the study, 13 elderly AD patients and 13 age-matched healthy control subjects (the patient's spouses) were enrolled. Sleep was recorded for 21 days by sleep diaries in all participants and checked by actigraphy in 4 of the AD patient/control couples. The samples of saliva and buccal mucosa were collected every 4 hours during the same 24 h-interval to detect melatonin and clock gene (PER1 and BMAL1) mRNA levels, respectively. The AD patients exhibited significantly longer inactivity interval during the 24 h and significantly higher number of daytime naps than controls. Daily profiles of melatonin levels exhibited circadian rhythms in both groups. Compared with controls, decline in amplitude of the melatonin rhythm in AD patients was not significant, however, in AD patients more melatonin profiles were dampened or had atypical waveforms. The clock genes PER1 and BMAL1 were expressed rhythmically with high amplitudes in both groups and no significant differences in phases between both groups were detected. Our results suggest moderate differences in functional state of the circadian system in patients with mild form of AD compared with healthy controls which are present in conditions of their home dwelling.


Differential dynamics and activity-dependent regulation of alpha- and beta-neurexins at developing GABAergic synapses.
Neurexins (NRXs) and neuroligins are key synaptic adhesion molecules that also recruit synaptic signaling machineries. Neurexins consist of α- and β-isoforms, but how they couple synaptic transmission and adhesion to regulate activity-dependent synapse development remains unclear, in part because of poor understanding of their cell biology and regulation in the relevant neurons. Here, we examined the subaxonal localization, dynamics, and regulation of NRX1α and NRX1β in cortical perisomatic inhibitory synapses. Both isoforms are delivered to presynaptic terminals but show significant and different turnover rate at the membrane. Although NRX1α is highly diffuse along developing axons and filopodia, NRX1β is strictly anchored at terminals through binding to postsynaptic ligands. The turnover rate of NRX1β is attenuated by neural activity and presynaptic GABA(B) receptors. NRXs, thus, are intrinsically dynamic but are stabilized by local transmitter release. Such an activity-adjusted adhesion system seems ideally suited to rapidly explore and validate synaptic partners guided by synaptic transmission.


Surgical referral coordination from a first-level hospital: a prospective case study from rural Nepal.
Patients in isolated rural communities typically lack access to surgical care. It is not feasible for most rural first-level hospitals to provide a full suite of surgical specialty services. Comprehensive surgical care thus depends on referral systems. There is minimal literature, however, on the functioning of such systems. We undertook a prospective case study of the referral and care coordination process for cardiac, orthopedic, plastic, gynecologic, and general surgical conditions at a district hospital in rural Nepal from 2012 to 2014. We assessed the referral process using the World Health Organization's Health Systems Framework. We followed the initial 292 patients referred for surgical services in the program. 152 patients (52%) received surgery and four (1%) suffered a complication (three deaths and one patient reported complication). The three most common types of surgery performed were: orthopedics (43%), general (32%), and plastics (10%). The average direct and indirect cost per patient referred, including food, transportation, lodging, medications, diagnostic examinations, treatments, and human resources was US$840, which was over 1.5 times the local district's per capita income. We identified and mapped challenges according to the World Health Organization's Health Systems Framework. Given the requirement of intensive human capital, poor quality control of surgical services, and the overall costs of the program, hospital leadership decided to terminate the referral coordination program and continue to build local surgical capacity. The results of our case study provide some context into the challenges of rural surgical referral systems. The high relative costs to the system and challenges in accountability rendered the program untenable for the implementing organization.


Expanded parietal cell pool in transgenic mice unable to synthesize histamine.
The histidine decarboxylase enzyme (HDC) is responsible for the synthesis of histamine in mammals. Histidine decarboxylase-deficient (HDC-/-) mice have recently been developed by targeted mutation of the HDC gene. The impact of prolonged histamine deficiency was studied on gastric morphology (by immunohistochemistry and morphometry), gastric acid secretion (by a wash-through method for basal gastric acid secretion and by pylorus ligation for stimulated gastric acid secretion) and gastrin levels (by radioimmunoassay) in homozygous HDC-/- mice kept on a low-histamine diet. A double maximal gastric acid secretory response was found in knockouts after exogenous histamine administration. In contrast, the gastric acid secretion was significantly reduced after gastrinergic and cholinergic stimulation in the absence of histamine. The oxynthic gland area of HDC-/- mice was thickened with an increased parietal cell count compared to wild types. Substantially elevated serum and antral tissue gastrin levels of HDC-/- mice could be possible indications of both an expanded parietal cell mass and/or an increased histamine-induced maximal gastric acid secretory capacity of this genotype. These data suggest that not enough compensatory mechanisms develop in HDC-/- mice during a prolonged low-histamine diet to maintain/restore normal gastric acid secretion. An expanded parietal cell pool was also demonstrated in HDC-/- mice kept on a low-histamine diet, probably caused by a trophic effect of sustained hypergastrinaemia. The HDC-/- strain is a suitable model for studying the effects of achlorhydria and consequent hypergastrinaemia as an approach to human conditions such as atrophic gastritis or long-term antisecretory therapies.


Diagnostic utility of androgen receptor expression in discriminating poorly differentiated urothelial and prostate carcinoma.
Pathological separation of poorly differentiated urothelial and prostate carcinoma is difficult, but imperative because of the impact on patient management. Tumour morphology, in conjunction with a panel of immunohistochemistry (IHC), such as prostate-specific antigen (PSA), prostatic acid phosphatase (PSAP), CK7, CK20, p63 and high molecular weight keratins (HMWKs) are usually employed to resolve this issue. Androgen receptor (AR) expression is maintained in high-grade, undifferentiated prostate carcinoma, and thus, could be considered as a potentially useful adjunct to the conventional panel of markers. We performed an institutional review of all cases from 2006 to 2012 in which AR IHC had been performed to determine its diagnostic utility in discriminating between poorly differentiated urothelial and prostate carcinoma. Of the eligible cases (n=40), there were 9 high-grade urothelial carcinomas, 27 prostate carcinomas and 4 with both prostate and bladder tumours. All diagnoses were made by integrating the clinical, radiological, morphological and IHC results. In all the prostate carcinomas, there was diffuse, intense nuclear staining for AR. The urothelial tumours were either negative, had cytoplasmic staining or showed occasionally weak nuclear staining. The difference was highly significant with p<0.0001 (Mann-Whitney U test). We conclude that AR is an important marker as it is best able to distinguish between poorly differentiated urothelial and prostate carcinoma. AR appears superior to PSA and PSAP, which are not consistently expressed in high-grade prostate carcinoma. Also, high-grade urothelial carcinoma may be negative for CK20, p63/HMWK and occasionally CK7. We advocate the inclusion of AR in the panel of markers to differentiate these tumours.


Financial Affordability, Health Insurance, and Use of Health Care Services by the Elderly: Findings From the China Health and Retirement Longitudinal Study.
The rapidly growing aging population has attracted global attention. This study explores the associations between 3 basic health insurances, and it identifies factors associated with health care services among the elderly populations. This study is based on multistage stratified cluster sampling method from the 2013 China Health and Retirement Longitudinal Study (CHARLS) resulting in 7589 participants. Medical Insurance for Urban Employees (MIUE) members were more likely to use inpatient health care services. Health insurance programs were associated with inpatient services usage but not outpatient services usage. There are significant disparities in medical costs and health care service usage among the 3 insurance programs. Health insurance program is only associated with inpatient care. These findings may provide some suggestions to support improvements to the Chinese health care system.


The pyridyloxobutyl DNA adduct, O6-[4-oxo-4-(3-pyridyl)butyl]guanine, is detected in tissues from 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-treated A/J mice.
The tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), is a potent pulmonary carcinogen. This unsymmetric nitrosamine can be metabolically activated to lung DNA methylating and pyridyloxobutylating intermediates. The methyl DNA adducts are well characterized. The pyridyloxobutyl adducts are unstable under DNA hydrolysis conditions and decompose to release 4-hydroxy-1-(3-pyridyl)-1-butanone (HPB). One of the HPB-releasing adducts,O6-[4-oxo-4-(3-pyridyl)butyl]guanine (O6-pobG), has been detected in DNA reacted in vitro with the model pyridyloxobutylating agent, 4-(acetoxymethylnitrosamino)-1-(3-pyridyl)-1-butanone (NNKOAc). To determine whether this adduct was formed in vivo, A/J mice were treated with 10 mumol of [5-3H]NNK and sacrificed 24 h postinjection. The mutagenic O6-pobG was detected in liver but not lung DNA from these animals. Since 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) is a major metabolite of NNK, it is also possible that these animals are activating NNAL to a pyridylhydroxybutylating agent. Therefore, we also measured the levels of O6-[4-hydroxy-4-(3-pyridyl)butyl]guanine (O6-phbG) in these DNA samples. While radioactivity did coelute with synthetic standard for this potential NNAL adduct in one lung DNA sample, significant levels of O6-phbG were not detected in any other lung or liver DNA samples. The pyridyloxobutyl adduct, O6-pobG, was also observed in lung and liver DNA from mice treated with 4.2 mumol of [5-3H]NNKOAc in the presence but not absence of 2.5 mumol of O6-benzylguanine, a known depletor of the repair protein O6-alkylguanine-DNA alkyltransferase (AGT). These data indicate that this adduct is formed in vivo but is repaired in part by AGT. Cell-free extracts from A/J mouse lung and liver were used to determine the relative rate of O6-alkylguanine repair. O6-mG and O6-pobG were removed from DNA to the same extent in a competitive assay, suggesting that low levels of O6-pobG in lungs of NNK-treated mice did not result from preferential repair of O6-pobG by AGT. It is more likely that initial levels of O6-pobG are much lower than initial levels of O6-mG in lung DNA from NNK-treated A/J mice. These data are consistent with previous studies, which indicate that DNA methylation is the critical pathway for NNK-induced lung carcinogenesis in A/J mice.


Coffee and caffeine intake in relation to symptoms of psychological disorders among adults.
Given that there is an inconsistency in the findings related to the relationship between coffee and caffeine consumption and symptoms of psychological disorders, we performed a cross-sectional analysis to examine the association between coffee and caffeine intake and symptoms of psychological disorders among adults. In this cross-sectional study, 3362 participants were included. We assessed the coffee and caffeine intakes using a self-completed food frequency questionnaire (FFQ). Symptoms of depression, anxiety, and psychological distress were assessed using HADS and GHQ screening tools. The mean age of participants in this study was 36.2±7.8 years. After controlling for potential confounders, individuals who consumed coffee weekly or more had a significantly lower odds of symptoms of depression (OR: 0.67; 95% CI: 0.46-0.96) and symptoms of anxiety (OR: 0.57; 95% CI: 0.34-0.95) compared with those who did not consume coffee. However, no significant association was found between coffee intake and symptoms of psychological distress (OR: 0.98; 95%CI: 0.68-1.42). No significant relationship was found between caffeine intake and odds of symptoms of depression (OR: 0.94; 95% CI: 0.75-1.16), symptoms of anxiety (OR: 0.90; 95% CI: 0.67-1.20), and symptoms of psychological distress (OR: 1.13; 95% CI: 0.89-1.42). Compared with lack of coffee intake, weekly or more coffee consumption might be correlated with symptoms of depression and anxiety.


Human Milk Hormone Intake in the First Month of Life and Physical Growth Outcomes in Preterm Infants.
Human milk contains hormones that regulate metabolism. Extrauterine growth restriction remains common among preterm infants, but the effect of ingesting milk hormones on preterm infant growth is poorly understood. To quantify associations of longitudinal exposure to leptin, adiponectin, and insulin in milk with physical growth of preterm infants. In 50 preterm neonates (median gestational age 29.4 weeks), we sampled maternal milk on day-of-life 7, 14, 21, and 28 and measured hormone levels in whole milk by ELISA. Milk leptin levels were available for a subset of 18 infants. We calculated milk hormone doses by multiplying the hormone level by the milk volume ingested on each day and estimated the area under the curve (AUC) to reflect longitudinal exposure. We analyzed associations of milk hormone exposure with growth outcomes in generalized estimated equations. Weight gain velocity and z-scores in weight, length, head circumference, and body mass index at 36 weeks' postmenstrual age (PMA). Higher leptin intake was associated with greater weight gain (2.17g/kg/day [95% CI, 1.31, 3.02]) and weight z-score at 36 weeks' PMA (0.30 [0.08, 0.53] higher z-score per tertile). Higher adiponectin intake was associated with greater length z-score (0.41 [0.13, 0.69]), however, this association was nullified after adjustment of protein and calorie intake. Higher adiponectin was associated with smaller head circumference z-score (-0.36 [-0.64, -0.07]). Insulin was not associated with growth outcomes. Milk leptin and adiponectin exposures may affect growth of preterm infants. The long-term effects of milk hormones warrant further investigation.


Allele-specific repression of lymphotoxin-alpha by activated B cell factor-1.
Genetic variation at the human LTA locus, encoding lymphotoxin-alpha, is associated with susceptibility to myocardial infarction, asthma and other diseases. By detailed haplotypic analysis of the locus, we identified a single-nucleotide polymorphism (SNP) at LTA+80 as a main predictor of LTA protein production by human B cells. We found that activated B-cell factor-1 (ABF-1) binds to this site in vitro and suppresses reporter gene expression, but only in the presence of the LTA+80A allele. Using haplotype-specific chromatin immunoprecipitation, we confirmed that ABF-1 is preferentially recruited to the low-producer allele in vivo. These findings provide a molecular model of how LTA expression may be genetically regulated by allele-specific recruitment of the transcriptional repressor ABF-1.


Learning SPECT detector angular response function with neural network for accelerating Monte-Carlo simulations.
A method to speed up [Formula: see text] simulations of single photon emission computed tomography (SPECT) imaging is proposed. It uses an artificial neural network (ANN) to learn the angular response function (ARF) of a collimator-detector system. The ANN is trained once from a complete simulation including the complete detector head with collimator, crystal, and digitization process. In the simulation, particle tracking inside the SPECT head is replaced by a plane. Photons are stopped at the plane and the energy and direction are used as input to the ANN, which provides detection probabilities in each energy window. Compared to histogram-based ARF, the proposed method is less dependent on the statistics of the training data, provides similar simulation efficiency, and requires less training data. The implementation is available within the GATE platform.


Research Documents for Populations with Limited English Proficiency: Translation Approaches Matter.
To avoid excluding individuals with limited English proficiency from participating in research, the consent form and other documents should be presented to them in their primary language and in a format that is understandable. However, evidence suggests that, when documents are translated for prospective and actual research participants with limited English proficiency, these individuals often fail to engage with the documents and the research in the same terms as their English-speaking counterparts do. We argue that this is because methodological challenges remain after a decision to translate has been made. This study investigated how translation approaches affected reader response and intelligibility. Participants were asked to review two translated versions of a survey (which reflected a functionalist and a literal approach to translation) followed by semistructured interviews. Quantitative and qualitative analysis revealed a preference for a functionalist translation and a higher number of problems raised in regard to the literal translation. The recommendations we offer here include considering the most appropriate translation approach for a specific genre and purpose.


Essential literature for the chiropractic profession: Results and implementation challenges from a survey of international chiropractic faculty.
Scientific literature applicable to chiropractic practice proliferates in quantity, quality, and source. Chiropractic is a worldwide profession and varies in scope between states or provinces and from country to country. It is logical to consider that the focus and emphasis of chiropractic education varies between programs as well. This original research study endeavored to determine "essential literature" recommended by chiropractic faculty. The purpose of this article is (1) to share our results and (2) to promote discussion and explore means for future collaboration of chiropractic faculty through a worldwide platform. A 2-phase recruitment occurred initially at the institutional level and subsequently at the faculty level. A Web-based survey used qualitative data collection methods to gather bibliographic citations. Descriptive statistics were calculated for demographics, and citation responses were ranked per number of recommendations, grouped into categories, and tabulated per journal source and publication date. Forty-one chiropractic programs were contacted, resulting in 30 participating chiropractic programs (16 US and 14 international). Forty-five faculty members completed the entire survey, submitting 126 peer-reviewed publications and 25 additional citations. Readings emphasized clinical management of spine pain, the science of spinal manipulation, effectiveness of manual therapies, teaching of chiropractic techniques, outcomes assessments, and professional issues. A systematic approach to surveying educators in international chiropractic institutions was accomplished. The results of the survey provide a list of essential literature for the chiropractic profession. We recommend establishing a chiropractic faculty registry for improved communication and collaboration.


The paradoxical role of thioredoxin on oxidative stress and aging.
In spite of intensive study, there is still controversy about the free radical or oxidative stress theory of aging, particularly in mammals. Our laboratory has conducted the first detailed studies on the role of thioredoxin (Trx) in the cytosol (Trx1) and in mitochondria (Trx2) on oxidative stress and aging using unique mouse models either overexpressing or down-regulating Trx1 or Trx2. The results generated from our lab and others indicate that: (1) oxidative stress and subsequent changes in signaling pathways could have different pathophysiological impacts at different stages of life; (2) changes in redox-sensitive signaling controlled by levels of oxidative stress and redox state could play more important roles in pathophysiology than accumulation of oxidative damage; (3) changes in oxidative stress and redox state in different cellular compartments (cytosol, mitochondria, or nucleus) could play different roles in pathophysiology during aging, and their combined effects show more impact on aging than changes in either oxidative stress or redox state alone; and (4) the roles of oxidative stress and redox state could have different pathophysiological consequences in different organs/tissues/cells or pathophysiological conditions. To critically test the role of oxidative stress on aging and investigate changes in redox-sensitive signaling pathways, further study is required.


[Rehabilitation networking illustrated by case management after occupational accidents].
No net without a spider! After work accidents the victims can rely on the infrastructure created by the German accident insurance scheme (Berufsgenossenschaften). A surgeon, a so-called transit physician, is responsible after acute treatments also for all phases of rehabilitation. A Case Manager (Berufshelfer), an employee of the Berufsgenossenschaften, advises the victim in all matters, including vocational rehabilitation and personal concerns. Both factors combine to form a network that orientates on the social needs of the injured worker, on the financial tasks of the insurance agency and on incentives to the rehabilitation facilities. The goals comprise "rehabilitation before compensation" and "job retention instead of job loss".


Efficacy and safety of avanafil for treating erectile dysfunction: results of a multicentre, randomized, double-blind, placebo-controlled trial.
Study Type--Therapy (RCT) Level of Evidence 1b. What's known on the subject? and What does the study add? Avanafil is a potent selective phosphodiesterase type 5 (PDE5) inhibitor newly developed for treating erectile dysfunction (ED). Preclinical and clinical phase I studies showed that avanafil had enhanced selectivity, faster onset of action and a favourable side-effect profile relative to currently available PDE5 inhibitors. As the result of phase III clinical trial for the efficacy and safety of avanafil treatment (100 and 200 mg), taken as needed over a period of 12 weeks, in Korean patients with ED, avanafil is an effective and well-tolerated therapy for ED of broad-spectrum aetiology and severity. • To evaluate the efficacy and safety of avanafil, a new potent selective phosphodiesterase type 5 (PDE5) inhibitor, in patients with erectile dysfunction (ED). • The present study was a multicentre, randomized, double-blind, placebo-controlled, fix-dosed phase three clinical trial involving 200 patients with ED. • The subjects were treated with placebo or avanafil (100 or 200 mg) for 12 weeks and were asked to complete the International Index of Erectile Function (IIEF), the Sexual Encounter Profile (SEP) diary, and the Global Assessment Questionnaire (GAQ). • The primary outcome variable was the change from baseline for IIEF erectile function domain (EFD) score. • The secondary outcome variables were SEP Q2 and Q3, the shift to normal rate (EFD ≥ 26), and response to the GAQ. • Compared with placebo, patients who took 100 or 200 mg of avanafil had significantly improved IIEF-EFD score. • There were similar results when comparing Q2 and Q3 in the SEP diary and the GAQ. • Flushing was the most common treatment-related adverse event. • Most adverse events were transient and mild or moderate in severity. • Avanafil is an effective and well-tolerated therapy for ED of broad-spectrum aetiology and severity.


The contribution of serum osteoprotegerin to bone mass and vertebral fractures in postmenopausal women.
Regulation of osteoclastic activity is critical for understanding bone loss associated with the postmenopausal period. In vitro and animal studies have revealed the role of OPG as a decoy receptor that neutralizes the effect of RANKL on the differentiation and activation of osteoclasts. However, the role of the OPG-RANKL system in postmenopausal osteoporosis is controversial. Thus, the aim of this study was to investigate the relationship among circulating levels of OPG, RANKL, bone turnover markers (BTM), bone mineral density (BMD) and vertebral fractures in postmenopausal women. We determined anthropometric parameters, circulating OPG and RANKL, BTM, estradiol, BMD by dual X-ray absorptiometry at the lumbar spine (LS) and femoral neck (FN), and pre-existing vertebral fractures in 206 ambulatory postmenopausal women of a mean age of 62 years (SD 7). Circulating OPG was significantly related to age (r =0.158; P =0.023), years since menopause (r =0.167; P =0.016) and BMD (LS Z-score: r =0.240; P =0.001, FN Z-score: r =0.156; P =0.025). Over half of the women had undetectable RANKL (n =113; 54.9%). There were no significant differences in clinical variables, BTM or BMD among women with detectable vs. undetectable RANKL. OPG was found to be independently associated with osteoporosis (OR: 2.9, 1.4-5.9) and prevalent vertebral fractures (OR: 2.5, 1.2-5.4). We conclude that serum OPG levels are independently associated with bone mass and prevalent vertebral fractures in postmenopausal women.


ZAP-70 enhances migration of malignant B lymphocytes toward CCL21 by inducing CCR7 expression via IgM-ERK1/2 activation.
ZAP-70 in chronic lymphocytic leukemia (CLL) has been associated with enhanced B-cell receptor (BCR) signaling, survival, and migration. We investigated whether ZAP-70 can directly govern migration and the underlying mechanisms. In the ZAP-70 stably transfected Ramos cell line, IgM stimulation, but no IgD, enhanced phosphorylation of ERK1/2, Akt and Syk, and delayed IgM and CD79b internalization. In contrast, in the Raji cell line, where ZAP-70 was constitutively phosphorylated, ERK1/2, but not Akt, was phosphorylated, suggesting that MAPK pathway mediates ZAP-70 effects. BCR stimulation modulated the expression of CCR7, CXCR4, CXCR5, CD44, CD49d, and CD62L, which were up-regulated in ZAP-70-positive CLL primary subclones. The most dramatic change after BCR engagement in ZAP-70-transfected cells was CCR7 up-regulation, this being impaired by ERK1/2 inhibition and translating into both increased signaling and migration toward CCL21. Primary CLL subclones with high ZAP-70 expression showed increased migration toward CCL21. In conclusion, ZAP-70 ectopic expression led to enhanced BCR signaling after IgM stimulation and increased the expression of CCR7 predominantly via ERK1/2, increasing the response and migration toward CCL21. In primary CLL samples, cellular subsets with high ZAP-70 expression had increased expression of adhesion molecules and chemokine receptors in addition to an enhanced ability to migrate toward CCL21.


Working Memory Training in Norwegian Children with Cerebral Palsy (CP) Show Minimal Evidence of Near and No Far Transfer Effects.
In children with cerebral palsy (CP), learning disabilities are well documented, and impairments in executive functions, such as attention, inhibition, shifting and working memory, represent significant burdens on patients, their families and the society. The aim of this study was to evaluate whether Cogmed RM working memory training could improve working memory in children with CP and investigate whether increased working memory capacity would generalize to other cognitive functions. Twenty-eight children completed the training and the results were compared to a waitlist control group (n = 32). The results yielded three main findings. First, children with CP improved with practice on trained working memory tasks. Second, the intervention group showed minimal near transfer effects to non-trained working memory tasks. Third, no effects on cognitive and behavioral far transfer measures were found.


Periostin: A Matricellular Protein With Multiple Functions in Cancer Development and Progression.
Tumor microenvironment is considered nowadays as one of the main players in cancer development and progression. Tumor microenvironment is highly complex and consists of non-tumor cells (i.e., cancer-associated fibroblast, endothelial cells, or infiltrating leukocytes) and a large list of extracellular matrix proteins and soluble factors. The way that microenvironment components interact among them and with the tumor cells is very complex and only partially understood. However, it is now clear that these interactions govern and modulate many of the cancer hallmarks such as cell proliferation, the resistance to death, the differentiation state of tumor cells, their ability to migrate and metastasize, and the immune response against tumor cells. One of the microenvironment components that have emerged in the last years with strength is a heterogeneous group of multifaceted proteins grouped under the name of matricellular proteins. Matricellular proteins are a family of non-structural matrix proteins that regulate a variety of biological processes in normal and pathological situations. Many components of this family such as periostin (POSTN), osteopontin (SPP1), or the CNN family of proteins have been shown to regulate key aspect of tumor biology, including proliferation, invasion, matrix remodeling, and dissemination to pre-metastatic niches in distant organs. Matricellular proteins can be produced by tumor cells themselves or by tumor-associated cells, and their synthesis can be affected by intrinsic and/or extrinsic tumor cell factors. In this review, we will focus on the role of POSTN in the development and progression of cancer. We will describe their functions in normal tissues and the mechanisms involved in their regulation. We will analyze the tumors in which their expression is altered and their usefulness as a biomarker of tumor progression. Finally, we will speculate about future directions for research and therapeutic approaches targeting POSTN.


Does endoscopic ultrasound-guided biliary drainage really have clinical impact?
The well established, gold standard method for treatment of obstructive jaundice involves biliary drainage under endoscopic retrograde cholangiopancreatography (ERCP) performed by pancreatobiliary endoscopists. Recently, interventions using endoscopic ultrasound (EUS) have been developed not only for obtaining cytological and histological diagnosis, but also for biliary drainage as alternative method. EUS-guided biliary drainage (EUS-BD) was first reported by Giovannini et al. EUS-BD broadly includes EUS-guided rendezvous technique, EUS-guided choledochoduodenostomy, and EUS-guided hepaticogastrostomy. More recently, EUS-guided antegrade stenting and EUS-guided gallbladder drainage have also been reported. many case reports, series, and retrospective studies on EUS-BD have been reported. However, because prospective studies and comparisons between the different biliary drainage methods have not been reported, the technical success, functional success, adverse events, and stent patency with long-term follow up of EUS-BD are still unclear. Therefore, prospective, randomized controlled studies addressing these issues are needed. Despite this, EUS-BD undoubtedly is clinically useful as an alternative biliary drainage method. EUS-BD has the potential to be a first-line biliary drainage method instead of ERCP if results of clinical trials are favorable and the technique is simplified.


Myocardial fibrosis and ventricular remodeling in severe chronic aortic regurgitation.
Significant symptomatic chronic aortic regurgitation (AR) leads to considerable left ventricular remodeling at the expense of myocyte hypertrophy and extracellular matrix remodeling. The relevance of interstitial fibrosis concentration in these patients is unknown. We analyzed the degree of fibrosis in the left ventricle (LV) in symptomatic patients with AR submitted to surgical treatment, and its relationship with functional and anatomical characteristics. To evaluate myocardial fibrosis in chronic severe aortic regurgitation. Twenty-eight patients with chronic symptomatic AR (16 with normal LV function and 12 with LV dysfunction) were selected and assessed pre- and postoperatively by echocardiography. Functional capacity was measured using maximal oxygen consumption (VO2max) through the cardiopulmonary test. Myocardial fibrosis volume fraction (MFV) was quantified through endomyocardial biopsy performed in all patients during surgery. We compared the histopathologic results with a nine-patient control group. The mean age was 39 +/- 12 years, 75% of the patients were male, and the rheumatic etiology accounted for 84% of the cases. Twenty-five patients remained in FC l and ll at the end of the study, and there was a significant reduction of the LV diameters between the preoperative and late postoperative timepoints. Three deaths occurred but they were not related to postoperative ventricular dysfunction. The parameters of the cardiopulmonary test were similar between pre- and postoperative timepoints. MFV in patients with AR was significantly higher than in the control group (3.47 +/- 1.9% vs 0.82 +/- 0.96%, respectively, p=0.001). There was no statistical correlation among LV fibrosis and LV diameters, LVEF and MVO2. In patients with significant symptomatic AR, the presence of limited myocardial fibrosis was not associated with clinical, echocardiographic or functional complications.


The transverse and longitudinal elastic constants of pulp fibers in paper sheets.
Cellulose fibers are a major industrial input, but due to their irregular shape and anisotropic material response, accurate material characterization is difficult. Single fiber tensile testing is the most popular way to estimate the material properties of individual fibers. However, such tests can only be performed along the axis of the fiber and are associated with problems of enforcing restraints. Alternative indirect approaches, such as micro-mechanical modeling, can help but yield results that are not fully decoupled from the model assumptions. Here, we compare these methods with nanoindentation as a method to extract elastic material constants of the individual fibers. We show that both the longitudinal and the transverse elastic modulus can be determined, additionally enabling the measurement of fiber properties in-situ inside a sheet of paper such that the entire industrial process history is captured. The obtained longitudinal modulus is comparable to traditional methods for larger indents but with a strongly increased scatter as the size of the indentation is decreased further.


Optical attenuation coefficient in individual ZnO nanowires.
Attenuation coefficient measurements for the propagation of bandedge luminescence are made on individual ZnO nanowires by combining the localized excitation capability of a scanning electron microscope (SEM) with near-field scanning optical microscopy (NSOM) to record the distribution and intensity of wave-guided emission. Measurements were made for individual nanostructures with triangular cross-sections ranging in diameter from 680 to 2300 nm. The effective attenuation coefficient shows an inverse dependence on nanowire diameter (d(-1)), indicating scattering losses due to non-ideal waveguiding behavior.


Transurethral electrovaporization of the prostate: one-year experience.
To determine the safety and efficacy of transurethral electrovaporization of the prostate (TVP) in men with lower urinary tract symptoms. A prospective trial of 114 consecutive patients who underwent TVP since August 1994 was conducted. The mean follow-up period was 12.3 months. Parameters evaluated included American Urological Association symptom score (Sx), peak urinary flow rate (Qmax), operative time, postoperative catheterization time, length of hospital stay, and loss of days from work. Of the 109 men available for follow-up, Sx decreased from 16.7 to 7.3, 6.5, 6.3, and 5.4 at 3, 6, 12, and 18 months, respectively (P < 0.001), whereas Qmax increased from 7.9 to 14.8, 15.6, 16.7, and 16.5 mL/s at 3, 6, 12, and 18 months, respectively (P < 0.001). Mean catheterization time was 10.4 hours; mean hospital period was 0.9 days, and average loss of days from work was 5.6. Complications included intermittent postoperative hematuria in 65 patients (57%). Clot retention in 6 (5%), and bulbar urethral stricture in 2 (2%). Of 74 men who were potent preoperatively, none had postoperative erectile dysfunction; retrograde ejaculation was noted in 62 (84%). Significant postoperative irritative symptoms were reported in 10 men (9%). On the basis of 1-year follow-up data, this study demonstrates that TVP is a safe and effective modality for treating lower urinary tract symptoms. However, longer, prospective, blinded studies are needed to determine efficacy relative to transurethral resection of the prostate.


Bad is a BH3 domain-containing protein that forms an inactivating dimer with Bcl-XL.
The Bcl-2 related protein Bad is a promoter of apoptosis and has been shown to dimerize with the anti-apoptotic proteins Bcl-2 and Bcl-XL. Overexpression of Bad in murine FL5.12 cells demonstrated that the protein not only could abrogate the protective capacity of coexpressed Bcl-XL but could accelerate the apoptotic response to a death signal when it was expressed in the absence of exogenous Bcl-XL. Using deletion analysis, we have identified the minimal domain in the murine Bad protein that can dimerize with Bcl-xL. A 26-amino-acid peptide within this domain, which showed significant homology to the alpha-helical BH3 domains of related apoptotic proteins like Bak and Bax, was found to be necessary and sufficient to bind Bcl-xL. To determine the role of dimerization in regulating the death-promoting activity of Bad and the death-inhibiting activity of Bcl-xL, mutations within the hydrophobic BH3-binding pocket in Bcl-xL that eliminated the ability of Bcl-xL to form a heterodimer with Bad were tested for the ability to promote cell survival in the presence of Bad. Several of these mutants retained the ability to impart protection against cell death regardless of the level of coexpressed Bad protein. These results suggest that BH3-containing proteins like Bad promote cell death by binding to antiapoptotic members of the Bcl-2 family and thus inhibiting their survival promoting functions.


Polarization-sensitive spectral-domain optical coherence tomography using a multi-line single camera spectrometer.
We describe a polarization sensitive spectral domain optical coherence tomography technique based on a single camera spectrometer that includes a multiplexed custom grating, camera lenses, and a high-speed three-line CCD camera. Two orthogonally polarized beams could be separately taken by two lines of the camera as a result of vertically different incident angles. The system could provide the imaging capabilities of a full camera speed and increased measurable depth. The proposed optical coherence tomography system could make a distinction between the normal muscle and cancerous tissue from the chest of a DSred GFP mouse and the OCT images were compared with those of in vivo confocal microscopy.


Celecoxib plus hormone therapy versus hormone therapy alone for hormone-sensitive prostate cancer: first results from the STAMPEDE multiarm, multistage, randomised controlled trial.
Long-term hormone therapy alone is standard care for metastatic or high-risk, non-metastatic prostate cancer. STAMPEDE--an international, open-label, randomised controlled trial--uses a novel multiarm, multistage design to assess whether the early additional use of one or two drugs (docetaxel, zoledronic acid, celecoxib, zoledronic acid and docetaxel, or zoledronic acid and celecoxib) improves survival in men starting first-line, long-term hormone therapy. Here, we report the preplanned, second intermediate analysis comparing hormone therapy plus celecoxib (arm D) with hormone therapy alone (control arm A). Eligible patients were men with newly diagnosed or rapidly relapsing prostate cancer who were starting long-term hormone therapy for the first time. Hormone therapy was given as standard care in all trial arms, with local radiotherapy encouraged for newly diagnosed patients without distant metastasis. Randomisation was done using minimisation with a random element across seven stratification factors. Patients randomly allocated to arm D received celecoxib 400 mg twice daily, given orally, until 1 year or disease progression (including prostate-specific antigen [PSA] failure). The intermediate outcome was failure-free survival (FFS) in three activity stages; the primary outcome was overall survival in a subsequent efficacy stage. Research arms were compared pairwise against the control arm on an intention-to-treat basis. Accrual of further patients was discontinued in any research arm showing safety concerns or insufficient evidence of activity (lack of benefit) compared with the control arm. The minimum targeted activity at the second intermediate activity stage was a hazard ratio (HR) of 0·92. This trial is registered with ClinicalTrials.gov, number NCT00268476, and with Current Controlled Trials, number ISRCTN78818544. 2043 patients were enrolled in the trial from Oct 17, 2005, to Jan 31, 2011, of whom 584 were randomly allocated to receive hormone therapy alone (control group; arm A) and 291 to receive hormone therapy plus celecoxib (arm D). At the preplanned analysis of the second intermediate activity stage, with 305 FFS events (209 in arm A, 96 in arm D), there was no evidence of an advantage for hormone therapy plus celecoxib over hormone therapy alone: HR 0·94 (95% CI 0·74-1·20). [corrected]. 2-year FFS was 51% (95% CI 46-56) in arm A and 51% (95% CI 43-58) in arm D. There was no evidence of differences in the incidence of adverse events between groups (events of grade 3 or higher were noted at any time in 123 [23%, 95% CI 20-27] patients in arm A and 64 [25%, 19-30] in arm D). The most common grade 3-5 events adverse effects in both groups were endocrine disorders (55 [11%] of patients in arm A vs 19 [7%] in arm D) and musculoskeletal disorders (30 [6%] of patients in arm A vs 15 [6%] in arm D). The independent data monitoring committee recommended stopping accrual to both celecoxib-containing arms on grounds of lack of benefit and discontinuing celecoxib for patients currently on treatment, which was endorsed by the trial steering committee. Celecoxib 400 mg twice daily for up to 1 year is insufficiently active in patients starting hormone therapy for high-risk prostate cancer, and we do not recommend its use in this setting. Accrual continues seamlessly to the other research arms and follow-up of all arms will continue to assess effects on overall survival. Cancer Research UK, Pfizer, Novartis, Sanofi-Aventis, Medical Research Council (London, UK).


Analytically monitored digestion of silver nanoparticles and their toxicity on human intestinal cells.
Orally ingested nanoparticles may overcome the gastrointestinal barrier, reach the circulatory system, be distributed in the organism and cause adverse health effects. However, ingested nanoparticles have to pass through different physicochemical environments, which may alter their properties before they reach the intestinal cells. In this study, silver nanoparticles are characterised physicochemically during the course of artificial digestion to simulate the biochemical processes occurring during digestion. Their cytotoxicity on intestinal cells was investigated using the Caco-2 cell model. Using field-flow fractionation combined with dynamic light scattering and small-angle X-ray scattering, the authors found that particles only partially aggregate as a result of the digestive process. Cell viabilities were determined by means of CellTiter-Blue® assay, 4',6-diamidino-2-phenylindole-staining and real-time impedance. These measurements reveal small differences between digested and undigested particles (1-100 µg/ml or 1-69 particles/cell). The findings suggest that silver nanoparticles may indeed overcome the gastrointestinal juices in their particulate form without forming large quantities of aggregates. Consequently, the authors presume that the particles can reach the intestinal epithelial cells after ingestion with only a slight reduction in their cytotoxic potential. The study indicates that it is important to determine the impact of body fluids on the nanoparticles of interest to provide a reliable interpretation of their nano-specific cytotoxicity testing in vivo and in vitro.


Decision-making competence and attempted suicide.
The propensity of people vulnerable to suicide to make poor life decisions is increasingly well documented. Do they display an extreme degree of decision biases? The present study used a behavioral-decision approach to examine the susceptibility of low-lethality and high-lethality suicide attempters to common decision biases that may ultimately obscure alternative solutions and deterrents to suicide in a crisis. We assessed older and middle-aged (42-97 years) individuals who made high-lethality (medically serious) (n = 31) and low-lethality suicide attempts (n = 29). Comparison groups included suicide ideators (n = 30), nonsuicidal depressed participants (n = 53), and psychiatrically healthy participants (n = 28). Attempters, ideators, and nonsuicidal depressed participants had nonpsychotic major depression (DSM-IV criteria). Decision biases included sunk cost (inability to abort an action for which costs are irrecoverable), framing (responding to superficial features of how a problem is presented), underconfidence/overconfidence (appropriateness of confidence in knowledge), and inconsistent risk perception. Data were collected between June 2010 and February 2014. Both high- and low-lethality attempters were more susceptible to framing effects as compared to the other groups included in this study (P ≤ .05, ηp2 = 0.06). In contrast, low-lethality attempters were more susceptible to sunk costs than both the comparison groups and high-lethality attempters (P ≤ .01, ηp2 = 0.09). These group differences remained after accounting for age, global cognitive performance, and impulsive traits. Premorbid IQ partially explained group differences in framing effects. Suicide attempters' failure to resist framing may reflect their inability to consider a decision from an objective standpoint in a crisis. Failure of low-lethality attempters to resist sunk cost may reflect their tendency to confuse past and future costs of their behavior, lowering their threshold for acting on suicidal thoughts.


Analogs of tetrahydroisoquinoline natural products that inhibit cell migration and target galectin-3 outside of its carbohydrate-binding site.
Cell migration is central to a number of normal and disease processes. Small organic molecules that inhibit cell migration have potential as both research probes and therapeutic agents. We have identified two tetrahydroisoquinoline natural product analogs with antimigratory activities on Madin-Darby canine kidney epithelial cells: a semisynthetic derivative of quinocarmycin (also known as quinocarcin), DX-52-1, and a more complex synthetic molecule, HUK-921, related to the naphthyridinomycin family. It has been assumed that the cellular effects of reactive tetrahydroisoquinolines result from the alkylation of DNA. We have reported previously that the primary target of DX-52-1 relevant to cell migration appears to be the membrane-cytoskeleton linker protein radixin. Here we extend the analysis of the protein targets of DX-52-1, reporting that the multifunctional carbohydrate-binding protein galectin-3 is a secondary target of DX-52-1 that may also be relevant to the antimigratory effects of both DX-52-1 and HUK-921. All known inhibitors of galectin-3 target its beta-galactoside-binding site in the carbohydrate recognition domain. However, we found that DX-52-1 and HUK-921 bind galectin-3 outside of its beta-galactoside-binding site. Intriguingly HUK-921, although a less potent inhibitor of cell migration than DX-52-1, had far greater selectivity for galectin-3 over radixin, exhibiting little binding to radixin, both in vitro and in cells. Overexpression of galectin-3 in cells led to a dramatic increase in cell adhesion on different extracellular matrix substrata as well as changes in cell-cell adhesion and cell motility. Galectin-3-overexpressing cells had greatly reduced sensitivity to DX-52-1 and HUK-921, and these compounds caused a change in localization of the overexpressed galectin-3 and reversion of the cells to a more normal morphology. The converse manipulation, RNA interference-based silencing of galectin-3 expression, resulted in reduced cell-matrix adhesion and cell migration. In aggregate, the data suggest that DX-52-1 and HUK-921 inhibit a carbohydrate binding-independent function of galectin-3 that is involved in cell migration.