Efficacy and Safety of Nivolumab Alone or in Combination With Ipilimumab in Patients With Mucosal Melanoma: A Pooled Analysis.
Purpose Mucosal melanoma is an aggressive malignancy with a poor response to conventional therapies. The efficacy and safety of nivolumab (a programmed death-1 checkpoint inhibitor), alone or combined with ipilimumab (a cytotoxic T-lymphocyte antigen-4 checkpoint inhibitor), have not been reported in this rare melanoma subtype. Patients and Methods Data were pooled from 889 patients who received nivolumab monotherapy in clinical studies, including phase III trials; 86 (10%) had mucosal melanoma and 665 (75%) had cutaneous melanoma. Data were also pooled for patients who received nivolumab combined with ipilimumab (n = 35, mucosal melanoma; n = 326, cutaneous melanoma). Results Among patients who received nivolumab monotherapy, median progression-free survival was 3.0 months (95% CI, 2.2 to 5.4 months) and 6.2 months (95% CI, 5.1 to 7.5 months) for mucosal and cutaneous melanoma, with objective response rates of 23.3% (95% CI, 14.8% to 33.6%) and 40.9% (95% CI, 37.1% to 44.7%), respectively. Median progression-free survival in patients treated with nivolumab combined with ipilimumab was 5.9 months (95% CI, 2.8 months to not reached) and 11.7 months (95% CI, 8.9 to 16.7 months) for mucosal and cutaneous melanoma, with objective response rates of 37.1% (95% CI, 21.5% to 55.1%) and 60.4% (95% CI, 54.9% to 65.8%), respectively. For mucosal and cutaneous melanoma, respectively, the incidence of grade 3 or 4 treatment-related adverse events was 8.1% and 12.5% for nivolumab monotherapy and 40.0% and 54.9% for combination therapy. Conclusion To our knowledge, this is the largest analysis of data for anti-programmed death-1 therapy in mucosal melanoma to date. Nivolumab combined with ipilimumab seemed to have greater efficacy than either agent alone, and although the activity was lower in mucosal melanoma, the safety profile was similar between subtypes.


Simple Neurectomy Versus Neurectomy With Intramuscular Implantation for Interdigital Neuroma: A Comparative Study.
Simple neurectomy is a standard treatment of interdigital nerve neuroma after failure of conservative treatment. Recently, neurectomy with intramuscular implantation of the proximal nerve stump has been proposed as a safe and effective alternative method providing significant pain improvement. However, there remains little evidence supporting one technique over the other. The purpose of this study was to compare functional outcomes and complications of simple neurectomy versus neurectomy with intramuscular implantation. Retrospective chart review along with prospectively collected data of 99 consecutive patients (105 feet with 118 neuromas) who were diagnosed with interdigital neuroma of the foot and underwent simple neurectomy (66 patients / 72 feet / 78 neuromas) and neurectomy with intramuscular implantation of proximal nerve stump into intrinsic muscle of foot (33 patients / 33 feet / 40 neuromas) between 2000 and 2013. The minimum follow-up to be included in the study was 6 months for both techniques (mean = 44.6 months, range = 6 to 150 months for simple neurectomy; and mean = 19.3 months, range = 6 to 66 months for neurectomy with intramuscular implantation of proximal nerve stump into the intrinsic muscle). The primary outcomes were Foot Function Index (FFI); pain, disability, activity limitation, and total score, Short Form-36 (SF-36: physical and mental component scores); and visual analog scale (VAS). Secondary outcomes included operative time and complications. Pre- and postoperative SF-36, and FFI, and pain (VAS) scores were obtained and compared using a paired t test. An independent t test was used to assess the functional outcomes and operative time between the 2 groups, and a chi-square test was used to compare the complications between the 2 techniques. Both groups demonstrated significant improvement of postoperative functional outcomes (FFI, SF-36, and VAS; P < .001, all) compared to the preoperative period. Neurectomy with intramuscular implantation demonstrated significant improvement of pain compared to simple neurectomy as measured with VAS (P = .002); however, the operative time was significantly longer than the simple neurectomy technique (P = .001). The rest of the functional outcomes measured were comparable between the 2 techniques. Complications in both simple neurectomy and implantation techniques were persistent pain (11.5% vs. 2.5%, P = .07), revision rate (5.1% vs. 0.0%, P = .08), and painful scar (5.1% vs. 5.0%, P = .83), respectively, but it did not reach statistical significance (P > .05, all). Both simple neurectomy and neurectomy with intramuscular implantation demonstrated significant improvement in terms of functional outcomes as measured with the FFI, SF-36, and VAS in patients with interdigital neuroma. Although requiring a longer operative time, neurectomy with intramuscular implantation technique might offer superior pain relief with comparable complications to the simple neurectomy technique.


Birth outcomes for Arabic-named women in California before and after September 11.
Persons who were perceived to be Arabs experienced a period of increased harassment, violence, and workplace discrimination in the United States in the weeks immediately following September 11, 2001. Drawing on prior studies that have hypothesized that experiences of discrimination increase the risk of preterm birth and low birth weight, this study explores whether there was an effect on birth outcomes for pregnant women of Arab descent. California birth certificate data are used to determine the relative risk of poor birth outcomes by race, ethnicity, and nativity for women who gave birth in the six months following September 2001, compared with the same six calendar months one year earlier. The relative risk of poor birth outcomes was significantly elevated for Arabic-named women and not for any of the other groups.


Household risk factors for colonization with multidrug-resistant Staphylococcus aureus isolates.
Antimicrobial resistance, particularly in pathogens such as methicillin-resistant Staphylococcus aureus (MRSA), limits treatment options and increases healthcare costs. To understand patient risk factors, including household and animal contact, potentially associated with colonization with multidrug-resistant MRSA isolates, we performed a prospective study of case patients colonized with MRSA on admission to a rural tertiary care hospital. Patients were interviewed and antimicrobial resistance patterns were tested among isolates from admitted patients colonized with MRSA in 2009-10. Prevalence of resistance was compared by case-patient risk factors and length-of-stay outcome among 88 MRSA case patients. Results were compared to NHANES 2003-04. Overall prevalence of multidrug resistance (non-susceptibility to ≥ four antimicrobial classes) in MRSA nasal isolates was high (73%) and was associated with a 1.5-day increase in subsequent length of stay (p = 0.008). History of hospitalization within the past six months, but not antimicrobial use in the same time period, was associated with resistance patterns. Within a subset of working-age case patients without recent history of hospitalization, animal contact was potentially associated with multidrug resistance. History of hospitalization, older age, and small household size were associated with multidrug resistance in NHANES data. In conclusion, recent hospitalization of case patients was predictive of antimicrobial resistance in MRSA isolates, but novel risk factors associated with the household may be emerging in CA-MRSA case patients. Understanding drivers of antimicrobial resistance in MRSA isolates is important to hospital infection control efforts, relevant to patient outcomes and to indicators of the economic burden of antimicrobial resistance.


Daytime sleepiness in epilepsy patients with special attention to traffic accidents.
The present study examined clinical variables related to excessive daytime sleepiness (EDS) and sleep disorders in patients with epilepsy (PWE), with special focus on antiepileptic drugs (AEDs), to determine whether sleep-related problems in PWE are correlated with their involvement in traffic accidents. 325 PWE completed the Epworth Sleepiness Scale (ESS) and 322 the Pittsburgh Sleep Quality Index (PSQI). 239 PWE with a valid driver's license were requested to answer questions related to traffic accidents. The presence of focal seizures with impaired awareness, age, and administration of lacosamide were each shown to have a significant impact on ESS score. Furthermore, administrations of valproate and lacosamide, as well as sleep-promoting agents other than AEDs (SPA) had a significant impact on the presence of sleep disorder diagnosed with the PQSI. In view of traffic accidents in total, age and LEV had an impact on traffic accident occurrence. In view of an accident in association with an epileptic seizure, SPA was the only variable with a significant impact. As for a traffic accident not related to epileptic seizure, no factors were found to have a significant impact on that dependent variable. No correlation was found between ESS score and any of those 3 traffic accident groupings, which was also true for PSQI. Neither daytime sleepiness nor sleep disorder was found to be correlated with traffic accidents by PWE who drove. Furthermore, no AED was shown to be correlated with daytime sleepiness or increased risk of a traffic accident.


The use of X-ray fluorescence to detect lead contamination of carpeted surfaces.
The recognition of the hazards to young children of low-level lead intoxication and the widespread distribution of lead in the urban environment have resulted in massive federal, state, and local lead awareness and abatement programs. Two of the most significant exposure routes of lead to young children are the soils and dusts found within the child's home. Most state and federal lead abatement programs deal with lead-based paint contamination but often do not address the issue of soft-surface contamination, such as that of carpets, furniture, and draperies. Carpets can be a reservoir of contaminated soils and dusts; currently, there exists no standard method to test carpeted surfaces for lead contamination.This paper describes a study that uses X-ray fluorescence (XRF) to test carpeted surfaces for lead contamination. XRF technology is the standard technology used in lead-based paint testing and is known to be an accurate technique to test for lead in soils. This study uses a controlled laboratory atmosphere to evaluate this technology; the objectives are to determine: (1) a lower limit of detection for the instrument; and (2) whether soil loading levels can be differentiated by XRF using trace elements also present in the soil. Results indicate that XRF can easily differentiate soil loading levels (g soil/m(2) carpet). The lower limit of detection of soil lead concentration on the carpet is a function of both soil lead concentration and soil loading; therefore, lead loading (mg Pb/m(2)) is a better indicator of detection limit than soil lead concentration. Lead loading detection levels from 108-258 mg Pb/m(2) were obtained, as compared to a level of 10 000 mg/m(2) (1 mg/cm(2)) for lead on painted surfaces as required by theLead-Based Paint Poisoning Prevention Act.XRF technology has the potential to be a fast, inexpensive screening technique for the evaluation of lead contamination on carpeted surfaces.


Surgical Outcomes of Hepatocellular Carcinoma With Bile Duct Tumor Thrombus: A Korea-Japan Multicenter Study.
To identify optimal surgical methods and the risk factors for long-term survival in patients with hepatocellular carcinoma accompanied by macroscopic bile duct tumor thrombus (BDTT). Prognoses of patients with hepatocellular carcinoma accompanied by BDTT have been known to be poor. There have been significant controversies regarding optimal surgical approaches and risk factors because of the low incidence and small number of cases in previous reports. Records of 257 patients from 32 centers in Korea and Japan (1992-2014) were analyzed for overall survival and recurrence rate using the Cox proportional hazard model. Curative surgery was performed in 244 (94.9%) patients with an operative mortality of 5.1%. Overall survival and recurrence rate at 5 years was 43.6% and 74.2%, respectively. TNM Stage (P < 0.001) and the presence of fibrosis/cirrhosis (P = 0.002) were independent predictors of long-term survival in the Cox proportional hazards regression model. Both performing liver resection equal to or greater than hemihepatectomy and combined bile duct resection significantly increased overall survival [hazard ratio, HR = 0.61 (0.38-0.99); P = 0.044 and HR = 0.51 (0.31-0.84); P = 0.008, respectively] and decreased recurrence rate [HR = 0.59 (0.38-0.91); P = 0.018 and HR = 0.61 (0.42-0.89); P = 0.009, respectively]. Clinical outcomes were mostly influenced by tumor stage and underlying liver function, and the impact of BDTT to survival seemed less prominent than vascular invasion. Therefore, an aggressive surgical approach, including major liver resection combined with bile duct resection, to increase the chance of R0 resection is strongly recommended.


The role of positive/negative outcome expectancy and refusal self-efficacy of Internet use on Internet addiction among college students in Taiwan.
Based on Bandura's social cognitive theory, this study was designed to examine positive and negative outcome expectancy and refusal self-efficacy of Internet use and their contribution to Internet addiction among college students by using hierarchical multiple regression analyses in a cross-sectional study design. Schools were first stratified into technical or nontechnical colleges and then into seven majors. A cluster random sampling by department was further applied to randomly choose participants from each major. A representative sample of 4,456 college students participated in this study. The Outcome Expectancy and Refusal Self-Efficacy of Internet Use Questionnaire and the Chen Internet Addiction Scale were used to assess the cognitive factors and the levels of Internet addiction. Results showed that both positive outcome expectancy and negative outcome expectancy were significantly and positively correlated with Internet addiction, and refusal self-efficacy of Internet use was significantly and negatively related to Internet addiction. Further analyses revealed that refusal self-efficacy of Internet use directly and negatively predicted Internet addiction. Moreover, we discovered that positive outcome expectancy positively predicted Internet addiction via refusal self-efficacy of Internet use; however, surprisingly, negative outcome expectancy had both a direct and indirect positive relationship in predicting Internet addiction via the refusal self-efficacy of Internet use. These results give empirical evidence to verify the theoretical effectiveness of the three cognitive factors to Internet addiction and should be incorporated when designing prevention programs and strategies for Internet addicted college students.


The effects of contrast bathing and compression therapy on muscular performance.
Contrast bathing (CB) and compression garments (CG) are widely used to promote recovery. To evaluate CB and CG as regeneration strategies after exercise-induced muscle damage (EIMD). Baseline values of muscle soreness, serum creatine kinase (CK) and myoglobin (Mb), joint range of motion, limb girth, 10- or 30-m sprint, countermovement jump (CMJ), and five repetition maximum squat were completed by 26 young men who then undertook a resistance exercise challenge (REC) to induce EIMD: 6 x 10 parallel squats at 100% body weight with 5-s one repetition maximum eccentric squat superimposed onto each set. After the REC, subjects were separated into three intervention groups: CB, CG, and control (CONT). Forty-eight hours after REC, the subjects exercise performance was reassessed. CK and Mb were also measured +1, +24, and +48 h post-REC. CK was elevated at +24 h ( upward arrow140%; upward arrow161%; upward arrow270%), and Mb was elevated at +1 h ( upward arrow523%; upward arrow458%; upward arrow682%) in CB, CG, and CONT. Within-group large effect sizes for loge[CK] were found for CB at +24 h (0.80) and +48 h (0.84). Area under the [Mb] curve was lower in CB compared with CG and CONT (P < or = 0.05). At +48 h, significant differences from baseline were found in all groups for CMJ (CG, downward arrow5.1%; CB, downward arrow4.4%; CONT, downward arrow8.5%) and soreness ( upward arrow213%; upward arrow284%; upward arrow284%). Soreness transiently fell at +1 h compared with post-REC in the CB group. At +48 h, midthigh girth increased in CB ( upward arrow1.4%) and CONT ( upward arrow1.6%), whereas 30-m sprint time increased in CG ( upward arrow2%). No hierarchy of recovery effects was found. Neither contrast bathing nor compression acted to promote acute recovery from EIMD any more effectively than passive conditions, although contrast bathing may transiently attenuate postexercise soreness.


Neurohormones implicated in the control of Malpighian tubule secretion in plant sucking heteropterans: The stink bugs Acrosternum hilare and Nezara viridula.
Plant sucking heteropteran bugs feed regularly on small amounts of K(+)-rich plant material, in contrast to their hematophagous relatives which imbibe large volumes of Na(+)-rich blood. It was anticipated that this would be reflected in the endocrine control of Malpighian tubule (MT) secretion. To explore this, neuroendocrine factors known to influence MT secretion were tested on MT of the pentatomid plant sucking stink bugs, Acrosternum hilare and Nezara viridula, and the results compared with previously published data from Rhodnius prolixus. Serotonin had no effect on N. viridula MT, although it stimulates secretion by R. prolixus MT >1000-fold, and initiates a rapid diuresis to remove excess salt and water from the blood meal. Kinins had no effect on stink bug MT, but secretion was increased by Zoone-DH, a CRF-like peptide, although the response was a modest 2-3-fold acceleration compared with 1000-fold in R. prolixus. Native CAPA peptides, which have diuretic activity in dipteran flies, had antidiuretic activity in MT of the stink bug (Acrhi/Nezvi-CAPA-1 and -2), as previously shown with Rhopr-CAPA-2 in R. prolixus. The antidiuretic activity of Rhopr-CAPA-2 has been linked with terminating the rapid diuresis, but results with stink bugs suggest it is a general feature of heteropteran MT.


Synergy between repellents and non-pyrethroid insecticides strongly extends the efficacy of treated nets against Anopheles gambiae.
To manage the kdr pyrethroid-resistance in Anopheline malaria vectors, new compounds or new strategies are urgently needed. Recently, mixing repellents (DEET) and a non-pyrethroid insecticide (propoxur) was shown to be as effective as deltamethrin, a standard pyrethroid, under laboratory conditions, because of a strong synergy between the two compounds. In the present study, the interactions between two repellents (DEET and KBR 3023) and a non-pyrethroid insecticide (pyrimiphos methyl or PM) on netting were investigated. The residual efficacy and the inhibition of blood feeding conferred by these mixtures were assessed against Anopheles gambiae mosquitoes. DEET and KBR 3023 were mixed with pyrimiphos methyl (PM), a organophosphate (OP) insecticide. The performance of mono- and bi-impregnated nets against adult mosquitoes was assessed using a miniaturized, experimental hut system (laboratory tunnel tests) that allows expression of behavioural responses to insecticide, particularly the mortality and blood feeding effects. Both mixtures (PM+DEET and PM+KBR3023) induced 95% mortality for more than two months compared with less than one week for each compound used alone, then reflecting a strong synergy between the repellents and PM. A similar trend was observed with the blood feeding rates, which were significantly lower for the mixtures than for each component alone. Synergistic interactions between organophosphates and repellents may be of great interest for vector control as they may contribute to increase the residual life of impregnated materials and improve the control of pyrethroid-resistance mosquitoes. These results prompt the need to evaluate the efficacy of repellent/non-pyrethroid insecticide mixtures against field populations of An. gambiae showing high level of resistance to Ops and pyrethroids.


Olfactory horizontal basal cells demonstrate a conserved multipotent progenitor phenotype.
Stem cells of adult regenerative organs share a common goal but few established conserved mechanisms. Within the neural stem cell niche of the mouse olfactory epithelium, we identified a combination of extracellular matrix (ECM) receptors that regulate adhesion and mitosis in non-neural stem cells [intercellular adhesion molecule-1 (ICAM-1), beta1, beta4, and alpha-1, -3, and -6 integrins] and on horizontal basal cells (HBCs), candidate olfactory neuro-epithelial progenitors. Using ECM receptors as our guide, we recreated a defined microenvironment in vitro that mimics olfactory basal lamina and, when supplemented with epidermal growth factor, transforming growth factor alpha, and leukemia inhibitory factor, allows us to preferentially expand multiple clonal adherent colony phenotypes from individual ICAM-1+ and ICAM-1+/beta1 integrin+-selected HBCs. The most highly mitotic colony-forming HBCs demonstrate multipotency, spontaneously generating more ICAM-positive presumptive HBCs, a combination of olfactory neuroglial progenitors, and neurons of olfactory and potentially nonolfactory phenotypes. HBCs thus possess a conserved adhesion receptor expression profile similar to non-neural stem cells, preferential self-replication in an in vitro environment mimicking their in vivo niche, and contain subpopulations of cells that can produce multiple differentiated neuronal and glial progeny from within and beyond the olfactory system in vitro.


Interaction of glia with a compliant, microstructured silicone surface.
Soft bioengineered surfaces offer a route towards modulating the tissue responses to chronically implanted devices and may enhance their functionality. In this communication we fabricate microtopographically rich and mechanically compliant silicone surfaces for use in soft neural interfaces. We observe the interaction of primary rat microglia and astroglia with arrays of tall and short (4.7 and 0.5μm) vertically oriented polydimethylsiloxane (PDMS) micropillars and a flat PDMS surface in vitro. With the pillar size and spacing that we use (1.3μm diameter and 1.6μm edge to edge), glia are found to engulf and bend tall pillars. The cytoskeleton of cells adhering to the pillar arrays lacks actin stress fibers; instead we observe actin ring formations around individual pillars. Tall, but not short pillar arrays are inhibitory to migration and spreading for both microglia and astrocytes. When compared to a flat PDMS surface and short pillar arrays, tall micropillar arrays cause nearly a 2-fold decrease in proliferation rates for both cell types. The antimitotic properties of tall pillar arrays may be useful for reducing the density of the glial capsule around brain-implanted devices.


Deciphering the Microstructure and Energy-Level Splitting of Tm3+-Doped Yttrium Aluminum Garnet.
Thulium-doped yttrium aluminum garnet (Tm:YAG) is an important solid-state laser crystal. The energy-level splitting within it is still an unresolved problem. Here, we perform a theoretical study on the microstructure of Tm3+-doped YAG using the CALYPSO structure search method in conjunction with first-principles calculations. The calculated results show that the 4.16% doping concentration of Tm3+ impurity causes an obvious structural distortion of YAG crystal, forming an orthorhombic phase in C222 symmetry. On the basis of our developed WEPMD method, we obtain a new and complete set of free-ion and crystal field parameters by a good fit (with proper irreducible representations) to 69 observed energy levels and determine the exact energy-level splitting of Tm3+ in YAG. The calculated Stark levels and electric dipole transitions are in excellent agreement with the measured data and similar theoretical calculations. Some promising emission lines between 3F3, 3F2, 1D2, and 1I6 states are presented. These findings offer fundamental insights and practical tools for further exploration of the structural and electronic properties of other transition-metal-doped YAG crystal.


Cystic fibrosis: a clinical view.
Cystic fibrosis (CF), a monogenic disease caused by mutations in the CFTR gene on chromosome 7, is complex and greatly variable in clinical expression. Airways, pancreas, male genital system, intestine, liver, bone, and kidney are involved. The lack of CFTR or its impaired function causes fat malabsorption and chronic pulmonary infections leading to bronchiectasis and progressive lung damage. Previously considered lethal in infancy and childhood, CF has now attained median survivals of 50 years of age, mainly thanks to the early diagnosis through neonatal screening, recognition of mild forms, and an aggressive therapeutic attitude. Classical treatment includes pancreatic enzyme replacement, respiratory physiotherapy, mucolitics, and aggressive antibiotic therapy. A significant proportion of patients with severe symptoms still requires lung or, less frequently, liver transplantation. The great number of mutations and their diverse effects on the CFTR protein account only partially for CF clinical variability, and modifier genes have a role in modulating the clinical expression of the disease. Despite the increasing understanding of CFTR functioning, several aspects of CF need still to be clarified, e.g., the worse outcome in females, the risk of malignancies, the pathophysiology, and best treatment of comorbidities, such as CF-related diabetes or CF-related bone disorder. Research is focusing on new drugs restoring CFTR function, some already available and with good clinical impact, others showing promising preliminary results that need to be confirmed in phase III clinical trials.


Alterations in sarcoplasmic reticulum calcium-storing proteins in pressure-overload cardiac hypertrophy.
The alterations of intracellular calcium (Ca2+) homeostasis may be responsible for the contractile defects in pressure-overload cardiac hypertrophy. The Ca(2+)-adenosinetriphosphatase (ATPase) protein level of the sarcoplasmic reticulum (SR) is reduced in the hypertrophied or failing heart. However, it is not known whether Ca(2+)-storing proteins, including calsequestrin and calreticulin, are also altered during cardiac hypertrophy. We quantified SR Ca(2+)-regulatory proteins using Western blot analysis in left ventricular (LV) muscle isolated from sham-operated control rats (n = 6) and rats with pressure overload 4 wk after abdominal aortic constriction (n = 7). The contractile function of isolated LV myocytes, assessed by the sarcomere motion measured with laser diffraction, was depressed in aortic-constricted rats. The SR Ca(2+)-ATPase protein level was decreased to 56 +/- 9% (SE) of the control value in hypertrophied myocardium (P < 0.01). The calsequestrin protein level was not altered, whereas calreticulin was increased by 120 +/- 3% of the control value in aortic-constricted rats (P < 0.05). The alterations in SR Ca(2+)-regulatory proteins were equally observed in hypertrophied hearts even when the results were normalized using the amounts of myosin heavy chain proteins in each sample. Immunohistochemical staining of calsequestrin in the control heart showed cross striations at the Z lines, whereas calreticulin was hardly observed within myocytes but was intense within interstitial fibroblasts. In the hypertrophied heart, calreticulin was observed at the perinuclear region within the myocyte cytoplasm. These data indicate that pressure-overload cardiac hypertrophy causes the alterations in SR Ca(2+)-storing proteins as well as in Ca(2+)-ATPase, which may contribute to the contractile dysfunction of the hypertrophied myocytes.


Guanine nucleotides modulate the binding affinity of the oligopeptide chemoattractant receptor on human polymorphonuclear leukocytes.
The oligopeptide chemoattractant receptor on human polymorphonuclear leukocyte (PMN) membranes exists in two affinity states. Since guanine nucleotides regulate the binding affinity and transductional activity of several other types of receptors, we examined the effect of nucleotides on the binding of N-formyl-methionyl peptides to their receptors on human PMN membranes. The addition of guanylylimidodiphosphate (0.1 mM), a nonhydrolyzable derivative of guanosine triphosphate (GTP), to PMN membrane preparations reduced the fraction of high-affinity receptors detected in equilibrium binding studies from 21.3 +/- 0.13 to 11.8 +/- 0.05% (P less than 0.03), without altering the binding affinities. Since the total number of receptors remained unchanged, the effect of guanylylimidodiphosphate was to convert a portion of the receptors from the high-affinity state to the low-affinity state. At the maximal concentration of guanine nucleotide tested, approximately 50% of the high-affinity sites were converted to low-affinity sites. The findings obtained by equilibrium binding were supported by kinetic studies since the dissociation of the radiolabeled oligopeptide chemoattractant N-formyl-methionyl-leucyl-[3H]phenylalanine from PMN membranes was accelerated in the presence of guanine nucleotide. The effect of guanine nucleotides was reversed upon washing, indicating that affinity conversion is bidirectional. The guanine nucleotide effects were greatest with nonhydrolyzable derivatives of GTP followed by GTP then guanosine diphosphate. Neither guanosine monophosphate nor any adenine nucleotide tested had an effect on receptor binding. These data suggest a role for guanine nucleotides in the regulation of stimulus-receptor coupling of chemoattractant receptors on human PMN.


Estrogen receptor-ligand complexes measured by chip-based nanoelectrospray mass spectrometry: an approach for the screening of endocrine disruptors.
In the present report, a method based on chip-based nanoelectrospray mass spectrometry (nanoESI-MS) is described to detect noncovalent ligand binding to the human estrogen receptor alpha ligand-binding domain (hERalpha LBD). This system represents an important environmental interest, because a wide variety of molecules, known as endocrine disruptors, can bind to the estrogen receptor (ER) and induce adverse health effects in wildlife and humans. Using proper experimental conditions, the nanoESI-MS approach allowed for the detection of specific ligand interactions with hERalpha LBD. The relative gas-phase stability of selected hERalpha LBD-ligand complexes did not mirror the binding affinity in solution, a result that demonstrates the prominent role of hydrophobic contacts for stabilizing ER-ligand complexes in solution. The best approach to evaluate relative solution-binding affinity by nanoESI-MS was to perform competitive binding experiments with 17beta-estradiol (E2) used as a reference ligand. Among the ligands tested, the relative binding affinity for hERalpha LBD measured by nanoESI-MS was 4-hydroxtamoxifen approximately diethylstilbestrol > E2 >> genistein >> bisphenol A, consistent with the order of the binding affinities in solution. The limited reproducibility of the bound to free protein ratio measured by nanoESI-MS for this system only allowed the binding constants (K(d)) to be estimated (low nanomolar range for E2). The specificity of nanoESI-MS combined with its speed (1 min/ligand), low sample consumption (90 pmol protein/ligand), and its sensitivity for ligand (30 ng/mL) demonstrates that this technique is a promising method for screening suspected endocrine disrupting compounds and to qualitatively evaluate their binding affinity.


Orthognathic Treatment of Skeletal Class III Malocclusion with Severe Facial Asymmetry.
A 26-year, 9-month-old woman had chief complaints of mandibular protrusion and facial asymmetry. Extraoral examination indicated mandibular deviation to the left side, severe facial asymmetry, and a concave profile. Because the patient had a vertical maxillary height difference and an occlusal plane cant together with maxillary retrusion, a differential downgraft and advancement surgery with Lefort I osteotomy was planned. To correct the facial asymmetry and mandibular protrusion, concurrent bilateral sagittal split osteotomy was performed. Double-jaw surgical procedures, including maxillary and mandibular movements, are effective in correcting severe facial asymmetry and skeletal Class III malocclusion.


Sugar antennae for guidance signals: syndecans and glypicans integrate directional cues for navigating neurons.
Attractive and repulsive signals guide migrating nerve cells in all directions when the nervous system starts to form. The neurons extend thin processes, axons, that connect over wide distances with other brain cells to form a complicated neuronal network. One of the most fascinating questions in neuroscience is how the correct wiring of billions of nerve cells in our brain is controlled. Several protein families are known to serve as guidance cues for navigating neurons and axons. Nevertheless, the combinatorial potential of these proteins seems to be insufficient to sculpt the entire neuronal network and the appropriate formation of connections. Recently, heparan sulfate proteoglycans (HSPGs), which are present on the cell surface of neurons and in the extracellular matrix through which neurons and axons migrate, have been found to play a role in regulating cell migration and axon guidance. Intriguingly, the large number of distinct modifications that can be put onto the sugar side chains of these PGs would in principle allow for an enormous diversity of HSPGs, which could help in regulating the vast number of guidance choices taken by individual neurons. In this review, we will focus on the role of the cell surface HSPGs syndecan and glypican and specific HS modifications in promoting neuronal migration, axon guidance, and synapse formation.


Mental Imagery in Depression: Phenomenology, Potential Mechanisms, and Treatment Implications.
Mental imagery is an experience like perception in the absence of a percept. It is a ubiquitous feature of human cognition, yet it has been relatively neglected in the etiology, maintenance, and treatment of depression. Imagery abnormalities in depression include an excess of intrusive negative mental imagery; impoverished positive imagery; bias for observer perspective imagery; and overgeneral memory, in which specific imagery is lacking. We consider the contribution of imagery dysfunctions to depressive psychopathology and implications for cognitive behavioral interventions. Treatment advances capitalizing on the representational format of imagery (as opposed to its content) are reviewed, including imagery rescripting, positive imagery generation, and memory specificity training. Consideration of mental imagery can contribute to clinical assessment and imagery-focused psychological therapeutic techniques and promote investigation of underlying mechanisms for treatment innovation. Research into mental imagery in depression is at an early stage. Work that bridges clinical psychology and neuroscience in the investigation of imagery-related mechanisms is recommended.


Conservation of the critically endangered eastern Australian population of the grey nurse shark (Carcharias taurus) through cross-jurisdictional management of a network of marine-protected areas.
Between 2001 and 2009, 26 marine-protected areas (MPA) were established on the east Australian seaboard, at least in part, to manage human interactions with a critically endangered population of grey nurse shark, Carcharias taurus. This network is spread across six MPA systems and includes all 19 sites outlined in the National Recovery Plan for C. taurus, though five sites remain open to some forms of fishing. The reserve network has complex cross-jurisdictional management, as the sharks occur in waters controlled by the Australian states of New South Wales (NSW) and Queensland, as well as by the Commonwealth (Federal) government. Jurisdiction is further complicated by fisheries and conservation departments both engaging in management activities within each state. This has resulted in protected area types that include IUCN category II equivalent zones in NSW, Queensland, and Commonwealth marine parks that either overlay or complement another large scaled network of protected sites called critical habitats. Across the network, seven and eight rule permutations for diving and fishing, respectively, are applied to this population of sharks. Besides sites identified by the recovery plan, additional sites have been protected as part of the general development of MPA networks. A case study at one of these sites, which historically was known to be occupied by C. taurus but had been abandoned, appears to shows re-establishment of an aggregation of juvenile and sub-adult sharks. Concurrent with the re-establishment of the aggregation, a local dive operator increased seasonal dive visitation rates at the site fourfold. As a precautionary measure, protection of abandoned sites, which includes nursery and gestating female habitats are options that may assist recovery of the east coast population of C. taurus.


"Time Traveling Is Just Too Dangerous" but Some Methods Are Worth Revisiting: The Advantages of Expected Loss Curves Over Cost-Effectiveness Acceptability Curves and Frontier.
Cost-effectiveness acceptability curves (CEACs) and the cost-effectiveness acceptability frontier (CEAF) are the recommended graphical representations of uncertainty in a cost-effectiveness analysis (CEA). Nevertheless, many limitations of CEACs and the CEAF have been recognized by others. Expected loss curves (ELCs) overcome these limitations by displaying the expected foregone benefits of choosing one strategy over others, the optimal strategy in expectation, and the value of potential future research all in a single figure. To revisit ELCs, illustrate their benefits using a case study, and promote their adoption by providing open-source code. We used a probabilistic sensitivity analysis of a CEA comparing 6 cerebrospinal fluid biomarker test-and-treat strategies in patients with mild cognitive impairment. We showed how to calculate ELCs for a set of decision alternatives. We used the probabilistic sensitivity analysis of the case study to illustrate the limitations of currently recommended methods for communicating uncertainty and then demonstrated how ELCs can address these issues. ELCs combine the probability that each strategy is not cost-effective on the basis of current information and the expected foregone benefits resulting from choosing that strategy (ie, how much is lost if we recommended a strategy with a higher expected loss). ELCs display how the optimal strategy switches across willingness-to-pay thresholds and enables comparison between different strategies in terms of the expected loss. ELCs provide a more comprehensive representation of uncertainty and overcome current limitations of CEACs and the CEAF. Communication of uncertainty in CEA would benefit from greater adoption of ELCs as a complementary method to CEACs, the CEAF, and the expected value of perfect information.


Optimising activity pacing to promote a physically active lifestyle in medical settings: A narrative review informed by clinical and sports pacing research.
Regular exercise can improve wellbeing, yet data are scarce on how persons with disabling conditions may benefit from active lifestyles, due to the complexities of exercise prescription in this population. A novel medical concept for exercise prescription called activity pacing is the subject of this review, which identifies the potential for this strategy to optimally integrate existing medical and sports medicine approaches in promoting physical activity in persons with disabling conditions. Activity pacing is a goal-directed behavioural process of empowering people to confidently develop decision-making and planning over how and where to distribute available energy across daily activities. Currently, different conceptual traditions and definitions of pacing exist with important implications for the implementation and subsequent effectiveness of activity pacing. Application of activity pacing has mostly focused on symptom-reduction to improve self-regulatory behaviour, and less on physical activity stimulation for health and wellbeing. Further studies and greater connection between medical and sports science research are needed on how to adapt, tailor and optimise activity pacing to make it successful. The potential of activity pacing to increase physical activity and lessen fatigue could be a powerful tool to help fight the growing incidence of physical inactivity, particularly in persons with disabling conditions.


Generative supervised classification using Dirichlet process priors.
Choosing the appropriate parameter prior distributions associated to a given bayesian model is a challenging problem. Conjugate priors can be selected for simplicity motivations. However, conjugate priors can be too restrictive to accurately model the available prior information. This paper studies a new generative supervised classifier which assumes that the parameter prior distributions conditioned on each class are mixtures of Dirichlet processes. The motivations for using mixtures of Dirichlet processes is their known ability to model accurately a large class of probability distributions. A Monte Carlo method allowing one to sample according to the resulting class-conditional posterior distributions is then studied. The parameters appearing in the class-conditional densities can then be estimated using these generated samples (following bayesian learning). The proposed supervised classifier is applied to the classification of altimetric waveforms backscattered from different surfaces (oceans, ices, forests, and deserts). This classification is a first step before developing tools allowing for the extraction of useful geophysical information from altimetric waveforms backscattered from nonoceanic surfaces.


Pancreatic cystic tumors.
Cystic tumors of the pancreas are less frequent than other tumors in neoplastic pancreatic pathology, but in recent years the literature has reported an increasing number. After the first report by Becourt in 1830, cystic tumors were classified into 2 different types by Compagno and Oertel in 1978: benign tumors with glycogen-rich cells and mucinous cystic neoplasms with overt and latent malignancy. The WHO classification of exocrine tumors of the pancreas, published in 1996, is based on the histopathological features of the epithelial wall, which are the main factor in differential diagnosis with cystic lesions of the pancreas. Thanks to the knowledge acquired up to now, a surgical procedure is not always required because the therapeutic choice is conditioned by the correct classification of this heterogeneous group of tumors. Clinical signs are not really useful in the clinical work up, most patients have no symptoms and when clinical signs are present, they may help us to pinpoint the organ of origin but never to identify the type of pathology. In the last few years, the great improvement in imaging has enabled us not only to discriminate cystic from solid lesions, but also to identify the features of the lesions and label them preoperatively. More invasive diagnostic procedures such as fine needle aspiration and intracystic fluid tumor marker level are not really useful because they are not sensitive and the cystic wall can show different degrees of dysplasia and de-epithelialization. These are the reasons for sending the entire specimen to pathology. Good cooperation between surgeons, pathologists, radiologists and gastroenterologists is mandatory to increase the chances of making a proper diagnosis. Therefore, we must analyze all the information we have, such as age, sex, clinical history, location of the tumor and radiological features, in order to avoid the mistake of treating a cystic neoplasm as a benign lesion or as a pseudocyst, as described in the literature. Except for inoperable cases due to the critical condition of the patient or non-resectable lesions, surgical treatment differs with the diagnosis. Cystic tumors of the pancreas, therefore, are a heterogeneous group of tumors, with a real problem regarding differential diagnosis between neoplastic and inflammatory lesions. Even with a proper work up, some perplexity may remain about the nature of the lesion and in these cases the surgical procedure has a therapeutic value as well as playing a diagnostic role. The role of surgery is central in the treatment of these tumors because it could be curative when complete resection is possible. In this way, the lack of good therapeutic results with chemotherapy and radiotherapy force the surgeon to go ahead with the procedure. Intraductal papillary mucinous neoplasms represent a new and, from the epidemiological point of view, important chapter in the world of cystic tumors. The margin of resection is important and the surgeon has to be aware that in order to have a curative resection, total pancreatectomy is sometimes required. In the last few years the therapeutic approach has changed thanks to new knowledge of the biological behavior of these tumors. In fact, from a surgical approach in all cases, we are now discussing the possibility of a follow-up not only for asymptomatic serous cystadenomas but also for the little branch side intraductal papillary mucinous neoplasms (IPMNs) in critical patients. A follow-up could be planned even for solid pseudopapillary tumors but it seems risky to leave untreated big tumors in young patients without a certain diagnosis and with so few studies reported in the literature.


[Bridging the genomic approach and the neurodevelopmental and neurodenerative hypothesis of schizophrenia].
Schizophrenia is hypothesized as a neurodevelopmental and neurodegenerative disorder based on the following findings. 1. MRI studies have revealed brain structural abnormalities from the onset of schizophrenia and the progress of these structural abnormalities. 2. Histopathological studies have elucidated cytoarchitectural abnormalities in schizophrenic brains without gliosis. 3. Obstetric complications are one of the risk factors for schizophrenia. 4. Relapse of schizophrenia results in a deteriorating progress of the disorder. Furthermore, data from family, twin and adoption studies show evidence of a substantial genetic component in schizophrenia, Thus, a molecular genetic study combined with a neurodevelopmental and neurodegenerative hypothesis is required to elucidate the pathophysiology of schizophrenia. The positive association between neuregulin 1 and Icelandic schizophrenia that has been reproduced in Scottish and North European schizophrenia is one of the intriguing examples of this type of research. Neuregulin 1 regulates the cytoarchitecture of brain. Mice mutated for neuregulin 1 show a behavioral phenotype that overlaps with mouse models for schizophrenia. Furthermore, the behavioral phenotypes of the neuregulin 1 hypomorphs are reversible with clozapine. We also demonstrated a positive association between schizophrenia and a 5-HT5A receptor polymorphism, Pro15Ser, that may have role in cell differentiation in the brain.


Cognitive Reflection and the 2016 U.S. Presidential Election.
We present a large exploratory study ( N = 15,001) investigating the relationship between cognitive reflection and political affiliation, ideology, and voting in the 2016 Presidential Election. We find that Trump voters are less reflective than Clinton voters or third-party voters. However, much (although not all) of this difference was driven by Democrats who chose Trump. Among Republicans, conversely, Clinton and Trump voters were similar, whereas third-party voters were more reflective. Furthermore, although Democrats/liberals were somewhat more reflective than Republicans/conservatives overall, political moderates and nonvoters were least reflective, whereas libertarians were most reflective. Thus, beyond the previously theorized correlation between analytic thinking and liberalism, these data suggest three additional consequences of reflectiveness (or lack thereof) for political cognition: (a) facilitating political apathy versus engagement, (b) supporting the adoption of orthodoxy versus heterodoxy, and (c) drawing individuals toward candidates who share their cognitive style and toward policy proposals that are intuitively compelling.


A review of electroretinography waveforms and models and their application in the dog.
Electroretinography (ERG) is a commonly used technique to study retinal function in both clinical and research ophthalmology. ERG responses can be divided into component waveforms, analysis of which can provide insight into the health and function of different types and populations of retinal cells. In dogs, ERG has been used in the characterization of normal retinal function, as well as the diagnosis of retinal diseases and measuring effects of treatment. While many components of the recorded waveform are similar across species, dogs have several notable features that should be differentiated from the responses in humans and other animals. Additionally, modifications of standard protocols, such as changing flash frequency and stimulus color, and mathematical models of ERG waveforms have been used in studies of human retinal function but have been infrequently applied to visual electrophysiology in dogs. This review provides an overview of the origins and applications of ERG in addition to potential avenues for further characterization of responses in the dog.


Population Coding in an Innately Relevant Olfactory Area.
Different olfactory cortical regions are thought to harbor distinct sensory representations, enabling each area to play a unique role in odor perception and behavior. In the piriform cortex (PCx), spatially dispersed sensory inputs evoke activity in distributed ensembles of neurons that act as substrates for odor learning. In contrast, the posterolateral cortical amygdala (plCoA) receives hardwired inputs that may link specific odor cues to innate olfactory behaviors. Here we show that despite stark differences in the patterning of plCoA and PCx inputs, odor-evoked neural ensembles in both areas are equally capable of discriminating odors, and exhibit similar odor tuning, reliability, and correlation structure. These results demonstrate that brain regions mediating odor-driven innate behaviors can, like brain areas involved in odor learning, represent odor objects using distributive population codes; these findings suggest both alternative mechanisms for the generation of innate odor-driven behaviors and additional roles for the plCoA in odor perception.


18F-meta-fluorobenzylguanidine (18F-mFBG) to monitor changes in norepinephrine transporter expression in response to therapeutic intervention in neuroblastoma models.
Targeted radiotherapy with 131I-mIBG, a substrate of the human norepinephrine transporter (NET-1), shows promising responses in heavily pre-treated neuroblastoma (NB) patients. Combinatorial approaches that enhance 131I-mIBG tumour uptake are of substantial clinical interest but biomarkers of response are needed. Here, we investigate the potential of 18F-mFBG, a positron emission tomography (PET) analogue of the 123I-mIBG radiotracer, to quantify NET-1 expression levels in mouse models of NB following treatment with AZD2014, a dual mTOR inhibitor. The response to AZD2014 treatment was evaluated in MYCN amplified NB cell lines (Kelly and SK-N-BE(2)C) by Western blot (WB) and immunohistochemistry. PET quantification of 18F-mFBG uptake post-treatment in vivo was performed, and data correlated with NET-1 protein levels measured ex vivo. Following 72 h AZD2014 treatment, in vitro WB analysis indicated decreased mTOR signalling and enhanced NET-1 expression in both cell lines, and 18F-mFBG revealed a concentration-dependent increase in NET-1 function. AZD2014 treatment failed however to inhibit mTOR signalling in vivo and did not significantly modulate intratumoural NET-1 activity. Image analysis of 18F-mFBG PET data showed correlation to tumour NET-1 protein expression, while further studies are needed to elucidate whether NET-1 upregulation induced by blocking mTOR might be a useful adjunct to 131I-mIBG therapy.


Degraded attentional modulation of cortical neural populations in strabismic amblyopia.
Behavioral studies have reported reduced spatial attention in amblyopia, a developmental disorder of spatial vision. However, the neural populations in the visual cortex linked with these behavioral spatial attention deficits have not been identified. Here, we use functional MRI-informed electroencephalography source imaging to measure the effect of attention on neural population activity in the visual cortex of human adult strabismic amblyopes who were stereoblind. We show that compared with controls, the modulatory effects of selective visual attention on the input from the amblyopic eye are substantially reduced in the primary visual cortex (V1) as well as in extrastriate visual areas hV4 and hMT+. Degraded attentional modulation is also found in the normal-acuity fellow eye in areas hV4 and hMT+ but not in V1. These results provide electrophysiological evidence that abnormal binocular input during a developmental critical period may impact cortical connections between the visual cortex and higher level cortices beyond the known amblyopic losses in V1 and V2, suggesting that a deficit of attentional modulation in the visual cortex is an important component of the functional impairment in amblyopia. Furthermore, we find that degraded attentional modulation in V1 is correlated with the magnitude of interocular suppression and the depth of amblyopia. These results support the view that the visual suppression often seen in strabismic amblyopia might be a form of attentional neglect of the visual input to the amblyopic eye.


Targeting USP22 Suppresses Tumorigenicity and Enhances Cisplatin Sensitivity Through ALDH1A3 Downregulation in Cancer-Initiating Cells from Lung Adenocarcinoma.
Loss of monoubiquitination of histone H2B (H2Bub1) was found to be associated with poor-differentiation and enhanced malignancy of lung adenocarcinoma. This study investigated the association and impact of the ubiquitin-specific peptidase 22 (USP22), an H2Bub1 deubiquitinase, on stem cell-like characteristics and cisplatin resistance in cancer-initiating cells (CIC) from primary lung adenocarcinoma. CICs were isolated, enriched, and characterized from patient-derived cancer tissues using both in vitro tumorsphere formation and in vivo xenograft assays. USP22 was determined to be predominantly expressed in CICs, a subpopulation of cells with high expression of the stem cell biomarkers, CD133 and CD44. The expression of USP22 in CICs is markedly reduced upon FBS/retinoic acid-induced differentiation. Moreover, knockdown of USP22 significantly suppressed tumorsphere formation and xenograft growth in NOD-SCID gamma (NSG) mice. Notably, USP22 and aldehyde dehydrogenase (ALDH) activity were elevated in tumorsphere cells that survived cisplatin treatment, whereas knockdown of USP22 significantly sensitizes tumorsphere cells to cisplatin. Interestingly, ALDH1A3, a predominant ALDH isozyme implicated in enhancing cisplatin resistance in lung adenocarcinoma, is significantly downregulated upon knockdown of USP22 in tumorsphere cells. Furthermore, knockdown of ALDH1A3 significantly sensitizes tumorsphere cells to cisplatin. Combined, these data demonstrate that USP22, predominantly expressed in CD133+ CICs, plays a critical role in tumorigenicity and cisplatin resistance in lung adenocarcinoma.Implications: Targeting USP22 represents a potential therapeutic approach to suppress CICs in lung adenocarcinoma partially through downregulation of ALDH1A3 expression. Mol Cancer Res; 16(7); 1161-71. ©2018 AACR.


Delayed catabolism of apoB-48 lipoproteins due to decreased heparan sulfate proteoglycan production in diabetic mice.
We used wild-type (WT) mice and mice engineered to express either apoB-100 only (B100 mice) or apoB-48 only (B48 mice) to examine the effects of streptozotocin-induced diabetes (DM) on apoB-100- and apoB-48-containing lipoproteins. Plasma lipids increased with DM in WT mice, and fat tolerance was markedly impaired. Lipoprotein profiles showed increased levels and cholesterol enrichment of VLDL in diabetic B48 mice but not in B100 mice. C apolipoproteins, in particular apoC-I in VLDL, were increased. To investigate the basis of the increase in apoB-48 lipoproteins in streptozotocin-treated animals, we characterized several parameters of lipoprotein metabolism. Triglyceride and apoB production rates were normal, as were plasma lipase activity, VLDL glycosaminoglycan binding, and VLDL lipolysis. However, beta-VLDL clearance decreased due to decreased trapping by the liver. Whereas LRP activity was normal, livers from treated mice incorporated significantly less sulfate into heparan sulfate proteoglycans (HSPG) than did controls. Hepatoma (HepG2) cells and endothelial cells cultured in high glucose also showed decreased sulfate and glucosamine incorporation into HSPG. Western blots of livers from diabetic mice showed a decrease in the HSPG core protein, perlecan. Delayed clearance of postprandial apoB-48-containing lipoproteins in DM appears to be due to decreased hepatic perlecan HSPG.


The total deviation index estimated by tolerance intervals to evaluate the concordance of measurement devices.
In an agreement assay, it is of interest to evaluate the degree of agreement between the different methods (devices, instruments or observers) used to measure the same characteristic. We propose in this study a technical simplification for inference about the total deviation index (TDI) estimate to assess agreement between two devices of normally-distributed measurements and describe its utility to evaluate inter- and intra-rater agreement if more than one reading per subject is available for each device. We propose to estimate the TDI by constructing a probability interval of the difference in paired measurements between devices, and thereafter, we derive a tolerance interval (TI) procedure as a natural way to make inferences about probability limit estimates. We also describe how the proposed method can be used to compute bounds of the coverage probability. The approach is illustrated in a real case example where the agreement between two instruments, a handle mercury sphygmomanometer device and an OMRON 711 automatic device, is assessed in a sample of 384 subjects where measures of systolic blood pressure were taken twice by each device. A simulation study procedure is implemented to evaluate and compare the accuracy of the approach to two already established methods, showing that the TI approximation produces accurate empirical confidence levels which are reasonably close to the nominal confidence level. The method proposed is straightforward since the TDI estimate is derived directly from a probability interval of a normally-distributed variable in its original scale, without further transformations. Thereafter, a natural way of making inferences about this estimate is to derive the appropriate TI. Constructions of TI based on normal populations are implemented in most standard statistical packages, thus making it simpler for any practitioner to implement our proposal to assess agreement.


A Clinical Diagnostic System for Late-Stage Neuropsychiatric Lyme Borreliosis Based upon an Analysis of 100 Patients.
Many late-stage chronic Lyme disease clinical findings are neuropsychiatric. A total clinical assessment is critical in diagnosis, especially since controversy surrounds the reliability of laboratory testing. The clinical findings of one hundred Lyme disease patients with chronic neuropsychiatric symptoms were entered into a database. The prevalence of each clinical finding pre-infection and post-infection was compared and calculated within the 95% confidence interval. Patients had minimal symptoms pre-infection, but a high post-infection prevalence of a broad spectrum of acquired multisystem symptoms. These findings included impairments of attention span, memory, processing, executive functioning, emotional functioning, behavior, psychiatric syndromes, vegetative functioning, neurological, musculoskeletal, cardiovascular, upper respiratory, dental, pulmonary, gastrointestinal, genitourinary, and other symptoms. The most prevalent symptoms included sustained attention impairments, brain fog, unfocused concentration, joint symptoms, distraction by frustration, depression, working memory impairments, decreased school/job performance, recent memory impairments, difficulty prioritizing multiple tasks, fatigue, non-restorative sleep, multitasking difficulties, sudden mood swings, hypersomnia, mental apathy, decreased social functioning, insomnia, tingling, word finding difficulties, name retrieval, headaches, sound hypersensitivity, paresis, anhedonia, depersonalization, cold intolerance, body temperature fluctuations, light sensitivity and dysfluent speech. The average patient had five symptoms pre-infection and 82 post-infection. Pattern recognition is critical in making a diagnosis. This study was used to develop three clinical assessment forms.


Therapeutic strategies against cancer cachexia.
Cancer cachexia has two main components: anorexia and metabolic alterations. The main changes associated with the development of this multi-organic syndrome are glucose intolerance, fat depletion and muscle protein hypercatabolism. The aim of this paper is to review the more recent therapeutic approaches designed to counteract the wasting suffered by the cancer patient with cachexia. Among the most promising approaches we can include the use of ghrelin agonists, beta-blockers, beta-adrenergic agonists, androgen receptor agonists and anti-myostatin peptides. The multi-targeted approach seems essential in these treatments, which should include the combination of both nutritional support, drugs and a suitable program of physical exercise, in order to ameliorate both anorexia and the metabolic changes associated with cachexia. In addition, another very important and crucial aspect to be taken into consideration in the design of clinical trials for the treatment of cancer cachexia is to staging cancer patients in relation with the degree of cachexia, in order to start as early as possible this triple approach in the course of the disease, even before the weight loss can be detected.


Experimental verification of the effect of refractive index mismatch on the light fluence in a turbid medium.
Diffusion theory is often used to model the transport of light within tissue. It can be used to calculate the light fluence rate in tissue, for example, during photodynamic therapy, or to measure the absorption and scattering properties of tissue. For both of these applications, the influence of the interface between the tissue and the exterior medium on the fluence rate inside the tissue must be known in order to make accurate calculations. We present an experimental investigation of the effect of the refractive index mismatch at the tissue interface on the internal light fluence rate and on the spatially resolved diffuse reflectance as the boundary conditions of the tissue/external medium are changed. The effects of changing the relative refractive index at the boundary are compared to predictions of diffusion theory. The effect of the refractive index mismatch is predicted correctly by diffusion theory.


Are meat options preferred to comparable vegetarian options? An experimental study.
Reducing meat consumption would have substantial benefits both in terms of health and environmental impact, but meat options may be more attractive to customers than meat-free options. This study tested this by presenting UK adults (n = 540) with a series of pictures showing two meal options and asking them to select which they would prefer to eat right now. They completed this task for every possible pair from a pool of six comparator meat-based options and six target options (66 pairs). Participants all saw identical comparator options, and were randomised to see the same pictures of target options but with descriptions that suggested they were either meat-based or vegetarian. Selections were used to rank the options for each individual from 1 (most-selected) to 12 (least-selected). Vegetarian target options were ranked worse [by 1.23 places (95% CI: 1.02, 1.44)] than meat target options. Higher self-reported consumption of meat predicted worse mean rankings of target options when these were vegetarian, but not when target options were meat-based. This suggests meat options are preferred to equivalent vegetarian options and may be more likely to be selected. This has implications for interventions aiming to reduce meat consumption to make diets healthier and more sustainable.


Safety of infliximab in children with IBD: the experience of an academic center in WV.
The immune-modulating drug, infliximab, is approved for Inflammatory Bowel Disease (IBD) treatment in children. Chronic therapy with infliximab is associated with the development of early and delayed infusion reactions. We reviewed our experience with infliximab treatment and its side effects in a cohort of children diagnosed with IBD who were treated in our clinic. A retrospective analysis of all IBD children treated with infliximab in our center from 2006-2011 was performed. The demographic, chronological and clinical data were recorded. The infiximab infusion was given at 5mg/ kg according to a standard protocol after pre-treatment with low dose steroid and diphenhydramine. Of 30 IBD patients (23 CD/7 UC) receiving 454 infusions (341 CD/113 UC), six (20%) patients experienced early infusion reactions. Two (6.7%) patients had a delayed reaction; of those, both required intestinal resection. Our study is the first to address the safety of infliximab infusion reactions in children in the state of WV. Our results lend support to the use and safety of infliximab in children with moderate to severe IBD.


Pacifier Use, Finger Sucking, and Infant Sleep.
Few studies to date have investigated the relationship between pacifier use or finger sucking and infant sleep. One hundred and four mothers of infants (ages 0-11 months) completed the Brief Infant Sleep Questionnaire (BISQ). Infants who engaged in finger sucking had fewer night wakings and longer stretches of nighttime sleep, although less daytime sleep. There were no significant differences in sleep patterns between pacifier users and infants who did not engage in nonnutritive sucking. Furthermore, no significant differences were found across groups for sleep ecology, including parental involvement at bedtime and following night wakings. Finally, infants were consistently able to retrieve their pacifiers independently by 7 months of age, although this did not appear to be associated with sleep outcomes. Results suggest that when parents are deciding whether to give their infant a pacifier, sleep may not be a critical factor. In contrast, parents of finger and thumb suckers should be reassured that this nonnutritive sucking is beneficial to sleep, at least in the first year of life.


Fungal palaeodiversity revealed using high-throughput metabarcoding of ancient DNA from arctic permafrost.
The taxonomic and ecological diversity of ancient fungal communities was assessed by combining next generation sequencing and metabarcoding of DNA preserved in permafrost. Twenty-six sediment samples dated 16 000-32 000 radiocarbon years old from two localities in Siberia were analysed for fungal ITS. We detected 75 fungal OTUs from 21 orders representing three phyla, although rarefaction analyses suggested that the full diversity was not recovered despite generating an average of 6677 ± 3811 (mean ± SD) sequences per sample and that preservation bias likely has considerable effect on the recovered DNA. Most OTUs (75.4%) represented ascomycetes. Due to insufficient sequencing depth, DNA degradation and putative preservation biases in our samples, the recovered taxa probably do not represent the complete historic fungal community, and it is difficult to determine whether the fungal communities varied geographically or experienced a composition shift within the period of 16 000-32 000 bp. However, annotation of OTUs to functional ecological groups provided a wealth of information on the historic communities. About one-third of the OTUs are presumed plant-associates (pathogens, saprotrophs and endophytes) typical of graminoid- and forb-rich habitats. We also detected putative insect pathogens, coprophiles and keratinophiles likely associated with ancient insect and herbivore faunas. The detection of putative insect pathogens, mycoparasites, aquatic fungi and endophytes broadens our previous knowledge of the diversity of fungi present in Beringian palaeoecosystems. A large group of putatively psychrophilic/psychrotolerant fungi was also detected, most likely representing a modern, metabolically active fungal community.


Donor funding for newborn survival: an analysis of donor-reported data, 2002-2010.
Neonatal mortality accounts for 43% of global under-five deaths and is decreasing more slowly than maternal or child mortality. Donor funding has increased for maternal, newborn, and child health (MNCH), but no analysis to date has disaggregated aid for newborns. We evaluated if and how aid flows for newborn care can be tracked, examined changes in the last decade, and considered methodological implications for tracking funding for specific population groups or diseases. We critically reviewed and categorised previous analyses of aid to specific populations, diseases, or types of activities. We then developed and refined key terms related to newborn survival in seven languages and searched titles and descriptions of donor disbursement records in the Organisation for Economic Co-operation and Development's Creditor Reporting System database, 2002-2010. We compared results with the Countdown to 2015 database of aid for MNCH (2003-2008) and the search strategy used by the Institute for Health Metrics and Evaluation. Prior to 2005, key terms related to newborns were rare in disbursement records but their frequency increased markedly thereafter. Only two mentions were found of "stillbirth" and only nine references were found to "fetus" in any spelling variant or language. The total value of non-research disbursements mentioning any newborn search terms rose from US$38.4 million in 2002 to US$717.1 million in 2010 (constant 2010 US$). The value of non-research projects exclusively benefitting newborns fluctuated somewhat but remained low, at US$5.7 million in 2010. The United States and the United Nations Children's Fund (UNICEF) provided the largest value of non-research funding mentioning and exclusively benefitting newborns, respectively. Donor attention to newborn survival has increased since 2002, but it appears unlikely that donor aid is commensurate with the 3.0 million newborn deaths and 2.7 million stillbirths each year. We recommend that those tracking funding for other specific population groups, diseases, or activities consider a key term search approach in the Creditor Reporting System along with a detailed review of their data, but that they develop their search terms and interpretations carefully, taking into account the limitations described. Please see later in the article for the Editors' Summary.


Effect of treatment with ginger on the severity of premenstrual syndrome symptoms.
Premenstrual syndrome (PMS) is a common disorder. Although the etiology of PMS is not clear, to relieve from this syndrome different methods are recommended. One of them is use of medicinal herbs. This study was carried out to evaluate effects of ginger on severity of symptoms of PMS. This study was a clinical trial, double-blinded work, and participants were randomly allocated to intervention (n = 35) and control (n = 35) groups. To determine persons suffering from PMS, participants completed daily record scale questionnaire for two consecutive cycles. After identification, each participant received two ginger capsules daily from seven days before menstruation to three days after menstruation for three cycles and they recorded severity of the symptoms by daily record scale questionnaire. Data before intervention were compared with date 1, 2, and 3 months after intervention. Before intervention, there were no significant differences between the mean scores of PMS symptoms in the two groups, but after 1, 2, and 3 months of treatment, there was a significant difference between the two groups (P < 0.0001). Based on the results of this study, maybe ginger is effective in the reduction of severity of mood and physical and behavioral symptoms of PMS and we suggest ginger as treatment for PMS.


Guideline implementation for breast healthcare in low- and middle-income countries: treatment resource allocation.
A key determinant of breast cancer outcome is the degree to which newly diagnosed cancers are treated correctly in a timely fashion. Available resources must be applied in a rational manner to optimize population-based outcomes. A multidisciplinary international panel of experts addressed the implementation of treatment guidelines and developed process checklists for breast surgery, radiation treatment, and systemic therapy. The needed resources for stage I, stage II, locally advanced, and metastatic breast cancer were outlined, and process metrics were developed. The ability to perform modified radical mastectomy is the mainstay of locoregional treatment at the basic level of breast healthcare. Radiation therapy allows for consideration of breast-conserving therapy, postmastectomy chest wall irradiation, and palliation of painful or symptomatic metastases. Systemic therapy with cytotoxic chemotherapy is effective in the treatment of all biologic subtypes of breast cancer, but its provision is resource intensive. Although endocrine therapy requires few specialized resources, it requires knowledge of hormone receptor status. Targeted therapy against human epidermal growth factor receptor 2 (anti-HER-2) is very effective in tumors that overexpress HER-2/neu receptors, but cost largely prevents its use in resource-limited environments. Incremental allocation of resources can help address economic disparities and ensure equity in access to care. Checklists and allocation tables can support the objective of offering optimal care for all patients. The use of process metrics can facilitate the development of multidisciplinary, integrated, fiscally responsible, continuously improving, and flexible approaches to the global enhancement of breast cancer treatment.


Geographic distribution ranges of terrestrial mammal species in the 1970s.
Here we provide geographic distribution ranges for 205 species of terrestrial non-volant mammals in the 1970s. We selected terrestrial non-volant mammals because they are among the most studied groups, have greater availability of historical distribution data for the 1970s decade, and also show the largest range contractions compared to other taxonomic groups. Species belong to 52 families and 16 orders. Range maps were extracted from scientific literature including published papers, books, and action plans. For Australian species, due to the absence of published maps, we collated occurrence data from individual data sets (maintained by museums and government agencies) and converted these into polygonal range maps. Taxonomic and geographic biases towards more studied (charismatic) species are inevitably present. Among the most abundant orders, the highest percentage representation is for Carnivora (55 species, corresponding to 21% of species in the order), Cetartiodactyla (24 species, 10% of the order), and Perissodactyla (six species, 38% of the order). In contrast, the percentage representation is low for Rodentia (66 species, 3% of species in the order), Primates (19 species, 4%), and Eulipotyphla (6 species, 1%). The proportional representation of less speciose orders is highly variable. The data set offers the opportunity to measure the recent (1970-2019) change in the distribution of terrestrial mammal species, and test ecological and biogeographical hypotheses about such change. It also allows us to identify areas where changes in species distribution were largest. No copyright or proprietary restrictions are associated with the use of this data set other than citation of this Data Paper.


Placenta accreta spectrum: pathophysiology and evidence-based anatomy for prenatal ultrasound imaging.
Placenta accreta spectrum is a complex obstetric complication associated with high maternal morbidity. It is a relatively new disorder of placentation, and is the consequence of damage to the endometrium-myometrial interface of the uterine wall. When first described 80 years ago, it mainly occurred after manual removal of the placenta, uterine curettage, or endometritis. Superficial damage leads primarily to an abnormally adherent placenta, and is diagnosed as the complete or partial absence of the decidua on histology. Today, the main cause of placenta accreta spectrum is uterine surgery and, in particular, uterine scar secondary to cesarean delivery. In the absence of endometrial reepithelialization of the scar area the trophoblast and villous tissue can invade deeply within the myometrium, including its circulation, and reach the surrounding pelvic organs. The cellular changes in the trophoblast observed in placenta accreta spectrum are probably secondary to the unusual myometrial environment in which it develops, and not a primary defect of trophoblast biology leading to excessive invasion of the myometrium. Placenta accreta spectrum was separated by pathologists into 3 categories: placenta creta when the villi simply adhere to the myometrium, placenta increta when the villi invade the myometrium, and placenta percreta where the villi invade the full thickness of the myometrium. Several prenatal ultrasound signs of placenta accreta spectrum were reported over the last 35 years, principally the disappearance of the normal uteroplacental interface (clear zone), extreme thinning of the underlying myometrium, and vascular changes within the placenta (lacunae) and placental bed (hypervascularity). The pathophysiological basis of these signs is due to permanent damage of the uterine wall as far as the serosa, with placental tissue reaching the deep uterine circulation. Adherent and invasive placentation may coexist in the same placental bed and evolve with advancing gestation. This may explain why no single, or set combination of, ultrasound sign(s) was found to be specific for the depth of abnormal placentation, and accurate for the differential diagnosis between adherent and invasive placentation. Correlation of pathological and clinical findings with prenatal imaging is essential to improve screening, diagnosis, and management of placenta accreta spectrum, and standardized protocols need to be developed.


[Depression of the mononuclear phagocyte system caused by high doses of narcotics].
We evaluated in human monocytes the effect of high doses of alfentanyl on the expression of vimentin filaments, the phagocytic activity and the membrane display of HLA-DR molecules in the subjects undergoing surgery. The study was performed on 30 patients, ASAI-II. The patients received 100 mcg/kg i.v. of Alfentanil and the maintenance of anaesthesia was made with Alfentanil (2-3 mcg/kg/min.). The patients were randomized in two groups. The patients were ventilated with N2O:O2 (1:1) (Group I) or air: O2 (1:1) (Group II). After surgery, all patients of the Group II received Naloxone (0.2-0.4 mg). Central venous blood samples were obtained before induction, one and two hours after induction of anaesthesia and at the end of surgery. Separation of monocytes was performed according to Boyum technique. CD35 and HLA-DR molecules and vimentin filaments were studied by indirect immunofluorescence method using monoclonal antibodies. Percentage of positive cells were read with a cytofluorometer. The phagocytic function of monocytes was determined by ingestion of latex particles. Cortisol and ACTH plasma levels were determined by RIA. High doses of Alfentanyl depress phagocytic function and membrane display of CD35 and HLA-DR molecules in monocyte and induce marked changes in the organization of vimentin filaments in these cells in patients undergoing surgery. This monocytic depression was more marked in the patients ventilated with N2O. In our results there was uninhibition of ACTH and cortisol plasma levels responses to surgical stress by Alfentanil administration. Since the effects of Alfentanil were reversed by Naloxone, an opioid receptor mechanism seems to mediate these events.


Brain-derived human immunodeficiency virus-1 Tat exerts differential effects on LTR transactivation and neuroimmune activation.
Molecular diversity within brain-derived HIV-1 sequences is highly variable depending on the individual gene examined and the neurological status of the patient. Herein, we examined different brain-derived human immunodeficiency virus (HIV)-1 tat sequences in terms of their effects on LTR transactivation and host gene induction in neural cells. Astrocytic and monocytoid cells co-transfected with prototypic tat clones derived from non-demented (ND) (n = 3) and demented (HAD) (n = 3) AIDS patients and different HIV-LTR constructs revealed that LTR transactivation mediated by tat clones derived from HAD patients was decreased (p < 0.05). A Tat-derived peptide containing the amino acid 24-38 domain from a ND clone caused down-regulation of the LTR transactivation (p < 0.05) in contrast to peptides from other Tat regions derived from HAD and ND tat clones. Both brain-derived HAD and ND tat constructs were able to induce the host immune genes, MCP-1 and IL-1beta. Microarray analysis revealed several host genes were selectively upregulated by a HAD-derived tat clone including an enzyme mediating heparan sulphate synthesis, HS3ST3B1 (p < 0.05), which was also found to be increased in the brains of patients with HAD. Expression of the pro-apoptotic gene, PDCD7, was reduced in cells transfected with the HAD-derived tat clone and moreover, this gene was also suppressed in monocytoid cells infected with a neurotropic HIV-1 strain. Thus, mutations within the HIV-1 tat gene may exert pathogenic effects contributing to the development of HAD, which are independent of its effects on LTR transactivation.


Genome sequence of a serotype M28 strain of group a streptococcus: potential new insights into puerperal sepsis and bacterial disease specificity.
Puerperal sepsis, a major cause of death of young women in Europe in the 1800s, was due predominantly to the gram-positive pathogen group A Streptococcus. Studies conducted during past decades have shown that serotype M28 strains are the major group A Streptococcus organisms responsible for many of these infections. To begin to increase our understanding of their enrichment in puerperal sepsis, we sequenced the genome of a genetically representative strain. This strain has genes encoding a novel array of prophage virulence factors, cell-surface proteins, and other molecules likely to contribute to host-pathogen interactions. Importantly, genes for 7 inferred extracellular proteins are encoded by a 37.4-kb foreign DNA element that is shared with group B Streptococcus and is present in all serotype M28 strains. Proteins encoded by the 37.4-kb element were expressed extracellularly and in human infections. Acquisition of foreign genes has helped create a disease-specialist clone of this pathogen.


Stigma about depression and its impact on help-seeking intentions.
Research has shown that people are reluctant to seek professional help for depression, especially from mental health professionals. This may be because of the impact of stigma which can involve people's own responses to depression and help-seeking (self stigma) as well as their perceptions of others' negative responses (perceived stigma). The aim of this article was to examine community help-seeking intentions and stigmatizing beliefs associated with depression. A total of 1,312 adults randomly sampled from the Australian community completed a questionnaire providing a depression vignette and measures of self- and perceived-stigmatizing responses, source-specific help-seeking intentions, current depressive symptoms and depression experience, and demographics. Many people reported they would feel embarrassed about seeking help from professionals, and believed that other people would have a negative reaction to them if they sought such help. Some expected professionals to respond negatively to them. Responses varied according to the sources of professional help. Self-embarrassment and expectations that others would respond negatively predicted the likelihood of help-seeking from professional sources. Self- and perceived-stigmatizing responses to help-seeking for depression are prevalent in the community and are associated with reluctance to seek professional help. Interventions should focus on minimizing expectations of negative responses from others and negative self-responses to help-seeking, and should target younger people.


Expanding the utility of the malignant self-regard construct.
The empirical and theoretical literature suggest that several proposed personality disorders (PDs) - Masochistic/Self-Defeating, Depressive, and Vulnerably Narcissistic - may be related through a common self-representation know as Malignant Self-Regard (MSR). To assess this construct, the MSR Questionnaire (MSRQ) was developed. Though its initial psychometric properties were very strong, the present study extended these findings by examining the relationship of the MSRQ with measures of other PDs and depressive subtypes, and by establishing four-week and eight-week test-retest reliability in two samples (Ns=840, 911) of undergraduate students. The MSRQ was internally consistent and temporally stable over four and eight weeks. It was positively correlated with measures of introjective and anaclitic depression, measures of Self-Defeating, Depressive, and Vulnerably Narcissistic personalities (rs ranging between 0.60 and 0.82), and other select PDs. After controlling for depressive symptoms and self-esteem, the highest remaining partial correlations were with Vulnerably Narcissistic, Self-Defeating, Depressive, and Avoidant personalities. A factor analysis of the MSRQ with measures of other PDs yielded a two-factor solution, with MSR loading most strongly on one factor, along with Vulnerably Narcissistic, Avoidant, Depressive, and Self-Defeating personalities. It is concluded that MSR is a psychometrically supported construct that might have good clinical utility in explaining personality pathology that has historically been difficult to assess.


A gain-of-function screen in zebrafish identifies a guanylate cyclase with a role in neuronal degeneration.
Manipulation of gene expression is one of the most informative ways to study gene function. Genetic screens have been an informative method to identify genes involved in developmental processes. In the zebrafish, loss-of-function screens have been the primary approach for these studies. We sought to complement loss-of-function screens using an unbiased approach to overexpress genes with a Gal4-UAS based system, similar to the gain-of-function screens in Drosophila. Using MMLV as a mutagenic vector, a cassette containing a UAS promoter was readily inserted in the genome, often at the 5' end of genes, allowing Gal4-dependent overexpression. We confirmed that genes downstream of the viral insertions were overexpressed in a Gal4-VP16 dependent manner. We further demonstrate that misexpression of one such downstream gene gucy2F, a membrane-bound guanylate cyclase, throughout the nervous system results in multiple defects including a loss of forebrain neurons. This suggests proper control of cGMP production is important in neuronal survival. From this study, we propose that this gain-of-function approach can be applied to large-scale genetic screens in a vertebrate model organism and may reveal previously unknown gene function.


Quality-guided orientation unwrapping for fringe direction estimation.
Fringe patterns produced by various optical interferometric techniques encode information such as shape, deformation, and refractive index. Denoising and demodulation are two important procedures to retrieve information from a single closed fringe pattern. Various existing denoising and demodulation techniques require fringe direction/orientation during the processing. Fringe orientation is often easier to obtain but fringe direction is needed in some demodulation techniques. A quality-guided orientation unwrapping scheme is proposed to estimate direction from orientation. Two techniques, one based on windowed Fourier ridges and the other based on fringe gradient, are proposed for the quality-guided orientation unwrapping scheme. The direction qualities are compared for both simulated and experimental fringe patterns. Their application to demodulation technique is also given.


Fresnel phase plate lenses for through-wafer optical interconnections.
While the advantages of optical over electrical interconnects for conventional 2-D VLSI and wafer-scaleintegrated (WSI) circuits have not been clearly demonstrated, for 3-D interconnection structures such as those necessary for stacked wafer and similar architectures, the trade-off between using optical or electrical methods for vertical links is not straightforward. Current work on fabricating a through-wafer optical interconnect within a hybrid-WSI environment is motivated by the need to obtain experimental data on the overall performance of an optical interconnect so that this trade-off can be clarified inthe case of hybrid-WSI and in the general case at least more well defined. This paper details the design and fabrication of SiO(2) Fresnel phase plate lens arrays for use in the experimental 1.3-microm wavelength through-wafer optical interconnects to be constructed. These 0.8-N.A. lenses have submicron minimum linewidths and are VLSI process compatible. Preliminary results are presented indicating that, with the use of these lens arrays, vertical optical interconnect densities comparable with that of on chip bonding pads ( approximately 250-microm pitch) are obtainable within these architectures.


LESS SKILLED READERS HAVE LESS EFFICIENT SUPPRESSION MECHANISMS.
One approach to understanding the component processes and mechanisms underlying adult reading skill is to compare the performance of more skilled and less skilled readers on laboratory experiments. The results of some recent experiments employing this approach demonstrate that less skilled adult readers suppress less efficiently the inappropriate meanings of ambiguous words (e.g., the playing card vs. garden tool meanings of spade), the incorrect forms of homophones (e.g., patients vs. patience), the typical-but-absent members of scenes (e.g., a tractor in a farm scene), and words superimposed on pictures. Less skilled readers are not less efficient in activating contextually appropriate information; in fact, they activate contextually appropriate information more strongly than more skilled readers do. Therefore, one conclusion that can be drawn from these experiments is that less skilled adult readers suffer from less efficient suppression mechanisms.


Frataxin expression rescues mitochondrial dysfunctions in FRDA cells.
Friedreich's ataxia (FRDA) is the result of mutations in the nuclear-encoded frataxin gene, which is expressed in mitochondria. Several lines of evidence have suggested that frataxin is involved in mitochondrial iron homeostasis. We have transfected the frataxin gene into lymphoblasts of FRDA compound heterozygotes (FRDA-CH) with deficient frataxin expression to produce FRDA-CH-t cells in which message and protein are rescued to near-physiological levels. FRDA-CH cells were more sensitive to oxidative stress by challenge with free iron, hydrogen peroxide and the combination, consistent with a Fenton chemical mechanism of pathophysiology, and this sensitivity was rescued to control levels in FRDA-CH-t cells. Iron challenge caused increased mitochondrial iron levels in FRDA-CH cells, and a decreased mitochondrial membrane potential (MMP), both of which were rescued in FRDA-CH-t cells. The rescue of the low MMP, and high mitochondrial iron concentration by frataxin overexpression suggests that these cellular phenotypes are relevant to the central pathophysiological process in FRDA which is aggravated by exposure to free iron. However, even at physiological iron concentrations, FRDA-CH cells had decreased MMP as well as lower activities of aconitase and ICDH (two enzymes supporting MMP), and twice the level of filtrable mitochondrial iron (but no increase in total mitochondrial iron), and the observed phenotypes were either fully or partially rescued in FRDA-CH-t cells. Free iron is known to be toxic. The observation that frataxin deficiency (either directly or indirectly) causes an increase in filtrable mitochondrial iron provides a new hypothesis for the mechanism of cell death in this disease, and could be a target for therapy.


Endothelial cell protection against ischemia/reperfusion injury by lecithinized superoxide dismutase.
Organs used for transplantation may experience long periods of cold ischemic preservation and consequently oxygen free radical-mediated damage following reperfusion. Lecithinized superoxide dismutase (lec-SOD) is a novel free radical scavenger that has been shown to bind with high affinity to cell membranes. The aim of this study was to determine whether lec-SOD bound to endothelial cells under organ preservation conditions to mediate direct antioxidant activity at the endothelial cell surface and thus offer protection against the harmful effects of ischemia/reperfusion injury. An in vitro study was performed on large vessel endothelial cells (HUVEC) and a human microvascular endothelial cell line HMEC-1, to investigate the potential therapeutic benefits of incorporating lec-SOD into organ preservation solution. A cold hypoxia/reoxygenation system was developed to examine lec-SOD binding affinity to endothelial cells, protection against hypoxia/reoxygenation-induced cell death, and neutrophil adhesion. Lec-SOD bound to endothelial cells with higher affinity than unmodified recombinant human superoxide dismutase (rhSOD) and significantly protected both HUVEC and HMEC-1 from cell death following 27 hours of cold hypoxia (P < 0.01). Furthermore, neutrophil adhesion to the endothelium stimulated by hypoxia and reoxygenation was significantly inhibited by treatment with lec-SOD but not by lecithin or rhSOD (P < 0.01). Analysis by flow cytometry demonstrated that E-selectin and ICAM-1 were up-regulated by hypoxia/reoxygenation that was inhibited in part by lec-SOD. The results from this study suggest that incorporation of lec-SOD into organ preservation solutions provides effective protection to endothelial cells against cold ischemia and reperfusion injury following transplantation.


Lifetime and treatment-phase costs associated with colorectal cancer: evidence from SEER-Medicare data.
This study provides detailed estimates of lifetime and phase-specific colorectal cancer (CRC) treatment costs. This retrospective cohort study included patients aged 66 years and older, newly diagnosed with CRC in a Surveillance Epidemiology and End Results (SEER) registry (1996-2002), matched 1:1 (by age, sex, and geographic region) to patients without cancer from a 5% sample of Medicare beneficiaries. The Kaplan-Meier sample average estimator was used to estimate observed 10-year costs, which then were extrapolated to 25 years. A secondary analysis computed costs on a per-survival-year basis to adjust for differences in mortality by stage and age. Costs were expressed in 2006 US$, with future costs discounted 3% per year. Our sample included 56,838 CRC patients (41,256 colon cancer [CC] patients and 15,582 rectal cancer [RC] patients; mean +/- SD age, 77.7 +/- 7.1 y; 55% women; and 86% white). Lifetime excess costs were $29,500 for CC and $26,500 for RC patients. Per survival year, stage IV CRC patients incurred $31,000 in excess costs compared with $3000 for stage 0 patients. CRC patients incurred excess costs of $33,500 in the initial phase, $4500/y in the continuing phase, and $14,500 in the terminal phase. RC patients had lower costs than CC patients in the initial phase, but higher costs in both the continuing and terminal phases. Excess costs associated with CRC are striking and vary considerably by treatment phase, cancer subsite, and stage at diagnosis. Interventions aimed at earlier diagnosis and prevention have the potential to reduce cancer-related health care costs.


Predominant Th2/Tc2 polarity of tumor-infiltrating lymphocytes in human cervical cancer.
Cytotoxic T lymphocytes (Tc) play a central role in cellular immunity against cancers. The cytotoxic potential of freshly isolated tumor-infiltrating lymphocytes (TILs) is usually not expressed. This suggests the possible existence of as yet unspecified and perhaps complex immunosuppressive factors or cytokines that affect the anti-tumor capacity of these TILs in the tumor milieu. In the present study, we demonstrated for the first time that TILs derived from human cervical cancer tissue consist mainly of Th2/Tc2 phenotypes. In vitro kinetic assays further revealed that cancer cells could direct the tumor-encountered T cells toward the Th2/Tc2 polarity. Cancer cells promote the production of IL-4 and down-regulate the production of IFN-gamma in cancer-encountered T cells. The regulatory effects of cervical cancer cells are mediated mainly by IL-10, and TGF-beta plays only a synergistic role. The cancer-derived effects can be reversed by neutralizing anti-IL-10 and anti-TGF-beta Abs. IL-10 and TGF-beta are present in cancer tissue and weakly expressed in precancerous tissue, but not in normal cervical epithelial cells. Our study strongly suggests important regulatory roles of IL-10 and TGF-beta in cancer-mediated immunosuppression.