Vasopressin- and oxytocin-induced activity in the central nervous system: electrophysiological studies using in-vitro systems.
During the last two decades, it has become apparent that vasopressin and oxytocin, in addition to playing a role as peptide hormones, also act as neurotransmitters/neuromodulators. A number of arguments support this notion: (i) vasopressin and oxytocin are synthesized not only in hypothalamo-neurohypophysial cells, but also in other hypothalamic and extrahypothalamic cell bodies, whose axon projects to the limbic system, the brainstem and the spinal cord. (ii) Vasopressin and oxytocin can be shed from central axons as are classical neurotransmitters. (iii) Specific binding sites, i.e. membrane receptors having high affinity for vasopressin and oxytocin are present in the central nervous system. (iv) Vasopressin and oxytocin can alter the firing rate of selected neuronal populations. (v) In-situ injection of vasopressin and oxytocin receptor agonists and antagonists can interfere with behavior or physiological regulations. Morphological studies and electrophysiological recordings have evidenced a close anatomical correlation between the presence of vasopressin and oxytocin receptors in the brain and the neuronal responsiveness to vasopressin or oxytocin. These compounds have been found to affect membrane excitability in neurons located in the limbic system, hypothalamus, circumventricular organs, brainstem, and spinal cord. Sharp electrode intracellular recordings and whole-cell recordings, done in brainstem motoneurons or in spinal cord neurons, have revealed that vasopressin and oxytocin can directly affect neuronal excitability by opening non-specific cationic channels or by closing K(+) channels. These neuropeptides can also influence synaptic transmission, by acting either postsynaptically or upon presynaptic target neurons or axon terminals. Whereas, in cultured neurons, vasopressin and oxytocin appear to mobilize intracellular Ca(++), in brainstem slices, the action of oxytocin is mediated by a second messenger that is distinct from the second messenger activated in peripheral target cells. In this review, we will summarize studies carried out at the cellular level, i.e. we will concentrate on in-vitro approaches. Vasopressin and oxytocin will be treated together. Though acting via distinct receptors in distinct brain areas, these two neuropeptides appear to exert similar effects upon neuronal excitability.


Continuous postive airways pressure treatment by a face chamber in idiopathic respiratory distress syndrome.
Continuous positive airways pressure treatment by a face chamber in idiopathic respiratory distress syndrome. During a 3-year period 45 infants with idiopathic respiratory distress syndrome (IRDS) requiring ventilatory support were treated in the neonatal unit. Continuous positive airways pressure (CPAP) via the face chamber was applied as initial therapy in 39 infants and during weaning from initial intermittent positive pressure ventilation (IPPV) treatment in 5 infants, whereas 1 infant received IPPV only. Among the 39 infants initially treated with CPAP 9 required IPPV as well. The overall survival rate was 37/45 or 82%. Incapacity to hyperoxygenate while breathing 100% oxygen was the indication for CPAP while occurrence of apnoeic attacks was the indication for IPPV. Pao2 during the hyperoxia test before ventilatory support was less than 50 mmHg in 10 infants and between 50 and 105 mmHg in 35 infants. Surviving infants were followed up with neurological and developmental control examinations as well as chest x-ray, and in several infants pulmonary function tests. 3/37 infants had moderate neurological sequelae and only 1/37 infants developed bronchopulmonary dysplasia. No deleterious effects of the face chamber were seen. As the face chamber is a noninvasive and easily applied technique for CPAP therapy without hazards, it is proposed that it should be used at a still earlier stage of IRDS in order to lesson the need for IPPV treatment and to increase the neurological and lung functional quality of survival.


Incidence of Multidrug-Resistant Pseudomonas Spp. in ICU Patients with Special Reference to ESBL, AMPC, MBL and Biofilm Production.
Multidrug-resistant (MDR) Pseudomonas spp. have been reported to be the important cause of ICU infections. The appearance of ESBL, AmpC and MBL genes and their spread among bacterial pathogens is a matter of great concern. Biofilm production also attributes to antimicrobial resistance due to close cell to cell contact that permits bacteria to more effectively transfer plasmids to one another. This study aimed at determining the incidence of ESBL, AmpC, MBL and biofilm producing Pseudomonas spp. in ICU patients. The clinical specimens were collected aseptically from 150 ICU patients from February 2012 to October 2013. Identification and antimicrobial susceptibility was performed according to Clinical and Laboratory Standards Institute (CLSI) guidelines. ESBLs and AmpC were detected phenotypically and genotypically. MBL was detected by modified Hodge and imipenem-EDTA double-disk synergy test. Pseudomonas spp. 35(28%) were the most prevalent pathogen in ICU infections. Multidrug resistance and biofilm production was observed in 80.1% and 60.4% isolates, respectively. Prevalence of ESBL, AmpC and MBL was 22.9%, 42.8% and 14.4%, respectively. The average hospital stay was 25 days and was associated with 20% mortality. A regular surveillance is required to detect ESBL, AmpC and MBL producers especially in ICU patients. Carbapenems should be judiciously used to prevent their spread. The effective antibiotics, such as fluoroquinolones and piperacillin-tazobactum should be used after sensitivity testing.


ERRATUM.
The poly(ADP-ribose) polymerase (PARP) enzymes play a key role in the regulation of cellular processes (e.g., DNA damage repair, genomic stability). It has been shown that PARP inhibitors (PARPIs) are selectively cytotoxic against cells having dysfunctions in genes involved in DNA repair mechanisms (synthetic lethality). Drug-induced PARP inhibition potentiates the activity of anticancer drugs such as 5-fluorouracil in enhancing DNA damage, whose repair involves PARP-1 activity. The aim of this study was to evaluate the inhibitory effects of a novel PARPI, HYDAMTIQ, on growth in human tumor cell lines characterized by different features with regard to DNA damage response pathways (BRCA mutational status, microsatellite status, and ATM expression level) and degree of sensitivity/resistance to 5-fluorouracil. HYDAMTIQ showed a more potent inhibitory effect on cell growth in a BRCA2 mutant cell line (CAPAN-1) compared with wild-type cells (C2-6, C2-12, and C2-14 CAPAN-1 clones, and MCF-7). No statistically significant difference was observed after HYDAMTIQ exposure between cells having a different MS status or a different MRE11 mutational status. HYDAMTIQ induced greater antiproliferative effects in SW620 cells expressing a low level of ATM than in H630 cells expressing a high level of ATM. Finally, the combination of HYDAMTIQ and 5-fluorouracil exerted a synergistic effect on the inhibition of SW620 cell growth and an antagonistic effect on that of H630 cell growth. Our results show that the novel PARP inhibitor HYDAMTIQ potently inhibits the growth of human tumor cells with defective DNA damage response pathways and exerts synergistic cytotoxicity in combination with 5-fluorouracil. These data provide relevant examples of synthetic lethality and evidence for further development of this novel PARPI.


Effect of Noninvasive Respiratory Strategies on Intubation or Mortality Among Patients With Acute Hypoxemic Respiratory Failure and COVID-19: The RECOVERY-RS Randomized Clinical Trial.
Continuous positive airway pressure (CPAP) and high-flow nasal oxygen (HFNO) have been recommended for acute hypoxemic respiratory failure in patients with COVID-19. Uncertainty exists regarding the effectiveness and safety of these noninvasive respiratory strategies. To determine whether either CPAP or HFNO, compared with conventional oxygen therapy, improves clinical outcomes in hospitalized patients with COVID-19-related acute hypoxemic respiratory failure. A parallel group, adaptive, randomized clinical trial of 1273 hospitalized adults with COVID-19-related acute hypoxemic respiratory failure. The trial was conducted between April 6, 2020, and May 3, 2021, across 48 acute care hospitals in the UK and Jersey. Final follow-up occurred on June 20, 2021. Adult patients were randomized to receive CPAP (n = 380), HFNO (n = 418), or conventional oxygen therapy (n = 475). The primary outcome was a composite of tracheal intubation or mortality within 30 days. The trial was stopped prematurely due to declining COVID-19 case numbers in the UK and the end of the funded recruitment period. Of the 1273 randomized patients (mean age, 57.4 [95% CI, 56.7 to 58.1] years; 66% male; 65% White race), primary outcome data were available for 1260. Crossover between interventions occurred in 17.1% of participants (15.3% in the CPAP group, 11.5% in the HFNO group, and 23.6% in the conventional oxygen therapy group). The requirement for tracheal intubation or mortality within 30 days was significantly lower with CPAP (36.3%; 137 of 377 participants) vs conventional oxygen therapy (44.4%; 158 of 356 participants) (absolute difference, -8% [95% CI, -15% to -1%], P = .03), but was not significantly different with HFNO (44.3%; 184 of 415 participants) vs conventional oxygen therapy (45.1%; 166 of 368 participants) (absolute difference, -1% [95% CI, -8% to 6%], P = .83). Adverse events occurred in 34.2% (130/380) of participants in the CPAP group, 20.6% (86/418) in the HFNO group, and 13.9% (66/475) in the conventional oxygen therapy group. Among patients with acute hypoxemic respiratory failure due to COVID-19, an initial strategy of CPAP significantly reduced the risk of tracheal intubation or mortality compared with conventional oxygen therapy, but there was no significant difference between an initial strategy of HFNO compared with conventional oxygen therapy. The study may have been underpowered for the comparison of HFNO vs conventional oxygen therapy, and early study termination and crossover among the groups should be considered when interpreting the findings. isrctn.org Identifier: ISRCTN16912075.


ENDOR characterization of an iron-alkene complex provides insight into a corresponding organometallic intermediate of nitrogenase.
A bio-organometallic intermediate, denoted PA, was previously trapped during the reduction of propargyl alcohol to allyl alcohol (AA) by nitrogenase, and a similar one was trapped during acetylene reduction, representing foundational examples of alkene binding to a metal center in biology. ENDOR spectroscopy led to the conclusion that these intermediates have η2 binding of the alkene, with the hydrogens on the terminal carbon structurally/magnetically equivalent and related by local mirror symmetry. However, our understanding of both the PA intermediate, and of the dependability of the ENDOR analysis on which this understanding was based, was constrained by the absence of reference iron-alkene complexes for EPR/ENDOR comparison. Here, we report an ENDOR study of the crystallographically characterized biomimetic iron(i) complex 1, which exhibits η2 coordination of styrene, thus connecting hyperfine and structural parameters of an Fe-bound alkene fragment for the first time. A tilt of the alkene plane of 1 from normal to the crystallographic Fe-C2-C1 plane causes substantial differences in the dipolar couplings of the two terminal vinylic protons. Comparison of the hyperfine couplings of 1 and PA confirms the proposed symmetry of PA, and that the η2 interaction forms a scalene Fe-C-C triangle, rather than an isosceles triangle. This spectroscopic study of a structurally characterized complex thus shows the exceptional sensitivity of ENDOR spectroscopy to structural details, while enhancing our understanding of the geometry of a key nitrogenase adduct.


Safety and Efficacy of Immune Checkpoint Inhibitors in Patients With Cancer Living With HIV: A Perspective on Recent Progress and Future Needs.
Recent studies have identified durable responses with the use of immune checkpoint inhibitors in patients with mismatch repair-deficient (MMR-D)/microsatellite instability-high (MSI-H) metastatic colorectal cancer (CRC). The dramatic improvement in clinical outcomes led to the US Food and Drug Administration approval of pembrolizumab, nivolumab, and nivolumab in combination with ipilimumab in metastatic patients with MSI-H/MMR-D CRC who previously experienced progression on cytotoxic therapies. In the clinical trials investigating these agents, HIV-seropositive patients were not included and therefore the clinical efficacy of these agents in patients with metastatic MSI-H/MMR-D CRC living with HIV is unclear. On the basis of growing evidence, immune checkpoint blockade therapies seem to be a safe approach in patients with well-controlled HIV infection. Research on immunotherapeutic approaches in patients living with HIV and cancer is an area of unmet medical need that can be addressed by clinical trial designs that are inclusive of patients with well-controlled seropositive HIV and trials that specifically evaluate immune therapies in patients living with HIV.


A first nation-wide assessment of soil-transmitted helminthiasis in Fijian primary schools, and factors associated with the infection, using a lymphatic filariasis transmission assessment survey as surveillance platform.
Soil-transmitted helminthiasis (STH) is endemic in Fiji but its prevalence is not known and likely to have changed after a decade of mass drug administration (MDA) for lymphatic filariasis (LF). By linking with LF transmission assessment surveys (LF-TAS), we undertook the first nation-wide assessment of STH in Fijian primary schools, as well as an analysis of factors associated with STH infections. A cross-sectional assessment for STH was conducted in all four Divisions of Fiji from 2014 to 2015. In the Western, Central, and Northern Divisions, schools were sub-sampled after LF-TAS, while, in the Eastern Division, schools were selected via simple random sampling. For the diagnosis of STH, stool samples were examined by coproscopy with a single Kato-Katz thick smear (KK) and the formol-ether-acetate concentration technique, except for the samples from the Eastern Division where only KK was used. Mean prevalence of any STH among class 1-2 students at the national level was 10.5% (95% CI: 6.9-15.5). Across the three Divisions via LF-TAS, the prevalence levels for ascariasis were 8.7% (95% CI: 4.3-16.6), hookworm 3.9% (95% CI: 2.3-6.6) and trichuriasis 0%. In the Eastern Division, ascariasis prevalence was 13.3% (95% CI: 6.4-25.6), and hookworm 0.7% (95% CI: 0.2-2.5), with one case of trichuriasis. Among class 3-8 students, ascariasis prevalence was lower. Lower risk of any STH was associated with wearing shoes (adjusted OR 0.54, 95% CI: 0.32-0.90) and having piped water from the Fiji Water Authority at home (adjusted OR 0.48, 95% CI: 0.25-0.92). After a decade of community-based LF-MDA, STH in school-age children in Fiji is now close to 10%, but localities of endemicity remain. Preventive chemotherapy should be maintained in areas with elevated STH prevalence alongside targeted delivery of integrated WASH interventions. LF-TAS has provided an opportunity to develop future public health surveillance platforms.


[Fetal and neonatal ascites: a report of 15 cases and a review of the literature].
Fifteen patients with non-immune fetal or neonatal ascites and absence of generalized edema are described. Nine patients were diagnosed prenatally. Nine patients were preterm. Artificial ventilation was necessary in twelve infants immediately after birth. In five cases, including two cases of transitory ascites, the etiology could not be established. In accordance with previous reports, we found the following underlying disorders in our patients: urinary tract obstruction, polycystic disease of the kidneys, chylous ascites, sepsis, intrahepatic atresia of the biliary ducts, hepatic and renal failure following severe asphyxia. 8 out of 15 patients died. A survey of the literature shows a variety of underlying disorders. Therefore, several diagnostic tests are necessary, in order to identify the etiology. Causative treatment is possible in some cases of urogenital , gastrointestinal, infectious and chylous ascites. Sophisticated perinatal management is essential for the outcome of patients with fetal or neonatal ascites; nevertheless the mortality rate is still about 50%.


Risk of anaphylaxis in complementary and alternative medicine.
Complementary and alternative medicine (CAM) use is widespread across the world. Patients with asthma and allergy regularly use CAM therapies. Allergic and anaphylactic reactions to CAM have been reported. Recent attempts to regulate and monitor adverse reaction to these therapies have given us further insight into potential causes of severe allergic reactions. Several culprits identified including Andrographis paniculata, Echinacea species, bee products, Ginkgo biloba and Ginseng are discussed here. Knowing the factors that increase the risk of anaphylaxis allows reactions to be recognized, reported and further investigated. Research to identify key causative allergens is necessary in the future. Collaboration between the allergy community and CAM practitioners can allow better understanding of allergy to these therapies.


Rational Integration of ZIF-8 and BiPO4 for Energy Storage and Environmental Applications.
Environmental pollution and energy storage are among the most pivotal challenges of today's world. The development of multifunctional materials is required to address these challenges. Our study presents the rational design and synthesis of a hybrid material (ZIF-8@BiPO4) with dual functionality: an outstanding supercapacitor electrode and an excellent photocatalyst. The ZIF-8@BiPO4 hybrid structure was obtained by conjoining zinc ions and 2-methylimidazole ligands toward BiPO4 by a one-pot stirring route at room temperature. The ZIF-8@BiPO4 resulted in considerably higher specific capacitance (Cs) (489 F g-1 at a scan rate of 5 mV s-1; 497 F g-1 at a current density of 1 A g-1) than that of pure BiPO4 (358; 443 F g-1) and ZIF-8 (185; 178 F g-1) under the same conditions in a three-electrode cell using the 2 M KOH aqueous electrolyte. Afterward, an asymmetric supercapacitor (ASC) device was fabricated with BiPO4 as the anode and ZIF-8@BiPO4 as the cathodes, acquiring an outstanding Cs of 255 F g-1 at a current density of 0.5 A g-1 with significant cycling stability (81% over 10,000 cycles). Moreover, the ASC has an energy density of 17.5 Wh kg-1and a power density of 13,695 W kg-1, which can be considered to be at the borderline between batteries and supercapacitors. The photocatalytic activity of ZIF-8@BiPO4 was further studied using a methylene blue (MB) dye and sildenafil citrate (SC) drug-active molecules. The degradation of MB was approximately 78% through the photocatalytic reduction after 180 min of UV irradiation. The outstanding characteristics together with the ecofriendly and low-cost preparation make ZIF-8@BiPO4 appealing for a broad range of applications.


Continuous elevation of intracellular Ca2+ is essential for the development of cerebral vasospasm.
Subarachnoid hemorrhage (SAH)-induced cerebral vasospasm causes serious neurological morbidity and mortality mainly because of the absence of effective treatment. Therefore, we reviewed the molecular mechanisms involved in the development of the cerebral vasospasm based on the experimental data in the two-hemorrhage canine model. The characteristic feature of vasospasm is a continuous elevation of intracellular Ca2+ levels in the cerebral artery, as indicated by the continuous activation of mu-calpain and Ca2+/calmodulin-dependent myosin light chain kinase (MLCK) phosphorylation of the myosin light chain. In contrast, KCl- or serotonin-induced vasocontraction displays a transient increase in Ca2+ concentration. The elevation of intracellular Ca2+ levels in vasospasm is induced through enhanced Ca2+ release from the sarcoplasmic reticulum and influx from the extracellular space by the activation of tyrosine kinase pathway and also probably by the proteolysis of Ca2+ channel by mu-calpain. Topical application of L-type Ca2+ channel blockers, ethylene-glycol-bis(beta-aminoethylether)N,N'-tetraacetic acid, genistein, calpeptin (a selective inhibitor of calpain), or ML-9 (a selective inhibitor of MLCK) induces the reversal of vasospasm probably as a result of a decrease in intracellular Ca2+ levels mainly due to a reduction of Ca2+ influx by these three inhibitors. Rho-kinase is also activated during vasospasm. It inhibits myosin phosphatase through phosphorylation at the myosin phosphatase target subunit 1 and also probably through phosphorylation of the 17-kDa smooth muscle-specific myosin phosphatase inhibitor (CPI-17) to bring about Ca2+-independent vasospasm. This interpretation is supported by the reversal of vasospasm with Y-27632, a specific inhibitor of Rho-kinase. Arachidonic acid produced during vasospasm might inhibit myosin phosphatase probably directly and via activation of Rho-kinase or atypical protein kinase C (PKC). PKC activated during vasospasm may inhibit myosin phosphates directly and by phosphorylating CPI-17. The protein levels of thin filament-associated proteins, calponin and caldesmon, are decreased in vasospasm, whereas their phosphorylation levels are increased. Both changes probably contribute to the enhancement of vascular smooth muscle contractility. Furthermore, contractile and cytoskeletal proteins appear to be degraded in vasospasm probably by proteolysis with mu-calpain, suggesting that degradation of the structural and functional mechanisms related to smooth muscle contraction occurs. Thus, the mechanisms responsible for the development of cerebral vasospasm are complicated, but the prevention of intracellular Ca2+ elevation induced by SAH may not activate MLCK, calpain and PKC to largely suppressing the development of vasospasm.


Nurse Stressors and Satisfiers in the NICU.
Working in a neonatal intensive care unit (NICU) can be both rewarding and stressful. Stressors can outweigh satisfiers, leading to job dissatisfaction and turnover. Nurse retention remains a problem, particularly for nurses within the first year of employment. The purpose of this study was to examine current nurse stressors, satisfiers, and coping processes in the NICU. Seventy-two neonatal nurses from 3 Magnet facilities in North Carolina completed the ICU Stressors Survey, the Ways of Coping Scale, demographic data questions, and free-text questions in Qualtrics, a secure online survey system. Questionnaires were analyzed using protocols developed and validated by instrument developers, and quantitative data were analyzed using SPSS statistical software. Free-text responses were analyzed using iterative coding and thematic grouping. Most nurses thought that NICU nursing was stressful, but they coped well with work stress. Nurses felt confident in their knowledge and patient care abilities and were not stressed by the NICU environment. Inadequate staffing was the most common stressor. Coping strategies were aimed at task completion. Nurses wanted better teamwork on their units. Nurses felt more respected by their peers and families than by their immediate supervisors and physicians. Attention to staffing patterns is paramount. Team-building activities may help foster mutual respect and collegiality among the nursing staff and between disciplines. Research investigating creative staffing patterns would be helpful. Interprofessional research may also reduce stressors and enhance team performance.


Sorafenib inhibits TPA-induced MMP-9 and VEGF expression via suppression of ERK/NF-κB pathway in hepatocellular carcinoma cells.
Invasion by hepatocellular carcinoma (HCC) has been reported to occur via the up-regulation of nuclear factor-kappaB (NF-κB). Sorafenib can improve the overall survival in patients with HCC, however, the association of its inhibitory mechanisms with the inactivation of NF-κB remains unclear. Here, Huh7 cell line transfected with NF-κB-luc2 vector was used to study the effects of sorafenib on NF-κB activity, on expressions of matrix metalloproteinase-9 (MMP-9) and vascular endothelial growth factor (VEGF), which were induced by 12-O-tetradecanoylphorbol-13-acetate (TPA). TPA increased the NF-κB activity and the expressions of MMP-9 and VEGF significantly, but its effects were suppressed by sorafenib in a dose-dependent manner. Similar results were found with PD98059, an inhibitor of extracellular signal-regulated kinase (ERK). Furthermore, transfection of Huh7 cell with an inhibitor of kappaB-α mutant vector, led to reduced TPA-induced MMP-9 and VEGF mRNA expressions. Sorafenib inhibits TPA-induced MMP-9 and VEGF expressions via the suppression of ERK/NF-κB pathway in HCC cells.


Nutritional Interventions for Mitochondrial OXPHOS Deficiencies: Mechanisms and Model Systems.
Multisystem metabolic disorders caused by defects in oxidative phosphorylation (OXPHOS) are severe, often lethal, conditions. Inborn errors of OXPHOS function are termed primary mitochondrial disorders (PMDs), and the use of nutritional interventions is routine in their supportive management. However, detailed mechanistic understanding and evidence for efficacy and safety of these interventions are limited. Preclinical cellular and animal model systems are important tools to investigate PMD metabolic mechanisms and therapeutic strategies. This review assesses the mechanistic rationale and experimental evidence for nutritional interventions commonly used in PMDs, including micronutrients, metabolic agents, signaling modifiers, and dietary regulation, while highlighting important knowledge gaps and impediments for randomized controlled trials. Cellular and animal model systems that recapitulate mutations and clinical manifestations of specific PMDs are evaluated for their potential in determining pathological mechanisms, elucidating therapeutic health outcomes, and investigating the value of nutritional interventions for mitochondrial disease conditions.


Performance-Based Risk-Sharing Arrangements for Pharmaceutical Products in the United States: A Systematic Review.
Value for money is a growing necessity in today's U.S. health care system in which drug spending is expected to increase by an average rate of 6.7% yearly through 2025. In response to uncertainty about real-world clinical and economic outcomes for many drugs, health insurers and pharmacy benefit managers (PBMs) have implemented various contracts and arrangements with drug manufacturers that can collectively be described as performance-based risk-sharing arrangements (PBRSAs). Little is known about U.S.-specific PBRSAs for drugs. To conduct a systematic review of U.S.-specific PBRSAs for drugs to describe (a) trends over time and (b) key aspects including outcome measures and terms of arrangements between stakeholders. A systematic review was conducted in MEDLINE (January 1, 1946-April 1, 2017), Embase (January 1, 1988-April 1, 2017), and the grey literature (up to April 1, 2017) to identify publicly disclosed PBRSAs. Articles and conference abstracts were included if they were published in English and described a U.S.-specific PBRSA for a drug. Articles and conference abstracts were excluded if they only described a PBRSA similar to a money-back guarantee to patients. They were also excluded if they only described a PBRSA between a PBM and a health insurer in which the latter would receive a discount for patients nonadherent to a drug. Results were summarized as counts and percentages. From the literature review, 26 publicly disclosed PBRSAs were identified. Of these, 16 (62%) were announced or initiated from 2015 to 2017, and 10 (38%) were announced or initiated from 1997 to 2012. Thirteen (50%) PBRSAs involved cardiometabolic indications; 5 (19%) involved oncology indications; and 8 (31%) involved other indications. Categorized by health insurer or PBM, 10 (38%) PBRSAs involved large multistate insurers; 5 (19%) involved the Centers for Medicare & Medicaid Services; 7 (27%) involved regional insurers; 3 (12%) involved PBMs; and 1 (4%) involved multiple unspecified insurers. Regarding the most active drug manufacturers, Amgen initiated 5 (19%) PBRSAs and Novartis initiated 4 (15%). Relative to the initial FDA approval of a treatment, 15 (58%) PBRSAs were announced or initiated within 5 years, and 11 (42%) were announced or initiated more than 5 years later. For data collection, electronic medical record (EMR) data would have been an appropriate source for 12 (46%) PBRSAs; claims data would have been an appropriate source for 11 (42%) PBRSAs; and EMR and claims data would have been appropriate sources for 2 (8%) PBRSAs; no description of the outcome measures was available for 1 (4%) PBRSA. The number of publicly disclosed U.S.-specific PBRSAs for drugs has increased over the years. This review's findings confirm the interest of stakeholders in such arrangements and their confidence in the use of the selected outcome measures. Each PBRSA represents a timely collaboration among stakeholders to provide access to a drug while generating evidence to better elucidate its clinical and economic value. No funding supported this systematic review. Yu is an employee and shareholder of Allergan. Chin reports personal fees from Formulary Resources. Oh and Farias have nothing to disclose. Study concept and design were primarily contributed by Yu, along with the other authors. All authors contributed to the collection and interpretation of the data. The manuscript was written by Yu, Chin, Oh, and Farias and revised by Yu and Chin, along with the other authors.


Development of Francisella tularensis antigen responses measured as T-lymphocyte proliferation and cytokine production (tumor necrosis factor alpha, gamma interferon, and interleukin-2 and -4) during human tularemia.
The lymphocyte immune reactivity of 12 tularemia patients to Francisella tularensis antigens prepared from the bacterial cell envelope was examined during a 14-week follow-up study. Lymphocyte blast transformation responses of peripheral blood mononuclear cells (PBMC) to different protein antigens appeared simultaneously 2 weeks after the first symptoms of tularemia, indicating that none of these antigens had any special role at the early phase of immunization. While the lymphocyte blast transformation responses of total lymphocytes to all bacterial antigens were negative in the week 1 samples, continuously growing F. tularensis-specific T-lymphocyte lines were obtained from PBMC at the same time, indicating that an immune response had already occurred. Later, the T-lymphocyte lines and lymphocyte blast transformation responses were similar. Lymphocyte activation among the PBMC was reflected in an increased number of HLA-DR antigen-expressing, CD4-positive T lymphocytes (CD4+ DR+). The mean secretion of soluble CD8 from F. tularemia antigen-stimulated PBMC increased 2 weeks after tularemia onset, but the mean number of CD8+ DR+ T lymphocytes did not vary during the study period and no correlation could be found between the soluble CD8 and number of CD8+ DR+ T lymphocytes. F. tularemia antigen-induced cytokine production was measured from the PBMC supernatants. High levels of tumor necrosis factor alpha were detected from the first week onwards. The highest levels of interleukin-2 and gamma interferon were recorded during the second and third weeks, respectively, after tularemia onset. Interleukin-4 could not be demonstrated in the lymphocyte supernatants.


The organisational climate of NHS Early Intervention Services (EIS) for psychosis: a qualitative analysis.
Cognitive remediation (CR) therapy for psychosis significantly improves recovery but is yet to be widely implemented in NHS services. It is likely to be of value at the earliest stages of psychosis development - at the first episode. Organisational climate is one factor likely to affect implementation into Early Intervention Services (EIS), which serve those experiencing first episode psychosis. We aimed to understand the organisational climate within UK NHS Early Intervention for Psychosis (EIP) services and the barriers and facilitators for the introduction of CR. We conducted semi structured interviews with 42 EIS members of four teams in four NHS Trusts. Thematic analysis was used to analyse the data. There were differences between teams, including leadership style, involvement in decision making and willingness to adopt CR. Resource shortages were considered the main barrier for implementation across all teams. The evidence base behind CR and the recognition of there being a clinical need was seen as the main facilitator. Teams with more democratic leadership, and knowledge of both the evidence base and need for CR, may feel better able to successfully incorporate it into their service. Despite enthusiasm for novel treatments, EIS teams are limited by their resources. An understanding of the local organisational variables can help teams establish a culture that values innovation. Clear communication of the evidence base for CR is key to help enable staff to implement novel treatments successfully despite these limited resources and time pressures.


Analysis of the relationship of extrahepatic portosystemic shunt morphology with clinical variables in dogs: 53 cases (2009-2012).
To investigate differences in clinical variables among dogs with extrahepatic portosystemic shunts (EHPSSs) of various morphologies. Retrospective case series. 53 dogs with EHPSSs. Medical records of dogs undergoing preoperative CT angiography of an EHPSS over a 3-year period were reviewed. Analysis was performed to investigate relationships of clinical variables with shunt morphology. Morphologies were analyzed individually as well as in several groups. Shunt morphologies included 10 splenocaval, 9 splenophrenic, 11 splenoazygos, 10 right gastric-caval, 12 right gastric-caval with a caudal loop, and 1 right gastric-azygos with a caudal loop. Several biochemical variables associated with EHPSS were lowest in dogs with splenocaval shunts. Preoperative clinical signs were more common in dogs that had shunts with vena caval than right azygos vein insertion (36/41 [88%] vs 7/12 [58%]) and insertion caudal to the liver than diaphragmatic insertion (29/32 [91%] vs 14/21 [67%]). Neurologic signs were more common when shunts inserted into the vena cava caudal to the liver than in other locations (21/32 [66%] vs 6/21 [29%]) and were most frequent with splenocaval shunts. Urinary tract signs were more common when shunts had right gastric vein origin than gastrosplenic vein origin (14/23 [61%] vs 10/30 [33%]). Splenocaval shunts caused more clinical abnormalities than did other shunt morphologies. Results suggested that dogs with shunt insertion in the caudal vena cava, especially caudal to the liver, were most likely to have clinical signs.


[The sacral perineural system--are there radiological criteria for an indication for surgery? First results and literature survey].
To establish recommendations for diagnostic imaging of cystic lesions of the sacral region and to evaluate for potential predictors of therapeutic outcome. Conventional imaging of the lumbar spine, conventional CT, myelography, post myelo-CT and MRI were performed in 7 symptomatic [corrected] patients. All patients underwent operative decompression and histological examination. The radiographic examinations were reevaluated retrospectively and correlated with the postoperative outcome. In one patient the differential diagnosis of a neurinoma could not be excluded with CT and CT-myelography alone. In all 7 patients MRI provided a definite diagnosis and a precise presentation of the cyst extension. A complete postoperative remission of symptoms was noticed in 4, a partial remission in three cases. The correlation of cyst extension, cyst shape, and the communication with the subarachnoid space did not provide predictive information concerning operative outcome. MR can be used as the sole imaging tool for demonstration of cystic lesions. Relevant disadvantages in comparison to myelography and myelo-CT were not evident. No imaging modality could predict the value of surgical intervention.


All-cause and potentially disease-related health care costs associated with venous thromboembolism in commercial, Medicare, and Medicaid beneficiaries.
Patients with venous thromboembolism (VTE) are at increased risk of developing recurrent VTE and post-thrombotic syndrome (PTS), a complication of deep vein thrombosis (DVT) characterized by venous reflux and residual venous obstruction that may manifest as chronic pain and swelling. Therefore, formulary/policy decision makers should understand the clinical and economic consequences associated with VTE. To describe the real-world clinical complications, such as recurrent VTE and PTS, associated with VTE and quantify the incremental direct all-cause and potentially disease-related health care costs associated with VTE. Health insurance claims between January 2004 and December 2008 from the Ingenix Impact database were used. Adult patients with an initial VTE diagnosis (index DVT, pulmonary embolism [PE], or both) with at least 12 months of enrollment prior to the index VTE were matched 1:1 with comparison patients without VTE. Matching criteria included demographic factors, baseline health care costs, and diagnoses of VTE risk factors such as multiple traumas, malignant cancer, or major surgery. Each patient's observation period began on the date of the index VTE, or corresponding study index date for comparison cases, and ended on the earliest of 1 year after the study index date, the health plan disenrollment date, or December 31, 2008. The proportions of patients with (a) recurrent hospital-documented VTE, defined as an inpatient episode with a diagnosis of VTE in any claim field; (b) PTS; and (c) other potentially disease-related diagnoses (thrombocytopenia, superficial venous thrombosis, venous ulcer, pulmonary hypertension, stasis dermatitis, and venous insufficiency) were calculated. Health care costs were defined as standardized net provider payments after subtraction of member cost-sharing amounts. All-cause incremental health care costs and disease-related costs, defined as provider payments for hospitalization or outpatient claims with a primary or secondary diagnosis of VTE, PTS, or any of the potentially disease-related diagnoses, were computed. Costs were calculated per patient per year (PPPY) by weighting each patient's total cost for up to 1 year post-index by the length of follow-up. The matched VTE and no-VTE cohorts included 16,969 subjects in each group. The index VTE event was DVT, PE, or both in 12,711, 2,473, and 1,785 patients, respectively. In the VTE cohort, the risks of recurrent VTE and PTS during the follow-up period (mean [SD] observation of 271.7 [121.6] days) were 3.6% and 7.1%, respectively. Patients with VTE had significantly higher average PPPY all-cause costs compared with the no-VTE patients (mean [SD] $33,531 [$70,393] vs. $17,590 [$42,011]; cost difference = $15,941, 95% CI = $14,819-$17,012). Corresponding potentially disease-related health care costs PPPY were also significantly higher for the VTE group (mean [SD] $3,141 [$17,055] vs. $228 [$3,221]; cost difference = $2,913, 95% CI = $2,693-$3,157) and represented 18.3% (i.e., $2,913 of $15,941) of the all-cause cost difference between the 2 groups. In this large matched-cohort study, VTE was associated with a 3.6% risk of hospital-documented recurrence and a 7.1% risk of PTS up to 1 year after index VTE. Potentially disease-related costs represented approximately one-fifth of the incremental all-cause costs associated with VTE.


Antigen specific quantification of sulfidoleukotrienes in patients allergic to Betalactam antibiotics.
After in vitro allergen-specific stimulation, basophils become activated and release sulfidoleukotrienes LTC4, LTD4 and LTE4. This can be detected by means of the CAST assay. We assessed the positivity criteria and the reliability of antigen-specific sulfidoleukotriene production (CAST) in the in vitro diagnosis of betalactam (BL) allergic patients. We studied a sample of 67 patients (age 48.94 +/- 15.76 years) who had presented with anaphylaxis or urticaria-angioedema within the first 60 minutes after administration of Amoxicillin (54/67), Penicillin G (7/67), Cefuroxime (5/67) or Cefazoline (1/67). All of them had a positive skin test to at least one of the antigenic determinants of Penicillin. As control group 30 adults with negative skin tests who tolerated BL were included. All of them underwent skin tests, oral provocation tests, specific IgE (CAP-FEIA, Pharmacia) and CAST. Positivity criteria were established by means of ROC curves: a sLT release induced by Betalactams of at least 100 pg/ml and greater than or equal to 3 times the basal value. The overall sensitivity of CAST is 47.7% and specificity 83.3%. Sensitivity of specific IgE is 37.8% and specificity 83.3%. We have established validated positivity criteria for the CAST technique in patients allergic to Betalactams. This technique is a useful in vitro diagnostic method in patients with IgE-mediated allergy to Betalactam antibiotics.


Rhabdomyolysis secondary to lovastatin therapy.
We report a case of lovastatin-induced rhabdomyolysis and resulting life-threatening renal failure. Lovastatin, a hypocholesterolemic agent, decreases endogenous cholesterol synthesis by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A reductase (EC 184.108.40.206). This agent has been implicated in causing rare serious side effects in various clinical settings; however, the mechanism of these adverse reactions is not understood. The clinical course of our patient was characterized by profound muscle weakness with marked increases in serum creatine kinase and myoglobin. Light- and electron-microscopic studies of skeletal muscle of our patient demonstrated a noninflammatory myopathy suggestive of ongoing rhabdomyolysis with vacuolization and focal degeneration of myocytes. The patient's symptoms and the laboratory values referable to rhabdomyolysis resolved after discontinuation of the drug. We speculate that the rhabdomyolysis was due to mitochondrial damage secondary to inadequate synthesis of coenzyme Q and heme A, members of the electron-transport system of the inner mitochondrial membrane.


Inactivation by ultraviolet light of an acriflavine-sensitive gene function in phage T4D.
Mutants of phage T4D can be isolated which multiply in the presence of concentrations of acriflavine inhibitory to the growth of wild-type phage. Bacteria mixedly infected with resistant and sensitive phage are unproductive in the presence of acriflavine. Irradiation of the sensitive phage with ultraviolet light results in inactivation of the function of the gene for acriflavine sensitivity, permitting the mixedly infected complexes to yield phage. This function is inactivated in an exponential manner and has a cross section comparable to cross sections of other gene functions in T4D.


The task dependence of staged versus cascaded processing: an empirical and computational study of Stroop interference in speech production.
The authors investigated the on-line relationship between overt articulation and the central processes of speech production. In 2 experiments manipulating the timing of Stroop interference in color naming, the authors found that naming behavior can shift between exhibiting a staged or cascaded mode of processing, depending on task demands: An effect of Stroop interference on naming durations arose only when there was increased pressure for speeded responding. In a simple connectionist model of information processing applied to color naming, the authors accounted for the current results by manipulating a single parameter, termed "gain," modulating the rate of information accrual within the network. Results are discussed in relation to mechanisms of strategic control and the link between cognition and action.


Euthanasia and assisted suicide in psychiatric patients: A systematic review of the literature.
The number of psychiatric patients requesting Euthanasia or Assisted Suicide (EAS) continues to increase. The aims of this systematic review were to: 1) describe the available data related to psychiatric patients having received or requesting EAS (pEAS) for each country in which is allowed; 2) and describe the ethically salient points that arise. PubMed, PsycINFO, and Scopus databases were searched to identify articles published up to September 2020. Among the retrieved publications, only studies on pEAS cases (pEAS-C), pEAS requests, or physician reports/attitude towards pEAS reporting some quantitative data on patients having received or requesting pEAS were retained. Among the 24 included studies, thirteen (54%) were about pEAS in the Netherlands, four (17%) in Belgium, and seven (29%) in Switzerland. Results were different across different countries. In the Netherlands, pEAS-C were mostly women (70-77%) and often had at least two psychiatric disorders (56-97%). Mood disorders were mainly represented (55-70%) together with personality disorders (52-54%). History of suicide attempts was present in 34-52%. Moreover, 37-62% of them had at least one comorbid medical condition. In Belgium pEAS-C were mostly women (75%), but the majority (71%) had a single diagnosis, mood disorder. In Switzerland available data were less detailed. As pEAS-C seem to be very similar to 'traditional suicides', pEAS procedures should be carefully revised to establish specific criteria of access and guidelines of evaluation of the request. A deeper focus on unbearable suffering, decision capacity and possibilities of improvements is warranted as well as the involvement of mental health professionals.


Topical treatment of radiation-induced dermatitis: current issues and potential solutions.
Approximately 95% of patients receiving radiotherapy (RT) will ultimately develop radiation-induced dermatitis (RID) during or after the course of treatment, with major consequences on quality of life and treatment outcomes. This paper reviews the pathophysiology of RID and currently used topical products for the prevention and treatment of RID. Although there is no consensus on the appropriate management, recent evidence suggests that the use of topical products supports to protect and promote tissue repair in patients with RID. Basic recommendations include advice to wear loose clothing, using electric razors if necessary, and avoiding cosmetic products, sun exposure or extreme temperatures. Based on mechanisms involved and on the clinical characteristics of oncological patients, the profile of the ideal topical product for addressing RID can be designed; it should have limited risk of adverse events, systemic adsorption and drug-drug interactions, should be characterized by multiple clinical activities, with a special focus on localized pain, and should have a careful formulation as some vehicles can block the RT beam.


Not all types of host contacts are equal when it comes to E. coli transmission.
The specific processes that facilitate pathogen transmission are poorly understood, particularly for wild animal populations. A major impediment for investigating transmission pathways is the need for simultaneous information on host contacts and pathogen transfer. In this study, we used commensal Escherichia coli strains as a model system for gastrointestinal pathogens. We combined strain-sharing information with detailed host contact data to investigate transmission routes in mountain brushtail possums. Despite E. coli being transmitted via the faecal-oral route, we revealed that, strain-sharing among possums was better explained by host contacts than spatial proximity. Furthermore, and unexpectedly, strain-sharing was more strongly associated with the duration of brief nocturnal associations than day-long den-sharing. Thus, the most cryptic and difficult associations to measure were the most relevant connections for the transmission of this symbiont. We predict that future studies that employ similar approaches will reveal the importance of previously overlooked associations as key transmission pathways.


Developmental link between sex and nutrition; doublesex regulates sex-specific mandible growth via juvenile hormone signaling in stag beetles.
Sexual dimorphisms in trait expression are widespread among animals and are especially pronounced in ornaments and weapons of sexual selection, which can attain exaggerated sizes. Expression of exaggerated traits is usually male-specific and nutrition sensitive. Consequently, the developmental mechanisms generating sexually dimorphic growth and nutrition-dependent phenotypic plasticity are each likely to regulate the expression of extreme structures. Yet we know little about how either of these mechanisms work, much less how they might interact with each other. We investigated the developmental mechanisms of sex-specific mandible growth in the stag beetle Cyclommatus metallifer, focusing on doublesex gene function and its interaction with juvenile hormone (JH) signaling. doublesex genes encode transcription factors that orchestrate male and female specific trait development, and JH acts as a mediator between nutrition and mandible growth. We found that the Cmdsx gene regulates sex differentiation in the stag beetle. Knockdown of Cmdsx by RNA-interference in both males and females produced intersex phenotypes, indicating a role for Cmdsx in sex-specific trait growth. By combining knockdown of Cmdsx with JH treatment, we showed that female-specific splice variants of Cmdsx contribute to the insensitivity of female mandibles to JH: knockdown of Cmdsx reversed this pattern, so that mandibles in knockdown females were stimulated to grow by JH treatment. In contrast, mandibles in knockdown males retained some sensitivity to JH, though mandibles in these individuals did not attain the full sizes of wild type males. We suggest that moderate JH sensitivity of mandibular cells may be the default developmental state for both sexes, with sex-specific Dsx protein decreasing sensitivity in females, and increasing it in males. This study is the first to demonstrate a causal link between the sex determination and JH signaling pathways, which clearly interact to determine the developmental fates and final sizes of nutrition-dependent secondary-sexual characters.


No, management is not a profession.
Because managers hold a status in society similar to that of doctors and lawyers, it is natural to think of business as a profession--and of business schools as professional schools. But, argues Barker, a professor at Cambridge University's Judge Business School, that can lead to inappropriate analysis and misguided perceptions. We turn to professionals for advice, he writes, because they have knowledge that we don't. We trust their advice because they've been guaranteed by professional associations that establish the boundaries of the field and reach consensus on what body of learning is required for formal training and certification. These associations make a market for professional services feasible. Although business schools might be able to reach consensus on what they should teach, the proper question is whether what they teach qualifies students to manage. After all, successful businesses are commonly run by people without MBAs. Managers' roles are inherently general, variable, and indefinable; their core skill is to integrate across functional areas, groups of people, and circumstances. Integration is learned in the minds of MBA students, whose experiences and careers are widely diverse, rather than taught in the content of program modules. Thus business education must be highly collaborative, with grading downplayed, and learning must differ according to the stage of a student's career. Business schools are not professional schools. They are incubators for business leadership.


Factors contributing to inconsistent condom use among heterosexual men in Curaçao.
This study explored, from a public health perspective, factors that contribute to inconsistent condom use by men in Curaçao through semi-structured face-to-face interviews with 21 heterosexual men. The findings show that there is an important disconnect between what is considered culturally appropriate sexual behaviour for men and women and condom use, that diverging from prescribed notions of masculinity and femininity in order to use condoms consistently is difficult, and that condom use is particularly problematic in the context of concurrent partnerships and sexual economic exchanges. Participants further reported that Caribbean family structures, whereby mothers assume the role as primary caregiver and fathers contribute biologically but, to a much lesser extent socially, also have an impact on condom use. Additionally, consistent condom use was reported to be impeded by a cultural taboo on talking seriously about sex and sexual health. In their totality, findings provide important input from men for the development of sexual health promotion interventions that are cognizant of the cultural context in which inconsistent condom use occurs, and that are geared not only to the individual level but also to the interpersonal and structural levels.


Lysosomal membrane stabilization by imipramine attenuates gentamicin-induced renal injury: Enhanced LAMP2 expression, down-regulation of cytoplasmic cathepsin D and tBid/cytochrome c/cleaved caspase-3 apoptotic signaling.
Nephrotoxicity is a serious complication commonly encountered with gentamicin (GTM) treatment. Permeabilization of lysosomes with subsequent cytoplasmic release of GTM and cathepsins is considered a crucial issue in progression of GTM toxicity. This study was designed to evaluate the prospective defensive effect of lysosomal membrane stabilization by imipramine (IMP) against GTM nephrotoxicity in rats. GTM (30 mg/kg/h) was intraperitoneally administered over 4 h daily (120 mg/kg/day) for 7 days. IMP (30 mg/kg/day) was orally administered for 14 days; starting 7 days before and then concurrently with GTM. On 15th day, samples (urine, blood, kidney) were collected to estimate biomarkers of kidney function, lysosomal stability, apoptosis, and inflammation. IMP administration to GTM-treated rats ameliorated the disruption in lysosomal membrane stability induced by GTM. That was evidenced by enhanced renal protein expressions of LAMP2 and PI3K, but reduced cathepsin D cytoplasmic expression in kidney sections. Besides, IMP guarded against apoptosis in GTM-treated rats by down-regulation of the pro-apoptotic (tBid, Bax, cytochrome c) and the effector cleaved caspase-3 expressions, while the anti-apoptotic Bcl-2 expression was enhanced. Additionally, the inflammatory cascade p38 MAPK/NF-κB/TNF-α was attenuated in GTM + IMP group along with marked improvement in kidney function biomarkers, compared to GTM group. These findings were supported by the obvious improvement in histological architecture. Furthermore, in vitro enhancement of the antibacterial activity of GTM by IMP confers an additional benefit to their combination. Conclusively, lysosomal membrane stabilization by IMP with subsequent suppression of tBid/cytochrome c/cleaved caspase-3 apoptotic signaling could be a promising protective strategy against GTM nephrotoxicity.


Iodine insufficiency in pregnant women from the State of São Paulo.
The intake of adequate amounts of iodine during pregnancy is essential for the neurological development of the fetus. The aim of this study was to assess iodine nutrition status in pregnant women from the state of São Paulo, Brazil. We analyzed urinary iodine concentration (UIC) in 191 pregnant and 58 non-pregnant women matched by age. We used the World Health Organization criteria to define sufficient iodine supply (median UIC: 150-249 µg/L among pregnant women, and 100-199 µg/L for non-pregnant women). Median UIC of the pregnant women studied was lower than the recommended value (median = 137.7 µg/L, 95% CI = 132.9 - 155.9), while non-pregnant women had UIC levels within the appropriate range (median = 190 μg/L; 95% IC = 159.3-200.1). UIC was below 150 µg/L in 57% of the pregnant women. Although a larger sample is needed to consolidate these findings, these results raise concerns about the adequacy of the iodine supply of pregnant women in Brazil, especially considering the new determinations of the Brazilian government, which have recently reduced the concentrations of iodine in table salt to 15-45 mg/kg of salt.


The nephrologist's role in the management of calcium-phosphorus metabolism in patients with chronic kidney disease.
In patients with chronic kidney disease (CKD), timely referral to a nephrologist has been shown to improve outcomes, but the specific care measures mediating these superior outcomes have not been sufficiently described. In a cohort of 3014 patients with CKD, we evaluated whether they had any indicators of calcium-phosphorus metabolism management prior to renal replacement therapy (RRT). These included measurement of parathyroid hormone (PTH) or vitamin D metabolites, or receipt of calcitriol or calcium-containing phosphate binders (CCPB) prior to RRT. Control patients without such care were selected by risk-set matching. We used multivariate conditional logistic regression analysis to test whether use of these interventions was associated with prior nephrologist consultation. We then used Cox proportional hazards models to assess whether implementation of such care was associated with differences in 1-year mortality once RRT was instituted. Only 3.4% of CKD patients had their PTH assessed prior to RRT, and 0.3% had vitamin D status measured. Use of calcitriol (12.2%) and CCPBs (16%) was slightly more prevalent. Seeing a nephrologist was highly associated with use of the tests and drugs studied (odds ratio, 1.28 to 6.46; all P values <0.001), but care by generalists or other specialists was not. Management of calcium-phosphorus metabolism was independently associated with a 35% decreased likelihood of death (hazards ratio=0.65; 95%CI, 0.51 to 0.84) in the first year of RRT. Improvements in management of calcium-phosphorus metabolism in patients with CKD are attributable to nephrologist care and appear to mediate the survival benefit seen in patients who see a nephrologist relatively early in the course of their CKD.


Increased anxiety-like behaviour is an early symptom of vitamin E deficiency that is suppressed by adrenalectomy in rats.
We previously reported that dietary vitamin E deficiency increased anxiety-like behaviour in rats exposed to social isolation. Here, we performed a detailed investigation of this phenomenon and its underlying mechanism. First, we fed Wistar rats with a vitamin E-free diet for 3 d, 1 week or 2 weeks and found an increase in anxiety-like behaviour after 1 and 2 weeks of vitamin E deficiency based on behavioural indicators. Next, we examined the effect of a control diet (150 mg all-racemic α-tocopheryl acetate/kg) on anxiety-like behaviours in rats that received a 4-week vitamin E-free diet. We found that increased anxiety-like behaviour was reversed to control levels after refeeding vitamin E for 7 d but not for 1 or 3 d. Further, anxiety-like behaviour increased or decreased gradually based on the amount of vitamin E intake; however, it had a quicker progression than physical symptoms of vitamin E deficiency. Moreover, rats fed with excess vitamin E (500 mg all-racemic α-tocopherol/kg diet) showed less anxiety-like behaviour than control rats, indicating that vitamin E supplementation is effective for preventing anxiety increase under social isolation stress. Since plasma corticosterone levels were higher in vitamin E-deficient rats, we investigated the effect of adrenalectomy on anxiety-like behaviour and found that adrenal hormones played an essential role in the increased anxiety-like behaviour induced by vitamin E deficiency. In conclusion, increased anxiety-like behaviour is a symptom that emerges earlier than physical vitamin E deficiency and is caused by adrenal hormone-dependent mechanisms.


The tomato carotenoid cleavage dioxygenase 1 genes contribute to the formation of the flavor volatiles beta-ionone, pseudoionone, and geranylacetone.
Volatile terpenoid compounds, potentially derived from carotenoids, are important components of flavor and aroma in many fruits, vegetables and ornamentals. Despite their importance, little is known about the enzymes that generate these volatiles. The tomato genome contains two closely related genes potentially encoding carotenoid cleavage dioxygenases, LeCCD1A and LeCCD1B. A quantitative reverse transcriptase-polymerase chain reaction analysis revealed that one of these two genes, LeCCD1B, is highly expressed in ripening fruit (4 days post-breaker), where it constitutes 0.11% of total RNA. Unlike the related neoxanthin cleavage dioxygenases, import assays using pea chloroplasts showed that the LeCCD1 proteins are not plastid-localized. The biochemical functions of the LeCCD1 proteins were determined by bacterial expression and in vitro assays, where it was shown that they symmetrically cleave multiple carotenoid substrates at the 9,10 (9',10') positions to produce a C14 dialdehyde and two C13 cyclohexones that vary depending on the substrate. The potential roles of the LeCCD1 genes in vivo were assessed in transgenic tomato plants constitutively expressing the LeCCD1B gene in reverse orientation. This over-expression of the antisense transcript led to 87-93% reductions in mRNA levels of both LeCCD1A and LeCCD1B in the leaves and fruits of selected lines. Transgenic plants exhibited no obvious morphological alterations. High-performance liquid chromatography analysis showed no significant modification in the carotenoid content of fruit tissue. However, volatile analysis showed a > or =50% decrease in beta-ionone (a beta-carotene-derived C13 cyclohexone) and a > or =60% decrease in geranylacetone (a C13 acyclic product likely derived from a lycopene precursor) in selected lines, implicating the LeCCD1 genes in the formation of these important flavor volatiles in vivo.


Autophagy Inhibition in Childhood Nephroblastoma and the Therapeutic Significance.
Autophagy is a physiological pathway characterized by lysosomedependent self-digestion to recycle damaged or superfluous cellular content. Deregulation of autophagy hampers the maintenance of cellular homeostasis and contributes to tumorigenesis. However, during anticancer therapy, autophagy activation contributes to development of resistance. Thus autophagy has been recognized as an important pathway and a therapeutic target in cancer. Nephroblastoma (Wilm's tumor) is a common childhood malignancy. The role of autophagy in nephroblastoma is largely uninvestigated. This study is to investigate the change of autophagy level in nephroblastoma, and whether autophagy could be a therapeutic target in anaplastic nephroblastoma. In clinical samples of childhood nephroblastoma, autophagy activity was evaluated by the expressions of selected autophagy markers as well as the presence of autophagosome ultrastructure. Use of autophagy inhibitors alone and in combination with conventional chemotherapeutics, was studied both in vivo and in vitro. In nephroblastoma, there was decrease in the Beclin 1 level and the number of autophagosomes, suggesting autophagy inhibition. Furthermore, in two anaplastic nephroblastoma cell lines, G401 and SK-NEP1, autophagy inhibitors further enhanced the efficacy of conventional chemotherapeutics including vincristine and cisplatin. In G401 tumor model established in nude mice, combinational use of chloroquine, an inhibitor of autophagy degradation, further decreased the tumor mass compared with single use of the chemotherapeutics vindesine, although no statistical significance was achieved. Our results suggest that autophagy deregulation is involved in nephroblastoma, and targeting autophagy can serve as a potential adjuvant strategy for the highly malignant cases.


Aplastic anemia and viral hepatitis. Non-A, Non-B, Non-C?
To test the hypothesis that the rare, often fatal, syndrome of hepatitis-associated aplasia is associated with hepatitis C virus infection. Case series. Tertiary referral centers in the United States, Japan, Italy, and Germany. Twenty-eight patients with onset of aplastic anemia within 90 days after seeking medical attention for jaundice, or having serum transaminase levels 150% or more of normal (hepatitis-associated aplasia patients) and three patients who developed aplastic anemia following liver transplantation for non-A, non-B hepatitis. Presence of hepatitis C in serum, bone marrow, and liver samples, detected by the polymerase chain reaction; antibody testing; and percentage of activated peripheral cytotoxic T lymphocytes determined by immunophenotyping. Hepatitis ribonucleic acid was present in the serum samples of 10 (36%) patients with hepatitis-associated aplasia. However, hepatitis C virus viremia was associated with transfusions received after the onset of aplasia: seven (58%) of 12 patients with hepatitis-associated aplasia who had received 21 or more units of blood products at the time of serum sampling were viremic, compared with only three (19%) of 16 patients with hepatitis-associated aplasia who had received 20 or less units of blood products (P less than .05). Hepatitis C virus was not found in blood and bone marrow samples of three National Institutes of Health case patients tested at the time of diagnosis. None of three livers from non-A, non-B hepatitis patients who developed aplastic anemia after liver transplantation contained hepatitis C virus ribonucleic acid. Activated CD8+ T lymphocytes were elevated three- to 20-fold early in the course of hepatitis-associated aplasia. Our results implicate a novel, non-A, non-B, and non-C agent in both hepatitis-associated aplasia and fulminant hepatitis.


Recurrent transient ischaemic attack and early risk of stroke: data from the PROMAPA study.
Many guidelines recommend urgent intervention for patients with two or more transient ischaemic attacks (TIAs) within 7 days (multiple TIAs) to reduce the early risk of stroke. To determine whether all patients with multiple TIAs have the same high early risk of stroke. Between April 2008 and December 2009, we included 1255 consecutive patients with a TIA from 30 Spanish stroke centres (PROMAPA study). We prospectively recorded clinical characteristics. We also determined the short-term risk of stroke (at 7 and 90 days). Aetiology was categorised using the TOAST (Trial of Org 10172 in Acute Stroke Treatment) classification. Clinical variables and extracranial vascular imaging were available and assessed in 1137/1255 (90.6%) patients. 7-Day and 90-day stroke risk were 2.6% and 3.8%, respectively. Large-artery atherosclerosis (LAA) was confirmed in 190 (16.7%) patients. Multiple TIAs were seen in 274 (24.1%) patients. Duration <1 h (OR=2.97, 95% CI 2.20 to 4.01, p<0.001), LAA (OR=1.92, 95% CI 1.35 to 2.72, p<0.001) and motor weakness (OR=1.37, 95% CI 1.03 to 1.81, p=0.031) were independent predictors of multiple TIAs. The subsequent risk of stroke in these patients at 7 and 90 days was significantly higher than the risk after a single TIA (5.9% vs 1.5%, p<0.001 and 6.8% vs 3.0%, respectively). In the logistic regression model, among patients with multiple TIAs, no variables remained as independent predictors of stroke recurrence. According to our results, multiple TIAs within 7 days are associated with a greater subsequent risk of stroke than after a single TIA. Nevertheless, we found no independent predictor of stroke recurrence among these patients.


[Determination of arteriovenous transit time of the choroid with indocyanine green].
We present a very sensitive, yet light-weight videosystem for infrared angiography with Indocyanine green. This system was used to quantify for the first time the choroidal arteriovenous passage time (chAVP) in eight healthy volunteers and eight patients with retinal detachment pre- and postoperatively. The mean normal value of the chAVP was measured to be 3,46 + 0,59 sec. Patients with retinal detachment could be divided into two groups. The chAVP did not change significantly (p = 0,298) from 3,37 + 0,55 sec. to 3,48 + 0,54 sec. in six patients (mean age 49,7 + 5,4 years), who had a simple scleral buckling procedure. In two further patients (63 and 70 years), who had been operated with an encircling band, a postoperative chAVP-delay of 0,72 and 1,48 sec. was detected. This verification of the clinically expected obstruction of choroidal venous outflow after encircling bands emphasizes the validity of the method. Nevertheless, since the procedure is time consuming and detects only marked disturbances, it must be taken as one basic step in the search for the quantification of the choroidal circulation.


Effective Treatment of Solitary Pituitary Metastasis with Panhypopituitarism in HER2-Positive Breast Cancer by Lapatinib.
Brain metastasis affects one third of patients with HER2-positive breast cancer after treatment with trastuzumab. Surgical resection and radiation therapy are often unsuccessful at accomplishing complete control of metastasis. Lapatinib is presumed to cross the blood-brain barrier, and exhibits clinical activities for treatment of HER2-positive breast cancer. A 43-year-old woman was treated for early breast carcinoma with total mastectomy, axillary lymph-node dissection, and adjuvant chemotherapy with cyclophosphamide plus doxorubicin. After the end of adjuvant trastuzumab therapy, she was diagnosed with panhypopituitarism due to pituitary metastasis. Surgical removal and whole brain radiation therapy were performed, but a portion of viable tumor remained. Only taking lapatinib, the size of the metastatic lesion began to shrink. Trastuzumab may have controlled the micro-metastasis of breast cancer, but it was unable to control its progression to the central nervous system. Lapatinib is a possible option for HER2-positive metastatic breast cancer patients with brain metastasis.


Robotic versus freehand S2 alar iliac fixation: in-depth technical considerations.
Achieving fixation and fusion across the lumbosacral junction has been a challenge for spinal deformity surgeons ever since the development of instrumentation. The S2 alar-iliac (S2AI) trajectory has been introduced as a method of pelvic fixation to decrease strain on S1 screws. The S2AI screws differ in several ways from traditional iliac screws. The trajectory of these screws helps avoid the use of offset connectors due to the screws alignment with the proximal pedicle screw instrumentation. Current literature shows that S2AI screws are effective with low complication rates, but the path of these screws is intimately associated with major neural and vascular structures. Use of robotic guidance to obtain the correct trajectory has been shown to be both safe and effective in obtaining proper trajectory of S2AI screws with over 95% accuracy. Herein, we report on the technical considerations and radiographic outcomes surrounding robotic and freehand insertion of S2AI screws.


Recombinant von Willebrand factor for severe gastrointestinal bleeding unresponsive to other treatments in a patient with type 2A von Willebrand disease: a case report.
: A recombinant von Willebrand factor (rVWF) was recently approved in the United States for on-demand treatment and control of bleeding episodes in adults with von Willebrand disease (VWD). In contrast to plasma-derived VWF products available in the United States, rVWF does not contain factor VIII (FVIII). To date, there is no published experience of rVWF in clinical practice. We report the acute and prophylactic use of rVWF in a patient with VWD type 2A and severe gastrointestinal bleeding. Dosing with plasma-derived VWF/FVIII concentrates was constrained by FVIII accumulation; the bleeding was unresponsive, and multiple red blood cell transfusions were required. After initiation of rVWF (4200 IU every other day), bleeding symptoms subsided, and no red blood cell transfusions were required during more than 3 months of prophylactic therapy (most recent dosage: 2800 IU every other day). rVWF may be effective in the prevention, as well as treatment, of severe bleeding symptoms in VWD.


Pain after episiotomy--a comparison of two methods of repair.
Episiotomy is a very common operation but little is known of its short-term or long-term morbidity.A prospective study was designed to record postpartum perineal discomfort and to investigate the presence and persistence of dyspareunia following episiotomy in 140 primigravidae. A comparison was made between those whose perineal skin was sutured with a subcuticular polyglycolic acid (;Dexon') stitch and those sutured with interrupted black silk stitches.Patients sutured with subcuticular ;Dexon' had significantly less perineal discomfort on the third, fourth, and fifth postpartum days. Patients who had epidural analgesia in labour had significantly more pain during the first five postpartum days irrespective of the suture material used.The timing of first coitus after delivery did not influence the presence or persistence of dyspareunia. Dyspareunia was commoner and lasted longer in patients sutured with ;Dexon' and it was also commoner in older primigravidae irrespective of the suture technique.


A practical approach to treatment of the obese patient.
Obesity is one of the most common conditions encountered by primary care physicians, yet both physicians and patients are often frustrated by current approaches to its management. Recent advances in our understanding of obesity enable the physician to evaluate the contributions of biologic and environmental factors to the patient's obesity, to determine the degree of medical risk posed by the obesity, and to establish realistic goals for treatment. The chronic and relapsing nature of obesity requires ongoing support and vigilance. An individualized approach to obesity management, based on careful evaluation of biologic, psychologic, and social factors, can be successfully developed and implemented by the office-based primary care physician.


Opposing effects of activin A and follistatin on developing skeletal muscle cells.
Activin and the activin-binding protein follistatin modulate a variety of biological processes and are abundant at sites of muscle development. Activin and follistatin were expressed in developing chick pectoral muscle in vivo and in primary cell culture. Addition of recombinant activin inhibited muscle development in a dose-dependent manner as measured by the number of nuclei in myosin heavy chain positive cells and creatine phosphokinase activity. Conversely, follistatin potentiated muscle development. The effects of activin were found to be distinct from those of the related protein transforming growth factor (TGF) beta1. Muscle development was repressed by activin at all time points investigated and did not recover with the removal of activin following a limited exposure. In contrast, while myogenic differentiation in TGFbeta1 was initially repressed, muscle marker expression recovered to control levels--even in the continued presence of TGFbeta1. Fibroblast growth factor (FGF) had little effect on inhibiton of muscle development caused by activin A. However, inhibition of development produced by TGFbeta increased with increasing concentrations of FGF. Finally, early expression of myoD and myf5 mRNA by muscle cultures in the presence of activin and follistatin was analyzed. Activin-treated cultures expressed reduced myoD and myf5 levels at 1.5 days after plating. Myf5 levels in follistatin-treated cultures were elevated, but, surprisingly, these cultures showed a reduction in myoD levels. These data suggest that endogenously expressed activin and follistatin are important modulators of muscle development.


Tibiotalar nonunion corrected by hindfoot arthrodesis.
A 65-year-old man without significant comorbidities was referred to the senior author (EG) 9 months after an ankle arthrodesis procedure with complaints of pain, swelling, and progressive hindfoot valgus. The patient had elected to have the index surgery because of severe ankle arthritis due to longstanding lateral ankle instability. Physical examination revealed a well-healed anterior, midline ankle incision with normal pulses and sensation. Painful, limited ankle and subtalar range of motion was noted along with 20 degrees of hindfoot valgus and subfibular impingement. Radiographs of the ankle revealed an attempted ankle fusion using a knee arthroplasty trabecular metal augment placed vertically at the tibiotalar joint. There were no screws or other hardware present to provide compression and stability of the fusion. A computed tomography scan showed a tibiotalar nonunion, erosion of the talar body, and severe tibiotalar and subtalar arthritis. Inflammatory markers were within normal range. Based on the findings of a failed fusion and progressive painful hindfoot deformity, it was determined that the patient would benefit from removal of the hardware and revision fusion surgery. Tibiotalocalcaneal (TTC) hindfoot fusion was planned because of the patient's talar collapse and tibiotalar/ subtalar arthritis. The TTC procedure was performed with a retrograde intramedullary nail, femoral head allograft, and morselized fibular autograft enriched with platelet-rich plasma. The femoral head was used as a structural allograft to fill the large bone defect, prevent limb shortening, and assist in correction of the hindfoot deformity. Intraoperative findings revealed severe metallic synovitis of the ankle and subtalar joints, metal debris at the site of the trabecular implant, and segmental defects of the distal tibia and talus. Weight bearing was permitted after 16 weeks when evidence of successful ankle fusion was confirmed radiographically. At 24 months, the patient was pain free and ambulating without difficulty.


Tripartite haemolysin BL: isolation and characterization of two distinct homologous sets of components from a single Bacillus cereus isolate.
Haemolysin BL (HBL), a three-component enterotoxic/necrotizing/vascular permeability toxin, is a likely virulence factor of Bacillus cereus diarrhoeal food poisoning and necrotic infections. This paper describes the isolation of two distinct homologous sets of all three HBL components from a single B. cereus isolate, MGBC 145. The proteins of one set (designated HBL, consisting of B, L(1) and L(2)), were about 87-100% identical in N-terminal amino acid sequences to their respective prototype components from strain F837/76, and the proteins of the homologous set (HBL(a), consisting of B(a), L(1a) and L(2a)) were all about 62-65% identical. Only the latter homologues differed immunochemically and physicochemically from the prototypes. HBL and HBL(a) exhibited similar haemolytic and vascular permeability potencies, and the homologues could be interchanged freely. There were no notable differences in activity between the L component homologues. However, components B and B(a) were significantly different. Both were secreted as monomers, but unlike B, B(a) was isolated as a relatively inactive complex that could be reactivated with urea. When B(a) was substituted for B in gel-diffusion assays the distinct discontinuous haemolysis pattern typical of the presence of B did not occur. In suspension assays, excess B inhibited the haemolysis of B-primed cells by L(1) (as previously described), but not that of B(a)-primed cells. Excess B(a) had the opposite effect and enhanced lysis of B(a)-primed cells, but not that of B-primed cells. These differences reveal details about how the toxin components interact on target cell membranes. The authors' observations indicate that HBL represents a new family of multicomponent toxins that was generated by a process of gene and operon duplication that occurred either intracellularly or by horizontal transfer, and raise the possibility of the existence of other related toxins in the genetically diverse B. cereus taxonomic group.


Infection of feline embryo adherent cells with feline leukemia virus: feline oncornavirus-associated cell membrane antigen expression and morphologic transformation.
Feline embryo adherent cells were infected with the Richard or Kawakami-Theilen strains of feline leukemia virus (FeLV) and examined for feline oncornavirus-associated cell membrane antigen (FOCMA), viral group-specific antigen (gsa) production, and in vitro evidence of transformation. As early as 10 days after infection, when more than half of the infected cells were gsa positive, FOCMA was detected on 5-10 percent of the cells. Transitory morphologic alterations (epithelioid appearance and rounding) were first noted in most cultures around 20-30 days post infection. At this time, approximately 50% of the cells in infected cultures expressed FOCMA. Morphologic characteristics of transformed fibroblastic cells (rounded shape, disordered alignment, and low adhesion to substratum), as well as enhanced agglutinability by plant lectins and ability to grow in agar, were demonstrated in one of four FeLV-infected, FOCMA-positive cultures. Findings showed that FOCMA may be expressed in FeLV-infected monolayer cells independent of transformation as assessed by in vitro criteria.


Inter-Comparison of UT1-UTC from 24-Hour, Intensives, and VGOS Sessions during CONT17.
This work focuses on the assessment of UT1-UTC estimates from various types of sessions during the CONT17 campaign. We chose the CONT17 campaign as it provides 15 days of continuous, high-quality VLBI data from two legacy networks (S/X band), i.e., Legacy-1 (IVS) and Legacy-2 (VLBA) (having different network geometry and are non-overlapping), two types of Intensive sessions, i.e., IVS and Russian Intensives, and five days of new-generation, broadband VGOS sessions. This work also investigates different approaches to optimally compare dUT1 from Intensives with respect to the 24 h sessions given the different parameterization adopted for analyzing Intensives and different session lengths. One approach includes the estimation of dUT1 from pseudo Intensives, which are created from the 24 h sessions having their epochs synchronized with respect to the Intensive sessions. Besides, we assessed the quality of the dUT1 estimated from VGOS sessions at daily and sub-daily resolution. The study suggests that a different approach should be adopted when comparing the dUT1 from the Intensives, i.e., comparison of dUT1 value at the mean epoch of an Intensive session. The initial results regarding the VGOS sessions show that the dUT1 estimated from VGOS shows good agreement with the legacy network despite featuring fewer observations and stations. In the case of sub-daily dUT1 from VGOS sessions, we found that estimating dUT1 with 6 h resolution is superior to other sub-daily resolutions. Moreover, we introduced a new concept of sub-daily dUT1-tie to improve the estimation of dUT1 from the Intensive sessions. We observed an improvement of up to 20% with respect to the dUT1 from the 24 h sessions.


Oral health status during pregnancy: rural-urban comparisons of oral disease burden among antenatal women in Sri Lanka.
Sri Lanka is a middle income country and 80% of its population lives in rural areas. There is a well organized maternal and child health program and oral health care has recently been incorporated. The aim of this study was to report the oral disease burden of rural and urban antenatal women in the Western Province of Sri Lanka, thus highlighting the need to provide oral health care to this group. The sample consisted of 459 rural pregnant women in their second trimester and 348 urban pregnant women in their third trimester. Data were collected using interviewer administered questionnaires and a clinical oral examination conducted by calibrated examiners. The mean Decayed Missing and Filled Teeth (DMFT) among rural antenatal women were 5.4 ± 3, with 2.27 (± 2.31) decayed teeth, 1.25 (± 1.97) missing teeth, and 1.90 (± 1.89) filled teeth. Among urban antenatal women, the mean DMFT was 3.69 (± 3.62) with 1.04 (± 2.15) decayed teeth, 1.07 (± 1.59) missing teeth and 1.59 (± 2.06) filled teeth. Rural antenatal women had a significantly higher experience of decayed teeth (p=0.001) and filled teeth (p=0.026), and twice as many untreated dental caries, compared with urban women. Moreover, almost 60% of rural women presented with bleeding gums. Similarly, the prevalence of calculus was 30.3% for rural women and 13.5% for urban women. The most significant finding was 3.5% prevalence of shallow periodontal pockets (4-5 mm) for rural women but 73.0% for urban women (p=0.0001). In the final model of multiple logistic regression analysis, significant predictors for dental caries experience were age (adjusted OR [95% CI]: 2.51 [1.55-4.06], p=0.0001) and location (urban vs rural adjusted OR [95% CI)]: 0.25 [0.11-0.55], p=0.001). However for periodontal status the only significant association was between age and Community Periodontal Index of Treatment Needs (CPITN): CPITN=0 versus CPITN>0 in bivariate analysis for the overall sample (p=0.001). Antenatal women in Sri Lanka have a high burden of dental caries and periodontal disease. Rural women had as twice as many untreated dental caries compared with urban women, but were unlikely to use oral healthcare services due to concerns about safety in receiving dental care during pregnancy. Oral healthcare provision to antenatal women in Sri Lanka can be improved.


Immunocytolocalization of extensin in developing soybean seed coats by immunogold-silver staining and by tissue printing on nitrocellulose paper.
In soybean seed coats the accumulation of the hydroxyproline-rich glycoprotein extensin is regulated in a developmental and tissue-specific manner. The time course of appearance of extensin during seed development was studied by Western blot analysis and by immunogold-silver localization. Using these techniques extensin was first detected at 16-18 d after anthesis, increasing during development to high levels at 24 d after anthesis. Immunogold-silver localization of extensin in the seed coat showed marked deposition of the glycoprotein in the walls of palisade epidermal cells and hourglass cells. The immunolocalization of extensin in developing soybean seeds was also made by a new technique--tissue printing on nitrocellulose paper. It was found that extensin is primarily localized in the seed coat, hilum, and vascular elements of the seed.


Major Complications after Male Anti-Incontinence Procedures: Predisposing Factors, Management and Prevention.
Significant post-prostatectomy incontinence (PPI) is a crippling condition and managed best through sling or artificial urinary sphincter (AUS) implantation. These procedures are often associated with complications requiring surgical intervention. The aim of our retrospective study was to evaluate the occurrence of major complications and identify risk factors. Between 2010 and 2018 ninety-one patients have been implanted with sling (22; 24.2%) or AUS (69; 75.8%) in our department. The cases where surgical revision was needed were examined regarding the etiology (mechanical failure (MF), urethral erosion (UE), urethral atrophy (UA), surgical site infection (SSI), combined reasons (COMB) and analyzed, using 16 possible perioperative risk factors. Surgical intervention was carried out by 19 / 91 (20.9%) patients. (In 16 / 69 cases after AUS (23.1%), 3 / 13 after slings (23%)). The indication was in 6 (31.6%) cases MF, in 3 (15.8 %) COMB, in 4 (21.1%) UE, in 5 (26.3 %) SSI, in 1 (5.2%) UA. The type of reoperation was either explantation (12 / 19), system replacement (6 / 19), or cuff replacement (1 /19). Regarding the surgical intervention requiring complications only preoperative bacteriuria (P = .006) and postoperative surgical site oedema (P = .002) proved to be independent predictive factors. Preoperative bacteriuria and surgical site oedema seemed to be good predictors for obligate surgical revision. Patients with AUS were more prone to have major complications. In most cases it was mechanical failure, infection or erosion. By reducing the frequency of these risk factors we might be able to decrease the amount of complications.


The emerging Medical and Geological Association.
The impact on human health by natural materials such as water, rocks, and minerals has been known for thousands of years but there have been few systematic, multidisciplinary studies on the relationship between geologic materials and processes and human health (the field of study commonly referred to as medical geology). In the past few years, however, there has been a resurgence of interest in medical geology. Geoscientists working with medical researchers and public health scientists have made important contributions to understanding novel exposure pathways and causes of a wide range of environmental health problems such as: exposure to toxic levels of trace essential and non-essential elements such as arsenic and mercury; trace element deficiencies; exposure to natural dusts and to radioactivity; naturally occurring organic compounds in drinking water; volcanic emissions, etc. By linking with biomedical/public health researchers geoscientists are finally taking advantage of this age-old opportunity to help mitigate environmental health problems. The International Medical Geology Association has recently been formed to support this effort.


Insulin promotes proliferation of pancreatic ductal epithelial cells by increasing expression of PLK1 through PI3K/AKT and NF-κB pathway.
Pancreatic cancer has a poor prognosis. Many epidemiological evidence show that diabetes is closely related to the occurrence of pancreatic cancer. The concentration of insulin in pancreas local tissues is higher than that in systemic circulation. In this study, we aimed to investigate the effect of insulin on pancreatic duct epithelial cells and identify the potential mechanisms. We found that insulin promoted the proliferation of pancreatic duct epithelial cells in the dependent of increased PLK1. Furthermore, PI3K/AKT and NF-κB pathway were involved in this process. By using PI3K/AKT inhibitor LY294002 and NF-κB shRNA, the increased PLK1 was reversed and cells proliferation was inhibited. Additionally, immunofluorescence analysis revealed the co-localization between PLK1 and β-catenin. We showed that insulin can promote the increased expression of β-catenin dependent on PLK1. This study showed that insulin may promotes cell proliferative vitality of pancreatic ductal epithelial cells by inducing PLK1 through PI3K/AKT and NF-κB pathway; The upregulation of PLK1 may reduce the degradation of β-catenin. This may be one of the mechanisms by which T2DM promotes pancreatic cancer.


Delineation of a Cardiac Planning Organ-At-Risk Volume Using Real-Time Magnetic Resonance Imaging for Cardiac Protection in Thoracic and Breast Radiation Therapy.
Cardiac radiation is associated with cardiotoxicity in patients with thoracic and breast malignancies. We conducted a prospective study using cine magnetic resonance imaging (MRI) scans to evaluate heart motion. We hypothesized that cine MRI could be used to define population-based cardiac planning organ-at-risk volumes (PRV). A total of 16 real-time acquisitions were obtained per subject on a 1.5 Tesla MRI (Philips Ingenia). Planar cine MRI was performed in 4 sequential sagittal and coronal planes at free-breathing (FB) and deep-inspiratory breath hold (DIBH). In-plane cardiac motion was assessed using a scale-invariant feature transformation-based algorithm. Subject-specific pixel motion ranges were defined in anteroposterior (AP), left-right (LR), and superoinferior (SI) planes. Averages of the 98% and 67% of the maximum ranges of pixel displacement were defined by subject, then averaged across the cohort to calculate PRV expansions at FB and DIBH. Data from 20 subjects with a total of 3120 image frames collected per subject in coronal and sagittal planes at DIBH and FB, and 62,400 total frames were analyzed. Cohort averages of 98% of the maximum cardiac motion ranges comprised margin expansions of 12.5 ± 1.1 mm SI, 5.8 ± 1.2 mm AP, and 6.6 ± 1.0 mm LR at FB and 6.7 ± 1.5 mm SI, 4.7 ± 1.3 mm AP, and 5.3 ± 1.3 mm LR at DIBH. Margins for 67% of the maximum range comprised 7.7 ± 0.7 mm SI, 3.2 ± 0.6 mm AP, and 3.7 ± 0.6 mm LR at FB and 4.1 ± 0.9 mm SI, 2.7 ± 0.8 mm AP, and 3.2 ± 0.8 mm LR at DIBH. Subsequently, these margins were simplified to form PRVs for treatment planning. We implemented scale-invariant feature transformation-based motion tracking for analysis of the cardiac cine MRI scans to quantify motion and create cohort-based cardiac PRVs to improve cardioprotection in breast and thoracic radiation.


Integration of lead-free ferroelectric on HfO2/Si (100) for high performance non-volatile memory applications.
We introduce a novel lead-free ferroelectric thin film (1-x)BaTiO3-xBa(Cu1/3Nb2/3)O3 (x = 0.025) (BT-BCN) integrated on to HfO2 buffered Si for non-volatile memory (NVM) applications. Piezoelectric force microscopy (PFM), x-ray diffraction, and high resolution transmission electron microscopy were employed to establish the ferroelectricity in BT-BCN thin films. PFM study reveals that the domains reversal occurs with 180° phase change by applying external voltage, demonstrating its effectiveness for NVM device applications. X-ray photoelectron microscopy was used to investigate the band alignments between atomic layer deposited HfO2 and pulsed laser deposited BT-BCN films. Programming and erasing operations were explained on the basis of band-alignments. The structure offers large memory window, low leakage current, and high and low capacitance values that were easily distinguishable even after ~10(6) s, indicating strong charge storage potential. This study explains a new approach towards the realization of ferroelectric based memory devices integrated on Si platform and also opens up a new possibility to embed the system within current complementary metal-oxide-semiconductor processing technology.


Diagnostic Accuracy of Transabdominal Ultrasound in Chronic Pancreatitis.
The performance of transabdominal ultrasound (US) in chronic pancreatitis (CP) following the advances in US technology made during recent decades has not been explored. Our aim in this prospective study was to evaluate the diagnostic accuracy of modern abdominal US compared with the Mayo score in CP. One hundred thirty-four patients referred for suspected CP were included in the study. Fifty-four patients were assigned the diagnosis CP. After inclusion, transabdominal US was performed. Ductal features (calculi, dilations and caliber variations, side-branch dilations and hyper-echoic duct wall margins) and parenchymal features (calcifications, cysts, hyper-echoic foci, stranding, lobulation and honeycombing) were recorded. Features were counted and scored according to a weighting system defined at the international consensus meeting in Rosemont, Illinois (Rosemont score). Diagnostic performance indices (95% confidence interval) of US were calculated: The unweighted count of features had a sensitivity of 0.69 (0.54-0.80) and specificity of 0.97 (0.90-1). The Rosemont score had a sensitivity of 0.81 (0.69-0.91) and specificity of 0.97 (0.90-1). Exocrine pancreatic failure was most pronounced in Rosemont groups I and II (p < 0.001). We conclude that using both unweighted and weighted scores, the diagnostic accuracy of modern transabdominal US is good. The extent of pancreatic changes detected by the method is correlated with exocrine pancreatic function.


Antibacterial activities of naturally occurring compounds against antibiotic-resistant Bacillus cereus vegetative cells and spores, Escherichia coli, and Staphylococcus aureus.
After demonstrating the lack of effectiveness of standard antibiotics against the acquired antibiotic resistance of Bacillus cereus (NCTC 10989), Escherichia coli (NCTC 1186), and Staphylococcus aureus (ATCC 12715), we showed that the following natural substances were antibacterial against these resistant pathogens: cinnamon oil, oregano oil, thyme oil, carvacrol, (S)-perillaldehyde, 3,4-dihydroxybenzoic acid (beta-resorcylic acid), and 3,4-dihydroxyphenethylamine (dopamine). Exposure of the three pathogens to a dilution series of the test compounds showed that oregano oil was the most active substance. The oils and pure compounds exhibited exceptional activity against B. cereus vegetative cells, with oregano oil being active at nanogram per milliliter levels. In contrast, activities against B. cereus spores were very low. Activities of the test compounds were in the following approximate order: oregano oil > thyme oil approximately carvacrol > cinnamon oil > perillaldehyde > dopamine > beta-resorcylic acid. The order of susceptibilities of the pathogens to inactivation was as follows: B. cereus (vegetative) >> S. aureus approximately E. coli >> B. cereus (spores). Some of the test substances may be effective against antibiotic-resistant bacteria in foods and feeds.