Accuracy of CBCT-based root canal length predetermination using new endodontic planning software compared to measurements performed with an electronic apex locator ex vivo.
To evaluate the accuracy of the new endodontic planning software (3D Endo Dentsply Sirona) based on cone beam computed tomography (CBCT) to predetermine root canal lengths compared with measurements performed with an electronic apex locator (Raypex 6; VDW) ex vivo. CBCT scans of forty extracted human maxillary (n = 20) and mandibular (n = 20) molars were taken, and root canal lengths were predetermined with the 3D Endo software using the apical foramen (AF) and the adjoining cusp as references. Root canal lengths were determined with the Raypex 6 using the same references. To evaluate the accuracy, absolute differences between both methods and the actual root canal length (gold standard) were calculated and statistically analyzed. Differences between lengths measured with the 3D Endo and the Raypex 6 compared with the gold standard showed no significant differences (P = 0.879). Mean differences were 0.37 mm versus 0.35 mm in the maxillary molars, and 0.30 mm versus 0.31 mm in the mandibular molars. A total of 75.8% (3D Endo) and 79.1% (Raypex 6) of all measurements were within the limits of ± 0.5 mm. Both methods showed a tendency to result in short measurements (P < 0.001). Within the limitations of this study, the 3D Endo software enables an accurate three-dimensional (3D) predetermination of root canal lengths.


A rational account of memory predicts left prefrontal activation during controlled retrieval.
What is the role of the left prefrontal cortex in the controlled retrieval of learned information? We present a theory of declarative retrieval that posits that the amount of control exerted by this region during retrieval is inversely proportional to 1) the frequency and recency of previous experiences with the retrieved memory and 2) the associative strength between the current context and the retrieved memory. This theory is rational in the sense that it claims that declarative retrieval is highly sensitive to the statistical regularities in the environment. We demonstrate how our theory produces precise predictions of response time and neural activity during recall and test these predictions in an experiment that manipulates the frequency of previous experiences and the associative strength to the retrieval cues. Our findings suggest that the control process performed by the left prefrontal cortex directly reflects the demands of the environment on memory.


Implementation lessons on the use of innovation in information technology in the developing world.
Information Technology (IT) innovation and its impact on health care is of particular relevance to the developing world, which spends a fraction of what health systems spend in OECD countries. Given the issues of accessibility, affordability and quality health services in the developing world, IT can play an important role by bringing marginalized communities closer to health care systems. Aga Khan University (AKU) and the eHealth Resource Center (eHRC), which are part of Aga Khan Development Network (AKDN), are active in the developing regions of East Africa, Central Asia and South East Asia and are currently initiating new changes in the use of IT and also the manner in which it is deployed. The eHealth programmes implemented and the lessons learned by AKU and eHRC in achieving its core values of impact, access, relevance, and quality through implementation of these innovations are described. These can be of value to health systems and academic medical centres in the developing world wanting to leverage scarce resources to create meaningful impact using IT.


Top predators, mesopredators and their prey: interference ecosystems along bioclimatic productivity gradients.
1. The Mesopredator Release Hypothesis (MRH) suggests that top predator suppression of mesopredators is a key ecosystem function with cascading impacts on herbivore prey, but it remains to be shown that this top-down cascade impacts the large-scale structure of ecosystems. 2. The Exploitation Ecosystems Hypothesis (EEH) predicts that regional ecosystem structures are determined by top-down exploitation and bottom-up productivity. In contrast to MRH, EEH assumes that interference among predators has a negligible impact on the structure of ecosystems with three trophic levels. 3. We use the recolonization of a top predator in a three-level boreal ecosystem as a natural experiment to test if large-scale biomass distributions and population trends support MRH. Inspired by EEH, we also test if top-down interference and bottom-up productivity impact regional ecosystem structures. 4. We use data from the Finnish Wildlife Triangle Scheme which has monitored top predator (lynx, Lynx lynx), mesopredator (red fox, Vulpes vulpes) and prey (mountain hare, Lepus timidus) abundance for 17 years in a 200 000 km(2) study area which covers a distinct productivity gradient. 5. Fox biomass was lower than expected from productivity where lynx biomass was high, whilst hare biomass was lower than expected from productivity where fox biomass was high. Hence, where interference controlled fox abundance, lynx had an indirect positive impact on hare abundance as predicted by MRH. The rates of change indicated that lynx expansion gradually suppressed fox biomass. 6. Lynx status caused shifts between ecosystem structures. In the 'interference ecosystem', lynx and hare biomass increased with productivity whilst fox biomass did not. In the 'mesopredator release ecosystem', fox biomass increased with productivity but hare biomass did not. Thus, biomass controlled top-down did not respond to changes in productivity. This fulfils a critical prediction of EEH. 7. We conclude that the cascade involving top predators, mesopredators and their prey can determine large-scale biomass distribution patterns and regional ecosystem structures. Hence, interference within trophic levels has to be taken into account to understand how terrestrial ecosystem structures are shaped.


A mixed-methods study to explore opinions of research translation held by researchers working in a Centre of Research Excellence in Australia.
There is a growing need for researchers to demonstrate impact, which is reliant on successful research translation. The Australian National Health and Medical Research Council funded a Centre of Research Excellence in Stroke Rehabilitation and Brain Recovery (CRE-Stroke) to enhance collaborations between researchers conducting different types of stroke rehabilitation research. The purpose of this study was to explore opinions about research translation held by CRE-Stroke researchers conducting preclinical and clinical research, in terms of scope, importance, responsibility and perceived skills and knowledge. Mixed-methods study, comprising a paper-based survey and semistructured interviews. Interview data were inductively coded and thematically analysed. Survey and interview data were compared and synthesised. 55 (7 preclinical, 48 clinical) researchers attending a CRE-Stroke research forum completed a paper-based survey. Semistructured interviews with 22 CRE-Stroke (5 preclinical, 17 clinical) researchers were conducted. Research translation was described as translating to other research and translating to clinical practice and policy. Most researchers (n=54, 98%) reported that research translation was important, particularly in terms of generating research impact, but the most common sign of project completion reported by researchers (n=7, 100% preclinical; n=37, 77% clinical) was publication. Most researchers (preclinical n=4, 57%; clinical n=37, 77%) reported having responsibility for translating research, but less than half reported having the necessary skills (n=1, 14% preclinical; n=17, 35% clinical) and knowledge (n=3, 43% preclinical; n=19, 40% clinical). Differing opinions about who should be responsible for translating findings to clinical practice were expressed. Stroke rehabilitation researchers appear confident to translate their research via the traditional mechanism of publications. To optimise impact, clarity is needed regarding who is best placed to translate research findings to clinical practice and policy. Education and skills development to apply broader translation processes are needed to maximise the use of research at all stages.


β-Blockers are associated with a reduction in COPD exacerbations.
While some retrospective studies have suggested that β-blocker use in patients with COPD is associated with a reduction in the frequency of acute exacerbations and lower mortality, there is concern that their use in patients with severe COPD on home oxygen may be harmful. Subjects with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 2-4 COPD participating in a prospective follow-up of the COPDGene cohort, a multicentre observational cohort of current and former smokers were recruited. Total and severe exacerbation rates were compared between groups categorised by β-blocker use on longitudinal follow-up using negative binomial regression analyses, after adjustment for demographics, airflow obstruction, %emphysema on CT, respiratory medications, presence of coronary artery disease, congestive heart failure and coronary artery calcification, and after adjustment for propensity to prescribe β-blockers. 3464 subjects were included. During a median of 2.1 years of follow-up, β-blocker use was associated with a significantly lower rate of total (incidence risk ratio (IRR) 0.73, 95% CI 0.60 to 0.90; p=0.003) and severe exacerbations (IRR 0.67, 95% CI 0.48 to 0.93; p=0.016). In those with GOLD stage 3 and 4 and on home oxygen, use of β-blockers was again associated with a reduction in the rate of total (IRR 0.33, 95% CI 0.19 to 0.58; p<0.001) and severe exacerbations (IRR 0.35, 95% CI 0.16 to 0.76; p=0.008). Exacerbation reduction was greatest in GOLD stage B. There was no difference in all-cause mortality with β-blocker use. β-Blockers are associated with a significant reduction in COPD exacerbations regardless of severity of airflow obstruction. The findings of this study should be tested in a randomised, placebo-controlled trial. (ClinicalTrials.gov NCT00608764).


The influence of topical capsaicin on the local thermal control of skin blood flow in humans.
To test whether heat-sensitive receptors participate in the cutaneous vascular responses to direct heating, we monitored skin blood flow (SkBF; laser Doppler flowmetry) where the sensation of heat was induced either by local warming (T(Loc); Peltier cooling/heating unit) or by both direct warming and chemical stimulation of heat-sensitive nociceptors (capsaicin). In part I, topical capsaicin (0.075 or 0.025%) was applied to 12 cm(2) of skin 1 h before stepwise local warming of untreated and capsaicin-treated forearm skin. Pretreatment with 0.075% capsaicin cream shifted the SkBF/T(Loc) relationship to lower temperatures by an average of 6 +/- 0.8 degrees C (P < 0.05). In part II, we used a combination of topical capsaicin (0.025%) and local warming to evoke thermal sensation at one site and only local warming to evoke thermal sensation at a separate site. Cutaneous vasomotor responses were compared when the temperatures at these two sites were perceived to be the same. SkBF differed significantly between capsaicin and control sites when compared on the basis of actual temperatures, but that difference became insignificant when compared on the basis of the perceived temperatures. These data suggest heat-sensitive nociceptors are important in the cutaneous vasodilator response to local skin warming.


A retrospective evaluation of a treatment protocol for dental implant periapical lesions: long-term results of 39 implant apicoectomies.
The goal of this study was to evaluate retrospectively the efficacy of a treatment modality for a lesion at the apical portion of a nonmobile dental implant. All patients were treated with an intraoral treatment approach. A flap was elevated facial to the effected implant site, exposing the bone. A carbide bur was used to open a window in the bone. The bur was then used to cut the implant and completely remove the affected portion of the implant. The surgical site was then closed with interrupted vicryl sutures, and patients were prescribed. Thirty-nine implants in 35 patients with a mean age of 58.3 years were identified clinically and radiographically with the presence of a periapical lesion. These 39 implants, which constituted 9.9% of implants (39 of 395) placed in these 35 patients, were consecutively treated using the intraoral apicoectomy procedure. Thirty-eight of the 39 implants (97.4%) treated with this technique remained stable and continued in function with no further complication. Follow-up time averaged 4.54 years; the longest follow-up time exceeded 15 years. Based upon the results of this retrospective study, lesions in the apical region of implants can be treated successfully using an intraoral apicoectomy procedure.


Serological evaluation of O fever in humans: enhanced phase I titers of immunoglobulins G and A are diagnostic for Q fever endocarditis.
Serological parameters were compared in 15 cases of Coxiella burnetii infection comprising 5 cases each of primary Q fever, chronic granulomatous hepatitis, and endocarditis. The diagnosis was made on the basis of clinical history and serology and on the isolation of C. burnetii phase I from biopsy specimens of liver and bone marrow from two patients with granulomatous hepatitis and from the aortic valve vegetations of five patients with endocarditis. The temporal sequences of immunoglobulin levels, rheumatoid factor, and specific antibody responses to phase II and phase I antigens of C. burnetii were evaluated as predictive correlates of the three Q fever entities. Serum levels of immunoglobulin classes G, M, and A were variable in all the entities of Q fever. Increased mean levels (in milligrams per deciliter) of immunoglobulin G (IgG) and IgA were noted with chronic disease in the sera of some patients, whereas IgM levels were not significantly different from normal values. Rheumatoid factor was significantly elevated in chronic disease but not in primary Q fever. The temporal sequence of C. burnetii phase II and phase I antibodies were compared by microagglutination, complement fixation, and indirect microimmunofluorescence tests. All of these serological tests were useful in distinguishing primary from chronic disease. Thus, the ratio of anti-phase II to anti-phase I antibodies was greater than 1, greater than or equal to 1, and less than or equal to 1 for primary Q fever, granulomatous hepatitis, and Q fever endocarditis, respectively. Moreover, the high phase-specific IgA antibody titers in the indirect microimmunofluorescence test were diagnostic for endocarditis.


Enhanced polarizability of aromatic molecules placed in the vicinity of silver clusters.
We use a charge-dipole interaction model to study the polarizability of aromatic molecules that are placed between two silver clusters. In particular we examine the enhancement in polarizability induced by the clusters at plasmon-like resonant frequencies of the cluster-molecule-cluster system. The model used for these simulations relies on representation of the atoms by both a net electric charge and a dipole. By relating the time variation of the atomic charges to the currents that flow through the bonds of the structures considered, a least-action principle can be formulated that enables the atomic charges and dipoles to be determined. We consider benzene, naphthalene and anthracene for this study, comparing the polarizability of these aromatic molecules when placed in the middle between two Ag(120) clusters, with their polarizability as isolated molecules. We find that the polarizability of these molecules is enhanced by the clusters, and this increases the electromagnetic coupling between the two clusters. This results in significant red-shifting (by up to 0.8 eV) of the lowest energy optical transition in the cluster-molecule-cluster system compared to plasmon-like excitation in the cluster-cluster system. The resulting resonant polarizability enhancement leads to an electromagnetic enhancement in surface-enhanced Raman scattering of over 10(6).


Measuring the performance of urban healthcare services: results of an international experience.
The objective of this paper is to apply a framework for country-level performance assessment to the cities of Montreal, Canada, and Barcelona, Spain, and to use this framework to explore and understand the differences in their health systems. The UK National Health Service Performance Assessment Framework was chosen. Its indicators went through a process of selection, adaptation and prioritisation. Most of them were calculated for the period 2001-3, with data obtained from epidemiological, activity and economic registries. Montreal has a higher number of old people living alone and with limitations on performing one or more activities of daily life, as well as longer hospital stays for several conditions, especially in the case of elderly patients. This highlights a lack of mid-term, long-term and home care services. Diabetes-avoidable hospitalisation rates are also significant in Montreal, and are likely to improve following reforms in primary care. Efficient health policies such as generic drug prescription and major ambulatory surgery are lower in Barcelona. Rates of caesarean deliveries are higher in Barcelona, owing to demographics and clinical practice. Waiting times for knee arthroplasty are longer in Barcelona, which has triggered a plan to reduce them. In both cities, avoidable mortality and the prevalence of smoking have been identified as areas for improvement through preventive services. In conclusion, performance assessment fits perfectly in an urban context, as it has been shown to be a useful tool in designing and monitoring the accomplishment of programmes in both cities, to assess the performance of the services delivered, and for use in policy development.


Insulin-like growth factor binding protein-related protein 1 (IGFBP-rP1) is a potential tumor suppressor protein for prostate cancer.
Insulin-like growth factor binding protein-related protein-1 (IGFBP-rP1) has been shown to have decreased expression in the progression from benign to malignant prostate epithelial cells (V. Hwa et al., J. Clin Endocrinol. Metab., 83: 4355-4362, 1998). The present study was undertaken to determine the effects of the re-expression of IGFBP-rP1 in a cell line from a model of human prostate cancer, M12, in which IGFBP-rP1 expression had been demonstrated to decrease from the parent epithelial cell, P69, to the malignant subline, M12. An IGFBP-rP1 cDNA encoding the protein was transfected into M12 cells in a plasmid that resulted in constitutive-expression of IGFBP-rP1. Clones of transfected M12 cells were selected for low (L) and high (H) levels of expression, and the plasmid vector alone was transfected into M12 as a control. After transfection, there was a marked alteration in the morphology of the M12 cells such that the H clones had an elongated appearance when compared with the M12 control cells. The M12 clones overexpressing IGFBP-rP1 had a dose-related increase in population doubling time, decreased colony formation in soft agar, an increased propensity to undergo apoptosis in response to 6-hydroxyurea, and decreased tumor formation in male athymic, nude mice. These data suggest that IGFBP-rP1 may have a suppressive effect on prostate cancer development.


DNA-base guanine as hydrogen getter and charge-trapping layer embedded in oxide dielectrics for inorganic and organic field-effect transistors.
DNA-base small molecules of guanine, cytosine, adenine, and thymine construct the DNA double helix structure with hydrogen bonding, and they possess such a variety of intrinsic benefits as natural plentitude, biodegradability, biofunctionality, low cost, and low toxicity. On the basis of these advantages, here, we report on unprecedented useful applications of guanine layer as hydrogen getter and charge trapping layer when it is embedded into a dielectric oxide of n-channel inorganic InGaZnO and p-channel organic heptazole field effect transistors (FETs). The embedded guanine layer much improved the gate stability of inorganic FETs gettering many hydrogen atoms in the gate dielectric layer of FET, and it also played as charge trapping layer to which the voltage pulse-driven charges might be injected from channel, resulting in a threshold voltage (Vth) shift of FETs. Such shift state is very ambient-stable and almost irrevocable even under a high electric-field at room temperature. So, Boolean logics are nicely demonstrated by using our FETs with the guanine-embedded dielectric. The original Vth is recovered only under high energy blue photons by opposite voltage pulse (charge-ejection), which indicates that our device is also applicable to nonvolatile photo memory.


Successful use of Protek Duo cannula to provide veno-venous extra-corporeal membrane oxygenation and right ventricular support for acute respiratory distress syndrome in an adolescent with complex congenital heart disease.
Rescuing patients with the development of acute respiratory distress syndrome and right heart failure after left ventricular assist device placement remains a challenge in patients with congenital heart disease. TandemLife Protek Duo (TandemLife, Pittsburg, PA) is a double-lumen cannula introduced via the internal jugular vein that can provide veno-venous extra-corporeal membrane oxygenation and right heart support. To our knowledge, we report the first case of successfully using the TandemLife Protek Duo cannula to provide veno-venous extra-corporeal membrane oxygenation and right ventricle support in an adolescent male with an existing right ventricle-pulmonary artery conduit and the melody pulmonary valve who developed severe acute respiratory distress syndrome after the placement of left ventricular assist device. The stability of the cannula enabled minimal recirculation-related hypoxia events, early mobilization, and ambulation. Our patient was discharged home after lung recovery and currently awaiting a heart transplant.


The Family-Home Nutrition Environment and Dietary Intake in Rural Children.
Obesity and food insecurity rates are higher among rural compared to non-rural populations. Little is known, however, about how family-home environments influence childhood obesity-related behaviors, particularly in rural settings. This study examined associations between the family-home nutrition (FN) environment, food insecurity, and dietary intake (fruits, vegetables, whole grains, dairy, protein foods, and added sugars) in rural elementary school-age children (grades K-5/6; n = 102). Parents/caregivers completed surveys on FN, food insecurity, and the Block Kids Food Screener (BKFS). Body mass index (BMI, kg/m2) was calculated from measured height and weight. Approximately 33% of children were classified as overweight/obese and 28% of families were at-risk for food insecurity. Multivariable linear regression analyses examined associations between dietary intakes with FN and food insecurity. More favorable FN scores were associated with lower added sugar intake (B = -1.38, p = 0.04) and higher vegetable (B = 0.15, p < 0.001), fruit (B = 0.71, p = 0.01), and dairy (B = 0.31, p < 0.001) intakes. No significant associations were found between food insecurity and dietary intake. Given the association between higher FN scores and more favorable dietary intake, promoting healthy FN environments among rural children is warranted.


Cutoff values for alcoholic liver fibrosis using magnetic resonance elastography technique.
Due to the lack of cutoff values validated for specific liver diseases, the purpose of this study was to set up specific magnetic resonance elastography (MRE) cutoff values for asymptomatic liver fibrosis in alcoholic patients. Ninety patients underwent 3 clinical exams. The liver stiffness was measured locally with the Fibroscan, and globally through cartographies of shear modulus generated with MRE. The Fibroscan method was chosen as the gold standard to classify the fibrosis. The liver score was also obtained with the Fibrometer A, and the diagnostic performance of the methods was analyzed with receiver-operating characteristic (ROC) curves and cutoff values were calculated. Spearman correlation and area under the ROC curve revealed that MRE is a better diagnostic method than the Fibrometer A, to identify various levels of fibrosis. The results showed that the Fibrometer A was adapted for severe fibrosis. The MRE cutoff values are F1:2.20 kPa, F2:2.57 kPa, F3:3.31 kPa, and F4:4 kPa and were not influenced by the glutamic oxaloacetic transaminase level. By using the ultrasound cutoff values attributed for alcoholism, 66% of patients had a similar liver fibrosis diagnosis as the MRE cutoffs. However, both imaging techniques did not provide the same distribution for minor fibrosis. None of the imaging techniques (Fibroscan, MRE) could replace the gold standard of the biopsy. However, due to the risk and the unnecessary procedure for the present recruited alcoholic patients, the Fibroscan method was chosen as the reference. Since MRE is currently being used as a clinical exam, the present MRE cutoffs could aid clinicians with their diagnosis of liver fibrosis for alcoholism disease.


Efficacy of acupuncture for health conditions in children: a review.
Acupuncture has been used to treat a variety of childhood problems; however, the efficacy and safety of pediatric acupuncture remains unclear. This article reviews the existing empirical literature relating to the use of acupuncture for medical conditions in children. A systematic search of the literature revealed that acupuncture has been used to treat five main conditions in children, including pain, nocturnal enuresis, postoperative nausea/vomiting, laryngospasm/stridor, and neurological disorders. Despite a number of methodological issues, including limited sample sizes, lack of randomization, and inappropriate control groups, it is concluded that acupuncture represents a promising intervention for a variety of pediatric health conditions. To further address the safety, effectiveness, and acceptability of acupuncture in children, large-scale randomized controlled trials are needed.


Interpreting tree responses to thinning and fertilization using tree-ring stable isotopes.
• Carbon sequestration has focused renewed interest in understanding how forest management affects forest carbon gain over timescales of decades, and yet details of the physiological mechanisms over decades are often lacking for understanding long-term growth responses to management. • Here, we examined tree-ring growth patterns and stable isotopes of cellulose (δ(13)C(cell) and δ(18)O(cell)) in a thinning and fertilization controlled experiment where growth increased substantially in response to treatments to elucidate physiological data and to test the dual isotope approach for uses in other locations. • δ(13)C(cell) and δ(18)O(cell) results indicated that fertilization caused an increase in intrinsic water-use efficiency through increases in photosynthesis (A) for the first 3 yr. The combination treatment caused a much larger increase in A and water-use efficiency. Only the thinning treatments showed consistent significant increases in δ(18)O(cell) above controls. Changes in canopy microclimate are the likely drivers for δ(18)O(cell) increases with decreases in relative humidity and increases in leaf temperature associated with thinning being the most probable causes. • Tree-ring isotopic records, particularly δ(13)C(cell), remain a viable way to reconstruct long-term physiological mechanisms affecting tree carbon gain in response to management and climate fluctuations.


The AAA ATPase Cdc48/p97 and its partners transport proteins from the ER into the cytosol.
In eukaryotic cells, incorrectly folded proteins in the endoplasmic reticulum (ER) are exported into the cytosol and degraded by the proteasome. This pathway is co-opted by some viruses. For example, the US11 protein of the human cytomegalovirus targets the major histocompatibility complex class I heavy chain for cytosolic degradation. How proteins are extracted from the ER membrane is unknown. In bacteria and mitochondria, members of the AAA ATPase family are involved in extracting and degrading membrane proteins. Here we demonstrate that another member of this family, Cdc48 in yeast and p97 in mammals, is required for the export of ER proteins into the cytosol. Whereas Cdc48/p97 was previously known to function in a complex with the cofactor p47 (ref. 5) in membrane fusion, we demonstrate that its role in ER protein export requires the interacting partners Ufd1 and Npl4. The AAA ATPase interacts with substrates at the ER membrane and is needed to release them as polyubiquitinated species into the cytosol. We propose that the Cdc48/p97-Ufd1-Npl4 complex extracts proteins from the ER membrane for cytosolic degradation.


FTIR imaging of structural changes in visceral and subcutaneous adiposity and brown to white adipocyte transdifferentiation.
Obesity is a heterogeneous disorder which increases risks for multiple metabolic diseases, such as type 2 diabetes. The current study aims to characterize and compare visceral and subcutaneous adipose tissues in terms of macromolecular content and investigate transdifferentiation between white and brown adipocytes. Regarding this aim, Fourier transform infrared (FTIR) microspectroscopy and uncoupling protein 1 (UCP1) immunohistological staining were used to investigate gonadal (visceral) and inguinal (subcutaneous) adipose tissues of male Berlin fat mice inbred (BFMI) lines, which are spontaneously obese. The results indicated a remarkable increase in the lipid/protein ratio, accompanied with a decrease of UCP1 protein content which might be due to the transdifferentiation of brown adipocytes to white adipocytes in obese groups. It has been widely reported that brown adipose tissue has a strong effect on fatty acid and glucose homeostasis and it could provide an opportunity for the therapy of obesity. When the amount of brown adipose tissue was decreased, lower unsaturation/saturation ratio, qualitatively longer hydrocarbon acyl chain length of lipids and higher amount of triglycerides were obtained in both adipose tissues of mice lines. The results also revealed that subcutaneous adipose tissue was more prone to obesity-induced structural changes than visceral adipose tissue, which could originate from it possessing a lower amount of brown adipose tissue. The current study clearly revealed the power of FTIR microspectroscopy in the precise determination of obesity-induced structural and functional changes in inguinal and gonadal adipose tissue of mice lines.


Modulation of poly(ADP-ribose) polymerase during neutrophilic and monocytic differentiation of promyelocytic (NB4) and myelocytic (HL-60) leukaemia cells.
Poly(ADP-ribose) polymerase (PARP) is a nuclear enzyme which has been shown to play a role in the differentiation of haematopoietic cells. We report here that neutrophils are the first nucleated mammalian cell type demonstrated to be devoid of immunoreactive PARP. Both NB4 acute promyelocytic leukaemia and HL-60 (acute myelocytic leukaemia) cells were differentiated into non-malignant neutrophils with all-trans-retinoic acid (ATRA). Western blot analysis demonstrated that ATRA had no effect on PARP expression in HL-60 cells. However, PARP was completely down-regulated in NB4 cells within 36 h of treatment initiation. This decrease in PARP polypeptide coincided with growth arrest and preceded the appearance of neutrophilic differentiation features. NB4 cells require a combination of 1,25-dihydroxyvitamin D3 (1,25-D3) and phorbol 12-myristate 13-acetate (PMA) to differentiate completely into monocyte/macrophages, whereas HL-60 cells can be made to differentiate by combined or single agents. PARP expression was up-regulated 90-fold when NB4 cells were treated with PMA and 1,25-D3 together, and this increase accompanied expression of the monocyte/macrophage phenotype. Only modest changes in PARP expression were observed when each agent was used alone in NB4 cells or when HL-60 cells were differentiated along the monocyte/macrophage pathway. In addition, PARP activity was modulated in a pattern similar to protein levels when NB4 cells were induced to differentiate along the neutrophilic and monocyte/macrophage pathways. This suggests that the activity of PARP may be controlled through regulation of protein levels during NB4 cell differentiation. We conclude that PARP levels are dramatically modulated during monocyte/macrophage and neutrophilic differentiation. On the basis of the tremendous changes in PARP polypeptide and total activity during myeloid differentiation, we propose that modulation of PARP gene expression is required for cellular maturation in both lineages.


Murine epidermal Langerhans cells mature into potent immunostimulatory dendritic cells in vitro.
Murine epidermal Langerhans cells (LC) have been studied in tissue culture and compared to spleen dendritic cells (DC). LC comprised 3% of the starting cell suspensions and were distinguished from keratinocytes by cytology and reactivity with anti-Ia and anti-Mac-1 monoclonal antibodies. The LC were nonadherent, had a low buoyant density, did not proliferate, and could be enriched to 10-50% purity. LC continued to exhibit Ia and Mac-1 antigens for 4 d in culture. However, LC rapidly lost Birbeck granules, Fc receptors, F4/80 antigen, and cytochemical reactivity for nonspecific esterase and membrane ATPase. As a result, the ultrastructure and phenotype of cultured LC became remarkably similar to lymphoid DC. Stimulatory capacity for T cell proliferative responses (oxidative mitogenesis and the mixed leukocyte reaction) was monitored daily. Initially, stimulatory capacity was very weak, even though LC expressed substantial levels of Ia antigens. After 2-3 d in culture, LC had become 3-10 times more potent than spleen DC. 30 LC could induce significant responses in cultures of 3 X 10(5) responding T cells. Removal of Ia+ LC at the start of culture ablated the development of stimulatory activity, but exposure to 1,500 rad of ionizing irradiation did not. Mixing experiments showed that contaminating Ia- epidermal cells did not alter the function of Ia+ stimulators. Therefore, LC seem to be immunologically immature, but acquire many of the features of spleen DC during culture. We suggest that functioning lymphoid DC may, in general, be derived from less mature precursors located in nonlymphoid tissues.


Correlation between the suppressor of cytokine signaling-1 and 3 and hepatitis B virus: possible roles in the resistance to interferon treatment.
The suppressor of cytokine signaling family (SOCS) is an important negative regulator in the JAK-STAT signaling pathway. This study was designed to explore the correlation between SOCS-1, 2 and 3, Hepatitis B Virus (HBV) and interferon (IFN), and the relationship between SOCS and IFN therapeutic efficacy. Four types of mouse models were established. Mice were administered with HBV replicative plasmid pHBV4.1 and IFN inducer Poly IC (Group A), pHBV4.1 (Group B), Poly IC (Group C) and saline (Group D), respectively. Liver tissues were harvested from the mice and SOCS expression was determined. Meanwhile, patients with chronic hepatitis B (CHB) were treated with pegylated interferon α-2b for 24-48 weeks. Liver biopsy was collected and the baseline SOCS expression was determined. Serum assay was performed for efficacy evaluation and correlation analysis. In animal studies, the expression level of SOCS-1 and 3 was found in the descending order of B, A, C and D. The difference between Group B and D suggested that HBV could induce SOCS. The difference between Group A and C suggested that HBV could still induce SOCS with up-regulated endogenous IFN. The difference between Group C and D suggested that ploy IC could induce SOCS, while the difference between Group B and A suggested that Poly IC might have a stronger inhibition effect for SOCS. There was no difference in SOCS-2 expression. In clinical studies, eight of twenty-four enrolled patients achieved either complete or partial therapeutic response. The expression of both SOCS-1 and 3 was higher in CHB patients than in normal controls. The baseline HBV-DNA level was positively correlated with SOCS-1 and 3. The age, viral genotype, HBVDNA, SOCS-1 and SOCS-3 were found to be related to IFN efficacy. HBV could induce both SOCS-1 and 3 expression regardless of endogenous IFN level. Elevated IFN could directly up-regulate SOCS-1 and 3 expression, but it could also indirectly down-regulate SOCS-1 and 3 expression by inhibiting HBV replication. HBV might play a more important role in the SOCS up-regulation than IFN, a possible reason why patients with high HBV viral load encounter poor efficacy of IFN treatment.


Data management and sharing policy: the first step towards promoting data sharing.
Health-related research funders, regulators and journals expect that de-identified individual-level health data be shared widely, with as few restrictions as possible; yet, in reality, the volume of shared data remains low. Health researchers and other data producers are reluctant to share their data unless they are confident that their datasets are of high quality and reliable, and that they are used in accordance with the values and aims of their institutions. We argue that having an institutional, departmental or group data management and sharing policy is the first step towards encouraging researchers and healthcare professionals to share their data more widely. Our paper outlines the elements of a data management and sharing policy, which should include aims consistent with those of the institution as well as with data management procedures, models of data sharing, request procedures, consent models and cost recovery mechanisms. A policy would help an institution, department or group maximise the use of its data and protect the interests of the institution and its members. We base our recommendations on our experience collecting and curating data for large clinical trials conducted in low- and middle-income countries, facilitating the sharing of datasets with secondary users, whilst teaching data management and conducting empirical research on data sharing. Although the fundamentals of a policy are general, the paper is focused on the low- and middle-income country context. We argue that having an institutional, departmental or group data management and sharing policy is the first step in promoting data sharing.


Merit of anisodamine combined with opioid δ-receptor activation in the protection against myocardial injury during cardiopulmonary bypass.
Myocardial ischemia/reperfusion (MIR) injury easily occurrs during cardiopulmonary bypass surgery in elderly patients. In an attempt to develop an effective strategy, we employed a pig model of MIR injury to investigate the maximum rate of change of left ventricular pressure, left ventricular enddiastolic pressure, and left intraventricular pressure. Coronary sinus cardiac troponin T (TnT) and adenosine-triphosphate (ATP) content in myocardium were measured. The ultrastructures for MIR injury were visualized by transmission electron microscopy (TEM). The role of δ-opioid receptor activation using D-Ala2, D-Leu5-enkephalin (DADLE) in both early (D1) and late (D2) phases of cardioprotection was identified. Also, the merit of cardioprotection by DADLE in combination with anisodamine, the muscarinic receptor antagonist (D+M), was evaluated. Glibenclamide was employed at the dose sufficient to block ATP-sensitive potassium channels. Significant higher cardiac indicators, reduced TnT and increased ATP contents, were observed in D1, D2, and D+M groups compared with the control group. DADLE induced protection was better in later phase of ischemia that was attenuated by glibenclamide. DADLE after the ischemia showed no benefit, but combined treatment with anisodamine showed a marked postischemic cardioprotection. Thus, anisodamine is helpful in combination with DADLE for postischemic cardioprotection.


Surgeons' perceptions of public reporting of hospital and individual surgeon quality.
Hospital-specific and surgeon-specific public reporting of performance measures is expanding largely due to calls for transparency from the public and oversight agencies. Surgeons continue to voice concerns regarding public reporting. Surgeons' perceptions of hospital-level and individual-level public reporting have not been assessed. This study (1) evaluated surgeons' perceptions of public reporting of surgical quality; and (2) identified specific barriers to surgeons' acceptance of public reporting. All surgeons (n=185) at 4 hospitals (university, children's, 2 community hospitals), representing all surgical specialties, received a 41-item anonymous Internet-based survey. Twenty follow-up qualitative interviews were conducted to assess surgeons' interpretation of findings. The survey response rate was 66% (n=122). Most surgeons supported public reporting of quality metrics at the hospital level (80%), but opposed individual reporting (53%, P<0.01). Fewer surgeons expected that individual (26%) or hospital (47%) public reporting would improve outcomes (P<0.01). Few indicated that their practice would change with hospital (11%) or individual (18%) public reporting (P=0.20). Primary concerns regarding public reporting at the hospital level included patients misinterpreting data, surgeons refusing high-risk patients, and outcome metric validity. Individual-surgeon level concerns included outcome metric validity, adequate sample sizes, and patients misinterpreting data. To make public reporting more acceptable, surgeons recommended patient education, simplified data presentation, continued risk-adjustment refinement, and internal review before public reporting. Surgeons expressed concerns about public reporting of quality metrics, particularly reporting of individual surgeon performance. These concerns must be addressed to gain surgeons' acceptance and to use public reporting to improve health care quality.


Matrix metalloproteinase inhibitor BB-94 (batimastat) inhibits human colon tumor growth and spread in a patient-like orthotopic model in nude mice.
Matrix metalloproteinases have been implicated in the growth and spread of metastatic tumors. This role was investigated in an orthotopic transplant model of human colon cancer in nude mice using the matrix metalloproteinase inhibitor BB-94 (batimastat). Fragments of human colon carcinoma (1-1.5 mm) were surgically implanted orthotopically on the colon in 40 athymic nu/nu mice. Administration of BB-94 or vehicle (phosphate buffered saline, pH 7.4, containing 0.01% Tween 80) commenced 7 days after tumor implantation (20 animals/group). Animals received 30 mg/kg BB-94 i.p. once daily for the first 60 days and then 3 times weekly. Treatment with BB-94 caused a reduction in the median weight of the primary tumor from 293 mg in the control group to 144 mg in the BB-94 treated group (P < 0.001). BB-94 treatment also reduced the incidence of local and regional invasion, from 12 of 18 mice in the control group (67%) to 7 of 20 mice in the treated group (35%). Six mice in the control group were also found to have metastases in the liver, lung, peritoneum, abdominal wall, or local lymph nodes. Only two mice in the BB-94 group had evidence of metastatic disease, in both cases confined to the abdominal wall. The reduction in tumor progression observed in the BB-94-treated group translated into an improvement in the survival of this group, from a median survival time of 110 days in the control group to a median survival time of 140 days in the treated group (P < 0.01). Treatment with BB-94 was not associated with any obvious toxic effect, and these results suggest that such agents may be effective as adjunctive cancer therapies.


Costs and cost-effectiveness of HIV/noncommunicable disease integration in Africa: from theory to practice.
: The current article reviews economic aspects of selected HIV/noncommunicable disease (NCD) service delivery integration programs to assess the efficiency of integration in limited capacity settings. We define economies of scope and scale and their relevance to HIV/NCD integration. We summarize the results of a systematic review of cost and cost-effectiveness studies of integrated care, which identified 12 datasets (nine studies) with a wide range of findings driven by differences in research questions, study methods, and health conditions measured. All studies were done in Africa and examined screening interventions only. No studies assessed the cost of integrated, long-term disease management. Few studies estimated the cost-effectiveness of integrated screening programs. The additional cost of integrating NCD screening with HIV care platforms represented a 6-30% increase in the total costs of the programs for noncancer NCDs, with cervical cancer screening costs dependent on screening strategy. We conducted 11 key informant interviews to uncover perceptions of the economics of HIV/NCD integration. None of the informants had hard information about the economic efficiency of integration. Most expected integrated care to be more cost-effective than current practice, though a minority thought that greater specialization could be more cost-effective. In the final section of this article, we summarize research needs and propose a 'minimum economic dataset' for future studies. We conclude that, although integrated HIV/NCD care has many benefits, the economic justification is unproven. Better information on the cost, cost-effectiveness, and fiscal sustainability of integrated programs is needed to justify this approach in limited-resource countries.


Strategies for prevention of scars: what can we learn from fetal skin?
Fetal wound healing occurs rapidly and without scar formation early in gestation. Studying the mechanisms of scarless repair can lead to novel scar-preventive approaches. In fetal wounds, collagen is deposited early and is fine and reticular with less cross-linking. Several important differences of fetal vs. postgestational wound-healing response have been determined, such as the presence of less inflammation, higher hyaluronic acid concentration and a greater ratio of collagen type III to type I. Compared with typical wounds, there are also altered ratios of signaling molecules, such as higher ratios of transforming growth factor (TGF)-β3 to TGF-β1 and -β2, and matrix metalloproteinases to tissue inhibitors of metalloproteinases. Furthermore, fetal fibroblasts do not exhibit TGF-β1-induced collagen production compared with their mature counterparts. Patterning genes (homeobox genes) involved in organogenesis are more active in the fetal period and are believed to be the "first domino" in the fetal cutaneous wound repair regulatory cascade. The recommended scar-preventive agents, such as Scarguard MD®, silicone gel and sheet, Seprafilm® Bioresorbable Membrane, topical hyaluronan, onion extract, oral tamoxifen and 585-nm pulsed dye laser are reviewed in this study. Despite the lack of supporting evidence, there is a widespread false presumption that the acceleration of healing with the widely assumed scar-preventive commercial agents is associated with decreased scar formation. Humans are erroneously inclined to make a negative correlation between the healing rate and the degree of scar formation, while such a correlation does not exist in reality. Despite the importance of scar prevention, no FDA-approved therapy for this purpose is available in the 21st century, which reflects the important challenges, such as the presence of redundant pathways, that these approaches are facing.


CD161+ Tconv and CD161+ Treg Share a Transcriptional and Functional Phenotype despite Limited Overlap in TCRβ Repertoire.
Human regulatory T cells (Treg) are important in immune regulation, but can also show plasticity in specific settings. CD161 is a lectin-like receptor and its expression identifies an effector-like Treg population. Here, we determined how CD161+ Treg relate to CD161+ conventional T cells (Tconv). Transcriptional profiling identified a shared transcriptional signature between CD161+ Tconv and CD161+ Treg, which is associated with T helper (Th)1 and Th17 cells, and tissue homing, including high expression of gut-homing receptors. Upon retinoic acid (RA) exposure, CD161+ T cells were more enriched for CCR9+ and integrin α4+β7+ cells than CD161- T cells. In addition, CD161+ Tconv and CD161+ Treg were enriched at the inflamed site in autoimmune arthritis, and both CD161+ and CD161- Treg from the inflamed site were suppressive in vitro. CD161+ T cells from the site of autoimmune arthritis showed a diminished gut-homing phenotype and blunted response to RA suggesting prior imprinting by RA in the gut or at peripheral sites rather than during synovial inflammation. TCRβ repertoires of CD161+ and CD161- Tconv and Treg from blood showed limited overlap whereas there was clear overlap between CD161+ and CD161- Tconv, and CD161+ and CD161- Treg from the inflamed site suggesting that the inflamed environment may alter CD161 levels, potentially contributing to disease pathogenesis.


A single-nucleotide polymorphism in tumor suppressor gene SEL1L as a predictive and prognostic marker for pancreatic ductal adenocarcinoma in Caucasians.
SEL1L is a putative tumor suppressor gene that is frequently down-regulated in pancreatic ductal adenocarcinoma (PDA). A single-nucleotide polymorphism (SNP) rs12435998 in intron3 of SEL1L has previously been reported to be associated with susceptibility to Alzheimer's disease. We hypothesized that this SNP may influence clinical outcomes of patients with PDA. We analyzed DNA samples from 497 Caucasian patients with pathologically confirmed primary PDA. Of these, 98 had been enrolled in a clinical trial of neoadjuvant chemo-radiotherapy and 77 of the 98 had subsequently undergone pancreaticoduodenectomy (PD). We performed Kaplan-Meier analysis to evaluate the correlation between different SNP genotypes and age at diagnosis, survival time after diagnosis, and survival time after PD. In nonsmokers, we found a significant difference in median age at diagnosis between variant genotypes (AG/GG) carriers and wild-type genotype (AA) carriers (58 vs. 62 yr; log-rank test, P = 0.017). Patients with variant genotypes also showed an increased hazard ratio (HR) of 1.45 [95% confidence interval (CI), 1.07-1.97] relative to wild-type genotype. Among the patients in the clinical trial, the variant genotypes carriers had a median post-PD survival time that was 34.7 months shorter than wild-type genotype carriers (log-rank test, P = 0.019; HR, 1.91; 95% CI, 1.09-3.34). Our results suggest that the rs12435998 SNP in SEL1L gene plays a role in modifying age at diagnosis of PDA in Caucasian nonsmokers. In addition, this SNP may serve as a prognostic marker in PDA patients who undergo the same or similar treatment as the clinical trials.


Drosophila Cep135/Bld10 maintains proper centriole structure but is dispensable for cartwheel formation.
Cep135/Bld10 is a conserved centriolar protein required for the formation of the central cartwheel, an early intermediate in centriole assembly. Surprisingly, Cep135/Bld10 is not essential for centriole duplication in Drosophila, suggesting either that Cep135/Bld10 is not essential for cartwheel formation, or that the cartwheel is not essential for centriole assembly in flies. Using electron tomography and super-resolution microscopy we show that centrioles can form a cartwheel in the absence of Cep135/Bld10, but centriole width is increased and the cartwheel appears to disassemble over time. Using 3D structured illumination microscopy we show that Cep135/Bld10 is localized to a region between inner (SAS-6, Ana2) and outer (Asl, DSpd-2 and D-PLP) centriolar components, and the localization of all these component is subtly perturbed in the absence of Cep135/Bld10, although the ninefold symmetry of the centriole is maintained. Thus, in flies, Cep135/Bld10 is not essential for cartwheel assembly or for establishing the ninefold symmetry of centrioles; rather, it appears to stabilize the connection between inner and outer centriole components.


Characterization of the commercially-available fluorescent chloroquine-BODIPY conjugate, LynxTag-CQGREEN, as a marker for chloroquine resistance and uptake in a 96-well plate assay.
Chloroquine was a cheap, extremely effective drug against Plasmodium falciparum until resistance arose. One approach to reversing resistance is the inhibition of chloroquine efflux from its site of action, the parasite digestive vacuole. Chloroquine accumulation studies have traditionally relied on radiolabelled chloroquine, which poses several challenges. There is a need for development of a safe and biologically relevant substitute. We report here a commercially-available green fluorescent chloroquine-BODIPY conjugate, LynxTag-CQGREEN, as a proxy for chloroquine accumulation. This compound localized to the digestive vacuole of the parasite as observed under confocal microscopy, and inhibited growth of chloroquine-sensitive strain 3D7 more extensively than in the resistant strains 7G8 and K1. Microplate reader measurements indicated suppression of LynxTag-CQGREEN efflux after pretreatment of parasites with known reversal agents. Microsomes carrying either sensitive- or resistant-type PfCRT were assayed for uptake; resistant-type PfCRT exhibited increased accumulation of LynxTag-CQGREEN, which was suppressed by pretreatment with known chemosensitizers. Eight laboratory strains and twelve clinical isolates were sequenced for PfCRT and Pgh1 haplotypes previously reported to contribute to drug resistance, and pfmdr1 copy number and chloroquine IC50s were determined. These data were compared with LynxTag-CQGREEN uptake/fluorescence by multiple linear regression to identify genetic correlates of uptake. Uptake of the compound correlated with the logIC50 of chloroquine and, more weakly, a mutation in Pgh1, F1226Y.


Furan oxidation based cross-linking: a new approach for the study and targeting of nucleic acid and protein interactions.
Furan mediated nucleic acid cross-linking, initially developed for DNA interstrand duplex cross-linking, has matured into a versatile tool for the study of protein and nucleic acid interactions, ready to face its applications. The methodology was initially developed for easy and clean chemical generation of DNA interstrand cross-linked duplexes, but has been further expanded for use with other probes, targets and triggers, now allowing mild biologically significant cross-linking with potential therapeutic benefit. It was shown that the methodology could be repurposed for RNA interstrand cross-linking, which is very relevant in today's antisense approaches or miRNA target identification endeavors. This further illustrates the furan oxidation method's generality and mildness, especially when using red light for oxidation. A complementary antigene approach has been explored through duplex targeting with furan modified triplex forming oligonucleotides (TFOs) and DNA binding proteins. Also targeting of peptides and proteins by furan-modified DNA and peptides has been explored. Thorough methodology examination exploring variable reaction conditions in combination with a series of different furan-modified building blocks and application of different activation signals resulted in a detailed understanding of the mechanisms involved and factors influencing the yield and selectivity of the reaction. In order to draw the bigger picture of the scope and limitations of furan-oxidation cross-linking, we here provide a unique side by side comparison and discussion of our published data, supplemented with unpublished results, providing a clear performance report of the currently established furan toolbox and its application potential in various biomacromolecular complexes.


The Effects of Respiratory Muscle Training on Phonatory Measures in Individuals with Parkinson's Disease.
In individuals with Parkinson's disease (PD), respiratory muscle weakness and rigidity, bradykinesia of abdominal muscles and stiffness of the chest wall, affect the respiratory component of voice intensity due to reduced pulmonary capacity and airflow needed to vibrate the vocal folds. It may be possible to improve voice production by strengthening respiratory muscles. The purpose of this study was to evaluate the effects of inspiratory and expiratory muscle training on voice production outcomes in individuals with PD. Thirty-one participants with PD were randomly allocated to three study groups (control group n = 10, inspiratory training group, n = 11, and expiratory training group, n = 11). The inspiratory and expiratory group performed a home-based inspiratory and expiratory muscle training program, respectively (five sets of five repetitions). Both groups trained six times a week for 2 months using a progressively increased resistance. The control group performed expiratory muscle training using the same protocol and a fixed resistance. Phonatory measures, maximum inspiratory/expiratory pressure, and spirometric indexes were assessed before and at 2 months after training. Differences in peak subglottic pressure were moderate (d = 0.59) between expiratory and inspiratory groups, large between inspiratory and control groups (d = 1.32), and large between expiratory and control groups (d = 1.96). Differences in maximum phonation time were large (d = 1.26) between inspiratory and control groups, moderate (negative) between expiratory and inspiratory groups (d = -0.60), and moderate between expiratory and control groups (d = 0.72). Differences in peak sound pressure level were large (d = 1.27) between inspiratory and control groups, trivial between expiratory and inspiratory groups (d = -0.18), and large between expiratory and control groups (d = 1.10). Inspiratory muscle training is effective in improving maximum phonation time, and expiratory muscle training is more effective for improving peak subglottic pressure, and peak sound pressure level in individuals with PD.


Sibutramine: a novel anti-obesity drug. A review of the pharmacological evidence to differentiate it from d-amphetamine and d-fenfluramine.
Sibutramine (BTS 54 524; N-[1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl]-N,N-dimethylamine hydrochloride monohydrate) is a novel 5-HT (serotonin) and noradrenaline reuptake inhibitor (SNRI) anti-obesity drug. Sibutramine reduces the food intake of rodents and this effect is partially or completely reversed by pretreating with 5-HT or noradrenaline antagonists, indicating that both neurotransmitters are involved in sibutramine's hypophagic effect. In addition, fluoxetine and nisoxetine, which are selective reuptake inhibitors of 5-HT and noradrenaline, respectively, have no effect on food intake when given alone, but they profoundly inhibit food intake when given in combination (equivalent to the actions of the SNRI, sibutramine), demonstrating a synergistic interaction of those two monoamines in the control of ingestive behaviour. Sibutramine reduces food intake by enhancing the physiological response of post-ingestive satiety. This reduction of food intake is a CNS-mediated effect because it is induced by intracerebroventricular injection of sibutramine's potently active secondary and primary amine metabolites (BTS 54 354 and BTS 54 505). Sibutramine increases energy expenditure (thermogenesis) in rats. Once again, whilst fluoxetine and nisoxetine have no thermogenic effect when given alone, the combination of these two selective monoamine reuptake inhibitors profoundly enhances thermogenesis, demonstrating a synergistic interaction of 5-HT and noradrenaline neurotransmission in the regulation of energy expenditure. Sibutramine-induced thermogenesis is abolished by administration of a high non-selective dose of atenolol or ICI 118,551 which blocks beta3-adrenoceptors in addition to beta1- and beta2-adrenoceptors, but not by a low dose of atenolol or ICI 118,551 which blocks beta1- and beta2-adrenoceptors, respectively. Glucose utilization studies demonstrate that sibutramine-induced thermogenesis is mediated via selective sympathetic activation of brown adipose tissue, and it is a centrally mediated effect because it is prevented by pretreating the animals with the ganglionic blocker, chlorisondamine. The SNRI mode of action of sibutramine is clearly differentiated from those of the two major classes of anti-obesity drugs, viz, the 5-HT releasing agents, for example, fenfluramine and dexfenfluramine, and the noradrenaline + dopamine-releasing agents, for example, dexamphetamine. In the case of the 5-HT-releasing agents, this mechanism has been linked in animal studies to profound and prolonged depletion and dysfunction of CNS 5-HT neurons. With noradrenaline + dopamine-releasing agents, it is the enhancement of central dopaminergic function which is believed to be responsible for their stimulant, rewarding and reinforcing properties and it is their releasing mechanism which makes them such powerful psychostimulant drugs of abuse. By utilizing noradrenaline and 5-HT for its anti-obesity effects, sibutramine is differentiated from other weight-reducing drugs which act through either 5-HT alone or noradrenaline + dopamine. In addition, sibutramine is further differentiated because it enhances monoamine function by reuptake inhibition, rather than by monoamine release.


Education and training for preventing sharps injuries and splash exposures in healthcare workers.
In healthcare settings, health care workers (HCWs) are at risk of acquiring infectious diseases through sharps injuries and splash exposures to blood or bodily fluids. Education and training interventions are widely used to protect workers' health and safety and to prevent sharps injuries. In certain countries, they are part of obligatory professional development for HCWs. To assess the effects of education and training interventions compared to no intervention or alternative interventions for preventing sharps injuries and splash exposures in HCWs. We searched CENTRAL, MEDLINE, Embase, NHSEED, Science Citation Index Expanded, CINAHL and OSH-update (from all time until February 2016). In addition, we searched the databases of Global Health, AustHealth and Web of Science (from all time until February 2016). The original search strategy was re-run in November 2019, and again in February 2020. In April 2020, the search strategy was updated and run in CINAHL, MEDLINE, Scopus and Web of Science (from 2016 to current). We considered randomized controlled trials (RCTs), cluster-randomized trials (cluster-RCTs), controlled clinical trials (CCTs), interrupted time series (ITS) study designs, and controlled before-and-after studies (CBA), that evaluated the effect of education and training interventions on the incidence of sharps injuries and splash exposures compared to no-intervention. Two authors (SC, HL) independently selected studies, and extracted data for the included studies. Studies were analyzed, risk of bias assessed (HL, JL) , and pooled using random-effect meta-analysis, where applicable, according to their design types. As primary outcome we looked for sharps injuries and splash exposures and calculated them as incidence of injuries per 1000 health care workers per year. For the quality of evidence we applied GRADE for the main outcomes. Seven studies met our inclusion criteria: one cluster-RCT, three CCTs, and three ITS studies. The baseline rates of sharps injuries varied from 43 to 203 injuries per 1000 HCWs per year in studies with hospital registry systems. In questionnaire-based studies, the rates of sharps injuries were higher, from 1800 to 7000 injuries per 1000 HCWs per year. The majority of studies utilised a combination of education and training interventions, including interactive demonstrations, educational presentations, web-based information systems, and marketing tools which we found similar enough to be combined. In the only cluster-RCT (n=796) from a high-income country, the single session educational workshop decreased sharps injuries at 12 months follow-up, but this was not statistically significant either measured as registry-based reporting of injuries (RR 0.46, 95% CI 0.16 to 1.30, low-quality evidence) or as self-reported injuries (RR 0.41, 95% CI 0.14 to 1.21, very low-quality evidence) In three CCTs educational interventions decreased sharps injuries at two months follow-up (RR 0.68, 95% CI 0.48 to 0.95, 330 participants, very low-quality evidence). In the meta-analysis of two ITS studies with a similar injury rate, (N=2104), the injury rate decreased immediately post-intervention by 9.3 injuries per 1000 HCWs per year (95% CI -14.9 to -3.8). There was a small non-significant decrease in trend over time post-intervention of 2.3 injuries per 1000 HCWs per year (95% CI -12.4 to 7.8, low-quality evidence). One ITS study (n=255) had a seven-fold higher injury rate compared to the other two ITS studies and only three data points before and after the intervention. The study reported a change in injury rate of 77 injuries per 1000 HCWs (95% CI -117.2 to -37.1, very low-quality evidence) immediately after the intervention, and a decrease in trend post-intervention of 32.5 injuries per 1000 HCWs per year (95% CI -49.6 to -15.4, very low quality evidence). None of the studies allowed analyses of splash exposures separately from sharps injuries. None of the studies reported rates of blood-borne infections in patients or staff. There was very low-quality evidence of short-term positive changes in process outcomes such as knowledge in sharps injuries and behaviors related to injury prevention. AUTHORS' CONCLUSIONS: We found low- to very low-quality evidence that education and training interventions may cause small decreases in the incidence of sharps injuries two to twelve months after the intervention. There was very low-quality evidence that educational interventions may improve knowledge and behaviors related to sharps injuries in the short term but we are uncertain of this effect. Future studies should focus on developing valid measures of sharps injuries for reliable monitoring. Developing educational interventions in high-risk settings is another priority.


Appetite regulation in overweight, sedentary men after different amounts of endurance exercise: a randomized controlled trial.
Weight loss induced by endurance exercise is often disappointing, possibly due to an increase in energy intake mediated through greater appetite. The aim of this study was to evaluate fasting, postprandial, and postexercise appetite regulation after an intervention prescribing two amounts of endurance exercise. Sixty-four sedentary, overweight, healthy young men were randomized to control (CON), moderate-dose (MOD: ≈ 30 min/day), or high-dose (HIGH: ≈ 60 min/day) endurance exercise for 12 wk. Along with subjective appetite ratings, plasma ghrelin, glucagon, insulin, peptide YY3-36, glucose, free fatty acids, and glycerol were measured during fasting and in relation to a breakfast meal and an acute bout of exercise, both at baseline and at follow-up. Ad libitum lunch energy intake was evaluated 3 h after the breakfast meal. Despite different amounts of endurance exercise, the subjects lost similar amounts of fat mass (MOD: 4.2 ± 0.5 kg; HIGH: 3.7 ± 0.5 kg). Fasting and postprandial insulin decreased ≈ 20% in both exercise groups (P < 0.03 vs. CON). Appetite measurements were not upregulated in the fasting and postprandial states. On the contrary, fasting and postprandial ratings of fullness and postprandial PYY3-36 increased in HIGH (P < 0.001 vs. CON). Ad libitum lunch energy intake remained unchanged over the course of the intervention. In both exercise groups, plasma ghrelin increased in relation to acute exercise after training. Thus neither moderate nor high doses of daily endurance exercise increased fasting and postprandial measures of appetite, but a high dose of exercise was associated with an increase in fasting and meal-related ratings of fullness and satiety.


Dural repair with four spinal sealants: focused review of the manufacturers' inserts and the current literature.
Deliberate or traumatic dural fistulas are typically augmented by a "sealant" or "fibrin glue" to enhance the strength of dural closure. Little is known about the risks and complications associated with two specific "sealants" and two specific "fibrin glues" used for dural closure. Review of the manufacturers' inserts and a focused review of the literature concerning the pros and cons for two "sealants" (DuraSeal [Confluent Surgical Inc., Waltham, MA, USA] and BioGlue [Cryolife, Kennesaw, GA, USA]) and two "fibrin glues" (EVICEL [Johnson and Johnson Wound Management, Ethicon Inc., Somerville, NJ, USA] and Tisseel [fibrin sealant; Baxter International Inc., Westlake Village, CA, USA]) were assessed. A focused review of the literature using four different "sealants" or "fibrin glues" was performed. Documentation of persistent/recurrent postoperative cerebrospinal fluid fistulas was an end point for failure for the four different "sealants" and "fibrin glues." Manufacturers' inserts and a focused review of the literature concerning the relative safety and efficacy of two "sealants" (DuraSeal and BioGlue) and two "fibrin glues" (EVICEL and Tisseel) used to augment dural closure were assessed. Although DuraSeal is approved by the Federal Drug Administration (FDA) for intracranial and spinal application, two instances of paralysis are described in the literature. BioGlue is classified by the manufacturer as neurotoxic. EVICEL, one of the "fibrin glues," appeared in just two animal studies, whereas Tisseel, the other "fibrin glue," has been used in many large clinical series without adverse events. Despite the lack of FDA approval, Tisseel (fibrin glue) has seen wide adoption in "off-label" use. DuraSeal, which is FDA approved, was associated with two instances of paralysis. Alternatively, BioGlue was described as neurotoxic even by the manufacturer.


Characterization of polyploid wheat genomic diversity using a high-density 90,000 single nucleotide polymorphism array.
High-density single nucleotide polymorphism (SNP) genotyping arrays are a powerful tool for studying genomic patterns of diversity, inferring ancestral relationships between individuals in populations and studying marker-trait associations in mapping experiments. We developed a genotyping array including about 90,000 gene-associated SNPs and used it to characterize genetic variation in allohexaploid and allotetraploid wheat populations. The array includes a significant fraction of common genome-wide distributed SNPs that are represented in populations of diverse geographical origin. We used density-based spatial clustering algorithms to enable high-throughput genotype calling in complex data sets obtained for polyploid wheat. We show that these model-free clustering algorithms provide accurate genotype calling in the presence of multiple clusters including clusters with low signal intensity resulting from significant sequence divergence at the target SNP site or gene deletions. Assays that detect low-intensity clusters can provide insight into the distribution of presence-absence variation (PAV) in wheat populations. A total of 46 977 SNPs from the wheat 90K array were genetically mapped using a combination of eight mapping populations. The developed array and cluster identification algorithms provide an opportunity to infer detailed haplotype structure in polyploid wheat and will serve as an invaluable resource for diversity studies and investigating the genetic basis of trait variation in wheat.


Stomach region stimulated determines effects on duodenal motility in rats.
Gastric electrical stimulation (GES) is used clinically to promote proximal GI emptying and motility. In acute experiments, we measured duodenal motor responses elicited by GES applied at 141 randomly chosen electrode sites on the stomach serosal surface. Overnight-fasted (H2O available) anesthetized male rats (n = 81) received intermittent biphasic GES for 5 min (20-s-on/40-s-off cycles; I = 0.3 mA; pw = 0.2 ms; 10 Hz). A strain gauge on the serosal surface of the proximal duodenum of each animal was used to evaluate baseline motor activity and the effect of GES. Using ratios of time blocks compared with a 15-min prestimulation baseline, we evaluated the effects of the 5-min stimulation on concurrent activity, on the 10 min immediately after the stimulation, and on the 15-min period beginning with the onset of stimulation. We mapped the magnitude of the duodenal response (three different motility indices) elicited from the 141 stomach sites. Post hoc electrode site maps associated with duodenal responses suggested three zones similar to the classic regions of forestomach, corpus, and antrum. Maximal excitatory duodenal motor responses were elicited from forestomach sites, whereas inhibitory responses occurred with stimulation of the corpus. Moderate excitatory duodenal responses occurred with stimulation of the antrum. Complex, weak inhibitory/excitatory responses were produced by stimulation at boundaries between stomach regions. Patterns of GES efficacies coincided with distributions of previously mapped vagal afferents, suggesting that excitation of the duodenum is strongest when GES electrodes are situated over stomach concentrations of vagal intramuscular arrays, putative stretch receptors in the muscle wall.


Exploring biomolecular energy landscapes.
The potential energy landscape perspective provides both a conceptual and a computational framework for predicting, understanding and designing molecular properties. In this Feature Article, we highlight some recent advances that greatly facilitate structure prediction and analysis of global thermodynamics and kinetics in proteins and nucleic acids. The geometry optimisation procedures, on which these calculations are based, can be accelerated significantly using local rigidification of selected degrees of freedom, and through implementations on graphics processing units. Results of progressive local rigidification are first summarised for trpzip1, including a systematic analysis of the heat capacity and rearrangement rates. Benchmarks for all the essential optimisation procedures are then provided for a variety of proteins. Applications are then illustrated from a study of how mutation affects the energy landscape for a coiled-coil protein, and for transitions in helix morphology for a DNA duplex. Both systems exhibit an intrinsically multifunnel landscape, with the potential to act as biomolecular switches.


[Epidemiological analysis of mortality caused by solid tumors in the Metropolitan Region, Chile, 1999].
Chronic diseases are the leading cause of mortality in Chile and, among these, tumors are the second most frequent cause of death. The lOngest number of deaths occur in the Metropolitan Region. To describe the rates of mortality caused by solid tumors in the Metropolitan Region. Analysis of deaths that occurred in 1999 in the Metropolitan Region. Data from death certificates, gathered by the Ministry of Health, were used. Crude mortality rates and Potential Years of Life Lost (PYLL) caused by solid tumors were calculated. Among men, gastric cancer accounts for the higher rate of mortality, followed by lung cancer. Among women, gallbladder cancer is the most frequent cause of death, followed by breast cancer. Gastric cancer also accounts for the higher amount of PYLL among men, but among women, breast cancer outweighs gallbladder cancer in this parameter. Gastric cancer continues to be an important cause of mortality in Chile and there is a worrysome increase in the mortality caused by gallbladder cancer.


Morphological integration of the skull in craniofacial anomalies.
OBJECTIVES - To understand how surgical interventions impact the organization and internal integration of the major components of the skull, we address the functional and developmental relationships during perinatal development. METHODS - A number of methods for quantifying modularity and integration of morphological data are available. Here, measures derived from three-dimensional computed tomographic (CT) images are used to investigate the statistical relationships among measures of the cranial vault, face and cranial base. First, we establish the pattern of associations among quantitative measures in a sample of children unaffected by a craniofacial anomaly. We statistically compare these normative patterns of cranial integration to those of a sample of children with a facial anomaly (complete unilateral complete cleft lip and palate), and to children with a neurocranial anomaly (isolated sagittal synostosis). Finally, we test whether surgery affects the strength and pattern of associations among measures within the cranial base in the affected children. RESULTS - Our analyses reveal strong internal integration of the cranial base in unaffected children and in our samples of unoperated cleft lip and palate, and sagittal synostosis. Post-operatively, the magnitude of integration of the cranial base is reduced relative to the pre-operative condition in both samples of children with craniofacial anomalies. CONCLUSION - Our results show how the cranial base adjusts to its broader structural context, and provides added support for the developmental and structural integration of cranial base with both cranial vault and face.


Disruption of pupil size modulation correlates with voluntary motor preparation deficits in Parkinson's disease.
Pupil size is an easy-to-measure, non-invasive method to index various cognitive processes. Although a growing number of studies have incorporated measures of pupil size into clinical investigation, there have only been limited studies in Parkinson's disease (PD). Convergent evidence has suggested PD patients exhibit cognitive impairment at or soon after diagnosis. Here, we used an interleaved pro- and anti-saccade paradigm while monitoring pupil size with saccadic eye movements to examine the relationship between executive function deficits and pupil size in PD patients. Subjects initially fixated a central cue, the color of which instructed them to either look at a peripheral stimulus automatically (pro-saccade) or suppress the automatic response and voluntarily look in the opposite direction of the stimulus (anti-saccade). We hypothesized that deficits of voluntary control should be revealed not only on saccadic but also on pupil responses because of the recently suggested link between the saccade and pupil control circuits. In elderly controls, pupil size was modulated by task preparation, showing larger dilation prior to stimulus appearance in preparation for correct anti-saccades, compared to correct pro-saccades, or erroneous pro-saccades made in the anti-saccade condition. Moreover, the size of pupil dilation correlated negatively with anti-saccade reaction times. However, this profile of pupil size modulation was significantly blunted in PD patients, reflecting dysfunctional circuits for anti-saccade preparation. Our results demonstrate disruptions of modulated pupil responses by voluntary movement preparation in PD patients, highlighting the potential of using low-cost pupil size measurement to examine executive function deficits in early PD.


Bovine genomics update: making a cow jump over the moon.
Recent research in bovine genetics has focused on characterization of the biological differences underlying phenotypic variation for qualitative and quantitative traits of economic value in existing cattle populations. The much-anticipated benefits of DNA-based tools to routinely guide selection decisions for more efficient genetic gain and widened profit margins have not been fully met since the origin of this premise over two decades ago. However, the impending release of a high-quality draft genome sequence in 2005 should mark a turning point in these efforts. The following discussion summarizes how the bovine genetics research community has positioned itself to fully utilize a genome sequence resource and frames how genome sequence information can not only be applied to better implement marker-assisted selection, but also address rising consumer concerns relative to animal well-being and food safety.


Antimicrobial Compounds in the Volatilome of Social Spider Communities.
Social arthropods such as termites, ants, and bees are among others the most successful animal groups on earth. However, social arthropods face an elevated risk of infections due to the dense colony structure, which facilitates pathogen transmission. An interesting hypothesis is that social arthropods are protected by chemical compounds produced by the arthropods themselves, microbial symbionts, or plants they associate with. Stegodyphus dumicola is an African social spider species, inhabiting communal silk nests. Because of the complex three-dimensional structure of the spider nest antimicrobial volatile organic compounds (VOCs) are a promising protection against pathogens, because of their ability to diffuse through air-filled pores. We analyzed the volatilomes of S. dumicola, their nests, and capture webs in three locations in Namibia and assessed their antimicrobial potential. Volatilomes were collected using polydimethylsiloxane (PDMS) tubes and analyzed using GC/Q-TOF. We showed the presence of 199 VOCs and tentatively identified 53 VOCs. More than 40% of the tentatively identified VOCs are known for their antimicrobial activity. Here, six VOCs were confirmed by analyzing pure compounds namely acetophenone, 1,3-benzothiazole, 1-decanal, 2-decanone, 1-tetradecene, and docosane and for five of these compounds the antimicrobial activity were proven. The nest and web volatilomes had many VOCs in common, whereas the spider volatilomes were more differentiated. Clear differences were identified between the volatilomes from the different sampling sites which is likely justified by differences in the microbiomes of the spiders and nests, the plants, and the different climatic conditions. The results indicate the potential relevance of the volatilomes for the ecological success of S. dumicola.


The effect of two concentrations of heparin on arterial catheter patency.
The use of invasive lines with heparinized fluid for hemodynamic monitoring is a routine procedure in critical care areas. The main objective of this study was to compare the duration of patency of indwelling arterial catheter lines and patient coagulation values when the recommended dilution of 1.0 U heparin/mL was used versus the use of only 0.25 U heparin/mL. One hundred four intensive care unit (ICU) patients were studied. There were no significant differences between the two groups in patency or coagulation values. The results of the study demonstrated that 0.25 U heparin/mL was sufficient to maintain arterial line patency for patients with lines in place for up to 3 days.


An insight into tetrahydro-β-carboline-tetrazole hybrids: synthesis and bioevaluation as potent antileishmanial agents.
A series of 2,3,4,9-tetrahydro-β-carboline tetrazole derivatives (14a-u) have been synthesized utilizing the Ugi multicomponent reaction and were identified as potential antileishmanial chemotypes. Most of the screened derivatives exhibited significant in vitro activity against the promastigote (IC50 from 0.59 ± 0.35 to 31 ± 1.27 μM) and intracellular amastigote forms (IC50 from 1.57 ± 0.12 to 17.6 ± 0.2 μM) of L. donovani, and their activity is comparable with standard drugs miltefosine and sodium stibogluconate. The most active compound 14t was further studied in vivo against the L. donovani/golden hamster model at a dose of 50 mg kg-1 through the intraperitoneal route for 5 consecutive days, which displayed 75.04 ± 7.28% inhibition of splenic parasite burden. Pharmacokinetics of compound 14t was studied in the golden Syrian hamster, and following a 50 mg kg-1 oral dose, the compound was detected in hamster serum for up to 24 h. It exhibited a large volume of distribution (651.8 L kg-1), high clearance (43.2 L h-1 kg-1) and long mean residence time (10 h).


Links between serotonin reuptake inhibition during pregnancy and neurodevelopmental delay/spectrum disorders: A systematic review of epidemiological and physiological evidence.
To investigate possible linkages between neurodevelopmental delay and neurodevelopmental spectrum disorders and exposure to medication with effects on serotonin reuptake inhibition during pregnancy. We systematically reviewed the epidemiological literature for studies bearing on this relationship in children born with neurodevelopmental spectrum disorder and related conditions, as well as animal studies giving serotonin reuptake inhibitors to pregnant animals and in addition reviewed the literature for proposals as to possible mechanisms that might link effects on serotonin reuptake with cognitive changes post-partum.The epidemiological studies were analysed to produce Forest plots to illustrate possible relations. The odds ratio of Autistic Spectrum or related Disorders in children born to women taking serotonin reuptake inhibiting antidepressants during pregnancy in case control studies was 1.95 (95% C.I. 1.63, 2.34) and in prospective cohort studies was 1.96 (95% C.I. 1.33, 2.90). There appears to be a link between serotonin reuptake inhibition in pregnancy and developmental delay and spectrum disorders in infancy leading to cognitive difficulties in childhood. More work needs to be done to establish more precisely the nature of the difficulties and possible mechanisms through which this link might be mediated.


Outcomes of patients on dual-boosted PI regimens: experience of the Swiss HIV cohort study.
Dual-boosted protease inhibitors (DBPI) are an option for salvage therapy for HIV-1 resistant patients. Patients receiving a DBPI in the Swiss HIV Cohort Study between January1996 and March 2007 were studied. Outcomes of interest were viral suppression at 24 weeks. 295 patients (72.5%) were on DBPI for over 6 months. The median duration was 2.2 years. Of 287 patients who had HIV-RNA >400 copies/ml at the start of the regimen, 184 (64.1%) were ever suppressed while on DBPI and 156 (54.4%) were suppressed within 24 weeks. The median time to suppression was 101 days (95% confidence interval 90-125 days). The median number of past regimens was 6 (IQR, 3-8). The main reasons for discontinuing the regimen were patient's wish (48.3%), treatment failure (22.5%), and toxicity (15.8%). Acquisition of HIV through intravenous drug use and the use of lopinavir in combination with saquinavir or atazanavir were associated with an increased likelihood of suppression within 6 months. Patients on DBPI are heavily treatment experienced. Viral suppression within 6 months was achieved in more than half of the patients. There may be a place for DBPI regimens in settings where more expensive alternates are not available.


"Type 1 on type 2" diabetes mellitus: autoimmune type 1 diabetes superimposed on established type 2 diabetes.
To investigate clinical features and pathophysiology of a rare form of new-onset type 1 diabetes mellitus that was superimposed on established type 2 diabetes. We retrospectively analyzed 126 consecutive type 2 diabetic patients, who were admitted to the hospital 2 or more times from July 2000 to December 2005 and had been repeatedly examined for islet-associated autoantibodies and insulin secretory capacity over a period of years. We experienced 2 patients in whom autoantibodies including ICA, GADAb, and IA-2Ab were initially all negative, but in whom at least 1 of these antibodies later became positive, whose endogenous insulin secretion decreased, and who eventually reached an insulin-dependent stage. At the time of seroconversion of antibodies, the patients had 15 to 23 years' history of diabetes, and had microvascular complications specific to diabetes mellitus, and before seroconversion insulin secretory capacities were preserved. The patients had HLA types associated with susceptibility to Japanese type 1 diabetes mellitus. Our findings suggest that autoimmune type 1 diabetes mellitus may be superimposed on well-established type 2 diabetes.


The Long and Winding Road of Vagus Nerve Stimulation: Challenges in Developing an Intervention for Difficult-to-Treat Mood Disorders.
The Vagus Nerve Stimulation (VNS) Therapy System has been studied for more than 20 years in patients with severe, treatment-resistant, chronic mood disorder, i.e., difficult-to-treat depression (DTD). This review distills some of the implications of this research for future therapeutic trials in this population. A narrative review is provided on VNS in DTD. Protocols for a new, large, sham-controlled trial and a global, longitudinal observational study are described. Following encouraging results in open studies, a randomized, masked, sham-controlled trial of VNS for DTD failed to demonstrate an effect on the primary outcome. The negative results may have been partly due to inadequate treatment duration (10 weeks). In long-term observational studies, adjunctive VNS, combined with treatment-as-usual (VNS+TAU), was administered to more than 1100 DTD patients and compared with TAU alone in more than 400 patients. VNS+TAU had superior antidepressant effects, but maximal symptom reduction was often observed after 12 months or longer of stimulation. VNS+TAU had also marked superiority in durability of benefit. Sustained levels of symptom reduction below the traditional cutoff for response (i.e. < 50%) were associated with improved quality of life. Most comparisons of VNS+TAU and TAU were derived from observational, open label studies. The history of VNS in DTD has implications for interventional studies in this population, and perhaps other chronic medical disorders. The slow onset of benefit with VNS necessitates considerably longer controlled observation periods to establish efficacy. Durability of benefit should be routinely incorporated in efficacy assessment. New outcome metrics are needed to both categorically identify clinically meaningful benefit and to integrate information on symptom burden over time.


Regional-Scale Declines in Productivity of Pink and Chum Salmon Stocks in Western North America.
Sockeye salmon (Oncorhynchus nerka) stocks throughout the southern part of their North American range have experienced declines in productivity over the past two decades. In this study, we tested the hypothesis that pink (O. gorbuscha) and chum (O. keta) salmon stocks have also experienced recent declines in productivity by investigating temporal and spatial trends in productivity of 99 wild North American pink and chum salmon stocks. We used a combination of population dynamics and time series models to quantify individual stock trends as well as common temporal trends in pink and chum salmon productivity across local, regional, and continental spatial scales. Our results indicated widespread declines in productivity of wild chum salmon stocks throughout Washington (WA) and British Columbia (BC) with 81% of stocks showing recent declines in productivity, although the exact form of the trends varied among regions. For pink salmon, the majority of stocks in WA and BC (65%) did not have strong temporal trends in productivity; however, all stocks that did have trends in productivity showed declining productivity since at least brood year 1996. We found weaker evidence of widespread declines in productivity for Alaska pink and chum salmon, with some regions and stocks showing declines in productivity (e.g., Kodiak chum salmon stocks) and others showing increases (e.g., Alaska Peninsula pink salmon stocks). We also found strong positive covariation between stock productivity series at the regional spatial scale for both pink and chum salmon, along with evidence that this regional-scale positive covariation has become stronger since the early 1990s in WA and BC. In general, our results suggest that common processes operating at the regional or multi-regional spatial scales drive productivity of pink and chum salmon stocks in western North America and that the effects of these process on productivity may change over time.


Diabetic Skin Changes Can Benefit from Moisturizer and Cleanser Use: A Review
INTRODUCTION: Diabetes mellitus (DM) associated skin changes, which may be the first sign of DM in undiagnosed patients. Frequently these patients present with dry skin, which may benefit from the use of gentle cleansers and moisturizers. A review paper was developed to explore DM-associated skin changes and possible benefits of cleanser and moisturizer use. METHODS: For this purpose, an expert panel of physicians involved in the care of patients with DM selected information from literature searches coupled with expert opinions and experience of the panel. RESULTS: A defective skin barrier predisposes the skin to water loss leading to dryness, hyperkeratosis and inflammation. Skin changes that may benefit from the use of gentle cleansers and moisturizers are, amongst others, diabetic foot syndrome, ichthyosiform skin changes, xerosis, and keratosis pilaris. Adherence to treatment is a considerable challenge making education essential, especially about the need to keep skin clean and what skin care to use. Specifically designed diabetic skin care that contains anti-aging ingredients, urea, and essential ceramides, has demonstrated benefits for dry/itchy skin. CONCLUSIONS: Skin disorders are common complications among either diabetic patients with patients with DM and may lead to serious adverse events. Evidence suggests that daily application of optimal skin care using gentle cleansers and moisturizers is one of the measures that may help improve skin barrier dysfunction, preventing complications by providing early-stage treatment of patients with diabetes. J Drugs Dermatol. 2019;18(12):1211-1217.


Incidence of radiographic cam-type impingement in young patients (<50) after femoral neck fracture treated with reduction and internal fixation.
Cam-type femoral impingement is caused by structural abnormalities of the hip and is recognized as a cause of degenerative hip arthritis. Identifiable etiologies of this structural abnormality include congenital malformation, pediatric hip disease, and malunion of femoral neck fractures after internal fixation. The purpose of this study was to determine the prevalence of radiographic impingement in healed Orthopaedic Trauma Association (OTA) type 31B fractures treated with reduction and internal fixation. Seventy OTA 31B hip fractures treated with internal fixation were identified from our institutional trauma database and radiographs were retrospectively reviewed for signs of impingement. Mean follow-up was 53 months after fracture. Alpha angle, Mose templates, and femoral head retroversion were the measurements used to determine impingement. The overall prevalence of any sign of radiographic impingement was 75%. Alpha angle was elevated in 32 hips (46%), asphericity was present in 46 femoral heads (65%), and femoral head retroversion was present in 26 hips (37%). The rates were highest in displaced subcapital fractures (OTA 31B-3) with a 63% (13/19) prevalence of elevated alpha angle, 68% (14/19) prevalence of asphericity, and 47% (10/19) prevalence of retroversion. Prevalence of radiographic signs of impingement in this population is higher than expected based on population-based controls. Surgeons must be vigilant about reduction and fixation of femoral neck fractures. Malunion should be recognized as early intervention may be beneficial in improving long-term outcomes.


RNAi-mediated oncogene silencing confers resistance to crown gall tumorigenesis.
Crown gall disease, caused by the soil bacterium Agrobacterium tumefaciens, results in significant economic losses in perennial crops worldwide. A. tumefaciens is one of the few organisms with a well characterized horizontal gene transfer system, possessing a suite of oncogenes that, when integrated into the plant genome, orchestrate de novo auxin and cytokinin biosynthesis to generate tumors. Specifically, the iaaM and ipt oncogenes, which show approximately 90% DNA sequence identity across studied A. tumefaciens strains, are required for tumor formation. By expressing two self-complementary RNA constructions designed to initiate RNA interference (RNAi) of iaaM and ipt, we generated transgenic Arabidopsis thaliana and Lycopersicon esculentum plants that are highly resistant to crown gall disease development. In in vitro root inoculation bioassays with two biovar I strains of A. tumefaciens, transgenic Arabidopsis lines averaged 0.0-1.5% tumorigenesis, whereas wild-type controls averaged 97.5% tumorigenesis. Similarly, several transformed tomato lines that were challenged by stem inoculation with three biovar I strains, one biovar II strain, and one biovar III strain of A. tumefaciens displayed between 0.0% and 24.2% tumorigenesis, whereas controls averaged 100% tumorigenesis. This mechanism of resistance, which is based on mRNA sequence homology rather than the highly specific receptor-ligand binding interactions characteristic of traditional plant resistance genes, should be highly durable. If successful and durable under field conditions, RNAi-mediated oncogene silencing may find broad applicability in the improvement of tree crop and ornamental rootstocks.