Modeling human pediatric and adult gliomas in immunocompetent mice through costimulatory blockade.
Currently, human glioma tumors are mostly modeled in immunodeficient recipients; however, lack of interactions with adaptive immune system is a serious flaw, particularly in the era when immunotherapies dominate treatment strategies. Our group was the first to successfully establish the orthotopic transplantation of human glioblastoma (GBM) in immunocompetent mice by inducing immunological tolerance using a short-term, systemic costimulation blockade strategy (CTLA-4-Ig and MR1). In this study, we further validated the feasibility of this method by modeling pediatric diffuse intrinsic pontine glioma (DIPG) and two types of adult GBM (GBM1, GBM551), in mice with intact immune systems and immunodeficient mice. We found that all three glioma models were successfully established, with distinct difference in tumor growth patterns and morphologies, after orthotopic xenotransplantation in tolerance-induced immunocompetent mice. Long-lasting tolerance that is maintained for up to nearly 200 d in GBM551 confirmed the robustness of this model. Moreover, we found that tumors in immunocompetent mice displayed features more similar to the clinical pathophysiology found in glioma patients, characterized by inflammatory infiltration and strong neovascularization, as compared with tumors in immunodeficient mice. In summary, we have validated the robustness of the costimulatory blockade strategy for tumor modeling and successfully established three human glioma models including the pediatric DIPG whose preclinical study is particularly thwarted by the lack of proper animal models.


Glycated albumin causes pancreatic β-cells dysfunction through autophagy dysfunction.
Growing evidence suggests that advanced glycation end-products (AGEs) are cytotoxic to pancreatic β-cells. The aims of this study were to investigate whether glycated albumin (GA), an early precursor of AGEs, would induce dysfunction in pancreatic β-cells and to determine which kinds of cellular mechanisms are activated in GA-induced β-cell apoptosis. Decreased viability and increased apoptosis were induced in INS-1 cells treated with 2.5 mg/mL GA under 16.7mM high-glucose conditions. Insulin content and glucose-stimulated secretion from isolated rat islets were reduced in 2.5 mg/mL GA-treated cells. In response to 2.5 mg/mL GA in INS-1 cells, autophagy induction and flux decreased as assessed by green fluorescent protein-microtubule-associated protein 1 light chain 3 dots, microtubule-associated protein 1 light chain 3-II conversion, and SQSTM1/p62 in the presence and absence of bafilomycin A1. Accumulated SQSTM1/p62 through deficient autophagy activated the nuclear factor-κB (p65)-inducible nitric oxide synthase-caspase-3 cascade, which was restored by treatment with small interfering RNA against p62. Small interfering RNA treatment against autophagy-related protein 5 significantly inhibited the autophagy machinery resulting in a significant increase in iNOS-cleaved caspase-3 expression. Treatment with 500μM 4-phenyl butyric acid significantly alleviated the expression of endoplasmic reticulum stress markers and iNOS in parallel with upregulated autophagy induction. However, in the presence of bafilomycin A1, the decreased viability of INS-1 cells was not recovered. Glycated albumin, an early precursor of AGE, caused pancreatic β-cell death by inhibiting autophagy induction and flux, resulting in nuclear factor-κB (p65)-iNOS-caspase-3 cascade activation as well as by increasing susceptibility to endoplasmic reticulum stress and oxidative stress.


HIV-1 infection in pigtailed macaques.
Four pigtailed macaques were inoculated with autologous cells expressing low levels of human immunodeficiency virus type 1 (HIV-1). During the first 10 weeks, infectious virus was recovered from peripheral blood mononuclear cells (PBMCs) and lymph nodes from three of the animals. Subsequently, HIV-1 DNA was frequently detected in uncultured PBMCs from all three animals, and virus was isolated from one of them at weeks 38 and 61. The fourth animal, which was rechallenged at week 10 with cell-free virus isolated from one of the others, never became virus isolation positive, but harbored HIV-1 proviral genomes. These virus infections were accompanied by the development of varied HIV-1-specific humoral immune responses. Antibodies to gp160 were first apparent at week 8 in the three initially infected animals and persisted. The animal from whom virus was isolated at late times also developed persisting antibodies to HIV-1 p24 and gp120. Antibodies to gp120 and gp160 became apparent in the rechallenged animal at 1 week following reinoculation, but they waned with time. In vivo passage of the virus was attempted at week 6. One recipient pigtailed macaque and one recipient cynomolgus monkey failed to become detectably infected following transfusion of virus-positive blood and lymph node cells. The long-term presence of HIV-1-specific antibodies and proviral genomes in these animals, and the recovery of infectious virus more than 1 year following inoculation, are indicative of persistent infection, and confirm previous reports that pigtailed macaques are susceptible to HIV-1.


Exploring the association of dairy product intake with the fatty acids C15:0 and C17:0 measured from dried blood spots in a multipopulation cohort: Findings from the Food4Me study.
The use of biomarkers in the objective assessment of dietary intake is a high priority in nutrition research. The aim of this study was to examine pentadecanoic acid (C15:0) and heptadecanoic acid (C17:0) as biomarkers of dairy foods intake. The data used in the present study were obtained as part of the Food4me Study. Estimates of C15:0 and C17:0 from dried blood spots and intakes of dairy from a Food Frequency Questionnaire were obtained from participants (n = 1180) across seven countries. Regression analyses were used to explore associations of biomarkers with dairy intake levels and receiver operating characteristic analyses were used to evaluate the fatty acids. Significant positive associations were found between C15:0 and total intakes of high-fat dairy products. C15:0 showed good ability to distinguish between low and high consumers of high-fat dairy products. C15:0 can be used as a biomarker of high-fat dairy intake and of specific high-fat dairy products. Both C15:0 and C17:0 performed poorly for total dairy intake highlighting the need for caution when using these in epidemiological studies.


A study of the reliability of the family history method in genetic studies of Alzheimer disease.
The reliability between 2 raters conducting independent family history interviews for Alzheimer disease-like and other dementias was investigated. The interviews were conducted at least 1 year apart with the second rater blind to the data collected by the first rater. Raters agreed on the presence and type of dementia in 153 relatives age 45 or older of 30 AD probands, the age at onset in secondary cases, and the age of nonaffected relatives.


Tilt-pair analysis of images from a range of different specimens in single-particle electron cryomicroscopy.
The comparison of a pair of electron microscope images recorded at different specimen tilt angles provides a powerful approach for evaluating the quality of images, image-processing procedures, or three-dimensional structures. Here, we analyze tilt-pair images recorded from a range of specimens with different symmetries and molecular masses and show how the analysis can produce valuable information not easily obtained otherwise. We show that the accuracy of orientation determination of individual single particles depends on molecular mass, as expected theoretically since the information in each particle image increases with molecular mass. The angular uncertainty is less than 1° for particles of high molecular mass (~50 MDa), several degrees for particles in the range 1-5 MDa, and tens of degrees for particles below 1 MDa. Orientational uncertainty may be the major contributor to the effective temperature factor (B-factor) describing contrast loss and therefore the maximum resolution of a structure determination. We also made two unexpected observations. Single particles that are known to be flexible showed a wider spread in orientation accuracy, and the orientations of the largest particles examined changed by several degrees during typical low-dose exposures. Smaller particles presumably also reorient during the exposure; hence, specimen movement is a second major factor that limits resolution. Tilt pairs thus enable assessment of orientation accuracy, map quality, specimen motion, and conformational heterogeneity. A convincing tilt-pair parameter plot, where 60% of the particles show a single cluster around the expected tilt axis and tilt angle, provides confidence in a structure determined using electron cryomicroscopy.


Lipid profiling as an effective approach for identifying biomarkers/adverse events associated with pediatric anesthesia.
Adverse effects related to central nervous system (CNS) function in pediatric populations may, at times, be difficult, if not impossible to evaluate. Prolonged anesthetic exposure affects brain excitability and anesthesia during the most sensitive developmental stages and has been associated with mitochondrial dysfunction, aberrant lipid metabolism and synaptogenesis, subsequent neuronal damage, as well as long-term behavioral deficits. There has been limited research evaluating whether and how anesthetic agents affect cellular lipids, the most abundant components of the brain other than water. Therefore, this review discusses: (1) whether the observed anesthetic-induced changes in lipid profiles seen in preclinical studies represents early signs of neurotoxicity; (2) the potential mechanisms underlying anesthetic-induced brain injury; and (3) whether lipid biomarker(s) identified in preclinical studies can serve as markers for the early clinical detection of anesthetic-induced neurotoxicity.


Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes.
Tumor protein p53 (TP53) is the most frequently mutated gene in cancer1,2. In patients with myelodysplastic syndromes (MDS), TP53 mutations are associated with high-risk disease3,4, rapid transformation to acute myeloid leukemia (AML)5, resistance to conventional therapies6-8 and dismal outcomes9. Consistent with the tumor-suppressive role of TP53, patients harbor both mono- and biallelic mutations10. However, the biological and clinical implications of TP53 allelic state have not been fully investigated in MDS or any other cancer type. We analyzed 3,324 patients with MDS for TP53 mutations and allelic imbalances and delineated two subsets of patients with distinct phenotypes and outcomes. One-third of TP53-mutated patients had monoallelic mutations whereas two-thirds had multiple hits (multi-hit) consistent with biallelic targeting. Established associations with complex karyotype, few co-occurring mutations, high-risk presentation and poor outcomes were specific to multi-hit patients only. TP53 multi-hit state predicted risk of death and leukemic transformation independently of the Revised International Prognostic Scoring System (IPSS-R)11. Surprisingly, monoallelic patients did not differ from TP53 wild-type patients in outcomes and response to therapy. This study shows that consideration of TP53 allelic state is critical for diagnostic and prognostic precision in MDS as well as in future correlative studies of treatment response.


Altered brain activity for phonological manipulation in dyslexic Japanese children.
Because of unique linguistic characteristics, the prevalence rate of developmental dyslexia is relatively low in the Japanese language. Paradoxically, Japanese children have serious difficulty analysing phonological processes when they have dyslexia. Neurobiological deficits in Japanese dyslexia remain unclear and need to be identified, and may lead to better understanding of the commonality and diversity in the disorder among different linguistic systems. The present study investigated brain activity that underlies deficits in phonological awareness in Japanese dyslexic children using functional magnetic resonance imaging. We developed and conducted a phonological manipulation task to extract phonological processing skills and to minimize the influence of auditory working memory on healthy adults, typically developing children, and dyslexic children. Current experiments revealed that several brain regions participated in manipulating the phonological information including left inferior and middle frontal gyrus, left superior temporal gyrus, and bilateral basal ganglia. Moreover, dyslexic children showed altered activity in two brain regions. They showed hyperactivity in the basal ganglia compared with the two other groups, which reflects inefficient phonological processing. Hypoactivity in the left superior temporal gyrus was also found, suggesting difficulty in composing and processing phonological information. The altered brain activity shares similarity with those of dyslexic children in countries speaking alphabetical languages, but disparity also occurs between these two populations. These are initial findings concerning the neurobiological impairments in dyslexic Japanese children.


Endometrial resection and ablation versus hysterectomy for heavy menstrual bleeding.
Heavy menstrual bleeding (HMB), which includes both menorrhagia and metrorrhagia, is an important cause of ill health in women. Surgical treatment of HMB often follows failed or ineffective medical therapy. The definitive treatment is hysterectomy, but this is a major surgical procedure with significant physical and emotional complications, as well as social and economic costs. Several less invasive surgical techniques (e.g. transcervical resection of the endometrium (TCRE), laser approaches) and various methods of endometrial ablation have been developed with the purpose of improving menstrual symptoms by removing or ablating the entire thickness of the endometrium. The objective of this review is to compare the effectiveness, acceptability and safety of techniques of endometrial destruction by any means versus hysterectomy by any means for the treatment of heavy menstrual bleeding. Electronic searches for relevant randomised controlled trials (RCTs) targeted but were not limited to the following: the Cochrane Menstrual Disorders and Subfertility Group Register of Trials, MEDLINE, EMBASE, PsycINFO and the Cochrane CENTRAL register of trials. Attempts were made to identify trials by examining citation lists of review articles and guidelines and by performing handsearching. Searches were performed in 2007, 2008 and 2013. Included in the review were any RCTs that compared techniques of endometrial destruction by any means with hysterectomy by any means for the treatment of heavy menstrual bleeding in premenopausal women. Two review authors independently searched for studies, extracted data and assessed risk of bias. Risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes were estimated from the data. Outcomes analysed included improvement in menstrual blood loss, satisfaction, change in quality of life, duration of surgery and hospital stay, time to return to work, adverse events and requirements for repeat surgery due to failure of the initial surgical treatment. Eight RCTs that fulfilled the inclusion criteria for this review were identified. For two trials, the review authors identified multiple publications that assessed different outcomes at different postoperative time points for the same women.An advantage in favour of hysterectomy compared with endometrial ablation was observed in various measures of improvement in bleeding symptoms and satisfaction rates. A slightly lower proportion of women who underwent endometrial ablation perceived improvement in bleeding symptoms at one year (RR 0.89, 95% confidence interval (CI) 0.85 to 0.93, four studies, 650 women, I(2) = 31%), at two years (RR 0.92, 95% CI 0.86 to 0.99, two studies, 292 women, I(2) = 53%) and at four years (RR 0.93, 95% CI 0.88 to 0.99, two studies, 237 women, I(2) = 79%). The same group of women also showed improvement in pictorial blood loss assessment chart (PBAC) score at one year (MD 24.40, 95% CI 16.01 to 32.79, one study, 68 women) and at two years (MD 44.00, 95% CI 36.09 to 51.91, one study, 68 women). Repeat surgery resulting from failure of the initial treatment was more likely to be needed after endometrial ablation than after hysterectomy at one year (RR 14.9, 95% CI 5.2 to 42.6, six studies, 887 women, I(2) = 0%), at two years (RR 23.4, 95% CI 8.3 to 65.8, six studies, 930 women, I(2) = 0%), at three years (RR 11.1, 95% CI 1.5 to 80.1, one study, 172 women) and at four years (RR 36.4, 95% CI 5.1 to 259.2, one study, 197 women). Most adverse events, both major and minor, were significantly more likely after hysterectomy during hospital stay. Women who had a hysterectomy were more likely to experience sepsis (RR 0.2, 95% CI 0.1 to 0.3, four studies, 621 women, I(2) = 62%), blood transfusion (RR 0.2, 95% CI 0.1 to 0.6, four studies, 751 women, I(2) = 0%), pyrexia (RR 0.2, 95% CI 0.1 to 0.4, three studies, 605 women, I(2) = 66%), vault haematoma (RR 0.1, 95% CI 0.04 to 0.3, five studies, 858 women, I(2) = 0%) and wound haematoma (RR 0.03, 95% CI 0.00 to 0.5, one study, 202 women) before hospital discharge. After discharge from hospital, the only difference that was reported for this group was a higher rate of infection (RR 0.2, 95% CI 0.1 to 0.5, one study, 172 women).For some outcomes (such as a woman's perception of bleeding and proportion of women requiring further surgery for HMB), a low GRADE score was generated, suggesting that further research in these areas is likely to change the estimates. Endometrial resection and ablation offers an alternative to hysterectomy as a surgical treatment for heavy menstrual bleeding. Both procedures are effective, and satisfaction rates are high. Although hysterectomy is associated with longer operating time (particularly for the laparoscopic route), a longer recovery period and higher rates of postoperative complications, it offers permanent relief from heavy menstrual bleeding. The initial cost of endometrial destruction is significantly lower than that of hysterectomy, but, because retreatment is often necessary, the cost difference narrows over time.


Tunable electronic properties of partially edge-hydrogenated armchair boron-nitrogen-carbon nanoribbons.
We employ a first-principles calculations based density-functional-theory (DFT) approach to study the electronic properties of partially and fully edge-hydrogenated armchair boron-nitrogen-carbon (BNC) nanoribbons (ABNCNRs), with widths between 0.85 nm to 2.3 nm. Due to the partial passivation of edges, the electrons, which do not participate in the bonding, form new energy states located near the Fermi-level. Because of these additional bands, some ABNCNRs exhibit metallic behavior, which is quite uncommon in armchair nanoribbons. Our calculations reveal that metallic behavior is observed for the following passivation patterns: (i) when the B atom from one edge and the N atom from another edge are unpassivated. (ii) when the N atoms from both the edges are unpassivated. (iii) when the C atom from one edge and the N atom from another edge are unpassivated. Furthermore, spin-polarization is also observed for certain passivation schemes, which is also quite uncommon for armchair nanoribbons. Thus, our results suggest that the ABNCNRs exhibit a wide range of electronic and magnetic properties in that the fully edge-hydrogenated ABNCNRs are direct band gap semiconductors, while the partially edge-hydrogenated ones are either semiconducting, or metallic, while simultaneously exhibiting spin polarization, based on the nature of passivation. We also find that the ribbons with larger widths are more stable as compared to the narrower ones.


The influence of changing climate on the ecology and management of selected Laurentian Great Lakes fisheries.
The Laurentian Great Lakes Basin provides an ecological system to evaluate the potential effect of climate change on dynamics of fish populations and the management of their fisheries. This review describes the physical and biological mechanisms by which fish populations will be affected by changes in timing and duration of ice cover, precipitation events and temperature regimes associated with projected climate change in the Great Lakes Basin with a principal focus on the fish communities in shallower regions of the basin. Lake whitefish Coregonus clupeaformis, walleye Sander vitreus and smallmouth bass Micropterus dolomieu were examined to assess the potential effects of climate change on guilds of Great Lakes cold, cool and warm-water fishes, respectively. Overall, the projections for these fishes are for the increased thermally suitable habitat within the lakes, though in different regions than they currently inhabit. Colder-water fishes will seek refuge further north and deeper in the water column and warmer-water fishes will fill the vacated habitat space in the warmer regions of the lakes. While these projections can be modified by a number of other habitat elements (e.g. anoxia, ice cover, dispersal ability and trophic productivity), it is clear that climate-change drivers will challenge the nature, flexibility and public perception of current fisheries management programmes. Fisheries agencies should develop decision support tools to provide a systematic method for incorporating ecological responses to climate change and moderating public interests to ensure a sustainable future for Great Lakes fishes and fisheries.


Poor responsiveness to antiplatelet drugs in acute coronary syndromes: clinical relevance and management.
Cardiovascular diseases are the most common cause of mortality and morbidity in Western countries, accounting for more than 40% of total mortality. An optimal pharmacological management in these patients is of major importance and antiplatelet agents remain the cornerstone of acute coronary syndrome (ACS) therapy at hospital admission and during percutaneous coronary interventions (PCI). The recently described poor biological responses to aspirin and clopidogrel have been source of major concern, especially in era of drug eluting stent implantation. Indeed, insufficient platelet inhibition at the time of PCI has been consistently associated with an increased risk of complications and recurrence of ischemic events. Despite the lack of uniformly accepted definitions of aspirin and clopidogrel poor response, we sought to describe the current evidence and gaps in knowledge. While trials on the potential benefit of an increased antiplatelet maintenance dose after PCI have shown only marginal benefits, the strengthening of the initial antiplatelet regimens by additional loading doses of clopidogrel, by the administration of glycoprotein IIb/IIIa receptor inhibitors or phosphodiesterase inhibitors might further improve outcomes during ACS and PCI in patients with poor responsiveness to conventional dual antiplatelet therapy. Overall, tailoring the antiplatelet treatment on the basis of the individual biological response improves the short-term outcome after PCI. New and more potent antiplatelet drugs may overcome the clinical consequences of the poor response to antiplatelet agents.


Pseudarthrosis in adult spinal deformity following multisegmental instrumentation and arthrodesis.
There have been few detailed reports concerning pseudarthrosis following spinal instrumentation and arthrodesis in adults with spinal deformity since the introduction of modern segmental fixation techniques. The purposes of this study were to analyze the prevalence, risk factors, and outcome scores on the Scoliosis Research Society Instrument-24 associated with pseudarthrosis following instrumentation and arthrodesis for the treatment of spinal deformity in adults. A clinical and radiographic assessment of 232 adults with spinal deformity who were treated surgically at a single institution was conducted. The average age of the patients was 40.8 years, and the operation was a primary procedure in 150 patients and a revision procedure in eighty-two patients. All patients who underwent a long (four vertebrae or more) spinal instrumentation and arthrodesis with a minimum follow-up of two years were included in the analysis. Clinical outcomes were assessed with the Scoliosis Research Society questionnaire. Forty patients had a pseudarthrosis. Factors that were found to be significantly associated with pseudarthrosis were preoperative thoracolumbar kyphosis of >20 degrees (p < 0.0001), an age of more than fifty-five years (p = 0.001), arthrodesis to S1 compared with arthrodesis to L5 or a cephalad level (p = 0.002), and arthrodesis of more than twelve vertebrae (p = 0.037). Patients with a pseudarthrosis had lower total outcome scores on the Scoliosis Research Society questionnaire, on the average, than those without a pseudarthrosis (p = 0.001). The prevalence of pseudarthrosis following long arthrodesis with use of modern segmental spinal instrumentation for the treatment of spinal deformity in adults was 17%, and the clinical outcome in these patients can be negatively affected by the pseudarthrosis.


Evaluation of sequentially-coupled POP fluxes estimated from simultaneous measurements in multiple compartments of an air-water-sediment system.
Bulk atmospheric deposition fluxes, air-water exchange fluxes, particle settling fluxes out of the upper water column, sediment trap fluxes in deep waters, and sediment burial fluxes of polychlorinated biphenyls (PCBs) and polycyclic aromatic hydrocarbons (PAHs) were simultaneously measured in the Koster Fjord, eastern Skagerak, on the Swedish west coast. The aim of the study was to compare the magnitude and direction of the compound fluxes in the system in order to diagnose key fate processes. The PCB and PAH fluxes via net atmospheric deposition, settling particles out of the surface and through deep waters, as well as into the accreting underlying sediments were shown to be remarkably similar, agreeing within a factor of a few for any given target compound. Fluxes of all PCB and PAH target compounds remained fairly constant with water column depth. Thus there was no evidence for net desorption from sinking particles. The net unidirectional and near balancing of vertical fluxes suggests a net transport of PCBs and PAHs from the atmosphere to the continental shelf sediments in the Koster Fjord, which is consistent with the hypothesis that the shelf sediments are important sinks for these compounds.


Comparative Diagnostic Accuracy of Frozen Sections and Scrape Cytology in Ovarian Neoplasms.
Frozen section is a well-established method for providing rapid and accurate intraoperative diagnosis. Cytological techniques such as imprint and scrape cytology and intraoperative fine-needle aspiration cytology are conventionally considered as less accurate alternatives to the frozen section. However, inexperienced hands, scrape cytology has been shown to provide remarkably accurate results comparable to the frozen section. The aims of this study are as follows: (1) To evaluate the diagnostic utility of scrape cytology in the intraoperative diagnosis of ovarian neoplasms. (2) To compare the accuracy of scrape cytology with frozen section in the intraoperative diagnosis of ovarian neoplasms. This study was conducted over a period of 3 years from 2014 to 2017. A total of 60 cases of clinically and radiologically suspected ovarian masses were included in the study. Thirty cases were evaluated using frozen section and 30 cases using scrape cytology alone. The intraoperative diagnosis of both was compared with the final paraffin section histopathology. The diagnostic accuracy of scrape cytology and frozen section in determining a benign and malignant nature of neoplasm was 96% and 100%, respectively. In 93% of cases, scrape cytology enabled correct categorization of the tumor as surface epithelial, germ-cell tumor, sex cord-stromal, or others. Scrape cytology is an adjunct to frozen section for providing an intraoperative diagnosis; however, in resource-poor settings, it can be used as a stand-alone method for aiding intraoperative decision-making.


Development of North American consensus guidelines for medical laboratories that perform and interpret platelet function testing using light transmission aggregometry.
Platelet function testing is important for the diagnostic evaluation of common and rare bleeding disorders. Our study goals were to promote best practices and reduce unnecessary testing variances by developing North American guidelines on platelet function testing. Guidelines were developed by consensus for expert recommendations (minimum level for approval, 70%) that included recommendations on the evaluation and interpretation of light transmission platelet aggregometry (LTA). To assess consensus, medical opinions on recommendations were gathered from diagnostic laboratories that perform LTA, in collaboration with the Quality Management Program-Laboratory Services (QMP-LS) in Ontario, Canada (10 laboratories), and the North American Specialized Coagulation Laboratory Association (NASCOLA; 47 laboratories, 5 overlapping the QMP-LS group). Adequate consensus was achieved for all and 89% of recommendations for the QMP-LS and NASCOLA groups, respectively. The recommendations adopted provide North American laboratories with additional guidance on platelet function testing, including how to interpret LTA abnormalities.


A population-based study of neonatal mortality and maternal care utilization in the Indian state of Bihar.
A substantial reduction in neonatal deaths is required in India to meet the Millennium Development Goal of a two-thirds reduction in child mortality by 2015. We report neonatal mortality estimates and utilisation of maternal care in the Indian state of Bihar. A representative population-based sample of 14,293 women who had a live birth in the last 12 months based on multistage sampling from all 38 districts of Bihar was selected for interview in early 2012. We estimated neonatal mortality rate and its associations using multiple logistic regression, assessed maternal care coverage and its inequality by wealth index, and retention of mothers in the health system for the full sequence of maternal care services. Neonatal mortality rate for Bihar was 32.2 (95% confidence interval [CI] 27.6-36.8) per 1,000 live births. Postnatal care related variables were significantly associated with neonatal deaths - no delayed bathing of new born (odds ratio [OR] 3.45, 95% CI 2.47-4.81) and no kangaroo care immediately after birth (OR 2.20, 95% CI 1.49-3.25). History of maternal complications and delivery in a private sector health facility had nearly twice the odds of neonatal death; the latter was driven by the very high neonatal mortality associated with private facility delivery in the lower two wealth index quartiles. A pattern of mass deprivation was seen for coverage of 4 or more ANC visits, health facility delivery and postnatal care for the same woman, with only 5.2% of women receiving this overall; this coverage was low for the highest wealth index quartile as well at 12.2%. Coverage of 4 or more ANC visits was 7.4% and 27.7% in the lowest and the highest wealth quartiles, respectively. Giving birth in a health facility was reported by 49.5% of women in the lowest wealth index quartile and by 77.7% in the highest quartile. Only 21.2% women reported post-natal care within 2 weeks of delivery in the lowest wealth index quartile, and 42.2% in the highest quartile. Neonatal mortality continues to be relatively high in Bihar, and the utilization of maternal care very low and inequitable. Interventions need to address these deficiencies.


Evolutionary biology and practical conservation: bridging a widening gap.
At the ecosystem, species and population level, available measures suggest that average rates of loss of populations and habitats are now around 1% per year and seem likely to increase in the future. Habitat conversion continues in most parts of the world, especially in areas of high species richness, and novel threats, especially climate change, will pose new challenges. With this pressure, maintaining evolutionary processes in natural populations will be critical to longer term persistence, and will often require specific planning relevant to the context. However, in many areas of policy and practice, urgent actions tend to focus on pattern-based analyses and considerations of evolutionary and ecological processes are neglected. At a variety of levels, from setting goals to implementing conservation management at the site or species level, there are simple adjustments that can be made. Improved methods for integrating the work of scientists and policymakers is recommended, from the beginning to end of the planning process.


Abnormal renal function and autoregulation in essential hypertension.
The goal of this presentation has been to emphasize two fundamental mechanisms in the development of essential hypertension. These are: 1) The basic cause of essential hypertension is the inability of the kidneys to excrete an adequate volume of urine at normal arterial pressure. Therefore, fluid accumulates in the body until the pressure rises high enough to balance fluid output with fluid intake. This fluid balancing act is an infinite gain feedback system for controlling arterial pressure to a very precise level determined by the kidneys. Furthermore, this infinite gain allows the kidney mechanism to dominate the other pressure control mechanisms for long-term pressure control. Because of this domination, as long as a person has normal intake of water and electrolytes, essential hypertension cannot develop without an elevated pressure setting of the kidneys. 2) An increase in total peripheral resistance will not cause hypertension as long as the kidneys can still excrete normal amounts of water and electrolytes at normal arterial pressure, because loss of excess fluid volume at high pressures will simply reduce the cardiac output until the pressure falls back to normal. Therefore, what is the cause of the very high total peripheral resistance found in almost all patients with essential hypertension? The answer is likely the long-term blood flow autoregulation mechanism that occurs in virtually all tissues of the body. That is, when the pressure rises too high for whatever reason, this in turn forces too much blood flow through the tissues. In response, the local blood flow control mechanisms all over the body increase the vascular resistances until the flows return to normal.(ABSTRACT TRUNCATED AT 250 WORDS)


Excess mortality following hip fracture in patients with diabetes according to age: a nationwide population-based cohort study of 154,047 hip fracture patients.
to test the hypothesis that excess mortality conferred by diabetes following hip fracture decreases with advancing age. a nationwide population-based cohort study including 154,047 patients who were admitted with a hip fracture in Denmark from 1996 to 2012. Information on hip fracture diagnosis, diabetes, other comorbidities, and the primary outcome all-cause mortality was collected using the national Danish health registries. The association between diabetes and all-cause mortality according to age was assessed using Cox proportional hazards regression in the age categories: <50, 50-59, 60-69, 70-79, 80-89 and ≥90 years. during a median follow-up of 3 years (interquartile range: 1-6 years, 603,091 person-years) 114,990 died from any cause. In total, 8% (n = 12,158) of the patients had diabetes at baseline and had unadjusted, and age, sex and Charlson Comorbidity Index adjusted hazard ratios for all-cause mortality of 1.19 (95% confidence interval: 1.16-1.21) and 1.14 (1.12-1.17) as compared to patients without diabetes. The sex and Charlson Comorbidity Index adjusted hazard ratios according to age were 1.64 (1.34-2.02) for patients <50 years, 1.26 (1.12-1.40) for patients 50-59 years, 1.21 (1.13-1.29) for patients 60-69 years, 1.11 (1.07-1.16) for patients 70-79 years, 1.10 (1.07-1.14) for patients 80-89 years and 1.09 (1.02-1.16) for patients ≥90 years. There was a statistically significant interaction between diabetes and age (P < 0.001). diabetes is associated with excess mortality following hip fracture across all ages, but the excess mortality decreases with advancing age.


Policies, Political-Economy, and Swidden in Southeast Asia.
For centuries swidden was an important farming practice found across the girth of Southeast Asia. Today, however, these systems are changing and sometimes disappearing at a pace never before experienced. In order to explain the demise or transitioning of swidden we need to understand the rapid and massive changes that have and are occurring in the political and economic environment in which these farmers operate. Swidden farming has always been characterized by change, but since the onset of modern independent nation states, governments and markets in Southeast Asia have transformed the terms of swiddeners' everyday lives to a degree that is significantly different from that ever experienced before. In this paper we identified six factors that have contributed to the demise or transformation of swidden systems, and support these arguments with examples from China (Xishuangbanna), Laos, Thailand, Malaysia, and Indonesia. These trends include classifying swiddeners as ethnic minorities within nation-states, dividing the landscape into forest and permanent agriculture, expansion of forest departments and the rise of conservation, resettlement, privatization and commoditization of land and land-based production, and expansion of market infrastructure and the promotion of industrial agriculture. In addition we note a growing trend toward a transition from rural to urban livelihoods and expanding urban-labor markets.


Oscillations in meta-generalized-gradient approximation potential energy surfaces for dispersion-bound complexes.
Meta-generalized-gradient approximations (meta-GGAs) in density-functional theory are exchange-correlation functionals whose integrands depend on local density, density gradient, and also the kinetic-energy density. It has been pointed out by Johnson et al. [Chem. Phys. Lett. 394, 334 (2004)] that meta-GGA potential energy curves in dispersion-bound complexes are susceptible to spurious oscillations unless very large integration grids are used. This grid sensitivity originates from the saddle-point region of the density near the intermonomer midpoint. Various dimensionless ratios involving the kinetic-energy density, found in typical meta-GGAs, may be ill-behaved in this region. Grid sensitivity thus arises if the midpoint region is sampled by too sparse a grid. For most meta-GGAs, standard grids do not suffice. Care must be taken to avoid this problem when using, or constructing, meta-GGAs.


Reducing the number of sputum samples examined and thresholds for positivity: an opportunity to optimise smear microscopy.
Urban health clinic, Nairobi. To evaluate the impact on tuberculosis (TB) case detection and laboratory workload of reducing the number of sputum smears examined and thresholds for diagnosing positive smears and positive cases. In this prospective study, three Ziehl-Neelsen stained sputum smears from consecutive pulmonary TB suspects were examined blind. The standard approach (A), > or = 2 positive smears out of 3, using a cut-off of 10 acid-fast bacilli (AFB)/100 high-power fields (HPF), was compared with approaches B, > or = 2 positive smears (> or = 4 AFB/100 HPF) out of 3, one of which is > or = 10 AFB/100 HPF; C, > or = 2 positive smears (> or = 4 AFB/100 HPF) out of 3; D, > or = 1 positive smear (> or = 10 AFB/100 HPF) out of 2; and E, > or = 1 positive smear (> or = 4 AFB/100 HPF) out of 2. The microscopy gold standard was detection of at least one positive smear (> or = 4 AFB/100 HPF) out of 3. Among 644 TB suspects, the alternative approaches detected from 114 (17.7%) (approach B) to 123 cases (19.1%) (approach E) compared to 105 cases (16.3%) for approach A (P < 0.005). Sensitivity ranged between 82.0% (105/128) for A and 96.1% (123/128) for E. The single positive smear approaches reduced the number of smears by 36% compared to approach A. Reducing the number of specimens and the positivity threshold to define a positive case increased the sensitivity of microscopy and reduced laboratory workload.


Normal hematologic and serum clinical chemistry values for captive chimpanzees (Pan troglodytes).
In the study reported here, reference intervals for hematologic and serum clinical chemistry variables in the chimpanzee (Pan troglodytes) were developed and characterized. Data were collected longitudinally across a 10-year period for 86 subjects at the Primate Foundation of Arizona (PFA). Variables included nine standard hematologic and 25 standard serum clinical chemistry values. An analysis of variance (ANOVA) was used to test for main effects by age and sex. In addition, PFA mean and range values were compared with those published for humans and six other chimpanzee colonies. The ANOVA results suggest an age effect on hematologic (mean corpuscular hemoglobin, mean corpuscular volume, neutrophils) and serum clinical chemical (creatinine, total protein, globulin, tryglycerides, direct bilirubin, iron, (gamma-glutamyltransferase, alanine transaminase, creatine kinase) values. In addition, sex had a main effect on several variables (red blood cells, hemoglobin concentration, hematocrit, uric acid and sodium concentrations, and aspartate transminase and creatine kinase activities); values for males were greater than those for females. Further, human and chimpanzee mean and range values often were indistinguishable from one another. However, changes in human and chimpanzee values associated with age differ and suggest that hematologic and serum clinical chemistry values may be differentially affected by physical and sexual maturation in humans and chimpanzees.


The high prevalence of substance use disorders among recent MDMA users compared with other drug users: Implications for intervention.
In light of the resurgence in MDMA use and its association with polysubstance use, we investigated the 12-month prevalence of substance use disorders (SUDs) among adult MDMA users to determine whether they are at risk of other drug-related problems that would call for targeted interventions. Data were drawn from the 2006 National Survey on Drug Use and Health. Past-year adult drug users were grouped into three mutually exclusive categories: 1) recent MDMA users, who had used the drug within the past year; 2) former MDMA users, who had a history of using this drug but had not done so within the past year; and 3) other drug users, who had never used MDMA. Logistic regression procedures were used to estimate the association between respondents' SUDs and MDMA use while adjusting for their socioeconomic status, mental health, age of first use, and history of polydrug use. Approximately 14% of adults reported drug use in the past year, and 24% of those past-year drug users reported a history of MDMA use. Recent MDMA users exhibited the highest prevalence of disorders related to alcohol (41%), marijuana (30%), cocaine (10%), pain reliever/opioid (8%), and tranquilizer (3%) use. Adjusted logistic regression analyses revealed that, relative to other drug users, those who had recently used MDMA were twice as likely to meet criteria for marijuana and pain reliever/opioid use disorders. They were also about twice as likely as former MDMA users to meet criteria for marijuana, cocaine, and tranquilizer use disorders. Seven out of ten recent MDMA users report experiencing an SUD in the past year. Adults who have recently used MDMA should be screened for possible SUDs to ensure early detection and treatment.


Antileishmanial Activity of Disulfiram and Thiuram Disulfide Analogs in an Ex Vivo Model System Is Selectively Enhanced by the Addition of Divalent Metal Ions.
Current treatments for cutaneous and visceral leishmaniasis are toxic, expensive, difficult to administer, and limited in efficacy and availability. Disulfiram has primarily been used to treat alcoholism. More recently, it has shown some efficacy as therapy against protozoan pathogens and certain cancers, suggesting a wide range of biological activities. We used an ex vivo system to screen several thiuram disulfide compounds for antileishmanial activity. We found five compounds (compound identifier [CID] 7188, 5455, 95876, 12892, and 3117 [disulfiram]) with anti-Leishmania activity at nanomolar concentrations. We further evaluated these compounds with the addition of divalent metal salts based on studies that indicated these salts could potentiate the action of disulfiram. In addition, clinical studies suggested that zinc has some efficacy in treating cutaneous leishmaniasis. Several divalent metal salts were evaluated at 1 μM, which is lower than the normal levels of copper and zinc in plasma of healthy individuals. The leishmanicidal activity of disulfiram and CID 7188 were enhanced by several divalent metal salts at 1 μM. The in vitro therapeutic index (IVTI) of disulfiram and CID 7188 increased 12- and 2.3-fold, respectively, against L. major when combined with ZnCl2. The combination of disulfiram with ZnSO4 resulted in a 1.8-fold increase in IVTI against L. donovani. This novel combination of thiuram disulfides and divalent metal ions salts could have application as topical and/or oral therapies for treatment of cutaneous and visceral leishmaniasis.


Droplet-train induced spatiotemporal swelling regimes in elastomers.
In this work, we perform a combined experimental and numerical analysis of elastomer swelling dynamics upon impingement of a train of solvent droplets. We use time scale analysis to identify spatiotemporal regimes resulting in distinct boundary conditions that occur based on relative values of the absorption timescale and the droplet train period. We recognize that when either timescale is significantly larger than the other, two cases of quasi-uniform swelling occur. In contrast, when the two timescales are comparable, a variety of temporary geometrical features due to localized swelling are observed. We show that the swelling feature and its temporal evolution depends upon geometric scaling of polymer thickness and width relative to the droplet size. Based on this scaling, we identify six cases of localized swelling and experimentally demonstrate the swelling features for two cases representing limits of thickness and width. A finite element model of local swelling is developed and validated with experimental results for these two cases. The model is subsequently used to explore the swelling behavior in the rest of the identified cases. We show that depending upon the lateral dimension of the sample, swelling can locally exhibit mushroom, mesa, and cap like shapes. These deformations are magnified during the droplet-train impact but dissipate during post-train polymer equilibration. Our results also show that while swelling shape is a function of lateral dimensions of the sample, the extent of swelling increases with the elastomer sample thickness.


The impact of overdiagnosis on the selection of efficient lung cancer screening strategies.
The U.S. Preventive Services Task Force (USPSTF) recently updated their national lung screening guidelines and recommended low-dose computed tomography (LDCT) for lung cancer (LC) screening through age 80. However, the risk of overdiagnosis among older populations is a concern. Using four comparative models from the Cancer Intervention and Surveillance Modeling Network, we evaluate the overdiagnosis of the screening program recommended by USPSTF in the U.S. 1950 birth cohort. We estimate the number of LC deaths averted by screening (D) per overdiagnosed case (O), yielding the ratio D/O, to quantify the trade-off between the harms and benefits of LDCT. We analyze 576 hypothetical screening strategies that vary by age, smoking, and screening frequency and evaluate efficient screening strategies that maximize the D/O ratio and other metrics including D and life-years gained (LYG) per overdiagnosed case. The estimated D/O ratio for the USPSTF screening program is 2.85 (model range: 1.5-4.5) in the 1950 birth cohort, implying LDCT can prevent ∼3 LC deaths per overdiagnosed case. This D/O ratio increases by 22% when the program stops screening at an earlier age 75 instead of 80. Efficiency frontier analysis shows that while the most efficient screening strategies that maximize the mortality reduction (D) irrespective of overdiagnosis screen through age 80, screening strategies that stop at age 75 versus 80 produce greater efficiency in increasing life-years gained per overdiagnosed case. Given the risk of overdiagnosis with LC screening, the stopping age of screening merits further consideration when balancing benefits and harms.


Hip Labral Augmentation With Tibialis Anterior Tendon Allograft Using the Knotless Pull-Through Technique.
The importance of the labrum in the biomechanics of the hip joint is well documented. Labral tears are the most common pathology in patients undergoing hip arthroscopy and therefore appropriate labral management is vital. Labral preservation has been advocated as a superior alternative to labral excision in terms of clinical outcomes. While reconstruction of the labrum is recommended for irreparable tears, labral augmentation is a viable alternative for labral function restoration under certain indications. This Technical Note will describe a method for arthroscopic hip labral augmentation using an anterior tibialis tendon allograft and the pull-through technique.


Acidic pH changes receptor binding specificity of Helicobacter pylori: a binary adhesion model in which surface heat shock (stress) proteins mediate sulfatide recognition in gastric colonization.
The gastric pathogen helicobacter pylori is one of a number of bacteria which bind specifically to gangliotetraosylceramide, gangliotriaosylceramide, and phosphatidylethanolamine in vitro at neutral pH. Since this organism encounters an acid pH during initial infection of the stomach, we have monitored the effect of pH on receptor binding specificity and found induction of specific binding to sulfoglycolipids (sulfatide) following brief treatment at low pH. We have previously shown that heat shock proteins (hsps) bind to sulfatide, and the suspicion that this was a stress-induced response is supported by the fact that a similar change in H. pylori binding specificity was observed if the organisms were briefly exposed to heat shock treatment. Following the stress stimulus, the change in glycolipid binding specificity was prevented by the inclusion of inhibitors of protein synthesis or by incubation with anti-hsp antibodies. Expression of hsps in the surface extract and surface reactivity with anti-hsp antibodies correlated with the change in glycolipid binding specificity. Despite the presence of high levels of H. pylori cell surface urease activity which may neutralize the microenvironmental pH, the acid-induced change in binding specificity was enhanced in the presence of urea. These studies suggest that cell surface hsps mediate sulfatide recognition by this organism under stress conditions. A binary receptor model is proposed for gastric colonization by H. pylori.


Drug formularies--good or evil? The clinical perspective.
Drug formularies, designed to encourage more clinically effective and cost effective prescribing, are now in widespread use in the secondary care system in the UK. Amongst their disadvantages, formularies are expensive to produce and require regular updating and policing. In addition, formularies do not consider alternate non-prescribing cost containment measures, and over-rigid application of formulary systems may alienate senior medical staff. In order to maximize the acceptability of formularies to all doctors, it is essential that the local Drugs and Therapeutics Committee has wide representation and focuses on clinical efficacy rather than simply on cost. Realistically, it is important that formulary committees are sufficiently flexible to allow the introduction of innovative, albeit expensive, new compounds. Enforcement of formularies into general practice is not presently achievable, but many primary care teams, realizing the benefits, have successfully introduced their own formularies to improve clinical drug usage and cost containment. If a reduction in costs is the primary aim, the global introduction of formulary systems may not be the best solution, and specific targeting of drug therapy may prove a more effective alternative. Indeed, in the South Glamorgan Health Authority, the introduction of a targeting system for the ten therapeutic areas with the highest expenditure allowed substantial savings to be made.


Multiple variable motivators involved in the recruitment of physicians for the Indian Health Service.
Attracting physicians to serve in isolated areas, often with marginal facilities, support staff, and remuneration, has long been a problem of the Indian Health Service (IHS). Until recently the physician draft was instrumental in motivating physicians to accept such assignments. Realizing that this "negative incentive" would no longer operate when the draft ended as of July 1, 1973, in the fall of 1972 the IHS staff launched some major "positive" efforts to recruit physicians. The mass media and other communication techniques were used to try to sell U.S. physicians and medical students on what the Service could offer them in terms of adventure, challenge, personal fulfillment, idealism, and the opportunity to be part of a progressive, comprehensive health system. Such efforts assisted in recruiting 69 physicians to begin service in July 1973. These 69 were in addition to approximately 100 who had already been recruited from among persons who had expressed interest in joining the Indian Health Service or who had applied to it before inception of this major recruitment effort. As of July 1, 1973, however, the Service was still approximately 30 physicians short of filling 200 vacancies. In June and July of 1973, an evaluation was done to determine what had motivated the 169 physicians to join the Indian Health Service. They were asked an open ended question: What prompted you to seek employment with the Indian Health Service? Whether physicians listed personal, subjective motivators or recruitment techniques was of as much interest as the specific answers they gave. More than 75 percent (100 of 129) mentioned recruitment techniques, such as magazine advertisements, rather than personal motivating factors, such as challenge. Personal contact with a present or former IHS physician seemed to be especially influential in attracting physicians. The present state of the recruitment art does not provide the means to adequately identify, qualify, quantify, and rank the multiple motivators that prompt physicians to join a program such as that of the Indian Health Service; nor does it allow for meaningful, predetermined identification of a limited pool of physicians who would have a high probability of joining such a program. At present, the best recruitment strategy appears to be to saturate the entire physician "marketplace" stressing with a variety of techniques the positive aspects of IHS employment. Physicians then select themselves for such employment by exhibiting a more than casual interest in the Indian Health Service.


Tandem diastereo- and enantioselective preparation of aryl and alkyl cyclopropyl carbinols with three adjacent stereocenters using perhydrobenzoxazines and diethylzinc.
The enantio- and diastereoselective one-pot ethylation/cyclopropanation is efficiently promoted by a chiral perhydrobenzoxazine. The catalytic system tolerates a wide range of di- and trisubstituted α,β-unsaturated aldehydes and has been found to be highly diastereo- and enantioselective. Enals leading to intermediates lacking allylic strain or with either A(1,2) or A(1,3) strain afford the corresponding syn hydroxycyclopropanes very selectively. While α-methyl enals are successfully ethylated/cyclopropanated, the presence of bulky substituents at the alpha position of the enal constitutes a limitation to the substrate scope. The use of 1,1-diiodoethane allows the obtention of the corresponding enantioenriched cyclopropylcarbinol, which bears carbon-substituents at all three positions of the ring, with good enantiocontrol, although moderate diastereoselectivity. A procedure for the asymmetric one-pot arylation/cyclopropanation of enals is proposed, which involves the use of triarylboroxin, diethylzinc and diiodomethane.


Hybridization properties of DNA sequences directing the synthesis of messenger RNA and heterogeneous nuclear RNA.
The relationship of the DNA sequences from which polyribosomal messenger RNA (mRNA) and heterogeneous nuclear RNA (NRNA) of mouse L cells are transcribed was investigated by means of hybridization kinetics and thermal denaturation of the hybrids. Hybridization was performed in formamide solutions at DNA excess. Under these conditions most of the hybridizing mRNA and NRNA react at values of D(o)t (DNA concentration multiplied by time) expected for RNA transcribed from the nonrepeated or rarely repeated fraction of the genome. However, a fraction of both mRNA and NRNA hybridize at values of D(o)t about 10,000 times lower, and therefore must be transcribed from highly redundant DNA sequences. The fraction of NRNA hybridizing to highly repeated sequences is about 1.7 times greater than the corresponding fraction of mRNA. The hybrids formed by the rapidly reacting fractions of both NRNA and mRNA melt over a narrow temperature range with a midpoint about 11 degrees C below that of native L cell DNA. This indicates that these hybrids consist of partially complementary sequences with approximately 11% mismatching of bases. Hybrids formed by the slowly reacting fraction of NRNA melt within 4 degrees -6 degrees C of native DNA, indicating very little, if any, mismatching of bases. Hybrids of the slowly reacting components of mRNA, formed under conditions of sufficiently low RNA input, have a high thermal stability, similar to that observed for hybrids of the slowly reacting NRNA component. However, when higher inputs of mRNA are used, hybrids are formed which have a strikingly lower thermal stability. This observation can be explained by assuming that there is sufficient similarity among the relatively rare DNA sequences coding for mRNA so that under hybridization conditions, in which these DNA sequences are not truly in excess, reversible hybrids exhibiting a considerable amount of mispairing are formed. The fact that a comparable phenomenon has not been observed for NRNA may mean that there is less similarity among the relatively rare DNA sequences coding for NRNA than there is among the rare sequences coding for mRNA.


E-cadherin-mediated cell-cell adhesion prevents invasiveness of human carcinoma cells.
The ability of carcinomas to invade and to metastasize largely depends on the degree of epithelial differentiation within the tumors, i.e., poorly differentiated being more invasive than well-differentiated carcinomas. Here we confirmed this correlation by examining various human cell lines derived from bladder, breast, lung, and pancreas carcinomas. We found that carcinoma cell lines with an epithelioid phenotype were noninvasive and expressed the epithelium-specific cell-cell adhesion molecule E-cadherin (also known as Arc-1, uvomorulin, and cell-CAM 120/80), as visualized by immunofluorescence microscopy and by Western and Northern blotting, whereas carcinoma cell lines with a fibroblastoid phenotype were invasive and had lost E-cadherin expression. Invasiveness of these latter cells could be prevented by transfection with E-cadherin cDNA and was again induced by treatment of the transfected cells with anti-E-cadherin mAbs. These findings indicate that the selective loss of E-cadherin expression can generate dedifferentiation and invasiveness of human carcinoma cells, and they suggest further that E-cadherin acts as an invasion suppressor.


Methods in comparative phylogeography, and their application to studying evolution in the north american aridlands.
Historical biogeography and comparative phylogeography have much in common. Both seek to discover common historical patterns in the elements of biotas, although typically at different tiers of evolutionary history. Comparative phylogeography is based on phylogeographic analyses of multiple taxa, usually widespread species. By comparing the phylogeographic structures of numerous widespread sympatric species, one can infer whether the current fauna has been historically stable, as evidenced by the relative frequency of geographically congruent reciprocally monophyletic groups. Alternatively, if species distributions are ephemeral over evolutionary time, a mixture of phylogeographic structures is expected. Coalescence analyses contribute information about history irrespective of whether haplotype phylogenies are structured or not. In the aridlands of North America, several isolating events are evident in the phylogeographic patterns of birds, mammals and herps. A mid-peninsular seaway in Baja California, dated at ca. one million years before present, had a pervasive effect, with 13 of 16 assayed species showing a concordant split. Hence, this community appears to have been a stable assemblage of species over the past one million years. In contrast, the avifauna of the Sonoran-Chihuahuan deserts consists of two species with a concordant split and three other species that are undifferentiated across both deserts. Hence, the species in this area have had different histories. The Baja biota appears to resemble its ancestral configuration to a greater degree than the Sonoran-Chihuahuan one. A deeper evolutionary event separated taxa in Baja California from the eastern deserts, showing that the aridlands fauna was affected by events at different times resulting in overlain tiers of history.


Dynamics of cohesin proteins REC8, STAG3, SMC1 beta and SMC3 are consistent with a role in sister chromatid cohesion during meiosis in human oocytes.
Sister chromatid cohesion is essential for ordered chromosome segregation at mitosis and meiosis. This is carried out by cohesin complexes, comprising four proteins, which seem to form a ring-like complex. Data from animal models suggest that loss of sister chromatid cohesion may be involved in age-related non-disjunction in human oocytes. Here, we describe the distribution of cohesins throughout meiosis in human oocytes. We used immunofluorescence in human oocytes at different meiotic stages to detect cohesin subunits REC8, STAG3, SMC1 beta and SMC3, [also synaptonemal complex (SC) protein 3 and shugoshin 1]. Samples from euploid fetuses and adult women were collected, and 51 metaphase I (MI) and 113 metaphase II (MII) oocytes analyzed. SMC1 beta transcript levels were quantified in 85 maturing germinal vesicle (GV) oocytes from 34 women aged 19-43 years by real-time PCR. At prophase I, cohesin subunits REC8, STAG3, SMC1 beta and SMC3 overlapped with the lateral element of the SC. Short cohesin fibers are observed in the oocyte nucleus during dictyate arrest. All four subunits are observed at centromeres and along chromosomal arms, except at chiasmata, at MI and are present at centromeric domains from anaphase I to MII. SMC1 beta transcripts were detected (with high inter-sample variability) in GV oocytes but no correlation between SMC1 beta mRNA levels and age was found. The dynamics of cohesins REC8, STAG3, SMC1 beta and SMC3 suggest their participation in sister chromatid cohesion throughout the whole meiotic process in human oocytes. Our data do not support the view that decreased levels of SMC1 beta gene expression in older women are involved in age-related non-disjunction.


Assessment of the prebiotic effect of quinoa and amaranth in the human intestinal ecosystem.
Quinoa and amaranth belong to the group of the so called "superfoods" and have a nutritional composition that confers multiple benefits. In this work, we explored the possibility of these foods exhibiting a prebiotic effect. These pseudocereals were subjected to an in vitro digestion and used as carbon sources in batch cultures with faecal human inocula. The effects on the microbiota composition and their metabolic products were determined by assessment of variations in pH, short-chain fatty acid (SCFA) production and changes in the dynamic bacterial populations by fluorescence in situ hybridization (FISH). After 48 h of incubation, the total SCFAs were 106.5 mM for quinoa and 108.83 mM for amaranth, in line with the decrease in pH. Considerable differences (p < 0.05) were found in certain microbial groups, including Bifidobacterium spp., Lactobacillus-Enterococcus, Atopobium, Bacteroides-Prevotella, Clostridium coccoides-Eubacterium rectale, Faecalibacterium prausnitzii and Roseburia intestinalis. Our research suggests that these pseudocereals can have the prebiotic potential and that their intake may improve dysbiosis or maintain the gastrointestinal health through a balanced intestinal microbiota, although additional studies are necessary.


The indirect nature of social motives: the relation of social approach and avoidance motives with likeability via extraversion and agreeableness.
The current study tested assumptions derived from the whole-trait theory (Fleeson, 2012), which proposes a connection between personality and motivation. We hypothesized that individual differences in social approach and avoidance motives are associated with personality as observed by others. In addition, we expected that observed personality links social approach and avoidance motives to interpersonal outcomes. The sample was composed of 83 young adults (25.3% males, Mage = 21.66 years) who had recently moved into a shared apartment. Roommates (N = 83; 50.6% males, Mage = 22.83 years) evaluated the newcomers on Extraversion, Agreeableness, and likeability. Approach motives had an indirect positive effect on likeability through other-reported Extraversion and Agreeableness. Although avoidance motives had some negative effects on likeability mediated through low Extraversion, they were positively associated with Agreeableness. These results demonstrate the complexity of social approach and avoidance motives. Moreover, they highlight the importance of motivational factors for observed personality.


[A meta-analysis of randomized controlled trials of tianeptine versus SSRI in the short-term treatment of depression].
A meta-analysis was performed to compare the efficacy of tianeptine and selective serotonin reuptake inhi-bitors (SSRI) in the short-term treatment of depression. Consecutive selection and inclusion processes allowed five stu-dies to be selected: two studies on tianeptine versus fluoxetine, two studies on tianeptine versus paroxetine, and one study on tianeptine versus sertraline. A total of 1 348 patients were included in the five studies; 681 subjects received an SSRI and 667 tianeptine. A strict step-by-step methodology was applied in order to legitimize this meta-analysis and to interpret the results. Considering all the patients or those with a Montgomery-Asberg Depression Rating Scale (MADRS) inclusion score greater or equal than 28, none of the assessed parameters (MADRS total score and responder rate) revealed any significant difference between the two treatment groups. Further analysis based on clinical global impression (CGI) items found no significant difference, except for CGI item 3 (therapeutic index), where a tendency (p=0.06 or 0.07 depending on the methodology) was found in favor of tianeptine. All in all, this study confirmed that tianeptine is at least as effective as SSRI, with a trend for a better acceptability profile in the treatment of depressed patients.


Antifungal effects of the nonlinear pharmacokinetics of cilofungin, a 1,3-beta-glucan synthetase inhibitor, during continuous and intermittent intravenous infusions in treatment of experimental disseminated candidiasis.
Cilofungin (LY-121019) is a fungicidal cell wall-active 1,3-beta-glucan synthetase inhibitor with a short plasma half-life and saturable nonlinear plasma pharmacokinetics. To optimize the in vivo efficacy of this compound, we studied the effects of its linear and nonlinear pharmacokinetics during continuous versus intermittent intravenous infusion of cilofungin in the treatment of experimental disseminated candidiasis in persistently granulocytopenic rabbits. Six groups of rabbits were studied, untreated controls (n = 32) and five cilofungin dosage regimen groups consisting of the following: 25 mg/kg of body weight intravenously twice daily (VLoINT) (n = 9); 50 mg/kg twice daily (LoINT) (n = 9); 90 mg/kg twice daily (HiINT) (n = 11); 5 mg/kg/h for 18 h/day (LoCI) (n = 7); and 10 mg/kg/h for 18 h/day (HiCI) (n = 7). All regimens achieved plasma concentrations exceeding the MIC for Candida albicans (0.25 microgram/ml). In vitro timed kill assays found that the fungicidal activity and rate of kill by cilofungin above the MIC for C. albicans was concentration dependent. At the lower dosage regimens (VLoINT, LoINT, and LoCI), cilofungin followed linear plasma pharmacokinetics, whereas at higher doses (HiCI and HiINT), nonlinear kinetics consistent with a saturated elimination pathway(s) were observed. Only HiCI and HiINT produced a 10(3)- to 10(4)-fold reduction in CFU per gram in candidiasis of the brain (P less than or equal to 0.001). HiCI and HiINT also significantly reduced infection in the choroid (P less than or equal to 0.05). All regimens, except VLoInt, significantly (P less than or equal to 0.01) reduced tissue infections in lung, liver, spleen, and kidney. However, only the regimens with nonlinear saturation kinetics (HiCI and HiINT) produced a 10(6) reduction in the spleen and a > 10(5) reduction of C. albicans in the kidney and liver. A simple doubling of the dosage from LoCI to HiCI resulted in tissue concentrations that were 10 times higher and a 10(2)- to 10(4)-fold-greater antifungal effect. There was a direct correlation (r2 = 0.83) between tissue concentrations of cilofungin and antifungal activity. Thus, continuous and intermittent infusion dosage regimens that elicit nonlinear saturation plasma pharmacokinetics of cilofungin were associated with increased antifungal activity against experimental disseminated candidiasis.


Spring Wheat Tolerance and Resistance to Heterodera avenae in the Pacific Northwest.
The cereal cyst nematode Heterodera avenae reduces wheat yields in the Pacific Northwest. Previous evaluations of cultivar resistance had been in controlled environments. Cultivar tolerance had not been evaluated. Seven spring wheat trials were conducted in naturally infested fields in three states over 2 years. A split-plot design was used for all trials. Five trials evaluated both tolerance and resistance in 1.8-by-9-m plots treated or not treated with nematicides. Two trials evaluated resistance in 1-m head rows where each wheat entry was paired with an adjacent row of a susceptible cultivar. Cultivars with the Cre1 resistance gene ('Ouyen' and 'Chara') reduced the postharvest density of H. avenae under field conditions, confirming Cre1 parents as useful for germplasm development. Ouyen was resistant but it was also intolerant, producing significantly lower grain yield in controls than in plots treated with nematicides. Susceptible cultivars varied in tolerance. Undefined resistance was identified in one commercial cultivar ('WB-Rockland) and four breeding lines (UC1711, SO900163, SY-B041418, and SY-97621-05). This research was the first systematic field demonstration of potential benefits to be derived through development and deployment of cultivars with resistance plus tolerance to cereal cyst nematode in North America.


Association of Sickle Cell Trait and Hemoglobin S Percentage with Physical Fitness.
This study aimed to determine the association between sickle cell trait (SCT) as a binary variable and hemoglobin S percentage as a stratified categorical variable with aerobic and anaerobic fitness. This retrospective cohort study included all recruits who entered US Air Force Basic Training between January 2009 and December 2014. Fitness parameters among recruits with and without SCT were compared using a standardized fitness assessment of a 1.5-mile timed run, 1 min of push-ups, and 1 min of sit-ups. Performance was further compared by stratifying those with SCT by their hemoglobin S percentage (20%-29.99%, 30%-39.99%, and ≥40%). Of all recruits (N = 210,461) who entered training during the surveillance period, 2161 (1.0%) had SCT. After adjusting for age, sex, race, body mass index, and ambient temperature while conducting the fitness assessment, recruits with SCT were slower on their initial run than their peers without SCT by a mean (standard error) of 9.4 s (2.6 s) (P < 0.001) and completed 0.5 (0.3) fewer push-ups (P < 0.05); sit-up completion was statistically equivalent between the two groups. When retested 6 wk later, recruits with SCT improved their run time by a margin of 4.3 s (2.1 s) over their counterparts without SCT (P < 0.05). Baseline physical fitness was largely consistent across strata of hemoglobin S percentages; increased percentages were modestly correlated with faster run times (R = 0.374) and fewer push-ups (R = 0.339). As compared with their peers, recruits with SCT had slightly inferior aerobic fitness and similar anaerobic fitness at the outset of basic training, and gaps further narrowed over 6 wk of training. Stratifying recruits by their hemoglobin S percentage did not dramatically change the strength or direction of association.


Impact of Protective Footwear on Floor and Air Contamination of Intensive Care Units.
Use of protective footwear before entering the intensive care units is enforced with the assumption that it lowers the incidence of bacterial floor colonization. The present study was carried out to find the efficacy of protective footwear on bacterial floor colonization. The study was carried out in the intensive care unit of a tertiary care hospital. The study was divided into two phases of two weeks each, phase I with and phase II without use of protective footwear. Samples were taken at six different sites namely footwear exchange area; visitors /staff route; partitioned patient cubicle; central monitoring area; open patient cubicle and scrub up areas. Floor samples were taken at 0600, 1100, 1700 and 2200 hours and air samples at 0600 and 1700 hours. Bacteria were identified and colony forming units (cfu) measured from floor and colony forming units/metre(3) (cfu/m3) from air sample cultures. A total of 9521 bacterial colony forming units were isolated from 192 samples in phase I from the floor samples and 9971cfu from 192 samples in phase II. From 96 air samples in each phase, a mean of 262 cfu/m(3) in phase I and 220cfu/m(3) in phase II were isolated. The difference between the two phases was statistically not significant (p value > 0.05 for both). Floor and air colony counts showed no significant difference in the two phases with and without protective footwear. Protective footwear had no significant impact on bacterial contamination of floors.


A caballo regalao no se le mira el colmillo: Colonial mentality and Puerto Rican depression.
Dignifying the colonizer and depreciating the colonized is a reflection of internalized colonial oppression (i.e., colonial mentality). The current study examined the effect of colonial mentality on depression symptoms in a sample of mainland Puerto Ricans (N = 352). A structural equation model was examined, in which colonial mentality was hypothesized to be directly and positively associated with depression symptoms. The proposed model also tested the indirect effect of colonial mentality on depression symptoms via acculturative stress. Results indicated that a full mediation structural equation model (SEM) had a better fit to the data than our hypothesized partial mediation model. Bias-corrected bootstrapping indicated that the effect of colonial mentality on depressive symptoms was mediated by acculturative stress. That is, colonial mentality increased the risk of experiencing depression symptoms in Puerto Ricans when they felt pressured to maintaining a connection with Puerto Rican culture and society and when they experienced rejection by the society they want to emulate (acculturative stress). The current results underscore the need for researchers and clinicians to consider and assess colonial mentality when conceptualizing depression symptoms among mainland Puerto Ricans. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Visceral fat adipokine secretion is associated with systemic inflammation in obese humans.
Although excess visceral fat is associated with noninfectious inflammation, it is not clear whether visceral fat is simply associated with or actually causes metabolic disease in humans. To evaluate the hypothesis that visceral fat promotes systemic inflammation by secreting inflammatory adipokines into the portal circulation that drains visceral fat, we determined adipokine arteriovenous concentration differences across visceral fat, by obtaining portal vein and radial artery blood samples, in 25 extremely obese subjects (mean +/- SD BMI 54.7 +/- 12.6 kg/m(2)) during gastric bypass surgery at Barnes-Jewish Hospital in St. Louis, Missouri. Mean plasma interleukin (IL)-6 concentration was approximately 50% greater in the portal vein than in the radial artery in obese subjects (P = 0.007). Portal vein IL-6 concentration correlated directly with systemic C-reactive protein concentrations (r = 0.544, P = 0.005). Mean plasma leptin concentration was approximately 20% lower in the portal vein than in the radial artery in obese subjects (P = 0.0002). Plasma tumor necrosis factor-alpha, resistin, macrophage chemoattractant protein-1, and adiponectin concentrations were similar in the portal vein and radial artery in obese subjects. These data suggest that visceral fat is an important site for IL-6 secretion and provide a potential mechanistic link between visceral fat and systemic inflammation in people with abdominal obesity.


Hazardous air pollutants and primary liver cancer in Texas.
The incidence of hepatocellular carcinoma (HCC), the most common primary liver cancer, is increasing in the US and tripled during the past two decades. The reasons for such phenomenon remain poorly understood. Texas is among continental states with the highest incidence of liver cancer with an annual increment of 5.7%. Established risk factors for HCC include Hepatitis B and C (HBV, HCV) viral infection, alcohol, tobacco and suspected risk factors include obesity and diabetes. While distribution of these risk factors in the state of Texas is similar to the national data and homogeneous, the incidence of HCC in this state is exceptionally higher than the national average and appears to be dishomogeneous in various areas of the state suggesting that other non-recognized risk factors might play a role. No population-based studies are currently available investigating the effect of exposure to Hazardous Air Pollutants (HAPs) as a contributing risk factor for liver cancer. Incidence rate of liver cancer in Texas by counties for the time period between 2002 and 2012 was obtained from the Texas Cancer Registry (TCR). Through Principal Component Analysis (PCA) a subgroup of pollutants, explaining almost all the dataset variability, were identified and used to cluster Texas counties. The analysis generated 4 clusters showing liver cancer rate either higher or lower than national average in association with either high or low levels of HAPs emission in the environment. The study shows that the selected relevant HAPs, 10 among 253 analyzed, produce a significant correlation (P = 0.01-0.05) and some of these have been previously identified as carcinogens. An association between the increased production and consequent exposure to these HAPs and a higher presence of liver cancer in certain counties is suggested. This study provides a new insight on this complex multifactorial disease suggesting that environmental substances might play a role in the etiology of this cancer.


Hypovitaminosis D and bone mineral metabolism and bone density in hyperthyroidism.
Little is known about the impact of concomitant vitamin D deficiency on bone mineral density in hyperthyroidism. Therefore, we evaluated bone mineral measures in vitamin D-deficient and sufficient patients with hyperthyroidism. Thirty newly diagnosed consecutive patients with hyperthyroidism were included. Blood samples were used for measurement of calcium, phosphate, alkaline phosphatase, 25-hydroxy vitamin D [25(OH) D], and parathyroid hormone (PTH). Bone mineral density (BMD) was measured at the hip, spine, and forearm. The patients were divided into vitamin D-deficient (< 25 nmol/L) and vitamin D-sufficient groups (≥ 25 nmol/L). Eight (26.6%) patients had 25(OH) D levels less than 25 nmol/L, with mean ± standard deviation (SD) level of 16.5 ± 3.2 (vitamin D-deficient group 1), and the remainder had a mean ± SD of 46.0 ± 13.5 nmol/L (vitamin D-sufficient group 2). Serum-intact PTH levels were significantly higher in group 1 compared with those in group 2 (31.2 ± 16.3 vs 18.0 ± 13.1 pg/mL; p=0.041). In the vitamin D-deficient group, the mean BMD T-scores were in the osteoporotic range at hip and forearm (-2.65 ± 1.13 and -3.04 ± 1.3) and in the osteopenia range at lumbar spine (-1.83 ± 1.71). However, in vitamin D-sufficient group, the mean BMD T-scores were in the osteopenia range (-1.64 ± 1.0, -1.27 ± 1.6, and -1.60 ± 0.7) at hip, forearm, and lumbar spine, respectively. The mean BMD Z-scores were also significantly lower in vitamin D-deficient group compared with those in vitamin D-sufficient group. Finally, BMD values (gm/cm(2)) at the hip and forearm were significantly lower in the vitamin D-deficient group compared with those in the vitamin D-sufficient group. In conclusion, hyperthyroid patients with concomitant vitamin D deficiency had lower BMD compared with vitamin D-sufficient patients.


Swedish Lung Cancer Radiation Study Group: predictive value of age at diagnosis for radiotherapy response in patients with non-small cell lung cancer.
The aim of the present study was to investigate the impact of age at diagnosis on prognosis in patients treated with curatively intended radiotherapy for NSCLC. This is a joint effort among all the Swedish Oncology Departments that includes all identified patients with a diagnosed non-small cell lung cancer that have been subjected to curatively intended irradiation (≥50 Gy) treated during 1990 to 2000. Included patients had a histopathological/cytological diagnosis date as well as a death date or a last follow-up date. The following variables were studied in relation to overall and disease-specific survival: age, gender, histopathology, time period, smoking status, stage and treatment. The median overall survival of all 1146 included patients was 14.7 months, while the five-year overall survival rate was 9.5%. Younger patients (<55 years), presented with a more advanced clinical stage but had yet a significantly better overall survival compared with patients in the age groups 55-64 years (p = 0.035) and 65-74 years (p = 0.0097) in a multivariate Cox regression analysis. The overall survival of patients aged ≥75 years was comparable to those aged <55 years. In this large retrospective study we describe that patients younger than 55 years treated with curatively intended radiotherapy for NSCLC have a better overall survival than patients aged 55-64 and 65-74 years and that younger patients seem to benefit more from the addition of surgery and/or chemotherapy to radiotherapy. Due to the exploratory nature of the study, these results should be confirmed in future prospective trials.


Tracking of marine predators to protect Southern Ocean ecosystems.
Southern Ocean ecosystems are under pressure from resource exploitation and climate change1,2. Mitigation requires the identification and protection of Areas of Ecological Significance (AESs), which have so far not been determined at the ocean-basin scale. Here, using assemblage-level tracking of marine predators, we identify AESs for this globally important region and assess current threats and protection levels. Integration of more than 4,000 tracks from 17 bird and mammal species reveals AESs around sub-Antarctic islands in the Atlantic and Indian Oceans and over the Antarctic continental shelf. Fishing pressure is disproportionately concentrated inside AESs, and climate change over the next century is predicted to impose pressure on these areas, particularly around the Antarctic continent. At present, 7.1% of the ocean south of 40°S is under formal protection, including 29% of the total AESs. The establishment and regular revision of networks of protection that encompass AESs are needed to provide long-term mitigation of growing pressures on Southern Ocean ecosystems.


HSP90 functions in the circadian clock through stabilization of the client F-box protein ZEITLUPE.
The autoregulatory loops of the circadian clock consist of feedback regulation of transcription/translation circuits but also require finely coordinated cytoplasmic and nuclear proteostasis. Although protein degradation is important to establish steady-state levels, maturation into their active conformation also factors into protein homeostasis. HSP90 facilitates the maturation of a wide range of client proteins, and studies in metazoan clocks implicate HSP90 as an integrator of input or output. Here we show that the Arabidopsis circadian clock-associated F-box protein ZEITLUPE (ZTL) is a unique client for cytoplasmic HSP90. The HSP90-specific inhibitor geldanamycin and RNAi-mediated depletion of cytoplasmic HSP90 reduces levels of ZTL and lengthens circadian period, consistent with ztl loss-of-function alleles. Transient transfection of artificial microRNA targeting cytoplasmic HSP90 genes similarly lengthens period. Proteolytic targets of SCF(ZTL), TOC1 and PRR5, are stabilized in geldanamycin-treated seedlings, whereas the levels of closely related clock proteins, PRR3 and PRR7, are unchanged. An in vitro holdase assay, typically used to demonstrate chaperone activity, shows that ZTL can be effectively bound, and aggregation prevented, by HSP90. GIGANTEA, a unique stabilizer of ZTL, may act in the same pathway as HSP90, possibly linking these two proteins to a similar mechanism. Our findings establish maturation of ZTL by HSP90 as essential for proper function of the Arabidopsis circadian clock. Unlike metazoan systems, HSP90 functions here within the core oscillator. Additionally, F-box proteins as clients may place HSP90 in a unique and more central role in proteostasis.


CLONIDINE STIMULATION TEST FOR GH DEFICIENCY: A NEW LOOK AT SAMPLE TIMING.
In the glucagon stimulation test (GST), the occurrence of peak growth hormone (GH) levels at typical times is an indication of normal secretion. This has not been studied for the clonidine stimulation test (CST). The 120-minute time is rarely the peak, and previous reports suggest it can be omitted. This study aimed to evaluate the meaning and utility of peak time in the CST and the significance of shortening the test. CSTs performed on 250 consecutive subjects in a single center were evaluated for results (GH sufficient or deficient) and result of confirmatory GST with respect to the peak time of the CST. Peak GH occurred typically at 30, 60, and 90 minutes (91.6% of tests, versus 60% expected) (P<.001). A total of 132 of 155 (85.15%) sufficient tests occurred at typical times, versus 66 of 97 (68%) deficient tests (P<.05). Typicality of timing did not follow in the confirmatory GST and did not predict the final result of testing. Removal of the 120-minute sample affected the final result in 0.4% of evaluations. The timing of the GH peak is not useful when interpreting the CST. The CST is equally effective when terminated at 90 minutes from stimulation.


Physiological assessment of coronary artery disease in the cardiac catheterization laboratory: a scientific statement from the American Heart Association Committee on Diagnostic and Interventional Cardiac Catheterization, Council on Clinical Cardiology.
With advances in technology, the physiological assessment of coronary artery disease in patients in the catheterization laboratory has become increasingly important in both clinical and research applications, but this assessment has evolved without standard nomenclature or techniques of data acquisition and measurement. Some questions regarding the interpretation, application, and outcome related to the results also remain unanswered. Accordingly, this consensus statement was designed to provide the background and evidence about physiological measurements and to describe standard methods for data acquisition and interpretation. The most common uses and support data from numerous clinical studies for the physiological assessment of coronary artery disease in the cardiac catheterization laboratory are reviewed. The goal of this statement is to provide a logical approach to the use of coronary physiological measurements in the catheterization lab to assist both clinicians and investigators in improving patient care.


Experimental meningococcal sepsis in congenic transgenic mice expressing human transferrin.
Severe meningococcal sepsis is still of high morbidity and mortality. Its management may be improved by an experimental model allowing better understanding of its pathophysiology. We developed an animal model of meningococcal sepsis in transgenic BALB/c mice expressing human transferrin. We studied experimental meningococcal sepsis in congenic transgenic BALB/c mice expressing human transferrin by transcriptional profiling using microarray analysis of blood and brain samples. Genes encoding acute phase proteins, chemokines and cytokines constituted the largest strongly regulated groups. Dynamic bioluminescence imaging further showed high blood bacterial loads that were further enhanced after a primary viral infection by influenza A virus. Moreover, IL-1 receptor-associated kinase-3 (IRAK-3) was induced in infected mice. IRAK-3 is a negative regulator of Toll-dependant signaling and its induction may impair innate immunity and hence result in an immunocompromised state allowing bacterial survival and systemic spread during sepsis. This new approach should enable detailed analysis of the pathophysiology of meningococcal sepsis and its relationships with flu infection.


Human immunodeficiency virus type 1-specific cytotoxic T lymphocytes release gamma interferon, tumor necrosis factor alpha (TNF-alpha), and TNF-beta when they encounter their target antigens.
Human immunodeficiency virus type 1 (HIV-1) infection is associated with elevated levels of inflammatory cytokines in the serum and cerebrospinal fluid of infected persons, but the sources of these proteins as well as the specific stimuli which trigger their production and release have not been fully defined. In this study, we evaluated the ability of HIV-1-specific cytotoxic T-lymphocyte (CTL) clones derived from seropositive persons to release gamma interferon (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), and TNF-beta upon contact with target cells presenting viral antigen. Peripheral blood- and cerebrospinal fluid-derived HIV-1-specific CD3+ CD4- CD8+ CTL clones as well as freshly isolated peripheral blood mononuclear cells from infected persons were tested in parallel for HIV-1-specific cytotoxicity and cytokine release. Target cells consisted of autologous and allogeneic B-lymphoblastoid cell lines sensitized with synthetic HIV-1 peptides containing the epitopes recognized by these CTL. Cytokine production was measured by specific enzyme-linked immunosorbent assay of culture supernatant fluid. HIV-1-specific CTL clones directed at envelope, Gag, reverse transcriptase, and Nef epitopes specifically released IFN-gamma, TNF-alpha, and TNF-beta upon contact with their relevant target epitopes but not following contact with irrelevant epitopes. These cytokines were released in an HLA class I-restricted fashion, and release was detectable as early as 4 to 6 h of incubation and remained elevated at 48 h. Fresh peripheral blood mononuclear cells from a seropositive person likewise released IFN-gamma in an antigen-specific and HLA class I-restricted manner when incubated with target cells presenting a peptide containing a CTL epitope, paralleling the HIV-specific cytolytic activity of these cells. These studies indicate that in addition to mediating direct cytotoxicity, HIV-1-specific CTL may affect other immune responses by releasing IFN-gamma, TNF-alpha, and TNF-beta. Elevated levels of these cytokines which have been detected in serum and cerebrospinal fluid of infected persons may be due at least in part to the persistent HIV-1-specific CTL response.


TNF and granulocyte macrophage-colony stimulating factor interdependence mediates inflammation via CCL17.
TNF and granulocyte macrophage-colony stimulating factor (GM-CSF) have proinflammatory activity and both contribute, for example, to rheumatoid arthritis pathogenesis. We previously identified a new GM-CSF→JMJD3 demethylase→interferon regulatory factor 4 (IRF4)→CCL17 pathway that is active in monocytes/macrophages in vitro and important for inflammatory pain, as well as for arthritic pain and disease. Here we provide evidence for a nexus between TNF and this pathway, and for TNF and GM-CSF interdependency. We report that the initiation of zymosan-induced inflammatory pain and zymosan-induced arthritic pain and disease are TNF dependent. Once arthritic pain and disease are established, blockade of GM-CSF or CCL17, but not of TNF, is still able to ameliorate them. TNF is required for GM-CSF-driven inflammatory pain and for initiation of GM-CSF-driven arthritic pain and disease, but not once they are established. TNF-driven inflammatory pain and TNF-driven arthritic pain and disease are dependent on GM-CSF and mechanistically require the same downstream pathway involving GM-CSF→CCL17 formation via JMJD3-regulated IRF4 production, indicating that GM-CSF and CCL17 can mediate some of the proinflammatory and algesic actions of TNF. Given we found that TNF appears important only early in arthritic pain and disease progression, targeting a downstream mediator, such as CCL17, which appears to act throughout the course of disease, could be effective at ameliorating chronic inflammatory conditions where TNF is implicated.


'Costa da Morte' ataxia is spinocerebellar ataxia 36: clinical and genetic characterization.
Spinocerebellar ataxia 36 has been recently described in Japanese families as a new type of spinocerebellar ataxia with motor neuron signs. It is caused by a GGCCTG repeat expansion in intron 1 of NOP56. Family interview and document research allowed us to reconstruct two extensive, multigenerational kindreds stemming from the same village (Costa da Morte in Galicia, Spain), in the 17th century. We found the presence of the spinocerebellar ataxia 36 mutation co-segregating with disease in these families in whom we had previously identified an ~0.8 Mb linkage region to chromosome 20 p. Subsequent screening revealed the NOP56 expansion in eight additional Galician ataxia kindreds. While normal alleles contain 5-14 hexanucleotide repeats, expanded alleles range from ~650 to 2500 repeats, within a shared haplotype. Further expansion of repeat size was frequent, especially upon paternal transmission, while instances of allele contraction were observed in maternal transmissions. We found a total of 63 individuals carrying the mutation, 44 of whom were confirmed to be clinically affected; over 400 people are at risk. We describe here the detailed clinical picture, consisting of a late-onset, slowly progressive cerebellar syndrome with variable eye movement abnormalities and sensorineural hearing loss. There were signs of denervation in the tongue, as well as mild pyramidal signs, but otherwise no signs of classical amyotrophic lateral sclerosis. Magnetic resonance imaging findings were consistent with the clinical course, showing atrophy of the cerebellar vermis in initial stages, later evolving to a pattern of olivo-ponto-cerebellar atrophy. We estimated the origin of the founder mutation in Galicia to have occurred ~1275 years ago. Out of 160 Galician families with spinocerebellar ataxia, 10 (6.3%) were found to have spinocerebellar ataxia 36, while 15 (9.4%) showed other of the routinely tested dominant spinocerebellar ataxia types. Spinocerebellar ataxia 36 is thus, so far, the most frequent dominant spinocerebellar ataxia in this region, which may have implications for American countries associated with traditional Spanish emigration.