Thiosemicarbazones reprogram pancreatic cancer bidirectional oncogenic signaling between cancer cells and stellate cells to suppress desmoplasia.

Standard treatments have shown dismal activity against pancreatic cancer (PC), due in part to the development of a dense stroma (desmoplasia). This perspective discusses the development of the di-2-pyridylketone thiosemicarbazones that overcomes bidirectional oncogenic signaling between PC cells and pancreatic stellate cells (PSCs), which is critical for desmoplasia development. This activity is induced by the up-regulation of the metastasis suppressor, N-myc downstream-regulated gene-1 (NDRG1), which inhibits oncogenic signaling via HGF, IGF-1 and Sonic Hedgehog pathway. More recent studies have deciphered additional pathways including those mediated by Wnt and tenascin C that are secreted by PSCs to activate ß-catenin and YAP/TAZ signaling in PC cells. Suppression of bidirectional signaling between cell types presents a unique therapeutic opportunity.

Corrected and Republished: Applicability of Boston University approach for prediction of mesiodistal width of canines and premolars in the primary schoolchildren of rural Bengaluru: An in vivo study.

INTRODUCTION: Boston University (BU) approach is a method for early prediction of unerupted permanent mandibular teeth widths based on the mesiodistal widths (MDWs) of primary mandibular canines and first molars. The present study was conducted to test the validity of BU approach by comparing it with Tanaka-Johnston (T/J) approach in the contemporary population. AIMS AND OBJECTIVE: The aim of the study was to determine the applicability of BU approach for prediction of the MDWs of canines and premolars in the primary schoolchildren of rural Bengaluru. MATERIALS AND METHODS: The study was conducted in 100 healthy schoolchildren of rural Bengaluru aged between 7 and 11 years. The MDWs of canines and premolars were predicted using both T/J and the considered BU approaches for all the children and were compared. RESULTS: The correlation coefficient showed a statistically significant correlation between the predicted tooth size from the two predicted methods in the upper and lower arches (P < 0.001), with Pearson's correlation coefficient showing the very strong positive relationship (r = 0.7). Significant differences were seen between the mean predicted width of canines and premolars by both the approaches (P < 0.001). CONCLUSION: In spite of the limitations, we recommend the use of BU approach to predict arch length-tooth material discrepancy at an early age and to get at least an approximate estimation of the required space. We also advocate the necessity of further research on this approach prospectively.

Applicability of Boston University approach for prediction of mesiodistal width of canines and premolars in the primary schoolchildren of rural Bengaluru: An in vivo study.

INTRODUCTION: Boston University (BU) approach is a method for early prediction of unerupted permanent mandibular teeth widths based on the mesiodistal widths (MDWs) of primary mandibular canines and first molars. The present study was conducted to test the validity of BU approach by comparing it with Tanaka-Johnston (T/J) approach in the contemporary population. AIMS AND OBJECTIVE: The aim of the study was to determine the applicability of BU approach for prediction of the MDWs of canines and premolars in the primary schoolchildren of rural Bengaluru. MATERIALS AND METHODS: The study was conducted in 100 healthy schoolchildren of rural Bengaluru aged between 7 and 11 years. The MDWs of canines and premolars were predicted using both T/J and the considered BU approaches for all the children and were compared. RESULTS: The correlation coefficient showed a statistically significant correlation between the predicted tooth size from the two predicted methods in the upper and lower arches (P < 0.001), with Pearson's correlation coefficient showing the very strong positive relationship (r = 0.7). Significant differences were seen between the mean predicted width of canines and premolars by both the approaches (P < 0.001). CONCLUSION: In spite of the limitations, we recommend the use of BU approach to predict arch length-tooth material discrepancy at an early age and to get at least an approximate estimation of the required space. We also advocate the necessity of further research on this approach prospectively.

Parkinson's disease: Alterations in iron and redox biology as a key to unlock therapeutic strategies.

A plethora of studies indicate that iron metabolism is dysregulated in Parkinson's disease (PD). The literature reveals well-documented alterations consistent with established dogma, but also intriguing paradoxical observations requiring mechanistic dissection. An important fact is the iron loading in dopaminergic neurons of the substantia nigra pars compacta (SNpc), which are the cells primarily affected in PD. Assessment of these changes reveal increased expression of proteins critical for iron uptake, namely transferrin receptor 1 and the divalent metal transporter 1 (DMT1), and decreased expression of the iron exporter, ferroportin-1 (FPN1). Consistent with this is the activation of iron regulator protein (IRP) RNA-binding activity, which is an important regulator of iron homeostasis, with its activation indicating cytosolic iron deficiency. In fact, IRPs bind to iron-responsive elements (IREs) in the 3ꞌ untranslated region (UTR) of certain mRNAs to stabilize their half-life, while binding to the 5ꞌ UTR prevents translation. Iron loading of dopaminergic neurons in PD may occur through these mechanisms, leading to increased neuronal iron and iron-mediated reactive oxygen species (ROS) generation. The "gold standard" histological marker of PD, Lewy bodies, are mainly composed of α-synuclein, the expression of which is markedly increased in PD. Of note, an atypical IRE exists in the α-synuclein 5ꞌ UTR that may explain its up-regulation by increased iron. This dysregulation could be impacted by the unique autonomous pacemaking of dopaminergic neurons of the SNpc that engages L-type Ca+2 channels, which imparts a bioenergetic energy deficit and mitochondrial redox stress. This dysfunction could then drive alterations in iron trafficking that attempt to rescue energy deficits such as the increased iron uptake to provide iron for key electron transport proteins. Considering the increased iron-loading in PD brains, therapies utilizing limited iron chelation have shown success. Greater therapeutic advancements should be possible once the exact molecular pathways of iron processing are dissected.

High risk HPV infection prevalence and associated cofactors: a population-based study in female ISSSTE beneficiaries attending the HPV screening and early detection of cervical cancer program.

BACKGROUND: Cervical cancer is the second cause leading of malignancy-related death among Mexican women. The present study determined the population-based prevalence of high risk Human Papillomavirus (HR-HPV) infection and associated cofactors in female beneficiaries of the Institute of Security and Social Services for State Workers (ISSSTE) attending the Program for HPV Screening and Early Detection of Cervical Cancer and registered in the Women's Cancer Detection System (SIDECAM). METHODS: In a cross-sectional study, cervical samples from 115,651 female users of the program for HPV screening and early detection of cervical cancer recruited in 23 ISSSTE care centers were analyzed for HR-HPV. Logistic regression analyses, adjusting for potential confounders, were performed to determine the association of HR-HPV infection with sexual health and behavior variables and with positivity to cervical premalignant lesions by cytology. RESULTS: The overall prevalence of HR-HPV infection among female ISSSTE beneficiaries in the 2013-2015 period was 13%. A bivariate analysis of relevant variables for HR-HPV infection showed a statistically significant association for age, number of sexual partners, use of hormonal contraceptives and smoking. A statistical association was found between infection by HR-HPV with the use of hormonal contraceptives, number of sexual partners and smoking and association of HPV 16 and other non-16/18 HR-HPV infection with number of lifetime sexual partners and tobacco use adjusted for age, history of hormonal contraception, number of sexual partners and tobacco use with the exception of exposition variable itself. Similarly, an association was found between HR-HPV infection, regardless of the virus genotype, with positivity to cervical premalignant lesions adjusted for age, number of lifetime sexual partners, history of hormonal contraception and tobacco use. CONCLUSIONS: HR-HPV prevalence in female ISSSTE Women's Cancer Program users is similar to the population-based prevalence previously reported in Mexican women without cervical alterations. The ISSSTE robust screening and early detection program, based on cytology studies and HPV co-testing, allows us to know the prevalence of HR-HPV infection among female users of the service.

Explant analysis of the Biomet Magnum/ReCap metal-on-metal hip joint.

OBJECTIVES: The high revision rates of the DePuy Articular Surface Replacement (ASR) and the DePuy ASR XL (the total hip arthroplasty (THA) version) have led to questions over the viability of metal-on-metal (MoM) hip joints. Some designs of MoM hip joint do, however, have reasonable mid-term performance when implanted in appropriate patients. Investigations into the reasons for implant failure are important to offer help with the choice of implants and direction for future implant designs. One way to assess the performance of explanted hip prostheses is to measure the wear (in terms of material loss) on the joint surfaces. METHODS: In this study, a coordinate measuring machine (CMM) was used to measure the wear on five failed cementless Biomet Magnum/ReCap/ Taperloc large head MoM THAs, along with one Biomet ReCap resurfacing joint. Surface roughness measurements were also taken. The reason for revision of these implants was pain and/or adverse reaction to metal debris (ARMD) and/or elevated blood metal ion levels. RESULTS: The mean wear rate of the articulating surfaces of the heads and acetabular components of all six joints tested was found to be 6.1 mm3/year (4.1 to 7.6). The mean wear rate of the femoral head tapers of the five THAs was 0.054 mm3/year (0.021 to 0.128) with a mean maximum wear depth of 5.7 µm (4.3 to 8.5). CONCLUSION: Although the taper wear was relatively low, the wear from the articulating surfaces was sufficient to provide concern and was potentially large enough to have been the cause of failure of these joints. The authors believe that patients implanted with the ReCap system, whether the resurfacing prosthesis or the THA, should be closely monitored.Cite this article: S. C. Scholes, B. J. Hunt, V. M. Richardson, D. J. Langton, E. Smith, T. J. Joyce. Explant analysis of the Biomet Magnum/ReCap metal-on-metal hip joint. Bone Joint Res 2017;6:113-122. DOI: 10.1302/2046-3758.62.BJR-2016-0130.R2.

Glutathione S-transferase and MRP1 form an integrated system involved in the storage and transport of dinitrosyl-dithiolato iron complexes in cells.

Nitrogen monoxide (NO) is vital for many essential biological processes as a messenger and effector molecule. The physiological importance of NO is the result of its high affinity for iron in the active sites of proteins such as guanylate cyclase. Indeed, NO possesses a rich coordination chemistry with iron and the formation of dinitrosyl-dithiolato iron complexes (DNICs) is well documented. In mammals, NO generated by cytotoxic activated macrophages has been reported to play a role as a cytotoxic effector against tumor cells by binding and releasing intracellular iron. Studies from our laboratory have shown that two proteins traditionally involved in drug resistance, namely multidrug-resistance protein 1 and glutathione S-transferase, play critical roles in intracellular NO transport and storage through their interaction with DNICs (R.N. Watts et al., Proc. Natl. Acad. Sci. USA 103:7670-7675, 2006; H. Lok et al., J. Biol. Chem. 287:607-618, 2012). Notably, DNICs are present at high concentrations in cells and are biologically available. These complexes have a markedly longer half-life than free NO, making them an ideal "common currency" for this messenger molecule. Considering the many critical roles NO plays in health and disease, a better understanding of its intracellular trafficking mechanisms will be vital for the development of new therapeutics.

Safeguarding adults.

The safeguarding of patients is a key concern for all health and care professionals. Research shows that more instances of unacceptable care are likely to occur due to an increase in population of those deemed to be vulnerable. Increasing professionals' awareness, knowledge and understanding of safeguarding and of the systems in place for reporting concerns is essential for best practice and for protecting patients and their families.

Divergent and synergistic regulation of matrix metalloprotease production by cytokines in combination with C-C chemokines.

The chemotactic effects of chemokines on cells has long been known, but it is now clear that chemokines also have much broader activities and are also involved in a number of disease pathologies, such as rheumatoid arthritis, cancer metastasis and other inflammatory processes. This study investigates the effects of four C-C chemokines, CCL2, CCL3, CCL4 and CCL5 either alone or in the presence of two regulatory cytokines TNF-alpha and TGF-beta and their effect on secretion of two matrix metalloproteases MMP, MMP-2 and MMP-9, and the expression of one membrane bound MMP, MMP-14, by a monocytic human cell line, MonoMac6. All four C-C chemokines were shown to be chemotactic, but only CCL2 and CCL4 had any significant stimulatory effect on MMP-9 and MMP-2, respectively. Both TNF-alpha and TGF-beta were found to divergently enhance MMP-9 and MMP-2 secretion respectively, with stimulation indexes of two and five respectively. Simultaneous treatment with TNF-alpha and chemokine resulted in up to a fifteen-fold stimulation of MMP-9 secretion and treatment with TGF-beta and chemokine resulted in up to a fifteen-fold stimulation of MMP-2 secretion, while TNF-alpha in combination with CCL4 stimulated MMP-14 expression five-fold. Chemokine receptor expression was also investigated using a calcium-sensitive dye and FACS analysis. CCL2, CCL3, and CCL5 all resulted in a detectable enhancement of cytoplasmic Ca2+concentration. CCL4 was unable to activate Ca2+ mobilization, despite the presence of CCR5, the receptor for CCL4. There appeared to be no correlation between MMP production and chemotaxis. The strong synergy between chemokines and cytokines and the enhanced production of MMP may signify the differential regulatory mechanisms of the two cytokines and chemokines in disease pathology.

Two-photon excitation and relaxation of the 3d-4d resonance in atomic Kr.

Two-photon excitation of a single-photon forbidden Auger resonance has been observed and investigated using the intense extreme ultraviolet radiation from the free electron laser in Hamburg. At the wavelength 26.9 nm (46 eV) two photons promoted a 3d core electron to the outer 4d shell. The subsequent Auger decay, as well as several nonlinear above threshold ionization processes, were studied by electron spectroscopy. The experimental data are in excellent agreement with theoretical predictions and analysis of the underlying multiphoton processes.

Two-photon inner-shell ionization in the extreme ultraviolet.

We have observed the simultaneous inner-shell absorption of two extreme-ultraviolet photons by a Xe atom in an experiment performed at the short-wavelength free electron laser facility FLASH. Photoelectron spectroscopy permitted us to unambiguously identify a feature resulting from the ionization of a single electron of the 4d subshell of Xe by two photons each of energy (93±1) eV. The feature's intensity has a quadratic dependence on the pulse energy. The results are discussed and interpreted within the framework of recent results of ion spectroscopy experiments of Xe obtained at ultrahigh irradiance in the extreme-ultraviolet regime.

Divergent effects of infliximab and anakinra therapies on macrophage phenotype from patients with refractory rheumatoid arthritis.

Previously, we documented the co-expression of the inducible nitric oxide synthase (NOS2) and protein kinase C-eta (PKC-eta) in peripheral blood-derived macrophages (PBDM) from moderate to severe rheumatoid arthritis (RA) patients with elevated plasma nitric oxide levels but not from those with non-inflammatory osteoarthritis (OA) or normal plasma NO levels. The presence of PKC-eta was found to be required before macrophages could acquire the NOS2-positive phenotype and make copious levels of NO. In the current study, we report the divergent effects of two biological-based RA therapies which target TNFalpha function (infliximab) or IL1 response (anakinra) on the development of the NOS2-positive phenotype by PBDM in patients with refractory RA. Both infliximab and anakinra were effective in improving disease symptoms. However, treatment with anakinra, but not infliximab led to a complete suppression of NOS2 expression in PBDM and consequently, a more pronounced reduction in plasma NO levels. Data also revealed a requirement of both TNF-alpha and IL-1 in the development of the NOS2-positive macrophage phenotype. Finally, the data have shed light on the molecular mechanisms by which NO production may be regulated during disease progression to severe RA, and thus, offer a novel insight into the identification of future therapeutic targets for the treatment of inflammatory diseases.

A case of amyoplasia in a monochorionic twin pregnancy: a sequela from twin-twin transfusion syndrome?

OBJECTIVE: To present and discuss the sonographic and clinical findings in one twin of a monochorionic pair affected by amyoplasia. METHODS: On ultrasound examination at 21 weeks in a monochorionic twin pregnancy, twin I was smaller, hydropic, with multiple contractures consistent with amyoplasia and oligohydramnios. Twin II was anatomically normal with polyhydramnios. RESULTS: The twins were delivered at 28 weeks' gestation. The clinical findings were consistent with twin-twin transfusion syndrome (TTTS). CONCLUSION: It is postulated that TTTS may be a causative factor in the excessive incidence of amyoplasia in monozygotic twin pregnancy.

Polarization control in two-color above-threshold ionization of atomic helium.

Two-color multiphoton ionization of atomic helium was investigated by combining extreme ultraviolet (XUV) radiation from the Free Electron Laser in Hamburg with an intense synchronized optical laser. In the photoelectron spectrum, lines associated with direct ionization and above-threshold ionization show strong variations of their amplitudes as a function of both the intensity of the optical dressing field and the relative orientation of the linear polarization vectors of the two fields. The polarization dependence provides direct insight into the symmetry of the outgoing electrons in above-threshold ionization. In the high field regime, the monochromaticity of the XUV radiation enables the unperturbed observation of nonlinear processes in the optical field.

Palivizumab prophylaxis of respiratory syncytial virus infection in high-risk infants.

Palivizumab prophylaxis significantly reduces hospitalization for respiratory syncytial virus (RSV) disease in preterm infants. However, palivizumab is very expensive. Data from a New Zealand cost-effectiveness analysis were considered by representatives of the Infectious Diseases and Immunisation, Fetus and Newborn, and Respiratory Committees of the Paediatric Society of New Zealand. Prophylaxis in all high-risk groups was associated with net cost. The consensus panel recommends that the priority for palivizumab be given to babies discharged on home oxygen with chronic lung disease, followed by babies born at 28 weeks or less gestation.

Score of neonatal acute physiology as a measure of illness severity in mechanically ventilated term babies.

UNLABELLED: The objectives of this population-based, case-control cohort study were to describe the use of the score of neonatal acute physiology (SNAP) as a measure of illness severity in mechanically ventilated term infants, to compare the SNAP scores of the different diagnostic groups, to assess the contribution of the individual SNAP items to the overall SNAP severity category, and to assess SNAP as a predictor of mortality and neonatal intensive care unit (NICU) resource utilization (length of stay (LOS) and duration of ventilation (LOV)). The study was carried out in Sydney and four large rural/urban health areas in New South Wales, Australia. The subjects--182 singleton term infants with no major congenital anomalies--were admitted to a tertiary NICU for mechanical ventilation. Highest mean (SD) SNAP scores occurred in infants ventilated for meconium aspiration (18 (9)), and perinatal asphyxia (17 (9)), compared with pulmonary hypertension (14 (6)) and respiratory distress syndrome (13 (5)). The individual SNAP items that contributed most to SNAP moderate and severe categories were blood gas items, creatinine, urine output, blood glucose, and seizures. Predictors of death included total SNAP score, individual SNAP items (urine output, pH, Oxygenation Index (OI)), 5-min Apgar, gestational age >40 wk, growth restriction, and ventilation for asphyxia/apnoea. SNAP alone was not a good predictor of NICU resource utilization (LOS, LOV) in term infants. The best predictors were LOV for LOS, and a combination of SNAP and the reason for ventilation for LOV. CONCLUSION: SNAP is a useful measure of severity of illness in sick term neonates admitted to a tertiary NICU. This measure can be used to predict neonatal morbidity and mortality, and to some extent NICU resource utililization.

Do very sick neonates born at term have antenatal risks? 1. Infants ventilated primarily for problems of adaptation to extra-uterine life.

AIMS: 1. Ascertain antenatal and intrapartum risk factors for term neonates ventilated primarily for 'perinatal asphyxia'. 2. Describe the neonatal morbidity and mortality. METHODS: Population-based case control cohort study. SETTING: Sydney and four large rural/urban health areas in New South Wales. SUBJECTS: Singleton term infants, no major congenital anomaly: subset of 83 infants ventilated primarily for 'asphyxia' from 182 cases admitted to a tertiary neonatal intensive care unit (NICU) for mechanical ventilation, 550 randomly selected controls. Outcome. Risk factors for case status by maternal, antenatal, labor, delivery, and combined epochs, adjusted odds ratios (OR), 95 per cent confidence intervals (CI), p < 0.05. RESULTS: Predictors of case status by multivariate epochs: Primigravida (1.8 [1.1, 2.8]), thyroid disease (7.8 [1.1, 57.0]), any antenatal complication (5.1 [3.0, 8.6]), growth restriction (4.2 [1.7, 10.4]), male gender (2.1 [1.3, 3.5]), gestational age >40 weeks (1.9 (1.1, 3.3)), prolonged rupture of membranes (9.7 [1.3, 72.5]), complicated labor (6.6 [3.7, 11.9]), induced labor (2.2 [1.3, 3.9]), prostaglandins 2.46 [1.23, 4.91]), maternal pyrexia (10.8 [2.8, 42.7]), placental hemorrhage in labor (OR 4.24 [1.45, 12.42]), forceps delivery (4.1 [1.9, 8.5]), emergency cesarean section (4.7 [2.6, 8.7]). Twenty case infants (24%) and no control infants died. CONCLUSIONS: This study has shown maternal and antepartum risk factors for severe neonatal morbidity in term infants. More centers need to become interested in the term baby, so that a larger multicenter study can further elucidate the heterogeneous causal pathways to term neonatal morbidity.

Do very sick neonates born at term have antenatal risks? 2. Infants ventilated primarily for lung disease.

AIMS: 1. Ascertain antenatal and intrapartum risk factors for term neonates ventilated primarily for respiratory problems. 2. Describe the neonatal morbidity and mortality. METHODS: Population-based case control cohort study. SETTING: Sydney and four large rural/urban Health Areas in New South Wales, 1996. SUBJECTS: Singleton term infants, no major congenital anomaly: subset of 99 infants ventilated primarily for respiratory problems from 182 cases admitted to a tertiary neonatal intensive care unit (NICU) for mechanical ventilation, and 550 randomly selected controls. OUTCOME: Risk factors for case status by maternal, antenatal, labor, delivery, and combined epochs, adjusted Odds Ratios (OR), 95 per cent Confidence Intervals (CI), p<0.05. RESULTS: Predictors of case status by multivariate epochs: mother's age > or =35 years (1.9 (1.1, 3.2) p=0.03), primigravida (1.8 (1.1, 2.8) p=0.01), any antenatal complication (3.8 (2.4, 5.9) p=0.0001), birth weight < 3rd percentile (3.7 (1.5, 9.1) p=0.006), gestational diabetes (2.9 (1.3, 6.9) p=0.01), maternal pyrexia (6.5 (1.6, 27.2) p=0.01), birth weight >90th percentile (1.8 (1.01, 3.2) p=0.047), gestation 37-38 weeks (2.3 (1.5, 3.6) p=0.0004), forceps (4.4 (2.1, 9.1) p=0.0001), elective cesarean section (3.7 (2.0, 6.5) p=0.0001), emergency cesarean section (4.5 (2.4, 8.4) p=0.0001). Case mortality rate was 5 per cent. CONCLUSION: The pathways to neonatal respiratory morbidity in term infants are multifactorial. Several areas which warrant more in-depth study are: elective cesarean section at 37-38 weeks gestation, fetal growth restriction, macrosomia and the pattern of in-utero growth, maternal weight gain during pregnancy, gestational diabetes, pyrexia in labor and the role of chorioamnionitis.

The cumulative effects of life event, personal and social resources on subjective well-being of elderly widowers.

A multidimensional Life Stress Model was used to test the independent contributions of background characteristics, personal resources, life event, and environmental influences on 200 widowers' levels of well-being, measured by the Affect Balance Scale. Stepwise regression analyses revealed that environmental resources were unrelated to negative affect which is influenced more by the life event and personal resource variables. The environmental resource variables, particularly interactions with friends and neighbors, mostly influenced positive affect. The explanatory model for well-being included multiple variables and explained 33 percent of the variance. Although background characteristics had the greatest impact, absence of hospitalization, higher mastery, higher self-esteem, contacts with friends, and interaction with neighbors enhanced well-being. The results support previous speculations on the importance of positive exchanges for positive affect. African-American widowers showed higher levels of well-being than Caucasian widowers did. The results advance knowledge about differences among elderly men.