Reducing the Burden of Difficult-to-Treat Major Depressive Disorder: Revisiting Monoamine Oxidase Inhibitor Therapy.
Difficult-to-treat depression (eg, depression with atypical or anxious symptoms, treatment-resistant depression, or depression with frequent recurrence) is a challenging real-world health issue. This critical review of the literature focuses on monoamine oxidase inhibitor (MAOI) therapy and difficult-to-treat forms of depression. A literature search was performed in November 2012 and refreshed through January 2013 with no date restrictions using key search terms including MAO inhibitor therapy or MAOI and depression and anxiety, atypical, treatment-resistant, recurrent, relapse, or refractory. Articles were selected to summarize the current needs in difficult-to-treat depression as well as the use of MAOI therapies in this area. Two strategies have fallen out of favor in the care of patients with major depressive disorder. The first is the use of MAOI therapy and the second is the proactive recognition of difficult-to-treat depression that may not respond as well to more frequently used antidepressants. The infrequent use of MAOIs stems from the perception that other oral therapies for depression are safer and easier to use than oral MAOIs; however, transdermal delivery is one potential strategy to improve the safety of this class of agents. Although food-related interactions with transdermal delivery of MAOI therapy can be lessened, clinicians still need to be vigilant for drug-drug interactions and serotonin syndrome. Clinicians should consider MAOIs for patients who have had several unsuccessful trials of antidepressants. Guidelines generally reserve MAOIs as third- and fourth-line treatments due to concerns over safety and tolerability; however, transdermal delivery of an MAOI may allay some of the safety and tolerability concerns. Patients should be provided education about MAOIs and their risks.


Exercise physiologists: essential players in interdisciplinary teams for noncommunicable chronic disease management.
Noncommunicable diseases (NCDs), such as obesity and type 2 diabetes mellitus, are a growing public health challenge in Australia, accounting for a significant and increasing cost to the health care system. Management of these chronic conditions is aided by interprofessional practice, but models of care require updating to incorporate the latest evidence-based practice. Increasing research evidence reports the benefits of physical activity and exercise on health status and the risk of inactivity to chronic disease development, yet physical activity advice is often the least comprehensive component of care. An essential but as yet underutilized player in NCD prevention and management is the "accredited exercise physiologist," a specialist in the delivery of clinical exercise prescriptions for the prevention or management of chronic and complex conditions. In this article, the existing role of accredited exercise physiologists in interprofessional practice is examined, and an extension of their role proposed in primary health care settings.


Development and Application of a Novel Model System to Study "Active" and "Passive" Tumor Targeting.
Macromolecular reagents can be targeted to tumors through active and passive mechanisms. "Active" targeting involves moieties, such as receptor ligands, to direct tumor cell binding, whereas "passive" targeting relies on long reagent circulating half-life, abnormal tumor vasculature, and poor lymphatic drainage for tumor entrapment. Here, we sought to study the impact of reagent circulating half-life on "active" and "passive" tumor uptake. The humanized prostate-specific membrane antigen (PSMA)-targeting antibody HuJ591 was used as the "active" targeting agent. HuJ591 was labeled with a Near Infrared (NIR) dye and its circulating half-life was modified by conjugation to high-molecular-weight Polyethylene Glycol (PEG). PEGylation did not negatively impact PSMA-binding specificity. "Active" and "passive" tumor targeting of intravenously injected antibody conjugates were then quantified by NIR fluorescent imaging of immunocompromised mice bearing bilateral isogenic PSMA-positive and PSMA-negative human tumor xenografts. Two isogenic tumor pairs were applied, PC3 ± PSMA (PC3-PIP/PC3-Flu) or LMD-MDA-MB-231 ± PSMA (LMD-PSMA/LMD). This study provided a unique model system to simultaneously observe "active" and "passive" tumor targeting within a single animal. "Passive" targeting was observed in all PSMA-negative tumors, and was not enhanced by increased HuJ591 size or extended circulating half-life. Interestingly, "active" targeting was only successful in some situations. Both PSMA-positive tumor models could be actively targeted with J591-IR800 and J591-PEG10K. However, the larger J591-PEG30K enhanced "active" targeting in the PC-3 tumor models, but inhibited "active" targeting the LMD-MDA-MB-231 tumor model. Successful "active" targeting was associated with higher PSMA expression. These results support the potential for "active" targeting to enhance overall macromolecular reagent uptake within tumors. Mol Cancer Ther; 15(10); 2541-50. ©2016 AACR.


The Preoperative CT-Scan Can Help to Predict Postoperative Complications after Pancreatoduodenectomy.
After pancreatoduodenectomy, complication rates are up to 40%. To predict the risk of developing postoperative pancreatic fistula or severe complications, various factors were evaluated. 110 consecutive patients undergoing pancreatoduodenectomy at our institute between January 2012 and September 2014 with complete CT scan were retrospectively identified. Pre-, per-, and postoperative patients and pathological information were gathered. The CT-scans were analysed for the diameter of the pancreatic duct, attenuation of the pancreas, and the visceral fat area. All data was statistically analysed for predicting POPF and severe complications by univariate and multivariate logistic regression analyses. The POPF rate was 18%. The VFA measured at umbilicus (OR 1.01; 95% CI = 1.00-1.02; P = 0.011) was an independent predictor for POPF. The severe complications rate was 33%. Independent predictors were BMI (OR 1.24; 95% CI = 1.10-1.42; P = 0.001), ASA class III (OR 17.10; 95% CI = 1.60-182.88; P = 0.019), and mean HU (OR 0.98; 95% CI = 0.96-1.00; P = 0.024). In conclusion, VFA measured at the umbilicus seems to be the best predictor for POPF. BMI, ASA III, and the mean HU of the pancreatic body are independent predictors for severe complications following PD.


Getting Black Men to Undergo Prostate Cancer Screening: The Role of Social Capital.
Despite higher rates of prostate cancer-related mortality and later stage of prostate cancer diagnosis, Black/African American men are significantly less likely than non-Hispanic White men to use early detection screening tools, like prostate-specific antigen (PSA) testing for prostate cancer. Lower screening rates may be due, in part, to controversy over the value of prostate cancer screenings as part of routine preventive care for men, but Black men represent a high-risk group for prostate cancer that may still benefit from PSA testing. Exploring the role of social factors that might be associated with PSA testing can increase knowledge of what might promote screening behaviors for prostate cancer and other health conditions for which Black men are at high risk. Using multilevel logistic regression, this study analyzed self-report lifetime use of PSA test for 829 Black men older than 45 years across 381 Philadelphia census tracts. This study included individual demographic and aggregated social capital data from the Public Health Management Corporation's 2004, 2006, and 2008 waves of the Community Health Database, and sociodemographic characteristics from the 2000 U.S. Census. Each unit increase in community participation was associated with a 3 to 3.5 times greater likelihood of having had a PSA test (odds ratio = 3.35). Findings suggest that structural forms of social capital may play a role in screening behaviors for Black men in Philadelphia. A better understanding of the mechanism underlying the link between social capital and screening behaviors can inform how researchers and interventionists develop tools to promote screening for those who need it.


Aldehyde-stabilized cryopreservation.
We describe here a new cryobiological and neurobiological technique, aldehyde-stabilized cryopreservation (ASC), which demonstrates the relevance and utility of advanced cryopreservation science for the neurobiological research community. ASC is a new brain-banking technique designed to facilitate neuroanatomic research such as connectomics research, and has the unique ability to combine stable long term ice-free sample storage with excellent anatomical resolution. To demonstrate the feasibility of ASC, we perfuse-fixed rabbit and pig brains with a glutaraldehyde-based fixative, then slowly perfused increasing concentrations of ethylene glycol over several hours in a manner similar to techniques used for whole organ cryopreservation. Once 65% w/v ethylene glycol was reached, we vitrified brains at -135 °C for indefinite long-term storage. Vitrified brains were rewarmed and the cryoprotectant removed either by perfusion or gradual diffusion from brain slices. We evaluated ASC-processed brains by electron microscopy of multiple regions across the whole brain and by Focused Ion Beam Milling and Scanning Electron Microscopy (FIB-SEM) imaging of selected brain volumes. Preservation was uniformly excellent: processes were easily traceable and synapses were crisp in both species. Aldehyde-stabilized cryopreservation has many advantages over other brain-banking techniques: chemicals are delivered via perfusion, which enables easy scaling to brains of any size; vitrification ensures that the ultrastructure of the brain will not degrade even over very long storage times; and the cryoprotectant can be removed, yielding a perfusable aldehyde-preserved brain which is suitable for a wide variety of brain assays.


Diurnal Cortisol Levels and Subjective Ratings of Effort and Fatigue in Adult Cochlear Implant Users: A Pilot Study.
Purpose There is a growing body of literature that suggests a linkage between impaired auditory function, increased listening effort, and fatigue in children and adults with hearing loss. Research suggests this linkage may be associated with hearing loss-related variations in diurnal cortisol levels. Here, we examine variations in cortisol profiles between young adults with and without severe sensorineural hearing loss and examine associations between cortisol and subjective measures of listening effort and fatigue. Method This study used a repeated-measures, matched-pair design. Two groups (n = 8 per group) of adults enrolled in audiology programs participated, 1 group of adults with hearing loss (AHL) and 1 matched control group without hearing loss. Salivary cortisol samples were collected at 7 time points over a 2-week period and used to quantify physiological stress. Subjective measures of listening effort, stress, and fatigue were also collected to investigate relationships between cortisol levels, perceived stress, and fatigue. Results Subjective ratings revealed that AHL required significantly more effort and concentration on typical auditory tasks than the control group. Likewise, complaints of listening-related fatigue were more frequent and more of a problem in everyday life for AHL compared to the control group. There was a significant association between subjective ratings of listening effort and listening-related fatigue for our AHL, but not for the control group. In contrast, there was no significant difference in cortisol measures between groups, nor were there significant associations between cortisol and any subjective measure. Conclusions Young AHL experience more effortful listening than their normal hearing peers. This increased effort is associated with increased reports of listening-related fatigue. However, diurnal cortisol profiles were not significantly different between groups nor were they associated with these perceived differences.


Effects of Cone-Shaped Bend Inlet Cannulas of an Axial Blood Pump on Thrombus Formation: An Experiment and Simulation Study.
BACKGROUND Cannula shape and connection style influence the risk of thrombus formation in the blood pump by varying the blood flow characteristics inside the pump. Inlet cannulas should be designed based on the need for anatomical fit and reducing the risk of thrombus generation in the blood pump. The effects on thrombus formation of the cone-shaped bend inlet cannulas of axial blood pumps should be studied. MATERIAL AND METHODS The cannulas were designed as cone-shaped, with 1 bent section connecting 2 straight sections. Both the silicone tube and novel cone-shaped cannula were simulated for comparison. The flow fields of a blood pump with inlet cannula were simulated by computational fluid dynamics (CFD) at flows of 2.0, 2.5, and 3.0 liters per minute (lpm), with pump rotational speeds of 7500, 8000, and 8500 rpm, respectively. Then, 6 two-dimensional (2D) particle image velocimetry (PIV) tests were conducted and the velocity distributions were analyzed. RESULTS A low-velocity region was located inside the pump entrance when a soft silicone tube was used. At 8500 rpm and 3.0 lpm working condition, the minimum velocity inside the pump with cone-shaped cannulas was 2.5×10^-1 m/s. The cone-shaped cannulas eliminated the low-velocity region inside the pump. Both CFD and PIV results showed that the low-velocity region did not spread to the entrance of the blood pump within the flow range from 2.0 lpm to 7.0 lpm. CONCLUSIONS The designed cone-shaped bent cannulas can eliminate the low-velocity region inside the blood pump and reduce the risk of thrombus formation in the blood pump.


Purification and characterization of alpha-L-arabinofuranosidase from Bacillus stearothermophilus T-6.
Bacillus stearothermophilus T-6 produced an alpha-L-arabinofuranosidase when grown in the presence of L-arabinose, sugar beet arabinan, or oat spelt xylan. At the end of a fermentation, about 40% of the activity was extracellular, and enzyme activity in the cell-free supernatant could reach 25 U/ml. The enzymatic activity in the supernatant was concentrated against polyethylene glycol 20000, and the enzyme was purified eightfold by anion-exchange and hydrophobic interaction chromatographies. The molecular weight of T-6 alpha-L-arabinofuranosidase was 256,000, and it consisted of four identical subunits as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and gel filtration. The native enzyme had a pI of 6.5 and was most active at 70 degrees C and at pH 5.5 to 6.0. Its thermostability at pH 7.0 was characterized by half-lives of 53, 15, and 1 h at 60, 65, and 70 degrees C, respectively. Kinetic experiments at 60 degrees C with p-nitrophenyl alpha-L-arabinofuranoside as a substrate gave a Vmax, a Km, and an activation energy of 749 U/mg, 0.42 mM, and 16.6 kcal/mol, (ca. 69.5 kJ/mol), respectively. The enzyme had no apparent requirement for cofactors, and its activity was strongly inhibited by 1 mM Hg2+. T-6 alpha-L-arabinofuranosidase released L-arabinose from arabinan and had low activity on oat spelt xylan. The enzyme acted cooperatively with T-6 xylanase in hydrolyzing oat spelt xylan, and L-arabinose, xylose, and xylobiose were detected as the end reaction products.(ABSTRACT TRUNCATED AT 250 WORDS)


Electronic Nose and Exhaled Breath NMR-based Metabolomics Applications in Airways Disease.
Breathomics, the multidimensional molecular analysis of exhaled breath, includes analysis of exhaled breath with gas-chromatography/mass spectrometry (GC/MS) and electronic noses (e-noses), and metabolomics of exhaled breath condensate (EBC), a non-invasive technique which provides information on the composition of airway lining fluid, generally by high-resolution nuclear magnetic resonance (NMR) spectroscopy or MS methods. Metabolomics is the identification and quantification of small molecular weight metabolites in a biofluid. Specific profiles of volatile compounds in exhaled breath and metabolites in EBC (breathprints) are potentially useful surrogate markers of inflammatory respiratory diseases. Electronic noses (e-noses) are artificial sensor systems, usually consisting of chemical cross-reactive sensor arrays for characterization of patterns of breath volatile compounds, and algorithms for breathprints classification. E-noses are handheld, portable, and provide real-time data. E-nose breathprints can reflect respiratory inflammation. E-noses and NMR-based metabolomics of EBC can distinguish patients with respiratory diseases such as asthma, COPD, and lung cancer, or diseases with a clinically relevant respiratory component including cystic fibrosis and primary ciliary dyskinesia, and healthy individuals. Breathomics has also been reported to identify patients affected by different types of respiratory diseases. Patterns of breath volatile compounds detected by e-nose and EBC metabolic profiles have been associated with asthma phenotypes. In combination with other -omics platforms, breathomics might provide a molecular approach to respiratory disease phenotyping and a molecular basis to tailored pharmacotherapeutic strategies. Breathomics might also contribute to identify new surrogate markers of respiratory inflammation, thus, facilitating drug discovery. Validation in newly recruited, prospective independent cohorts is essential for development of e-nose and EBC NMRbased metabolomics techniques.


Controllable optomechanically induced transparency and ponderomotive squeezing in an optomechanical system assisted by an atomic ensemble.
We propose a system for realizing controllable optomechanically induced transparency (OMIT) and ponderomotive squeezing. In this system, an atomic ensemble driven by an external optical field couples with the cavity field in a typical optomechanical cavity. When the cavity is driven by a coupling laser and a probe laser, we can produce a switch for the probe field and adjust the width of the transparency window flexibly by manipulating the coupling strength between the atomic ensemble and the external optical field. We also investigate the ponderomotive squeezing properties of the transmitted field by analyzing its spectrum. Interestingly, the coupling strength between the atomic ensemble and the cavity field plays an important role in controlling the squeezing properties and the squeezing spectrum presents distinct features at red-detuned and blue-detuned frequencies by adjusting the coupling strength.


Molecular Identification of Borrelia miyamotoi in Ixodes ricinus from Portugal.
Borrelia miyamotoi, a relapsing fever spirochete, has been found recently in Ixodes ricinus ticks; however, little is known about its spatial distribution and potential local impact on human health. A total of 640 ticks (447 nymphs and 193 adults) collected throughout Portugal were analyzed using two nested PCR protocols, one targeting the flagellin gene and the other the internal transcribed space region between the 5S and the 23S rRNA. As a result, B. miyamotoi was detected, for the first time, in one guesting I. ricinus nymph collected in the Lisboa district. In addition, a prevalence of 11% (71/640) for B. burgdorferi sensu lato was obtained. Even though no human relapsing fever cases due to infection by B. miyamotoi have been reported yet in Portugal, surveillance must be improved to provide better insight into the prevalence and distribution of this spirochete in ticks.


New therapies for chronic obstructive pulmonary disease.
Chronic obstructive pulmonary disease (COPD) is the most common lung disease, carrying a significant mortality and morbidity. None of the therapeutic interventions currently available alter the progression of the disease. As our understanding of the basic mechanisms of alveolar destruction and airflow limitation improves, new targets are identified that may eventually result in treatment options which will affect the progression of this disease. In this review, we discuss some of the novel therapeutic options recently developed that may have an impact on the management of COPD. Future directions in research and development of pharmacological agents based on improved understanding of COPD are also discussed.


An electronic case manager for diabetes control.
To evaluate the usage and safety of an electronic case manager (ECM) system designed to facilitate the task of glycemic control. Sustained improvement in blood glucose control is the proven treatment outcome that will reduce or eliminate the long-term complications of diabetes. A customized microcomputer system served as the ECM. Located at the clinic, this voice-interactive system required the remote patient to need only a touch-tone telephone. Patients accessed the system to report daily self-measured glucose levels or hypoglycemic symptoms together with associated lifestyle events. System beta-testing was in an open-case series (n = 184) in an academic diabetes center with the goal of evaluating the ECM in terms of utilization, frequency of crises, and fiscal matters. Of the patients, 58% (n = 107) actively used the ECM for their daily diabetes care, accumulating 788 patient-months of follow-up. Over 45,000 telephone calls were received by the ECM during the start-up year. Each call was processed instantly and automatically. Patients benefited from having 24-h access to the ECM. Prevalence of diabetes-related crises (hyperglycemia > 400 mg/dl [22 mmol/l] or hypoglycemia < 50 mg/dl [2.8 mmol/l]) decreased approximately threefold (P < 0.05), with a concomitant statistically significant decrease in HbA1c of 0.8% at 6 months (n = 45, P = 0.024) and 0.9% at 12 months (n = 30, P = 0.044). The ECM provided 24-h on-line assistance in adjusting daily insulin and/or tablet therapy, automatic generation of standardized medical reports, electronic medical-legal documentation, as well as a marked reduction in the time spent on the phone with patients. Clinic visits in managing complex diabetes were reduced approximately twofold (P < 0.0001), and the effort spent by case managers was estimated. Patients with diabetes who accessed the ECM system received timely, cost-effective, and reliable medical intervention. This reduced the incidence of diabetic crises and the need for frequent clinic visits. The ECM empowers case managers to provide safer and superior diabetes care.


Psychological well-being and incident frailty in men and women: the English Longitudinal Study of Ageing.
Observations that older people who enjoy life more tend to live longer suggest that psychological well-being may be a potential resource for healthier ageing. We investigated whether psychological well-being was associated with incidence of physical frailty. We used multinomial logistic regression to examine the prospective relationship between psychological well-being, assessed using the CASP-19, a questionnaire that assesses perceptions of control, autonomy, self-realization and pleasure, and incidence of physical frailty or pre-frailty, defined according to the Fried criteria (unintentional weight loss, weakness, self-reported exhaustion, slow walking speed and low physical activity), in 2557 men and women aged 60 to ≥ 90 years from the English Longitudinal Study of Ageing (ELSA). Men and women with higher levels of psychological well-being were less likely to become frail over the 4-year follow-up period. For a standard deviation higher score in psychological well-being at baseline, the relative risk ratio (RR) for incident frailty, adjusted for age, sex and baseline frailty status, was 0.46 [95% confidence interval (CI) 0.40-0.54]. There was a significant association between psychological well-being and risk of pre-frailty (RR 0.69, 95% CI 0.63-0.77). Examination of scores for hedonic (pleasure) and eudaimonic (control, autonomy and self-realization) well-being showed that higher scores on both were associated with decreased risk. Associations were partially attenuated by further adjustment for other potential confounding factors but persisted. Incidence of pre-frailty or frailty was associated with a decline in well-being, suggesting that the relationship is bidirectional. Maintaining a stronger sense of psychological well-being in later life may protect against the development of physical frailty. Future research needs to establish the mechanisms underlying these findings.


Macronutrients intake and risk of Parkinson's disease: A meta-analysis.
We carried out a meta-analysis to summarize the evidence from published studies on macronutrients intake and risk of Parkinson's disease (PD). Pertinent studies were identified by a search of PubMed and Embase. Study-specific effect was combined with the random-effect model. The dose-response relationship was assessed by the restricted cubic spline. For highest versus lowest level of intake, the relative risk (RR) of PD was 1.13 (95% CI 0.88-1.44) for protein (7 articles including 1570 PD cases among 357,827 subjects), RR 1.24 (95% CI 1.05-1.48) for carbohydrate (8 articles including 1482 PD cases among 232,869 subjects), RR 0.88 (95% CI 0.74-1.06) for fat (12 articles including 2936 PD cases among 374,124 subjects), RR 0.97 (95% CI 0.75-1.26) for cholesterol (6 articles including 1713 PD cases among 170,058 subjects) and 1.39 (95% CI 1.01-1.92) for energy (8 articles including 1553 PD cases among 170,317 subjects), respectively. Among prospective studies adjusting for smoking and coffee/caffeine, no associations were found between PD risk and intake of protein (RR 1.02, 95% CI 0.80-1.30), carbohydrate (RR 1.11, 95% CI 0.86-1.43), fat (RR 0.90, 95% CI 0.70-1.16), cholesterol (RR 0.89, 95% CI 0.74-1.09) and energy (RR 0.97, 95% CI 0.93-1.02); however, polyunsaturated fatty acid (RR 0.78, 95% CI 0.64-0.96) was inversely associated with PD risk. Limited data showed a linear dose-response relationship between the aforementioned macronutrients and PD risk. Dietary intake of protein, carbohydrate, cholesterol and energy might be not independently associated with PD risk. Higher intake of polyunsaturated fatty acid might be inversely associated with PD risk. Confounding by smoking and coffee/caffeine should be considered regarding the association between fat intake and PD risk in further studies.


A prospective evaluation of urine microscopy in septic and non-septic acute kidney injury.
Sepsis is the most common trigger for acute kidney injury (AKI) in critically ill patients. We sought to determine whether there are unique patterns to urine sediment in septic compared with non-septic AKI. Prospective two center cohort study of adult critically ill patients with septic and non-septic AKI, defined by the RIFLE criteria. Eligible patients had clinical, physiologic and laboratory data extracted. Blood and urine were sampled for urine biochemistry, microscopy and neutrophil gelatinase-associated lipocalin (NGAL). A urine microscopy score (UMS) was derived based on the observed quantification of renal tubular cells and casts in the sediment. The UMS was compared between septic and non-septic AKI and correlated with NGAL, worsening AKI, renal replacement therapy (RRT) and hospital mortality. Eighty-three patients were enrolled. Mean (SD) age was 64.3 (16.6) years, 60.2% were male, Charlson comorbidity score was 3.3 (2.8) and Acute Physiology and Chronic Health Evaluation II score was 21.4 (7.6). Septic AKI was present in 43 patients (51.8%). RIFLE class at enrollment was not different between groups (P = 0.43). Septic AKI was associated with higher UMS compared with non-septic AKI (P = 0.001). There was no correlation between UMS and fractional excretion of sodium (FeNa) or fractional excretion of urea (FeU). Elevated urine NGAL (uNGAL) correlated with higher UMS (P = 0.0003), while correlation with plasma NGAL was modest (P = 0.05). Worsening AKI occurred in 22.9% with no difference between septic and non-septic groups. A UMS score ≥ 3 was associated with increased odds of worsening AKI [adjusted odds ratio 8.0; 95% confidence intervals (CI), 1.03-62.5, P = 0.046]. For a UMS ≥3, sensitivity and specificity were 0.67 (95% CI, 0.39-0.86) and 0.95 (0.84-0.99) and positive and negative predictive values we re 0.80 (0.49-0.94) and 0.91 (0.78-0.96) for detecting worsening AKI, respectively. While there were no differences between septic and non-septic AKI, higher UMS correlated with need for RRT (15.7%, P = 0.02) and in-hospital death (30.1%, P = 0.01); however, this did not persist in multivariable analysis. Septic AKI is associated with greater urine microscopy evidence of kidney injury compared with non-septic AKI, despite similar severity of AKI. A UMS ≥ 3 correlated with higher uNGAL and was predictive of worsening AKI. Urine microscopy may have a complementary role for discerning septic from non-septic AKI, discriminating severity and predicting worsening AKI in critically ill patients.


Insecticide resistance management and industry: the origins and evolution of the Insecticide Resistance Action Committee (IRAC) and the mode of action classification scheme.
Insecticide resistance is a long-standing problem affecting the efficacy and utility of crop protection compounds. Insecticide resistance also impacts the ability and willingness of companies around the world to invest in new crop protection compounds and traits. The Insecticide Resistance Action Committee (IRAC) was formed in 1984 to provide a coordinated response by the crop protection industry to the problem of insecticide resistance. Since its inception, participation in IRAC has grown from a few agrochemical companies in Europe and the US to a much larger group of companies with global representation and an active presence (IRAC Country Groups) involving an even wider array of companies in more than 20 countries. The focus of IRAC has also evolved from that of defining and documenting cases of insecticide resistance to a pro-active role in addressing insecticide resistance management (IRM) providing an array of informational and educational tools (videos, posters, pamphlets) on insect pests, bioassay methods, insecticide mode of action and resistance management, all publicly available through its website (https://irac-online.org/). A key tool developed by IRAC is the Insecticide Mode of Action (MoA) Classification Scheme, which has evolved from a relatively simple acaricide classification started in 1998 to the far broader scheme that now includes biologics as well as insecticides and acaricides. A separate MoA Classification Scheme has also been recently developed for nematicides. The IRAC MoA Classification Scheme coupled with expanding use of MoA labeling on insecticide and acaricide product labels provides a straightforward means to implement IRM. An overview of the history of IRAC along with some of its notable accomplishments and future directions are reviewed. © 2021 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.


Medical and surgical management of chylothorax and associated outcomes.
Chylothorax is an uncommon form of pleural effusion that can be associated with traumatic and nontraumatic causes. Optimal management and outcome for patients with chylothorax remain unclear. This retrospective single-center study assessed the modes of management for chylothorax in 74 adult patients (> or =18 years old) and associated outcomes. The role of lymphangiographic imaging was also evaluated. Initial treatment approach was nonsurgical in 57 patients (77%) but a surgical procedure (pleurodesis, thoracic duct ligation, and/or surgical repair) was eventually performed in 44 patients (59%). The rate of resolution with initial treatment measures was significantly worse for patients with nontraumatic chylothorax compared with those with traumatic causes (27% versus 50%, P = 0.048). Even after additional therapeutic maneuvers including surgery, chylous effusion recurred more commonly in nontraumatic chylothorax when compared with the traumatic group (50% versus 13%, respectively, P < 0.001). Lymphatic imaging did not seem to materially influence management. Nonsurgical approaches may lead to resolution of the chylothorax in nearly one half of patients with traumatic chylothorax but in only a minority of those with nontraumatic chylothorax. The majority of patients with nontraumatic chylothorax will eventually require surgical maneuvers, but one third of such patients still fail to resolve their chylothorax.


Estimation of inspiratory muscle pressure in critically ill patients.
Recently, a new technology has been introduced aiming to monitor and improve patient ventilator interaction (PVI monitor). With the PVI monitor, a signal representing an estimation of the patient's total inspiratory muscle pressure (Pmus(PVI)) is calculated from the equation of motion, utilizing estimated values of resistance and elastance of the respiratory system. The aim of the study was to prospectively examine the accuracy of Pmus(PVI) to quantify inspiratory muscle pressure. Eleven critically ill patients mechanically ventilated on proportional assist ventilation with load-adjustable gain factors were studied at three levels of assist (30, 50 and 70%). Airway, esophageal, gastric and transdiaphragmatic (Pdi) pressures, volume and flow were measured breath by breath, whereas the total inspiratory muscle pressure (Pmus) was calculated using the Campbell diagram. For a given assist, Pmus(PVI) throughout inspiration did not differ from the corresponding values calculated using the Pdi and Pmus signals. Inspiratory and expiratory time did not differ among the various methods of calculation. Inspiratory muscle pressure decreased with increasing assist, and the magnitude of this decrease did not differ among the various methods of pressure calculation. A signal generated from flow, volume and airway pressure may be used to provide breath-by-breath quantitative information of inspiratory muscle pressure.


Plasmodium falciparum Infection of Human Volunteers Activates Monocytes and CD16+ Dendritic Cells and Induces Upregulation of CD16 and CD1c Expression.
Antigen-presenting cells (APCs) are key players in the induction and regulation of immune responses. In Plasmodium falciparum malaria, determination of which cells and pathways are activated in the network of APCs remains elusive. We therefore investigated the effects of a controlled human malaria infection in healthy, malaria-naive volunteers on the subset composition and activation status of dendritic cells (DCs) and monocytes. While subsets of monocytes increased in frequency during blood-stage infection, DC frequencies remained largely stable. Activation markers classically associated with peptide presentation to and priming of αβT cells, HLA-DR and CD86, were upregulated in monocytes and inflammatory CD16 myeloid DCs (mDCs) but not in the classical CD1c, BDCA2, or BDCA3 DC subsets. In addition, these activated APC subsets showed increased expression of CD1c, which is involved in glycolipid antigen presentation, and of the immune complex binding Fcγ receptor III (CD16). Our data show that P. falciparum asexual parasites do not activate classical DC subsets but instead activate mainly monocytes and inflammatory CD16 mDCs and appear to prime alternative activation pathways via induction of CD16 and/or CD1c. Changes in expression of these surface molecules might increase antigen capture and enhance glycolipid antigen presentation in addition to the classical major histocompatibility complex class II (MHC-II) peptide presentation and thereby contribute to the initiation of T-cell responses in malaria. (This study has been registered at Clinicaltrials.gov under registration no. NCT01086917.).


Postpartum related morbidities among women visiting government health facilities in Udupi Taluk, Karnataka, India.
Maternal morbidities are considered a leading contributor to the burden of disease among women. Especially, if postpartum morbidities are left untreated, this can cause a negative impact on the quality of life. The study was conducted to determine the proportion and types of postpartum morbidities among women visiting government health facilities in Udupi Taluk, Karnataka and to find out the association between the morbidities and various factors. A cross-sectional study was conducted in various government hospitals in Udupi Taluk, consisted of 229 postpartum women. These subjects were selected from mothers who accompanied their children for immunization from February 2013 to July 2013 using purposive sampling technique. Multiple logistic regression analysis was used to find out the association between the morbidities and various factors using SPSS version 15. Among 112 (48.9%) women who experienced postpartum morbidities, back pain (23.6%), and perineal pain (15.7%) were most commonly reported physical morbidities. Similarly, anxiety (10%) and irritability (7.9%) were the most common psychological problems. Demographic factors such as religion 2.4 (95% confidence interval [CI] 1.1, 5.4) and occupation 2.5 (95% CI 1.1, 5.9) were associated with the morbidities. Likewise, obstetric factors such as place of delivery 1.5 (95% CI 0.8, 2.9) and type of delivery 1.9 (95% CI 1.0, 3.6) were also associated with various morbidities. The findings showed a high proportion of postpartum morbidities being reported in our study settings. These observation priorities a need of health program for early recognition, treatment and improving awareness of postpartum morbidities among near mothers.


Implication of high risk human papillomavirus HR-HPV infection in prostate cancer in Indian population--a pioneering case-control analysis.
Prostate cancer is the second most common cancer with sexual history as a consistent risk factor. This is the pioneering study that evaluates the frequency of HPV infection in prostate cancer in India. Ninety five (95) histopathologically confirmed cancer and fifty five (55) BPH from Indian population were analyzed for HPV infection using a pair of consensus sequence primer followed by type specific PCRs for both high-risk and low-risk HPV types. The data demonstrate HPV infection in 41% of prostate tumor biopsies and 20% in BPH. Subsequent PCR- based HPV typing using type - specific primers revealed 32% were infected with HPV type 16 whereas 6% were found to be positive for HPV type 18, while in BPH controls only 5% of the BPH controls were infected with HPV 16 and this difference was highly significant (p = 0.0004). Significant proportion of HPV infected (74%) cases belonged to stage III and IV (p < 0.001) with a high Gleason score ≥ 8 (p = 0.003). The study represents for the first time the incidence of HPV infection in prostate cancer in Indian population and strengthens the hypothesis that HPV infection could be one of the co factor associated with progression of prostate cancer.


Bioinspired polymer vesicles and membranes for biological and medical applications.
Biological membranes play an essential role in living organisms by providing stable and functional compartments, preserving cell architecture, whilst supporting signalling and selective transport that are mediated by a variety of proteins embedded in the membrane. However, mimicking cell membranes - to be applied in artificial systems - is very challenging because of the vast complexity of biological structures. In this respect a highly promising strategy to designing multifunctional hybrid materials/systems is to combine biological molecules with polymer membranes or to design membranes with intrinsic stimuli-responsive properties. Here we present supramolecular polymer assemblies resulting from self-assembly of mostly amphiphilic copolymers either as 3D compartments (polymersomes, PICsomes, peptosomes), or as planar membranes (free-standing films, solid-supported membranes, membrane-mimetic brushes). In a bioinspired strategy, such synthetic assemblies decorated with biomolecules by insertion/encapsulation/attachment, serve for development of multifunctional systems. In addition, when the assemblies are stimuli-responsive, their architecture and properties change in the presence of stimuli, and release a cargo or allow "on demand" a specific in situ reaction. Relevant examples are included for an overview of bioinspired polymer compartments with nanometre sizes and membranes as candidates in applications ranging from drug delivery systems, up to artificial organelles, or active surfaces. Both the advantages of using polymer supramolecular assemblies and their present limitations are included to serve as a basis for future improvements.


A case of pulmonary edema: The critical role of lung-heart integrated ultrasound examination.
Cardiogenic pulmonary edema is a common presentation of acute heart failure normally treated with continuous positive airway pressure (CPAP), diuretics and nitrates. This therapy is contraindicated in case of cardiac tamponade. We describe a case of pulmonary edema due to cardiac tamponade in which integrated lung-heart ultrasound examination allowed prompt diagnosis and pericardiocentesis before administration of CPAP thus avoiding circulatory collapse.


Dynamics of SARS-CoV-2 infection hospitalisation and infection fatality ratios over 23 months in England.
The relationship between prevalence of infection and severe outcomes such as hospitalisation and death changed over the course of the COVID-19 pandemic. Reliable estimates of the infection fatality ratio (IFR) and infection hospitalisation ratio (IHR) along with the time-delay between infection and hospitalisation/death can inform forecasts of the numbers/timing of severe outcomes and allow healthcare services to better prepare for periods of increased demand. The REal-time Assessment of Community Transmission-1 (REACT-1) study estimated swab positivity for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection in England approximately monthly from May 2020 to March 2022. Here, we analyse the changing relationship between prevalence of swab positivity and the IFR and IHR over this period in England, using publicly available data for the daily number of deaths and hospitalisations, REACT-1 swab positivity data, time-delay models, and Bayesian P-spline models. We analyse data for all age groups together, as well as in 2 subgroups: those aged 65 and over and those aged 64 and under. Additionally, we analysed the relationship between swab positivity and daily case numbers to estimate the case ascertainment rate of England's mass testing programme. During 2020, we estimated the IFR to be 0.67% and the IHR to be 2.6%. By late 2021/early 2022, the IFR and IHR had both decreased to 0.097% and 0.76%, respectively. The average case ascertainment rate over the entire duration of the study was estimated to be 36.1%, but there was some significant variation in continuous estimates of the case ascertainment rate. Continuous estimates of the IFR and IHR of the virus were observed to increase during the periods of Alpha and Delta's emergence. During periods of vaccination rollout, and the emergence of the Omicron variant, the IFR and IHR decreased. During 2020, we estimated a time-lag of 19 days between hospitalisation and swab positivity, and 26 days between deaths and swab positivity. By late 2021/early 2022, these time-lags had decreased to 7 days for hospitalisations and 18 days for deaths. Even though many populations have high levels of immunity to SARS-CoV-2 from vaccination and natural infection, waning of immunity and variant emergence will continue to be an upwards pressure on the IHR and IFR. As investments in community surveillance of SARS-CoV-2 infection are scaled back, alternative methods are required to accurately track the ever-changing relationship between infection, hospitalisation, and death and hence provide vital information for healthcare provision and utilisation.


Frequency-comb-assisted broadband precision spectroscopy with cascaded diode lasers.
Frequency-comb-assisted diode laser spectroscopy, employing both the accuracy of an optical frequency comb and the broad wavelength tuning range of a tunable diode laser, has been widely used in many applications. In this Letter, we present a novel method using cascaded frequency agile diode lasers, which allows us to extend the measurement bandwidth to 37.4 THz (1355-1630 nm) at megahertz resolution with scanning speeds above 1 THz/s. It is demonstrated as a useful tool to characterize a broadband spectrum for molecular spectroscopy, and in particular it enables us to characterize the dispersion of integrated microresonators up to the 4th-order.


Malignant struma ovarii with a robust response to radioactive iodine.
Struma ovarii is a rare, usually benign ovarian tumour with malignancy occurring in <5% of cases. Metastases, particularly seeding to bone, are extremely rare. Presentation is variable but often features local pain and/or ascites and hyperthyroidism may occur. It is not established how to best treat and follow patients with extensive disease. Case reports of radioiodine (I131) ablative therapy following thyroidectomy have shown reduced recurrence. We describe the case of a 33-year-old woman who presented with bone pain and was diagnosed with skeletal metastases with features of follicular thyroid carcinoma. However, thyroid pathology was benign. She recalled that 5 years prior, an ovarian teratoma was excised, classified at that time as a dermoid cyst. Retrospective review of this pathology confirmed struma ovarii without obvious malignant features. The patient was found to have widespread metastases to bone and viscera and her thyroglobulin was >3000 µg/L following recombinant TSH administration prior to her first dose of I131. At 25 months following radioiodine treatment, she is in remission with an undetectable thyroglobulin and clear I131 surveillance scans. This case demonstrates an unusual presentation of malignant struma ovarii together with challenges of predicting metastatic disease, and demonstrates a successful radioiodine regimen inducing remission. Malignant transformation of struma ovarii (MSO) is extremely rare and even rarer are metastatic deposits in bone and viscera. MSO can be difficult to predict by initial ovarian pathology, analogous to the difficulty in some cases of differentiating between follicular thyroid adenoma and carcinoma. No consensus exists on the management for post operative treatment of MSO; however, in this case, three doses of 6Gbq radioiodine therapy over a short time period eliminated metastases to viscera and bone. Patients should continue to have TSH suppression for ~5 years. Monitoring thyroglobulin levels can predict recurrence.


Double-stranded RNA-dependent protein kinase mediates c-Myc suppression induced by type I interferons.
The antiproliferative functions of interferons result from specific effects that these cytokines exert on several cell cycle-controlling genes. The possible coupling between the interferon-responsive genes that are directly transactivated by the interferon signaling and the genes that constitute the basic machinery of the cell cycle is not clear yet. We report in this work that interferon-induced double-stranded RNA-activated kinase (PKR) is one of the specific mediators of the antiproliferative effects of the cytokine. Transfections of M1 myeloid leukemia cells with two catalytically inactive mutant forms of PKR abrogated the ability of interferon to suppress c-Myc without interfering with the pRB/cyclin D responses. As a consequence, these genetically manipulated cells displayed a small but significant reduction in their growth sensitivity to interferons, a phenotype that characterizes a single pathway disruption. Transfection of the parental M1 cells with the functional wild-type human PKR restricted their proliferation in the absence of interferons. This PKR-mediated growth inhibition could be efficiently rescued by the ectopic expression of deregulated c-myc. Taken together these results prove the existence of direct or indirect links between PKR and c-Myc suppression, thereby placing this gene along one of the complementary growth suppressive pathways that are triggered by interferons.


Nonlinear trade-offs allow the cooperation game to evolve from Prisoner's Dilemma to Snowdrift.
The existence of cooperation, or the production of public goods, is an evolutionary problem. Cooperation is not favoured because the Prisoner's Dilemma (PD) game drives cooperators to extinction. We have re-analysed this problem by using RNA viruses to motivate a model for the evolution of cooperation. Gene products are the public goods and group size is the number of virions co-infecting the same host cell. Our results show that if the trade-off between replication and production of gene products is linear, PD is observed. However, if the trade-off is nonlinear, the viruses evolve into separate lineages of ultra-defectors and ultra-cooperators as group size is increased. The nonlinearity was justified by the existence of real viral ultra-defectors, known as defective interfering particles, which gain a nonlinear advantage by being smaller. The evolution of ultra-defectors and ultra-cooperators creates the Snowdrift game, which promotes high-level production of public goods.


Model for the genetic evolution of human solid tumors.
A conceptual model is proposed for the genetic evolution of many human solid tumors that is based on the observations that cancer cells may spontaneously double their chromosome number; that cells with excessive chromosome numbers may be cytogenetically unstable, both losing chromosomes randomly during subsequent cell divisions, and often developing structural abnormalities in the chromosomes that are retained; and that some structural chromosome abnormalities may activate growth-promoting genes. The sequence of tetraploidization with chromosome loss can occur repeatedly in a given tumor. The available evidence supporting the model is reviewed. A computer simulation system that embodies these concepts is described and the model is used to generate distributions of chromosome number/cell under various simulated conditions and in a variety of simulated biological settings. A simulation of the time course of changes in chromosome number per cell that accompany the spontaneous neoplastic transformation of mouse fibroblasts in vitro is described. The best fit to the data was obtained when provision was made for the activation of at least two growth-promoting genes. The conditions for generating discrete aneuploid peaks in cytogenetic and flow cytometric studies were explored; our modeling studies suggest that the activation of a growth promoting gene is required in order to produce a discrete aneuploid peak. Our modeling studies suggest that the overrepresentation of individual oncogene-bearing chromosomes in aneuploid cell lines may require the activation of gene dose-dependent growth-promoting genes and is not likely to occur in cell lines in which at least two copies of each normal chromosome are required for cell survival. Overall, the results obtained using the model are consistent with a wide variety of flow cytometric and cytogenetic studies in human solid tumors.


A Specific PfEMP1 Is Expressed in P. falciparum Sporozoites and Plays a Role in Hepatocyte Infection.
Heterochromatin plays a central role in the process of immune evasion, pathogenesis, and transmission of the malaria parasite Plasmodium falciparum during blood stage infection. Here, we use ChIP sequencing to demonstrate that sporozoites from mosquito salivary glands expand heterochromatin at subtelomeric regions to silence blood-stage-specific genes. Our data also revealed that heterochromatin enrichment is predictive of the transcription status of clonally variant genes members that mediate cytoadhesion in blood stage parasites. A specific member (here called NF54varsporo) of the var gene family remains euchromatic, and the resultant PfEMP1 (NF54_SpzPfEMP1) is expressed at the sporozoite surface. NF54_SpzPfEMP1-specific antibodies efficiently block hepatocyte infection in a strain-specific manner. Furthermore, human volunteers immunized with infective sporozoites developed antibodies against NF54_SpzPfEMP1. Overall, we show that the epigenetic signature of var genes is reset in mosquito stages. Moreover, the identification of a strain-specific sporozoite PfEMP1 is highly relevant for vaccine design based on sporozoites.


Management of heel pain syndrome with acetic acid iontophoresis.
This study was undertaken to determine the effectiveness of acetic acid iontophoresis in the treatment of heel pain. Thirty-five patients with chronic heel pain were treated with acetic acid iontophoresis over a 4-year period. Ninety-four percent of patients had complete or substantial relief of heel pain after an average of 5.7 sessions of acetic acid iontophoresis over an average period of 2.8 weeks. Heel pain levels were rated from 0 to 10, with 10 representing the most severe pain. Heel pain prior to iontophoresis treatment received an average rating of 7.5; by the end of therapy, the average rating had decreased to 1.8. At an average follow-up time of 27 months, heel pain levels averaged 0.64, indicating continued reduction in heel pain. Ninety-four percent of participants said that they would recommend acetic acid iontophoresis to someone with similar heel pain.


Effect of HLA DQ2, dietary exposure and coeliac disease on the development of antibody response to gliadin in children.
To study the effect of HLA DQ2, dietary history and development of coeliac disease (CD) on the induction of antibody response to wheat gliadin and cow's milk, beta-lactoglobulin between 1 and 2.5 years of age in children who developed CD and in healthy children. Infants participating in a birth cohort study (the ABIS study) in Sweden were studied. Thirty-nine children developed CD (=cases), confirmed through biopsy, during follow-up until 2.5-5 years of age. A total of 181 healthy control children were matched for duration of exclusive breast-feeding, birth-weight, gender, maternal smoking and season of birth. IgG and IgA antigliadin and anti-beta-lactoglobulin antibodies were measured using enzyme immunoassay (EIA). The effects of HLA-risk genotypes, DQ2 and DQ8, on CD were also considered. Children who developed CD had higher IgG and IgA antigliadin and anti-beta-lactoglobulin antibody levels at 1 year of age than controls (all comparisons: p<0.001). Similar differences were seen between cases with as yet undiagnosed CD by 1 year of age and controls, and also when cases were compared with HLA-matched controls. Higher levels of IgG and IgA antibodies to beta-lactoglobulin (p=0.003; p=0.001), but not to gliadin, were found in treated cases versus controls at 2.5 years of age. HLA-DQ2-positive healthy children had lower levels of IgG and IgA antigliadin antibodies than HLA-DQ2 negative controls at 1 year of age (p=0.004; p=0.012). Enhanced humoral response emerging not only to gliadin, but also to other food antigens seems to be primarily associated with CD. Poor induction of antibody response to wheat gliadin in healthy children with the HLA-DQ2 risk molecule could at least partly explain the genetic predisposition to gluten intolerance and CD.


An acute bout of cycling does not induce compensatory responses in pre-menopausal women not using hormonal contraceptives.
There is a clear need to improve understanding of the effects of physical activity and exercise on appetite control. Therefore, the acute and short-term effects (three days) of a single bout of cycling on energy intake and energy expenditure were examined in women not using hormonal contraceptives. Sixteen active (n = 8) and inactive (n = 8) healthy pre-menopausal women completed a randomised crossover design study with two conditions (exercise and control). The exercise day involved cycling for 1 h (50% of maximum oxygen uptake) and resting for 2 h, whilst the control day comprised 3 h of rest. On each experimental day participants arrived at the laboratory fasted, consumed a standardised breakfast and an ad libitum pasta lunch. Food diaries and combined heart rate-accelerometer monitors were used to assess free-living food intake and energy expenditure, respectively, over the subsequent three days. There were no main effects or condition (exercise vs control) by group (active vs inactive) interaction for absolute energy intake (P > 0.05) at the ad libitum laboratory lunch meal, but there was a condition effect for relative energy intake (P = 0.004, ηp2 = 0.46) that was lower in the exercise condition (1417 ± 926 kJ vs. 2120 ± 923 kJ). Furthermore, post-breakfast satiety was higher in the active than in the inactive group (P = 0.005, ηp2 = 0.44). There were no main effects or interactions (P > 0.05) for mean daily energy intake, but both active and inactive groups consumed less energy from protein (14 ± 3% vs. 16 ± 4%, P = 0.016, ηp2 = 0.37) and more from carbohydrate (53 ± 5% vs. 49 ± 7%, P = 0.031, ηp2 = 0.31) following the exercise condition. This study suggests that an acute bout of cycling does not induce compensatory responses in active and inactive women not using hormonal contraceptives, while the stronger satiety response to the standardised breakfast meal in active individuals adds to the growing literature that physical activity helps improve the sensitivity of short-term appetite control.


A comparison between primary and secondary toe-to-hand transplantation.
Although primary toe-to-hand transplantation is performed with increasing frequency, its use is still controversial because of the lack of any comparative studies documenting its safety and efficacy. Between August of 1990 and December of 1993, 175 consecutive toe-to-hand transplantations for crush and avulsion injuries were performed in 122 patients. The average interval between injury and primary reconstruction was 7 days, and the average interval between injury and secondary reconstruction was 10.7 months. Follow-up ranged from 18 to 91 months, with an average follow-up of 58 months. There were 31 primary transplantations and 144 secondary transplantations. The survival rate was 96.8 percent (30 of 31) for primary reconstruction and 96.5 percent (139 of 144) for secondary reconstruction. Intraoperative anastomotic revision was necessary in 3.2 percent (one of 31) of primary transplantations and 7.6 percent (11 of 144) of secondary transplantations. Three primary toe-to-hand transplantations (9.7 percent) and 17 secondary toe-to-hand transplantations (11.8 percent) were re-explored in the postoperative period. Each group had one superficial infection. The infection rate was 6.5 percent and 0.7 percent in the primary and secondary groups, respectively. Other complications included partial skin loss, which occurred in one patient (3.2 percent) in the primary group and six patients (4.2 percent of 144 transplantations) in the secondary group. Secondary procedures to improve function were necessary in six secondary transplantations (4.2 percent) and in none of the primary transplantations. There was no statistical difference between the two groups in terms of survival, intraoperative anastomotic revision, re-exploration, future secondary procedure, infection, and complications. This series demonstrates that primary toe-to-hand transplantation can be performed in the suitable candidate safely with as much success as secondary reconstruction. Primary toe transplantation can potentially reduce the overall period of recovery and rehabilitation, allowing the patient to return to work sooner. Further study to evaluate and compare the final functional outcome and return to work time between primary and secondary toe-to-hand transplantation is needed.


Synergistic Effects of Doping and Thermal Treatment on Organic Semiconducting Nanowires.
Doping of small molecular donors or acceptors on conjugated organic materials can be used to improve the performance of organic electronics. Here we demonstrate highly aligned poly(3-hexylthiophene) (P3HT) nanowires (NWs) doped with 2,3,5,6-tetrafluoro-7,7,8,8-tetracyanoquinodimethane (F4-TCNQ) using electrohydrodynamic organic NW printing. The transistor based on p-doped NWs had an order of magnitude higher mobility than did the undoped NW device. This significant improvement resulted from the synergistic effects of p-type doping and thermal annealing on F4-TCNQ-doped P3HT NWs, which induce microstructure changes in P3HT chains.


Effectiveness of Health Promotion, Management, and Maintenance Interventions Within the Scope of Occupational Therapy for Community-Dwelling Older Adults: A Systematic Review.
This systematic review examined the effectiveness of health promotion, management, and maintenance interventions within the scope of occupational therapy to improve occupational performance and quality of life (QOL) and decrease health care utilization for community-dwelling older adults. Thirty-eight articles representing 36 studies were included in the review. Articles were published 2008-2015 and described studies of participants with a mean age of 65 or older who were living in the community. Strong evidence supports the use of group, individual, or a combination of group and individual interventions to improve occupational performance. Group interventions were also effective at improving QOL. The evidence was insufficient that any of these interventions decreased health care utilization. Addressing health promotion, management, and maintenance is within the scope of occupational therapy practice and has been shown to improve occupational performance and QOL for older adults. Implications for practice and future research are discussed.


Genome-wide array-CGH analysis reveals YRF1 gene copy number variation that modulates genetic stability in distillery yeasts.
Industrial yeasts, economically important microorganisms, are widely used in diverse biotechnological processes including brewing, winemaking and distilling. In contrast to a well-established genome of brewer's and wine yeast strains, the comprehensive evaluation of genomic features of distillery strains is lacking. In the present study, twenty two distillery yeast strains were subjected to electrophoretic karyotyping and array-based comparative genomic hybridization (array-CGH). The strains analyzed were assigned to the Saccharomyces sensu stricto complex and grouped into four species categories: S. bayanus, S. paradoxus, S. cerevisiae and S. kudriavzevii. The genomic diversity was mainly revealed within subtelomeric regions and the losses and/or gains of fragments of chromosomes I, III, VI and IX were the most frequently observed. Statistically significant differences in the gene copy number were documented in six functional gene categories: 1) telomere maintenance via recombination, DNA helicase activity or DNA binding, 2) maltose metabolism process, glucose transmembrane transporter activity; 3) asparagine catabolism, cellular response to nitrogen starvation, localized in cell wall-bounded periplasmic space, 4) siderophore transport, 5) response to copper ion, cadmium ion binding and 6) L-iditol 2- dehydrogenase activity. The losses of YRF1 genes (Y' element ATP-dependent helicase) were accompanied by decreased level of Y' sequences and an increase in DNA double and single strand breaks, and oxidative DNA damage in the S. paradoxus group compared to the S. bayanus group. We postulate that naturally occurring diversity in the YRF1 gene copy number may promote genetic stability in the S. bayanus group of distillery yeast strains.


The Promise of Improved Adherence With Long-Acting Antiretroviral Therapy: What Are the Data?
As with other chronic conditions, adherence to daily medications remains a challenge for many individuals living with HIV due to structural, behavioral, and social barriers. Unfortunately, high levels of adherence to antiretroviral therapy are required to maintain virologic suppression. Alternative approaches are being explored to decrease the burden of daily pill administration, including long-acting injectable, oral, and implantable products. Phase 3 data support the efficacy of nanoformulated injectable cabotegravir and rilpivirine for HIV treatment in patients with undetectable viremia, but we have yet to learn how this strategy may benefit those with medication adherence challenges. Despite this, the affected community and HIV providers are very interested in exploring the role of long-acting therapies to address some types of barriers to medication adherence. This review summarizes available information about the potential for long-acting therapy to improve adherence for some patients and outlines associated opportunities and challenges with the implementation of long-acting therapy for the treatment and prevention of HIV.


Duplication and selection in β-ketoacyl-ACP synthase gene lineages in the sexually deceptive Chiloglottis (Orchidaceace).
The processes of gene duplication, followed by divergence and selection, probably underpin the evolution of floral volatiles crucial to plant-insect interactions. The Australian sexually deceptive Chiloglottis orchids use a class of 2,5-dialkylcyclohexan-1,3-dione volatiles or 'chiloglottones' to attract specific male wasp pollinators. Here, we explore the expression and evolution of fatty acid pathway genes implicated in chiloglottone biosynthesis. Both Chiloglottis seminuda and C. trapeziformis produce chiloglottone 1, but only the phylogenetically distinct C. seminuda produces this volatile from both the labellum callus and glandular sepal tips. Transcriptome sequencing and tissue-specific contrasts of the active and non-active floral tissues was performed. The effects of the fatty acid synthase inhibitor cerulenin on chiloglottone production were tested. Patterns of selection and gene evolution were investigated for fatty acid pathway genes. Tissue-specific differential expression of fatty acid pathway transcripts was evident between active and non-active floral tissues. Cerulenin significantly inhibits chiloglottone 1 production in the active tissues of C. seminuda. Phylogenetic analysis of plant β-ketoacyl synthase I (KASI), a protein involved in fatty acid biosynthesis, revealed two distinct clades, one of which is unique to the Orchidaceae (KASI-2B). Selection analysis indicated a strong signal of positive selection at the split of KASI-2B followed by relaxed purifying selection in the Chiloglottis clade. By capitalizing on a phylogenetically distinct Chiloglottis from earlier studies, we show that the transcriptional and biochemical dynamics linked to chiloglottone biosynthesis in active tissues are conserved across Chiloglottis. A combination of tissue-specific expression and relaxed purifying selection operating at specific fatty acid pathway genes may hold the key to the evolution of chiloglottones.


Dealing with effect size multiplicity in systematic reviews and meta-analyses.
Systematic reviews often encounter primary studies that report multiple effect sizes based on data from the same participants. These have the potential to introduce statistical dependency into the meta-analytic data set. In this paper, we provide a tutorial on dealing with effect size multiplicity within studies in the context of meta-analyses of intervention and association studies, recommending a three-step approach. The first step is to define the research question and consider the extent to which it mainly reflects interest in mean effect sizes (which we term a convergent approach) or an interest in exploring heterogeneity (which we term a divergent approach). A second step is to identify the types of multiplicities that appear in the initial database of effect sizes relevant to the research question, and we propose a categorization scheme to differentiate them. The third step is to select a strategy for dealing with each type of multiplicity. The researcher can choose between a reductionist meta-analytic approach, which is characterized by inclusion of a single effect size per study, and an integrative approach, characterized by inclusion of multiple effect sizes per study. We present an overview of available analysis strategies for dealing with effect size multiplicity within studies and provide recommendations intended to help researchers decide which strategy might be preferable in particular situations. Last, we offer caveats and cautions about addressing the challenges multiplicity poses for systematic reviews and meta-analyses.


Beam array generation and holographic interconnections in a free-space optical switching network.
Free-space photonic switching systems that optically interconnect large arrays of simple processing elements have already been demonstrated [IEEE Photon. Technol. Lett. 2, 438,600 (1990); Appl. Opt. 31, 5431 (1992); Electron. Lett. 27, 1869 (1991)]. In these system experiments, diffractive optical elements served as critical components that provided functionality not easily assumed by conventional optics. In the latest optical switching network, binary phase gratings were used to generate arrays of uniformintensity beams to illuminate modulators in the processor array. In addition, space-invariant binary phase grating designs were integral in forming the Banyan interconnection network used to link arrays in the system. Here we discuss the function, design, and performance of these diffractive elements.


The scientific production in health and biological sciences of the top 20 Brazilian universities.
Brazilian scientific output exhibited a 4-fold increase in the last two decades because of the stability of the investment in research and development activities and of changes in the policies of the main funding agencies. Most of this production is concentrated in public universities and research institutes located in the richest part of the country. Among all areas of knowledge, the most productive are Health and Biological Sciences. During the 1998-2002 period these areas presented heterogeneous growth ranging from 4.5% (Pharmacology) to 191% (Psychiatry), with a median growth rate of 47.2%. In order to identify and rank the 20 most prolific institutions in these areas, searches were made in three databases (DataCAPES, ISI and MEDLINE) which permitted the identification of 109,507 original articles produced by the 592 Graduate Programs in Health and Biological Sciences offered by 118 public universities and research institutes. The 20 most productive centers, ranked according to the total number of ISI-indexed articles published during the 1998-2003 period, produced 78.7% of the papers in these areas and are strongly concentrated in the Southern part of the country, mainly in São Paulo State.


Between Privilege and Oppression: An Intersectional Analysis of Active Transportation Experiences Among Washington D.C. Area Youth.
The use of active transportation (AT), such as walking, cycling, or even public transit, as a means of transport offers an opportunity to increase youth physical activity and improve health. Despite the well-known benefits of AT, there are environmental and social variables that converge on the AT experiences of low-income youth and youth of color (YOC) that have yet to be fully uncovered. This study uses an intersectional framework, largely focusing on the race-gender-class trinity, to examine youth AT within a context of transportation inequity. Theoretically guided by the Ecological Model of Active Transportation, focus groups were completed with two groups of girls (15 participants) and two groups of boys (nine participants) ranging between the ages of 12-15 years who lived within the Washington D.C. area. This research found race, gender, and class to be inhibitors of AT for both boys and girls, but with more pronounced negative influences on girls.


The UK Obstetric Surveillance System: impact on patient safety.
The UK Obstetric Surveillance System is a national system that allows for the collection of information on a range of rare disorders of pregnancy, enabling national descriptive, case-control and cohort studies. The population-based nature of the studies conducted renders them less susceptible to the biases typically associated with observational studies. Data collected using The UK Obstetric Surveillance System and similar systems can be used to address a range of patient safety issues. These include assessing the safety of different treatment options, using the data as an aid to service planning, as part of ongoing quality-improvement initiatives, as a benchmark against which to compare hospital-level disease incidence and outcomes, to inform and audit national guidelines, and to monitor the effect of changes in practice or policy. Studies can be introduced rapidly in response to newly arising safety concerns. International comparisons can further enhance the utility of these data for improving patient safety.


Migration as a social determinant of health for irregular migrants: Israel as case study.
More than 150,000 irregular migrants reside in Israel, yet data regarding their utilization of and perceived barriers to health care services are limited. Drawing on semi-structured interviews conducted with 35 irregular migrant adults between January and September 2012, this article analyzes the role of migration as a social determinant of health for irregular migrants, and especially asylum seekers. We analyze two kinds of barriers faced by migrants when they attempt to access health care services: barriers resulting directly from their migration status, and barriers that are common among low-income communities but exacerbated by this status. Migration-related barriers included a lack of clear or consistent legislation; the threat of deportation; the inability to obtain work permits and resulting poverty and harsh living and working conditions; and discrimination. Barriers exacerbated by migrant status included prohibitive cost; poor and confusing organization of services; language barriers; perceived low quality of care; and social isolation. These findings support recent arguments that migrant status itself constitutes a social determinant of health that can intersect with other determinants to adversely affect health care access and health outcomes. Findings suggest that any meaningful effort to improve migrants' health will depend on the willingness of clinicians, public health officials, and policymakers to address the complex array of upstream political and socio-economic factors that affect migrants' health rather than focusing on narrower questions of access to health care.


RVD: a command-line program for ultrasensitive rare single nucleotide variant detection using targeted next-generation DNA resequencing.
Rare single nucleotide variants play an important role in genetic diversity and heterogeneity of specific human disease. For example, an individual clinical sample can harbor rare mutations at minor frequencies. Genetic diversity within an individual clinical sample is oftentimes reflected in rare mutations. Therefore, detecting rare variants prior to treatment may prove to be a useful predictor for therapeutic response. Current rare variant detection algorithms using next generation DNA sequencing are limited by inherent sequencing error rate and platform availability. Here we describe an optimized implementation of a rare variant detection algorithm called RVD for use in targeted gene resequencing. RVD is available both as a command-line program and for use in MATLAB and estimates context-specific error using a beta-binomial model to call variants with minor allele frequency (MAF) as low as 0.1%. We show that RVD accepts standard BAM formatted sequence files. We tested RVD analysis on multiple Illumina sequencing platforms, among the most widely used DNA sequencing platforms. RVD meets a growing need for highly sensitive and specific tools for variant detection. To demonstrate the usefulness of RVD, we carried out a thorough analysis of the software's performance on synthetic and clinical virus samples sequenced on both an Illumina GAIIx and a MiSeq. We expect RVD can improve understanding the genetics and treatment of common viral diseases including influenza. RVD is available at the following URL:http://dna-discovery.stanford.edu/software/rvd/.


Energy psychology: A review of the preliminary evidence.
Energy psychology utilizes imaginal and narrative-generated exposure, paired with interventions that reduce hyperarousal through acupressure and related techniques. According to practitioners, this leads to treatment outcomes that are more rapid, powerful, and precise than the strategies used in other exposure-based treatments such as relaxation or diaphragmatic breathing. The method has been exceedingly controversial. It relies on unfamiliar procedures adapted from non-Western cultures, posits unverified mechanisms of action, and early claims of unusual speed and therapeutic power ran far ahead of initial empirical support. This paper reviews a hierarchy of evidence regarding the efficacy of energy psychology, from anecdotal reports to randomized clinical trials. Although the evidence is still preliminary, energy psychology has reached the minimum threshold for being designated as an evidence-based treatment, with one form having met the APA Division 12 criteria as a "probably efficacious treatment" for specific phobias; another for maintaining weight loss. The limited scientific evidence, combined with extensive clinical reports, suggests that energy psychology holds promise as a rapid and potent treatment for a range of psychological conditions. (PsycINFO Database Record (c) 2010 APA, all rights reserved).


Users' perceptions of the risks and effects of taking ecstasy (MDMA): a questionnaire study.
This self-report questionnaire study examined ecstasy users' perceptions of the risks associated with their use of ecstasy, their precautions against such risks, and its perceived effects on their lives. Gender differences in these areas were also explored. The sample comprised 328 ecstasy users (139 female, 187 male, one transsexual) with a mean age of 22.5 years (SD = 4.9 years). Questionnaires were completed either in hard copy or through a website concerned with ecstasy use. The results showed that friends were the most common source of information about ecstasy for the sample overall, although females were more likely to utilize this source than males. None of the five categories of perceived risk (e.g. psychiatric, physical) showed a significant gender difference. Males were more likely to take rest breaks whilst females were more likely to limit consumption as a precaution against harm. Three factors emerged from a principal components analysis concerning perceived personal change since initiation of ecstasy use. Factor 1 (23.8% of the variance) concerned negative experiences (e.g. depression). Factor 2 (22.0% of the variance) concerned positive personal qualities (e.g. caring). Factor 3 (10.5% of the variance) concerned selective aspects of functioning (e.g. alertness). The pattern of Factor 1 and Factor 2 scores over time suggested that 6 years since initiation of ecstasy use might be a time when some long-term users may be open to reassess their use of the drug. Broader implications of the findings for health education initiatives aimed at ecstasy users are discussed.


FoodSwitch: A Mobile Phone App to Enable Consumers to Make Healthier Food Choices and Crowdsourcing of National Food Composition Data.
Front-of-pack nutrition labeling (FoPL) schemes can help consumers understand the nutritional content of foods and may aid healthier food choices. However, most packaged foods in Australia carry no easily interpretable FoPL, and no standard FoPL system has yet been mandated. About two thirds of Australians now own a smartphone. We sought to develop a mobile phone app that would provide consumers with easy-to-understand nutrition information and support the selection of healthier choices when shopping for food. An existing branded food database including 17,000 Australian packaged foods underpinned the project. An iterative process of development, review, and testing was undertaken to define a user interface that could deliver nutritional information. A parallel process identified the best approach to rank foods based on nutritional content, so that healthier alternative products could be recommended. Barcode scanning technology was identified as the optimal mechanism for interaction of the mobile phone with the food database. Traffic light labels were chosen as the preferred format for presenting nutritional information, and the Food Standards Australia New Zealand nutrient profiling method as the best strategy for identifying healthier products. The resulting FoodSwitch mobile phone app was launched in Australia in January 2012 and was downloaded by about 400,000 users in the first 18 months. FoodSwitch has maintained a 4-plus star rating, and more than 2000 users have provided feedback about the functionality. Nutritional information for more than 30,000 additional products has been obtained from users through a crowdsourcing function integrated within the app. FoodSwitch has empowered Australian consumers seeking to make better food choices. In parallel, the huge volume of crowdsourced data has provided a novel means for low-cost, real-time tracking of the nutritional composition of Australian foods. There appears to be significant opportunity for this approach in many other countries.


Gain structuration in dual-wavelength Nd:YSAG ceramic lasers.
We demonstrate a dual-wavelength Nd:YSAG ceramic laser in which the gain volume is structurated into two different regions providing gain at the wavelength of 1061 nm and 1064 nm respectively. We discuss the role of the nonuniform distribution of the temperature in structurating the gain region via the Boltzmann effect. We show that the two laser wavelengths can be switched by adjusting the size of the pump beam or by slightly modifying the geometrical parameters of the laser cavity, either the length of the cavity or the orientation of a mirror. Additionally, we demonstrate that the transverse modes at the two wavelengths are shaped according to the effect of gain filtering caused by the structuration of the gain region.


Antigenic diversity and size diversity of Plasmodium falciparum antigens in isolates from Gambian patients. I. S-antigens.
Ring-stage asexual parasites of P. falciparum were collected from six Gambian children and the S-antigens radiolabelled by 3H-glycine uptake during in vitro culture up to rupture of infected cells and merozoite release. Ouchterlony double diffusion of boiled culture supernatants against a panel of adult Gambian sera identified one S-antigen precipitin arc for five isolates and two precipitin arcs for one isolate. Five of the six isolates were serologically distinct. Analysis of S-antigens by comparison of SDS-polyacrylamide gel electrophoresis patterns of heat-treated soluble proteins revealed a more complex pattern of 3H-labelled S-antigens that was different for each isolate. There were between two and six different 3H-labelled bands for each isolate in the size range of molecular weight 137 000 to 285 000. This result confirms the large size range of S-antigens identified with culture adapted P. falciparum. Several bands were relatively weakly labelled with 3H-glycine, suggesting that natural isolates contain one or two predominant S-antigen phenotypes and several other S-antigen phenotypes expressed by minor parasite subpopulations. Immunoprecipitation was performed using a panel of sera from Gambian adults, or, acute and 3 week convalescent sera from the same patients used for S-antigen radiolabelling. Adult sera generally immunoprecipitated some of the S-antigens in each isolate, including antigens that must represent extremely minor parasite subpopulations since they could not be seen in the patterns of non-immunoprecipitated heat-stable proteins. Sera from convalescent children were generally negative on immunoprecipitation, even with the homologous isolate. In one case we observed the acquisition of specific immunoprecipitating antibody to one of the homologous S-antigens during the convalescent period. The antigenic and structural complexity of S-antigens in natural isolates that have not been submitted to the selection pressure of adaptation for in vitro culture is clearly greater than for culture adapted P. falciparum.


Clinical features, diagnosis, and treatment of erythema multiforme: a review for the practicing dermatologist.
Erythema multiforme (EM) is an uncommon, immune-mediated disorder that presents with cutaneous or mucosal lesions or both. In herpes simplex virus (HSV)-associated EM, the findings are thought to result from cell-mediated immune reaction against viral antigen-positive cells that contain the HSV DNA polymerase gene (pol). The target lesion, with concentric zones of color change, represents the characteristic cutaneous finding seen in this disorder. Although EM can be induced by various factors, HSV infection continues to be the most common inciting factor. Histopathologic testing and other laboratory investigations may be used to confirm the diagnosis of EM and to differentiate it from other clinical imitators. Imitators of EM include urticaria, Stevens-Johnson syndrome, fixed drug eruption, bullous pemphigoid, paraneoplastic pemphigus, Sweet's syndrome, Rowell's syndrome, polymorphus light eruption, and cutaneous small-vessel vasculitis. Because disease severity and mucosal involvement differ among patients, treatment should be tailored to each patient, with careful consideration of treatment risk vs benefit. Mild cutaneous involvement of EM can be managed primarily with a goal of achieving symptomatic improvement; however, patients with HSV-associated recurrent EM and idiopathic recurrent EM require treatment with antiviral prophylaxis. Inpatient hospitalization may be required for patients with severe mucosal involvement that causes poor oral intake and subsequent fluid and electrolyte imbalance. With this review, we strive to provide guidance to the practicing dermatologist in the evaluation and treatment of a patient with EM.


Life-giving caspases: revealing new roles during mouse embryo preimplantation development.
Caspases, cystein proteases traditionally related to programmed cell death, have recently been found to be involved in vital processes such as cell proliferation, adhesion and differentiation. Although caspases are expressed in mouse embryos before the blastocyst stage, their role is unclear, since apoptosis does not occur significantly before implantation. In this work, we have used mouse preimplantation development as a model to evaluate the existence of non-lethal caspase activities. The use of specific caspase inhibitors during in vitro embryo culture showed that caspase 8 activity, but not caspase 2 or 9, was relevant for development. The inhibition of caspase 8 affected the compaction of morulae and the progression to the blastocyst stage. In agreement with these results, caspase 8 was expressed in mouse embryos, as shown by indirect immunofluorescence and RT-PCR. An in silico approach was used to find putative caspase targets expressed in mouse preimplantation embryos. Large-scale management of sequence data from mouse embryos was used to predict caspase substrates by tools matrix-based on known cleavage sites. A total of 510 potential caspase targets expressed in mouse embryos were identified by this procedure. The functional characterization of these proteins by Gene Onthology associations showed that many of these putative caspase targets were previously related to non-apoptotic functions and only 63 had been previously reported to be actually cleaved by caspases. Interestingly, eleven knockout mice models for caspase substrates identified in our work, i.e. catenin alpha and beta, geminin, pescadillo, calpain-2, have preimplantation lethal phenotypes. This work supports the involvement of caspases in vital functions during mouse preimplantation development and proposes a model in which the regulated cleavage of caspase substrates could account for this role.


Amygdala activation and symptom dimensions in obsessive-compulsive disorder.
Despite knowledge of amygdala involvement in fear and anxiety, its contribution to the pathophysiology of obsessive-compulsive disorder (OCD) remains controversial. In the context of neuroimaging studies, it seems likely that the heterogeneity of the disorder might have contributed to a lack of consistent findings. To assess the influence of OCD symptom dimensions on amygdala responses to a well-validated emotional face-matching paradigm. Cross-sectional functional magnetic resonance imaging (fMRI) study of 67 patients with OCD and 67 age-, gender- and education-level matched healthy controls. The severity of aggression/checking and sexual/religious symptom dimensions were significantly associated with heightened amygdala activation in those with OCD when responding to fearful faces, whereas no such correlations were seen for other symptom dimensions. Amygdala functional alterations in OCD appear to be specifically modulated by symptom dimensions whose origins may be more closely linked to putative amygdala-centric processes, such as abnormal fear processing.


The presence of the antigliadin antibodies in autoimmune thyroid diseases.
To investigate the presence of the antigliadin antibodies in the patients with Graves' disease and Hashimoto's thyroiditis. Four hundred patients with autoimmune thyroid disease (280 Graves' disease and 120 Hashimoto's thyroiditis ) were included in the study. The patients with celiac sprue patients were excluded. For the diagnosis of autoimmune thyroiditis, blood levels of thyrotropin (TSH), free thyroxine (FT4), and the titration of thyroid autoantibodies (TgAb and TmAb) were measured, and the thyroid gland was ultrasonographycally evaluated. After the diagnosis of autoimmune thyroid disease was established, the titration of antigliadin antibodies (Ig A and B) were routinely detected. Twenty two patients (5.5 per cent) with autoimmune thyroiditis had positive antigliadin antibodies. Polyglandular endocrine syndrome was diagnosed in most of these patients. We claim that polyglandular endocrine syndrome is the commonest cause of positivity of antigliadin antibodies in the patients with autoimmune thyroid disease.


Pharmacological dissociation of modulatory effects of serotonin in Aplysia sensory neurons.
In the mollusk Aplysia the neurotransmitter serotonin (5HT) has a fundamental modulatory role in several forms of learning and memory that involve an increase in the efficacy of synaptic transmission between tail sensory neurons (SNs) and motor neurons. The classical 5HT antagonist cyproheptadine (CYP) permits dissociation of three forms of serotonergic modulation in these SNs: (i) CYP reversibly blocks spike-broadening induced either by exogenous application of 5HT or by sensitizing stimulation of a tail nerve. (ii) CYP does not block 5HT-induced or tail input-induced increases in SN somatic excitability. (iii) Concomitant with its block of spike-broadening, CYP reversibly blocks 5HT-induced facilitation of synaptic transmission from SNs. These results suggest that endogenously released 5HT may act at different receptor subtypes that are coupled to different forms of neuromodulation in tail SNs of Aplysia.


miR-10b*, a master inhibitor of the cell cycle, is down-regulated in human breast tumours.
Deregulated proliferation is a hallmark of cancer cells. Here, we show that microRNA-10b* is a master regulator of breast cancer cell proliferation and is downregulated in tumoural samples versus matched peritumoural counterparts. Two canonical CpG islands (5 kb) upstream from the precursor sequence are hypermethylated in the analysed breast cancer tissues. Ectopic delivery of synthetic microRNA-10b* in breast cancer cell lines or into xenograft mouse breast tumours inhibits cell proliferation and impairs tumour growth in vivo, respectively. We identified and validated in vitro and in vivo three novel target mRNAs of miR-10b* (BUB1, PLK1 and CCNA2), which play a remarkable role in cell cycle regulation and whose high expression in breast cancer patients is associated with reduced disease-free survival, relapse-free survival and metastasis-free survival when compared to patients with low expression. This also suggests that restoration of microRNA-10b* expression might have therapeutic promise.


Detection of Merkel cell polyomavirus in the human tissues from 41 Japanese autopsy cases using polymerase chain reaction.
It has recently been shown that approximately 80% of Merkel cell carcinomas harbor a novel polyomavirus named Merkel cell polyomavirus (MCPyV). MCPyV has been detected in human tissue samples. However, detailed distribution of MCPyV in non-neoplastic Japanese human tissues remains unclear. To address this, we used single or real-time quantitative polymerase chain reaction (PCR) for 41 autopsy cases. PCR revealed MCPyV-DNA in non-neoplastic samples: total, 29/41 (71%); adult, 29/39 (74%); fetus or infant, 0/2; men, 24/28 (86%); women, 5/13 (38%); total human tissues, 66/572 (12%); skin, 8/15 (53%); adrenal gland, 9/33 (27%), and other 16 organs (4-25%). This study first reported the presence of MCPyV-DNA in non-neoplastic tissues of thyroid gland, adrenal gland, spleen, bone marrow, stomach, gallbladder, pancreas, heart, and aorta. PCR revealed that viral load ranged from 0.00026 to 0.22 in all MCPyV-positive tissues compared with Merkel cell carcinoma samples. These detailed PCR data showed higher prevalence of MCPyV infection in Japanese men than women (p = 0.004) and broad distribution of MCPyV with low viral load in more non-neoplastic human tissues than in the previous reports. These data provide valuable insights for further studies of MCPyV infection and MCPyV-related diseases.


Preoptic aromatase cells project to the mesencephalic central gray in the male Japanese quail (Coturnix japonica).
Previous tract-tracing studies demonstrated the existence of projections from the medial preoptic nucleus (POM) to the mesencephalic central gray (GCt) in quail. GCt contains a significant number of aromatase-immunoreactive (ARO-ir) fibers and punctate structures, but no ARO-ir cells are present in this region. The origin of the ARO-ir fibers of the GCt was investigated here by retrograde tract-tracing combined with immunocytochemistry for aromatase. Following injection of fluorescent microspheres in GCt, retrogradely labeled cells were found in a large number of hypothalamic and mesencephalic areas and in particular within the three main groups of ARO-ir cells located in the POM, the ventromedial nucleus of the hypothalamus, and the bed nucleus striae terminalis. Labeling of these cells for aromatase by immunocytochemistry demonstrated, however, that aromatase-positive retrogradely labeled cells are observed almost exclusively within the POM. Double-labeled cells were abundant in both the rostral and caudal parts of the POM and their number was apparently not affected by the location of the injection site within GCt. At both rostro-caudal levels of the POM, ARO-ir retrogradely labeled cells were, however, more frequent in the lateral than in the medial POM. These data indicate that ARO-ir neurons located in the lateral part of the POM may control the premotor aspects of male copulatory behavior through their projection to GCt and suggest that GCt activity could be affected by estrogens released from the terminals of these ARO-ir neurons.


Single-cell RNA-seq analysis reveals the platinum resistance gene COX7B and the surrogate marker CD63.
Cancers acquire resistance to systemic treatment with platinum-based chemotherapy (eg, cisplatin [CDDP]) as a result of a dynamic intratumoral heterogeneity (ITH) and clonal repopulation. However, little is known about the influence of chemotherapy on ITH at the single-cell level. Here, mapping the transcriptome of cancers treated with CDDP by scRNA-seq, we uncovered a novel gene, COX7B, associated with platinum-resistance, and surrogate marker, CD63. Knockdown of COX7B in cancer cells decreased the sensitivity of CDDP whereas overexpression recovered the sensitivity of CDDP. Low COX7B levels correlated with higher mortality rates in patients with various types of cancer and were significantly associated with poor response to chemotherapy in urinary bladder cancer. Tumor samples from patients, who underwent CDDP therapy, showed decreased COX7B protein levels after the treatment. Analyzing scRNA-seq data from platinum-naïve cancer cells demonstrated a low-COX7B subclone that could be sorted out from bulk cancer cells by assaying CD63. This low-COX7B subclone behaved as cells with acquired platinum-resistance when challenged to CDDP. Our results offer a new transcriptome landscape of platinum-resistance that provides valuable insights into chemosensitivity and drug resistance in cancers, and we identify a novel platinum resistance gene, COX7B, and a surrogate marker, CD63.


[Influence of learning curve in the diagnosis of prostate cancer by ultrasound guided biopsy].
To analyze if there is a learning curve to get to perform high quality ultrasound guided prostate biopsies that enable to effectively perform the diagnosis of prostate cancer, taking the pathological result of the samples into consideration. We retrospectively reviewed data from 790 ultrasound-guided biopsies performed consecutively in our center between May 2009 and December 2012 by four surgeons. We reviewed the following data: Surgeon, date of intervention, patient age, PSA, rectal digital examination (DRE), ultrasound, prostate volume, number of cores obtained, pathology result of the biopsy. The surgeons were residents in Urology in their first year in the department. For statistical analysis the biopsies were grouped in blocks of 25 and 75 cases performed by a surgeon, in a chronological order. To evaluate the influence of the learning curve on diagnosis we performed univariate and multivariate analysis between the different variables and pathological report. Median age was 67 years (42-90). 300 biopsies (38%) were positive for prostate cancer. On univariate analysis, regarding cancer detection rate, the variables surgeon, PSA, DRE, ultrasound result, prostate volume, number of cores and groups of 75 showed statistically significant differences, this latter showing 32% in the first 75 biopsies and 43.2% in the last group. The variables age (p=0.11) and groups of 25 patients (p=0.07) did not show differences. Nevertheless, on multivariate analysis only PSA, DRE, prostate volume and groups of 75 patients were statistically significant, this latter with an OR of 1.35 (95%CI 1.09-1.66). The results obtained in our study show that the number of procedures performed, namely surgeon experience, does have an influence to achieve an optimal diagnostic yield in ultrasound guided prostatic biopsies.