[5-fluorouracil and colorectal tumors: use in clinical practice and the "MISURA" project].
5-fluorouracil, an antimetabolite inhibiting timidilate synthetase, is one of the most used drugs in the treatment of many solid tumor types. In particular it is still central in the treatment of colorectal cancer. Nevertheless 5-FU efficiency is limited, this is due to the rapidity of its metabolism (T1/2 10 min). Many attempts have been done to increase its efficiency: 1) combinations with other antitumor drugs have been tested, but no one showed improved response rates with respect to 5-FU alone; 2) use of biological modifiers such as folinic acid and methotrexate. They interact with the biological actions of 5-FU improving its therapeutic effects. These combinations appear to be more effective than 5-FU alone; 3) continuous infusion increases the percentage of susceptible tumor cells, it makes possible the use of a high intensity dose which is active in patients resistant to 5-FU administered as bolus-injection. There are many schedules and methods of administration of 5-FU in the treatment of CRC, each of them showing different types of toxicities. This explains why there is the need to obtain a profile of 5-FU in clinical practice. The project called MISURA is though to give us this kind of information. It will be a collection of data regarding patients affected by colorectal cancer and treated with 5-FU. The collected information will be about diagnosis; ways of use, schedules, doses and tolerability of the drug; obtained responses. The aims of the study are: 1) to evaluate the use of 5-FU in clinical practice; 2) to collect data about the use of supportive therapy; 3) to know the effective incidence and prevalence of CRC in Italy. The study is retrospective, the sample consists of all patients from the oncological departments chosen to represent the national territory. The analysis of the data will be descriptive.


Glomerular filtration and saturable absorption of iohexol in the rat isolated perfused kidney.
1. The renal handling of iohexol was examined in the rat isolated perfused kidney (IPK) over a perfusate concentration range of 5-20 micrograms ml-1. 2. At a concentration of 5 micrograms ml-1, a ratio of renal clearance over clearance by glomerular filtration (ClR/GF) of 0.63 +/- 0.06 could be determined. This ratio increased until 1.02 +/- 0.06 at 20 micrograms ml-1, indicating that a saturable mechanism is involved in the luminal disappearance of the drug. 3. Pretreatment of the kidneys with polylysine, probenecid or diatrizoate resulted in a significantly enhanced clearance of iohexol, probably due to inhibition of membrane binding. Renal clearance data were fitted to a kinetic model including filtration into the primary urine followed by saturable absorption at the luminal membrane. An absorption constant, KA, of 7.3 +/- 1.3 micrograms ml-1, and a maximum rate of absorption, VA,Max, of 1.4 +/- 0.1 micrograms min-1 were determined. 4. Iohexol accumulated in kidney tissue, reaching a concentration of 2 to 7.5 times the perfusate concentration. In freshly isolated proximal tubular cells and kidney cortex mitochondria, iohexol reduced the uncoupled respiratory rate at a concentration comparable to the highest tissue concentration found in the IPK. 5. In conclusion, iohexol is not only filtered by the kidney but also reabsorbed via a saturable mechanism, which results in tubular accumulation. Intracellularly sequestered iohexol may affect mitochondrial oxidative metabolism. Our results indicate that iohexol is not a true filtration marker.


Home enteral nutrition: Use of photo-elicitation to capture patient and caregiver experiences.
Despite the importance of home enteral nutrition (HEN), there is a lack of understanding within the medical and general community of how HEN impacts the lives of patients and caregivers. Using a theoretical orientation that attends to the materiality of both everyday and medical objects, we explored patients' and family caregivers' everyday experiences of administering feeds during HEN. Using the photo-elicitation interviewing method, patients on HEN and their family caregivers were asked to take up to 10 photographs to portray material items and activities that they considered foundational to HEN. They subsequently narrated their experiences and the participant-generated photographs in an interview. Participant-generated photographs (126) and accompanying narratives were analyzed using layered analysis, and results were theorized with attention to both social and material significance of HEN. Patients and caregivers detailed overcoming misconceptions of HEN, and through their use of photographs, they conveyed their expertise in developing their own HEN feeding systems and practices, that used both the material artifacts provided by the hospital (the tube, syringe, and formula) as well as everyday material items found in the patient's home. More than this, photographs and patient narratives depicted intimate involvement of patients' families in tube feeding. This yielded a more comprehensive understanding of the material and experiential realities of HEN. Home enteral nutrition was found to be a shared familial experience, that in addition to requiring medical equipment also incorporated ordinary material artifacts within the social setting of the home and family life. To more accurately convey the material, experiential, and social realities of HEN to future patients, our findings underscore the importance of drawing on both visual and textual forms of patient-produced information in the development of HEN patient educational materials.


The past, present, and future of ventilation during cardiopulmonary resuscitation.
To evaluate the past and present literature on ventilation during out of hospital cardiac arrest, highlighting research that has informed current guidelines. Previous studies have studied what are optimal compression-to-ventilation ratios, ventilation rates, and methods of ventilation. Continuous chest compression cardiopulmonary resuscitation (CPR) has not shown to provide a significant survival benefit over the traditional 30 : 2 CPR. The optimal ventilation rate is recommended at 8 to 10 breaths per minute. Methods such as capnography and thoracic impedance are being used to evaluate ventilation in research studies. Future out of hospital cardiac arrest studies are still exploring how to optimize the delivery of ventilation during the initial stages of resuscitation. More prospective studies focusing on ventilation are needed to inform guidelines.


Recruitment of the endosomal WASH complex is mediated by the extended 'tail' of Fam21 binding to the retromer protein Vps35.
The retromer complex is a conserved endosomal protein sorting complex that sorts membrane proteins into nascent endosomal tubules. The recognition of membrane proteins is mediated by the cargo-selective retromer complex, a stable trimer of the Vps35 (vacuolar protein sorting 35), Vps29 and Vps26 proteins. We have recently reported that the cargo-selective retromer complex associates with the WASH (Wiskott-Aldrich syndrome homologue) complex, a multimeric protein complex that regulates tubule dynamics at endosomes. In the present study, we show that the retromer-WASH complex interaction occurs through the long unstructured 'tail' domain of the WASH complex-Fam21 protein binding to Vps35, an interaction that is necessary and sufficient to target the WASH complex to endosomes. The Fam21-tail also binds to FKBP15 (FK506-binding protein 15), a protein associated with ulcerative colitis, to mediate the membrane association of FKBP15. Elevated Fam21-tail expression inhibits the association of the WASH complex with retromer, resulting in increased cytoplasmic WASH complex. Additionally, overexpression of the Fam21-tail results in cell-spreading defects, implicating the activity of the WASH complex in regulating the mobilization of membrane into the endosome-to-cell surface pathway.


Varying Effects of Body Mass Index and Mortality in Different Risk Groups.
It is unclear why high body mass index (BMI) is associated with a lower risk of death in patients with cardiovascular disease (CVD). We hypothesized that the impact of higher BMI varies by the patient's baseline risk of death. We analyzed data from 14 prospective studies conducted by us in 50 countries of 170,470 patients: 22.8% without CVD, 29.4% with stable CVD and 47.8% with acute coronary syndromes (ACS). Compared with overweight (BMI 25 to 29.9 kg/m2), normal weight (BMI 20 to 24.9 kg/m2), and underweight (BMI < 20 kg/m2) were associated with higher mortality in all cohorts. Compared with overweight, the risk of death among those with obesity (BMI ≥ 30 kg/m2) varied depending on the population studied: HR (95% confidence interval) in those without CVD, with stable CVD, and with ACS were 1.20 (1.01 to 1.45; p = 0.04), 1.08 (1.02 to 1.15; p = 0.01), and 1.01 (0.93 to 1.10; p = 0.72), respectively. The BMI associated with lowest mortality increased as cohort risk increased (no-CVD 27.2 kg/m2, stable CVD 28.1 kg/m2, and ACS 30.9 kg/m2; p <0.001). Within each cohort, the optimal BMI value was higher in the high-risk subgroup. In the ACS cohort, low-risk patients had an optimal BMI value of 29.1 kg/m2 while in the high-risk group higher BMI was associated with lower risk of death (interaction-p <0.001). In conclusion, between and within cohorts of people without CVD, stable CVD, and ACS, higher BMI was associated with lower risk of death in higher risk groups. The benefits of increased body fat (i.e., increased caloric reserve) may counteract the hazards in high-risk groups, suggesting an alternative explanation of the obesity paradox.


Physicochemical properties of Venezuelan breadfruit (Artocarpus altilis) starch.
Artocarpus altilis, seedless variety, is a fruit-producing plant which is cultived in Margarita Island, Venezuela, and is consumed by the inhabitants of the region. Its chemical composition and physical characteristics were determined. The chemical (AOAC and AACC methods), physicochemical, morphometric characteristics, viscoamylographic properties and digestibility in vitro of starch from Artocarpus were studied. The starch yield was 18.5 g/100 g (dw)w with a purity of 98.86%, 27.68 and 72.32% of amylose and amylopectin, respectively. Scanning electron microscopy showed irregular-rounded granules. Swelling power, water absorption and solubility values were determined and found to be higher than that of corn and amaranth starch. The amylographic study showed a gelatinization temperature at 73.3 degrees C, with high stability during heating and cooling cycles. Artocarpus starch could also be categorized in the group of mixed short chain branched/long chain branched glucan starches, this agrees with digestibility results that showed a high degree of digestibility in vitro. These results might be advantageous in medical and food use.


High susceptibility to zoliflodacin and conserved target (GyrB) for zoliflodacin among 1209 consecutive clinical Neisseria gonorrhoeae isolates from 25 European countries, 2018.
Novel antimicrobials for treatment of gonorrhoea are imperative. The first-in-class spiropyrimidinetrione zoliflodacin is promising and currently in an international Phase 3 randomized controlled clinical trial (RCT) for treatment of uncomplicated gonorrhoea. We evaluated the in vitro activity of and the genetic conservation of the target (GyrB) and other potential zoliflodacin resistance determinants among 1209 consecutive clinical Neisseria gonorrhoeae isolates obtained from 25 EU/European Economic Area (EEA) countries in 2018 and compared the activity of zoliflodacin with that of therapeutic antimicrobials currently used. MICs of zoliflodacin, ceftriaxone, cefixime, azithromycin and ciprofloxacin were determined using an agar dilution technique for zoliflodacin or using MIC gradient strip tests or an agar dilution technique for the other antimicrobials. Genome sequences were available for 96.1% of isolates. Zoliflodacin modal MIC, MIC50, MIC90 and MIC range were 0.125, 0.125, 0.125 and ≤0.004-0.5 mg/L, respectively. The resistance was 49.9%, 6.7%, 1.6% and 0.2% to ciprofloxacin, azithromycin, cefixime and ceftriaxone, respectively. Zoliflodacin did not show any cross-resistance to other tested antimicrobials. GyrB was highly conserved and no zoliflodacin gyrB resistance mutations were found. No fluoroquinolone target GyrA or ParC resistance mutations or mutations causing overexpression of the MtrCDE efflux pump substantially affected the MICs of zoliflodacin. The in vitro susceptibility to zoliflodacin was high and the zoliflodacin target GyrB was conserved among EU/EEA gonococcal isolates in 2018. This study supports further clinical development of zoliflodacin. However, additional zoliflodacin data regarding particularly the treatment of pharyngeal gonorrhoea, pharmacokinetics/pharmacodynamics and resistance selection, including suppression, would be valuable.


Management of the kidney transplant patient with chronic hepatitis C infection.
Chronic Hepatitis C (HCV) infection is an important cause of morbidity and mortality in patients with end-stage renal disease. Renal transplantation confers a survival advantage in HCV-infected patients. Renal transplant candidates with serologic evidence of HCV infection should undergo a liver biopsy to assess for fibrosis and cirrhosis. Patients with Metavir fibrosis score ≤3 and compensated cirrhosis should be evaluated for interferon-based therapy. Achievement of sustained virological response (SVR) may reduce the risks for both posttransplantation hepatic and extrahepatic complications such as de novo or recurrent glomerulonephritis associated with HCV. Patients who cannot achieve SVR and have no live kidney donor may be considered for HCV-positive kidneys. Interferon should be avoided after kidney transplant except for treatment of life-threatening liver injury, such as fibrosing cholestatic hepatitis. Early detection, prevention, and treatment of complications due to chronic HCV infection may improve the outcomes of kidney transplant recipients with chronic HCV infection.


Facile entry to substituted decahydroquinoline alkaloids. Total synthesis of lepadins A-E and H.
Condensation of a L-alanine derived delta-bromo-beta-silyloxy-propylamine with 1,3-cyclohexadione followed by alkylative cyclization produces a bicyclic enone. Diastereoselective Pt/C-catalyzed hydrogenation of this enone in HOAc provides a 5-oxo-cis-fused decahydroquinoline. Wittig olefination of this decahydroquinoline and subsequent epimerization of the resulting 5-formyl intermediate gives rise to a 5-beta-formyl decahydroquinoline exclusively. In a parallel procedure, Peterson reaction of this decahydroquinoline and subsequent hydrogenation of the generated 5-exo-olefin provides a decahydroquinoline with a 5-alpha-substituent predominantly. For these two diastereoselective processes, using the intermediates without N-protection as the substrates is essential because the corresponding N-Boc intermediates give poor diastereoselectivity. The intermediate with beta-form side chain is further converted into lepadins A-C via carbon chain elongation, while the intermediate with alpha-form side chain is transformed into lepadins D, E, and H and corresponding 5'-epimers via connection with two sulfones generated from two Sharpless epoxidation products. By comparison of the rotations and NMR data, the stereochemistry of lepadins D, E, and H is assigned as 2S,3R,4aS,5S,8aR,5'R.


Aβ-induced Ca(2+) influx regulates astrocytic BACE1 expression via calcineurin/NFAT4 signals.
The β-site APP cleaving enzyme (BACE1) is required for the production of β-amyloid peptides, which give rise to β-amyloid (Aβ) deposits in the brains of Alzheimer's disease (AD) patients. In brains, BACE1 is primarily expressed by neurons, however BACE1 expression has also been observed in reactive astrocytes in close proximity to β-amyloid plaques in the brains of aged Tg2576 AD model mice. To date, the direct effects of Aβ on BACE1 gene expression in astrocytes is unknown. We found that Aβ42 or Aβ25-35 treatment induced BACE1 expression in primary astrocytes as well as human astrocytoma cell line. Aβ neurotoxicity has been associated with the disruption of intracellular calcium homeostasis both in neurons and in glial cells. Here, we demonstrated that NFAT4, a transcription factor tightly regulated by the calcium/calmodulin-dependent phosphatase, calcineurin, was activated in astrocytes applied with calcium ionophore or Aβ. Aβ-activated NFAT4 proteins were associated with astrocytic BACE1 gene expression via direct interaction with the BACE1 promoter region.


A case of pathologically complete response after preoperative chemotherapy in a pancreatic acinar cell carcinoma patient with portal vein tumor thrombosis.
Preoperative treatment is being proposed as a standard treatment for pancreatic ductal adenocarcinoma though few cases show a pathologically complete response. On the other hand, there is no consensus regarding preoperative chemotherapy for pancreatic acinar cell carcinoma (ACC). The present study described a rare case of ACC in the pancreatic head with portal vein tumor thrombosis (PVTT) treated with preoperative chemotherapy using modified FOLFIRINOX, which achieved a pathologically complete response. A 65-year-old man was referred for consideration of treatment strategy. Contrast-enhanced abdominal computed tomography revealed a pancreatic tumor and PVTT. The pancreatic tumor was diagnosed as ACC by an endoscopic ultrasound-guided fine-needle aspiration biopsy. Initially, the tumor was assessed as unresectable due to the presence of PVTT, and therefore, a chemotherapy using modified FOLFIRINOX was administered. After 14 courses of the chemotherapy, imaging studies revealed that the tumor and PVTT showed marked reduction in size; thus, the patient underwent pancreaticoduodenectomy with combined resection of the portal vein (PV). A pathological examination uncovered a complete degeneration of the primary tumor and the PV embolus without any residue of carcinoma. The patient did not receive adjuvant chemotherapy and survived with no evidence of recurrence for 33 months after surgery. The chemotherapy using modified FOLFIRINOX could give a complete response in patients with pancreatic ACC with PVTT.


Implications of FLT3 mutations in the therapy of acute myeloid leukemia.
FMS-like tyrosine kinase 3 (FLT3) is a type III receptor tyrosine kinase that is expressed on the surface of hematopoietic stem cells and plays an important role in normal hematopoiesis. FLT3 is mutated in approximately one-third of cases of acute myeloid leukemia (AML) with normal karyotype. The mutations are most commonly internal tandem duplications found in the juxtamembrane domain of the FLT3 receptor. There are also cases of point mutations within the tyrosine kinase domain. The presence of a FLT3 mutation confers a poorer prognosis in disease-free survival and overall survival. Patients with an FLT3 mutation have poorer outcomes even with a concomitant nucleophosmin1 (NMP1) mutation, which is normally a good prognostic factor. These observations raise the question about how best to treat patients with AML who have FLT3 mutations. There are some retrospective data that allogeneic stem cell transplantation should be offered to patients with FLT3 mutations who have achieved a first remission, but prospective trials are lacking. There are a number of FLT3 inhibitors that are in various stages of clinical testing. It is hoped that this new class of drugs will be combined with traditional cytotoxic therapies to treat AML and improve outcomes in this difficult-to-treat patient population.


Electrical activity of the proventriculus of the polychaete worm Syllis spongiphila.
The straited myoepithelial cells of the proventriculus of Syllis spongiphila are composed of only one or two sarcomeres that may reach 40 mum in length. Experiments were performed to study some of their electrophysiological properties and their synaptic control. The mean resting potentials recorded in two different bathing media were 59-1 +/- 5-5 mV (S.D., n=91) and 62-5 +/- 6-3 mV (S.D., n=98). At rest the membrane potential is determined largely by permeability of the membrane to K+ ions, but the membrane is also permeable to other ions. On a semilogarithmic plot of membrane potential v. [K]o the mean slope of the data points from 9 to 90 mM-[K]o was 48 +/- 3 mV for a 10-fold change in [K]o. The anterior end of the animal was stimulated with a suction electrode to elicit activity of nerve fibres that innervate the proventriculus. Single indirect stimuli usually evoked hyperpolarizing or biphasic responses, and occasionally depolarizing responses, from the myoepithelial cells. The depolarizing synaptic potentials exhibited a faster time course than the hyperpolarizing ones. The rise time to peak ranged from 20 to 35 ms for simple depolarizations (n=32) and 25-75 ms for simple hyperpolarizations (n=103). Time to decay to half amplitude ranged from 20 to 55 ms for depolarizations (n=29) and 62-135 ms for hyperpolarizations (n=87). Low frequency (is less than or equal to 4 Hz) trains of indirectly applied stimuli elicited mainly hyperpolarizing responses; higher frequency (5-40 Hz) trains elicited complex responses composed of hyperpolarizations and depolarizations. Hyperpolarizations were selectively and reversibly abolished in chloride-free solutions. The reversal potential of the hyperpolarizing synaptic potential was -104 +/- 3 mV (S.D., n=8, 2 preparations). In calcium-free solution both hyperpolarizations and depolarizations were almost completely abolished. 4 mM-Mn2+ added to the bath almost completely abolished the depolarization but not the hyperpolarization. It was not clear whether Mn2+ acted at the presynaptic membrane, the postsynaptic membrane or both. The myoepithelial cells are electrically coupled. The mean space constant of five preparations was 0-52 mm (range 0-40-0-66 mm).


A six degree of freedom nanomanipulator design based on carbon nanotube bundles.
Scanning probe imaging and manipulation of matter is of crucial importance for nanoscale science and technology. However, its resolution and ability to manipulate matter at the atomic scale is limited by rather poor control over the fine structure of the probe. In the present paper, a strategy is proposed to construct a molecular nanomanipulator from ultrathin single-walled carbon nanotubes. Covalent modification of a nanotube cap at predetermined atomic sites makes the nanotube act as a support for a functional 'tooltip' molecule. Then, a small bundle of nanotubes (three or four) with aligned ends can act as an extremely high aspect ratio parallel nanomanipulator for a suspended molecule, where protraction or retraction of individual nanotubes results in controlled tilting of the tooltip in two dimensions. Together with the usual scanning probe microscopy three degrees of freedom and augmented with rotation of the system as a whole, the design offers six degrees of freedom for imaging and manipulation of matter with the precision and freedom so much needed for advanced nanotechnology. A similar design might be possible to implement with other high aspect ratio nanostructures, such as oxide nanowires.


Impact of Mid-Life Symptoms of Alcoholism on the Health and Wellbeing of Aging Parents of Adults with Disabilities.
The study examined the effect of adult children's disability on parents' physical health in later life and the extent to which parents' symptoms of alcoholism in mid-life moderates the link between children's disability and later life parental health. Analyses are based on data from the Wisconsin Longitudinal Study. The analytic sample included parents of children with developmental disabilities (n = 145) or mental health problems (n = 200) and 2,432 parents of unaffected children. The results showed that the negative health consequences in later life of having a child with a developmental disability were greater for those who showed more symptoms of alcoholism in mid-life. However, symptoms of alcoholism in mid-life did not significantly moderate the impact of an adult child's mental health problems on parents' later life physical health. The findings suggest a potential area where gerontological social workers could intervene, given the negative impact of symptoms of alcoholism on the health of aging parents of children with a disability who may be significantly more susceptible to the negative health impacts of alcohol compared to their younger counterparts.


[Optimising patient isolation due to methicllin-resistant Staphylococcus aureus].
Isolation of patients is used to control the spread of certain microorganisms in the hospital, e.g. meticillin-resistant Staphylococcus aureus (MRSA). Recent investigations have shown that the quality of care for patients in isolation is affected significantly. However, this is not accompanied by an effect on the morbidity or mortality. The successful Dutch policy on MRSA is based largely on strict isolation of patients colonised with MRSA. If MRSA becomes endemic, this is accompanied by increases in morbidity and mortality as well as costs. The disadvantages of isolation are recognised and should be prevented as far as possible. New diagnostic and therapeutic developments can shorten the duration of isolation significantly, which will further improve the quality of care.


Waldenström's macroglobulinemia: treatment approaches for newly diagnosed and relapsed disease.
Waldenström's macroglobulinemia is a B-cell malignancy characterized by a lymphoplasmacytic infiltration into the bone marrow and a monoclonal immunoglobulin M (IgM) protein in the serum. It remains incurable despite advances in current therapy, and the decision to treat patients as well as the choice of treatment administered can be rather complex. Management of this disease should utilize a risk-adapted approach. Patients with smoldering or asymptomatic Waldenström's macroglobulinemia with preserved hematological function should be observed without initial therapy. Symptomatic patients with modest hematological compromise, IgM-related neuropathy requiring therapy or hemolytic anemia unresponsive to corticosteroids should receive standard doses of rituximab alone without maintenance therapy. Patients who have significant constitutional symptoms, profound hematological compromise, symptomatic bulky disease or hyperviscosity should be treated with combination therapy. Any patient with symptoms of hyperviscosity should be treated with plasmapheresis. For patients who relapse after an initial response to therapy of greater than two years in duration, the original therapy should be repeated. For patients who had an inadequate response to initial therapy or a response of less than two years duration, an alternative agent or combination should still be used. An autologous stem cell transplant should be considered in all eligible patients with relapsed disease.


Orthology prediction methods: a quality assessment using curated protein families.
The increasing number of sequenced genomes has prompted the development of several automated orthology prediction methods. Tests to evaluate the accuracy of predictions and to explore biases caused by biological and technical factors are therefore required. We used 70 manually curated families to analyze the performance of five public methods in Metazoa. We analyzed the strengths and weaknesses of the methods and quantified the impact of biological and technical challenges. From the latter part of the analysis, genome annotation emerged as the largest single influencer, affecting up to 30% of the performance. Generally, most methods did well in assigning orthologous group but they failed to assign the exact number of genes for half of the groups. The publicly available benchmark set (http://eggnog.embl.de/orthobench/) should facilitate the improvement of current orthology assignment protocols, which is of utmost importance for many fields of biology and should be tackled by a broad scientific community.


Improved Strength and Recovery After Velocity-Based Training: A Randomized Controlled Trial.
The present intervention study examined the effects of intensity-matched velocity-based strength training with a 10% velocity loss (VL10) versus traditional 1-repetition maximum (1RM) based resistance training to failure (TRF) on 1RM and maximal oxygen uptake (V˙O2max) in a concurrent training setting. Using the minimization method, 21 highly trained rowers (4 females and 17 males; 19.6 [2.1] y, 1.83 [0.07] m, 74.6 [8.8] kg, V˙O2max: 64.9 [8.5] mL·kg-1·min-1) were either assigned to VL10 or TRF. In addition to rowing endurance training (about 75 min·d-1), both groups performed strength training (5 exercises, 80% 1RM, 4 sets, 2-3 min interset recovery, 2 times/week) over 8 weeks. Squat, deadlift, bench row, and bench press 1RM and V˙O2max rowing-ergometer ramp tests were completed. Overall recovery and overall stress were monitored every evening using the Short Recovery and Stress Scale. Large and significant group × time interactions (P < .03, ηp2>.23, standard mean differences [SMD] > 0.65) in favor of VL10 (averaged +18.0% [11.3%]) were observed for squat, bench row, and bench press 1RM compared with TRF (averaged +8.0% [2.9%]). V˙O2max revealed no interaction effects (P = .55, ηp2=.01, standard mean difference < .23) but large time effects (P < .05, ηp2>.27). Significant group × time interactions (P = .001, ηp2>.54, SMD > |0.525|) in favor of VL10 were also observed for overall recovery and overall stress 24 and 48 hours after strength training. VL10 serves as a promising means to improve strength capacity at lower repetitions and stress levels in highly trained athletes. Future research should investigate the interference effects of VL10 in strength endurance sports and its effects when increasing weekly VL10 sessions within one macrocycle.


Knowledge and understanding of antibiotic resistance and the risk of becoming a carrier when travelling abroad: a qualitative study of Swedish travellers.
Increasing globalisation, with the migration of people, animals and food across national borders increases the risk of the spread of antibiotic-resistant bacteria. To avoid becoming a carrier of antibiotic-resistant bacteria when travelling, knowledge about antibiotic resistance is important. We aimed to describe the knowledge and understanding of antibiotic-resistant bacteria, and of the risk for becoming a carrier of such bacteria, among Swedish travellers before their travel to high-risk areas. A questionnaire with three open-ended questions was distributed to 100 individuals before departure. The travellers' answers were analysed using content analysis, resulting in the theme 'To be an insecure traveller who takes control over one's own journey'. Our results showed that the travellers were aware of what the term 'antimicrobial resistance' meant, but did not understand its real significance, nor the consequences for the individual nor for society. They also distanced themselves from the problem. Few thought that their travel would entail a risk of becoming a carrier of resistant bacteria. The lack of knowledge caused an uncertainty among the travellers, whom tried to master the situation by using coping strategies. They proposed a number of measures to prevent carriership. The measures were general and primarily aimed at avoiding illness abroad, particularly acute gastro-intestinal infection. In health care and vaccination clinics, there is a need for improved information for persons intending to travel to high-risk areas, both about the risks of contracting antibiotic-resistant bacteria and about effective preventive measures.


Growth characteristics of human skin fibroblasts in vitro: a simple experimental approach for the identification of hereditary adenomatosis of the colon and rectum.
Kinetic parameters of cell growth have been studied in cultured skin fibroblasts derived from individuals with hereditary adenomatosis of the colon and rectum. The growth parameters consisted of saturation density, plating density, cloning efficiency and colony-forming ability. The results suggest deployment of these selective assays to distinguish skin fibroblasts of presumptive ACR positive individuals from those of normal subjects in vitro.


Roles of three distinct neurogenic motor patterns during pellet propulsion in guinea-pig distal colon.
Enteric neural circuits enable isolated preparations of guinea-pig distal colon to propel solid and fluid contents by a self-sustaining neuromechanical loop process. In addition there are at least three neural mechanisms which are not directly involved in propulsion: cyclic motor complexes, transient neural events and distal colon migrating motor complexes. In excised guinea-pig colon we simultaneously recorded high resolution manometry, video-imaging of colonic wall movements and electrophysiological recordings from smooth muscle, which enabled us to identify mechanisms that underlie the propulsion of colonic content. The results show that the intermittent propulsion during emptying of the multiple natural faecal pellets is due to the intermittent activation of cyclic motor complexes and this is facilitated by transient neural events. Loss or dysfunction of these activities is likely to underlie disordered gastrointestinal transit. It is well known that there are different patterns of electrical activity in smooth muscle cells along different regions of the gastrointestinal tract. These different patterns can be generated by myogenic and/or neurogenic mechanisms. However, what patterns of electrical activity underlie the propulsion of natural faecal content remains unknown, particularly along the large intestine, where large quantities of water are reabsorbed and semi-solid faeces form. In this study, we developed a novel approach which enables for the first time the simultaneous recording of high resolution intraluminal manometry, electrophysiology from the smooth muscle, and spatio-temporal video imaging of colonic wall movements. Using this approach we were able to reveal the nature of enteric neuromuscular transmission and patterns of motor activity responsible for the movement of content. Three distinct neurogenic patterns of electrical activity were recorded even in the absence of propulsive movement. These were the cyclic motor complexes (CMCs), the transient neural events (TNEs) and the slowly propagating distal colonic migrating motor complexes (DCMMCs). We present evidence that the initiation of pellet propulsion is due to a cyclic motor complex (CMC) occurring oral to the pellet. Furthermore, we discovered that the intermittent propulsion of natural faecal pellets is generated by intermittent activation of CMCs; and this propulsion is facilitated by hexamethonium-sensitive TNEs. However, TNEs were not required for propulsion. The findings reveal the patterns of electrical activity that underlie propulsion of natural colonic content and demonstrate that propulsion is generated by a complex interplay between distinct enteric neural circuits.


Treatment of membranous nephropathy in children.
Membranous nephropathy (MN) is not a common pediatric glomerular disease and not a common cause of idiopathic nephrotic syndrome (NS) in children. Because of the rarity of the disease, there is only a limited amount of uncontrolled data and no controlled data available in children regarding the treatment of MN. Older uncontrolled data indicate that nearly a quarter of children with NS, whether untreated or treated with various immunosuppressive agents, develop chronic renal failure. Current recommendations for treatment both for children presenting with or without NS therefore are based on controlled data obtained in adults with MN. All children should receive angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs). Children with NS may be treated initially with corticosteroids. If a satisfactory response is not obtained with corticosteroids, then treatment with cyclosporine or chlorambucil can be tried. The protocols of treatment with these drugs are described in this article.


[Necrotizing hepatitis after taking herbal remedies].
Two unrelated women, aged 39 and 42 years, had been admitted (at different times) to hospital because of "recurrence of an aetiologically uncertain acute hepatitis". Both patients had a history of acute hepatitis with GPT concentration of 796 and 755 U/l, respectively. Each of them had experienced recurrences of hepatitis, each of them preceded by taking herbal remedies as alternative medication, containing kava or common (or lesser) celandine, respectively. In each patient physical examination had been unremarkable. Maximal values of GPT in the two patients were 422 and 350 U/l, respectively. Viral, autoimmune and metabolic causes of the hepatitis were excluded. In each of them liver biopsy revealed the picture of acute necrotizing hepatitis. As it was suspected that the hepatitis was medication-induced, the intake of the mentioned herbal preparations was stopped. The liver function tests quickly became normal. In view of the rapid response to their withdrawal, a causal connection between intake of the herbal preparations and the recurrences of acute hepatitis is the most likely explanation in both cases.


Blockade of the ATP-sensitive K+ channel by 5-hydroxydecanoate in guinea pig ventricular myocytes.
Effects of a novel antiarrhythmic agent, 5-hydroxydecanoate (5-HD), were investigated on the electrical activity of the guinea pig ventricular myocytes. The shortening of action potential duration induced by applying iodoacetate (IAA) for 5 to 10 min was reversed completely by 5-HD (100 microM) in the papillary muscle. The single channel current recording in the cell-attached configuration revealed both activation of the ATP-sensitive K+ channel during the treatment with IAA and after depression of the channel by the additional application of 100 microM 5-HD. The quick rundown of the ATP-sensitive K+ channel activity interfered the analysis of the drug effect in the usual inside-out patch configuration. The channel activity in the isolated patch was partially recovered and stabilized by applying a tissue extract, which was prepared from guinea pig ventricle. Under this condition relationship between the 5-HD concentration and the K+ channel open probability was characterized with a K1/2 of 0.16 microM and a Hill coefficient of 0.88. The open- and close-time analysis revealed a decrease of the mean duration of the bursting channel opening and an increase of the interburst time under the effect of 5-HD. The inward-rectifier K+ channel, responsible for the resting K+ conductance, was not affected by 5-HD. It was concluded that the curative effect of 5-HD on the shortened action potential in the IAA-treated myocytes is mediated by the depression of the ATP-sensitive K+ channel.


Large multicenter trials: what do they achieve and what should be done in perfusion?
There have been a vast number of publications in the perfusion and cardiac surgical literature suggesting possible therapeutic benefits from many perfusion interventions. Most of the reports are case series and other observational studies; few are randomized trials, and most of these are small, focusing on surrogate endpoints. We know there are many factors that can affect outcome after cardiac surgery, and some of these can bias results of clinical studies. Evidence-based medicine has highlighted the importance of avoiding bias with good study design, critical appraisal, and careful application into clinical practice. Associations shown in observational studies do not provide reliable evidence of effect (causation). Random allocation to treatment groups accounts for many sources of bias, but small randomized trials can still be unreliable because they may identify a spurious positive finding by chance (type I error), as well as providing imprecise estimates of effect, as shown by wide confidence intervals. Obtaining data on actual outcomes with enough study power requires a large number of patients. Meta-analysis of small randomized trials can increase power, but this introduces other sources of bias. Large randomized pragmatic trials, using straightforward interventions reflecting routine clinical practice, can optimize the ability to generalize and therefore are clinically relevant and reliable. They thus provide the best evidence of effectiveness.


Performance of mouse lines divergently selected for heat loss when exposed to different environmental temperatures. II. Feed intake, growth, fatness, and body organs.
Mouse populations differing in metabolic rate have been developed through selection for high (MH) and low (ML) heat loss, along with the unselected controls (MC). Objectives of the study were to compare the MH, ML, and MC lines for feed intake, growth, body fatness, and organ weights when reared at 12, 22, and 31 degrees C, and investigate potential line x environment interactions. Feed intake was recorded weekly from 3 to 9 wk of age, and BW at 3, 6, and 9 wk of age. Body fat percent and organ weights were measured at 9 wk of age. No line x environment interactions were detected for any of the traits measured. The MH mice consumed more feed than ML mice from 5 to 9 wk of age. Between 8 and 9 wk of age, MH mice consumed 13% more feed than the ML mice, but they were relatively leaner (14.45 vs. 16.32% body fat); MC mice were intermediate for both traits. Mice in the cold environment consumed the greatest amount of feed, and those in the hot environment consumed the least. Males consumed more feed than females, and the difference was greater in the cold than in the hot environment. No differences in BW were found between the lines. Mice in the 22 degrees C environment were heavier than their age-matched counterparts in the other two environments, and males were heavier than females at all ages. Relative to BW, the three lines had similar tail length, body length, and liver weight. Mice in the cold environment had heavier spleens and livers than those in the hot environment but relatively shorter bodies and tails; the normal environment was intermediate for these traits. Results from this study indicate that selection to decrease maintenance requirements did not produce mice with any less ability to grow and perform under an array of environmental temperatures.


Steatosis and fibrosis in patients with chronic hepatitis C.
Steatosis is present on liver biopsy in approximately 50% of patients with hepatitis C; its association with stage of fibrosis has been reported, but its relation to other fibrosis associated factors is unknown. To study the relation between steatosis and other histological features in patients with hepatitis C, and changes in steatosis with time. Cross sectional study: 233 routine liver biopsies from 219 patients with hepatitis C; hepatectomy specimens from 65 patients transplanted for hepatitis C cirrhosis. Longitudinal study: 41 patients with two biopsies and 10 patients with three biopsies performed over 2-8 years. Biopsies were scored by the Ishak scheme, and degree of steatosis assessed subjectively. Multivariate analysis was used to study the interaction of fibrosis associated factors. Changes in steatosis over time in individual patients were explored in the longitudinal study. Steatosis was present in 50% of biopsies. It correlated strongly with fibrosis in non-cirrhotic samples, but declined in cirrhosis, and was unusual in transplant hepatectomy specimens. On multivariate analysis of non-cirrhotic biopsies, steatosis was associated with increasing patient age and remained significantly associated with fibrosis independent of portal inflammation and interface hepatitis. In the longitudinal study, steatosis persisted and increased over time, except in patients developing cirrhosis. Steatosis is associated with fibrosis independently of necroinflammation, but declines in cirrhosis. It may represent a pathogenic pathway distinct from necroinflammatory activity in the generation of liver fibrosis, and should be included in the assessment of biopsies for clinical and research purposes.


Secretion of proinflammatory eicosanoid-like substances precedes allergen release from pollen grains in the initiation of allergic sensitization.
It is commonly believed that allergic sensitization starts when an allergen contacts the surface of an antigen-presenting cell in mucosal or skin epithelia. Most studies dealing with this aspect use allergen extracts as stimulus. Under natural exposure conditions, however, the bioavailability of allergen depends on allergen liberation from internal binding sites within the allergen carrier, e.g. pollen grains. In comparing total protein and major allergen release from timothy grass (Phleum pratense L.) pollen freshly collected on rural meadows or near high-traffic roads, there was a striking difference between the pollen, with higher allergen release rates from rural meadow pollen grains. Thus, allergen release does not explain the higher prevalence rates of atopic sensitization and disease observed in many epidemiological studies in children exposed to automobile exhaust. Therefore, other possible effectors from pollen grains were investigated. Pollen grains incubated in protein- free buffer were found to secrete significant amounts of eicosanoid-like substances, namely leukotriene (LT) B(4)-like and prostaglandin E(2)-like substances, in a pH-, time- and temperature-dependent fashion. The highest values of eicosanoid secretion were found in birch, grass and mugwort pollen, while pine (Pinus sylvestris L.) pollen showed only marginal eicosanoid-like secretion. Additionally, the release of these substances was significantly higher from pollen which had been collected near roads with heavy traffic, indicating a stronger proinflammatory activity of these pollen grains. In order to investigate the effects of air pollutants, native pollen grains were exposed in a dose- and time-dependent fashion in a fluidized bed reactor to traffic-related pollutants, e.g. volatile organic compounds (toluene, m-xylene), leading again to a significant increase in the secretion of LTB(4)-like immunoreactivity, in contrast to exposure with sulfur dioxide. This finding opens a new dimension of understanding of the early events in allergic sensitization, indicating that proinflammatory effects of the allergen carrier, e.g. the pollen grain itself, can lead to activation of the mucosal membrane. These findings might help to also explain the higher prevalence rates of pollen allergy in areas with high automobile exhaust emissions. Furthermore, the allergenic 'potency' of various allergens has to be redefined at the allergen carrier level with regard to different stages of allergen and mediator release prior to the contact with the host's immune system.


Fast fabrication of stable cartilage-like tissue using collagen hydrogel microsphere culture.
Mesenchymal stem cells (MSCs) had been increasingly regarded as a potent cell source for cartilage repair. However, due to the instability of MSC-derived chondrocyte phenotype and ossification of the synthesised cartilage matrix, regenerating a stable cartilage tissue by MSCs is still challenging. The fate of chondrogenesis from MSCs is regulated by their local microenvironment, which is of vital importance to the cell behaviours, chondrogenic phenotype and matrix synthesis. In this study, we fabricated cartilage-like tissues by the chondrogenesis of MSC in three different microenvironments, including cell pellets, collagen hydrogel bulk (CHB) and collagen hydrogel microspheres (CHMs) in vitro. After 15 days in culture, the cell number was increased to 472.6% in CHMs, compared to a 58.6% decrease in CHB and a 46.6% decrease in pellets; resulting in a 230% increase in CHM size, but a 36.8% decrease in CHB and only a 20.1% increase in pellets. Histological staining demonstrated a more intensive but less homogeneous glycosaminoglycan (GAG) pattern in pellets than in CHMs. The outer area of CHB showed a stronger GAG staining than its inner area from day 5 to day 15, but the staining was weaker than that in both pellets and CHMs. The PCR results showed that CHMs achieved a significantly higher chondrogenic gene (AGG, COL2A1, SOX9) expression and a lower hypertrophic gene (COL10A1) expression than pellets and CHB, suggesting a better chondrogenic differentiation potential with a more stable phenotype in CHMs. In summary, this study highlights the advantages of CHM microenvironments over those of CHB and pellets by a better mimicking of the natural MSC proliferation process and enhancing mass exchange in vitro. The CHM culture demonstrated potential to fabricate stable cartilage-like tissue in MSC based cartilage tissue regeneration.


Who Applies an Intervention to Influence Cultural Attributes in a Quality Improvement Collaborative?
Organizational culture change has been recognized as one of the promising ways to reduce error and increase safety. However, it is still unclear what factors support health care teams implementing interventions aimed to influence the cultural attributes that bolster continuous quality improvement. This study aimed to identify factors related to teams' adoption of the Comprehensive Unit-based Safety Program (CUSP), an approach to improving patient safety culture among intensive care units (ICUs) participating in a bloodstream infection reduction collaborative. We analyzed data from the 103 ICUs participating in the Keystone ICU project. We conducted logistic regressions to assess baseline factors associated with ICU teams' use of CUSP. Predictors included safety climate scales (teamwork climate, safety climate, job satisfaction, stress recognition, perceptions of management, and working conditions) as measured by the Safety Attitudes Questionnaire, central line-associated bloodstream infection rates, bloodstream infection prevention intervention phase, ICU type, hospital bed size, and hospital teaching status. Intensive care units with lower perceived safety climate, greater stress recognition, higher perceptions of management, and better working conditions were more likely to adopt CUSP. Intensive care units that implemented the infection prevention interventions late were less likely to adopt CUSP. Mixed ICUs and ICUs in large hospitals were also less likely to use CUSP. Staff-perceived safety climate, ICU type, and hospital size were related to ICUs' implementation of CUSP. Better baseline safety climate or lower perceived organizational support reduced uptake. The findings can help hospital leaders and collaborative experts identify units that are less likely to implement cultural interventions.


Relation of preclinical toxicology to findings in early clinical trials.
The evolution of the Division of Cancer Treatment's preclinical toxicology protocols over the last decade, a description of the current protocol, and the progress of this protocol regarding quantitative and qualitative relationships to current clinical findings are presented in this report. Data are reviewed for seven experimental antineoplastic drugs. Preliminarily, the following conclusions can be made from preclinical and clinical toxicology experience with these first seven drugs. The 1/10 MELD10 establishes a safe human starting dose. Six of seven drugs could have started at 1/10 MELD10 with no adverse effects. Toxicity data from the beagle dog did not effectively predict whether the 1/10 MELD10 dose level represents a hazard to humans. Clinical dose escalation procedures can not be efficiently predicted from currently acquired preclinical information. Toxicity studies in dogs were effective in disclosing the human dose-limiting toxic effects and approximated the maximally tolerated dose for six of seven drugs. In the exceptional case, the dose level predicted for human toxicity was grossly underestimated in both experimental species. We conclude that the preclinical toxicity data from the beagle dog are valuable in predicting the potential risk to humans, even though the safety of the entry-level doses is occasionally underpredicted.


Omitting of bougie appears to be safe for the performance of the fundal wrap at laparoscopic Nissen fundoplication.
Some operative techniques in fundoplication seem to increase the incidence of obstructive symptoms. Some authors believe that using intraesophageal bougie and preparing a short and floppy valve in laparoscopic Nissen fundoplication will help to decrease any possible tight crus repair and wrap and so it is effective to decrease the prevalence of postoperative dysphagia. The aim of this study is to show that there is no absolute benefit of routine insertion of a bougie during laparoscopic Nissen fundoplication in relation to post-operative dysphagia. All patients who underwent laparoscopic Nissen fundoplication by a single surgeon between January 2001 and August 2011 were reviewed retrospectively. Esophageal bougie intubation was performed in none of the 154 patients. The operation technique, the duration of the operation, hospital stay and the improvement of the symptoms were assessed. The patients who had esophagitis with Barrett's esophagus and who had hiatal hernia that could not get benefit from medical therapy, were selected for the surgery. Laparoscopic Nissen fundoplication with cruroraphy were done in all patients. Ninety-six of the patients were female and 58 were male. The mean symptom duration was 3.6±0.6 years. The only complication was dysphagia. In eighth week, dysphagia resolved in all patients. Laparoscopic Nissen fundoplication can be safely performed without the routine use of an esophageal bougie and it does not increase the postoperative dysphagia rate.


Degradation Products of Benzophenone-3 in Chlorinated Seawater Swimming Pools.
Oxybenzone (2-hydroxy-4-methoxyphenone, benzophenone-3) is one of the UV filters commonly found in sunscreens. Its presence in swimming pools and its reactivity with chlorine has already been demonstrated but never in seawater swimming pools. In these pools, chlorine added for disinfection results in the formation of bromine, due to the high levels of bromide in seawater, and leads to the formation of brominated disinfection byproducts, known to be more toxic than chlorinated ones. Therefore, it seems important to determine the transformation products of oxybenzone in chlorinated seawater swimming pools; especially that users of seawater swimming pools may apply sunscreens and other personal-care products containing oxybenzone before going to pools. This leads to the introduction of oxybenzone to pools, where it reacts with bromine. For this purpose, the reactivity of oxybenzone has been examined as a function of chlorine dose and temperature in artificial seawater to assess its potential to produce trihalomethanes and to determine the byproducts generated following chlorination. Increasing doses of chlorine and increasing temperatures enhanced the formation of bromoform. Experiments carried out with excess doses of chlorine resulted in the degradation of oxybenzone and allowed the determination of the degradation mechanisms leading to the formation of bromoform. In total, ten transformation products were identified, based on which the transformation pathway was proposed.


[Variants of retroperitoneal vascular structure in patients with early-stage cervical cancer who underwent systematic paraaortic and pelvic lymphadenectomy].
The aim of this study was to identify variants of retroperitoneal vascular structure during systematic paraaortic lymphadenectomy in patients with early-stage cervical cancer and to investigate the effects of these anomalies in surgical procedures. 79 patients who had undergone systematic paraaortic and bilateral pelvic lymph node dissection between 2006 and 2013 were included. Normal architecture and structural anomalies of inferior vena cava, renal arteries and veins, common iliac vein and ovarian vessels were studied. Variants of major retroperitoneal vascular structure were present in 10 patients (12.7%). Variants of renal vessels were identified in 8 patients (10.1%): supernumerary renal arteries and veins observed in 5 patients (6.3%); retroaortic left renal vein type I and II - in 3 patients (3.8%). A rare variant as double vena cava inferior was detected in 1 patient (1.3%). Vessel injury was present no one case in patients with variants of vascular structures and in 1 of 69 (1.4%) patients without variants of retroperitoneal vascular structure. There was no difference in intraoperative hemorrhage, transfusion red blood cell and rate of intraoperative hemoglobin between the groups. Thus the acquisition of knowledge and visualization of vascular variations decrease complications during systematic paraaortic and bilateral pelvic lymphadenectomy.


Risk Management for Opioid Prescribing in the Treatment of Patients With Pain From Cancer or Terminal Illness: Inadvertent Oversight or Taboo?
As the United States experiences an epidemic of prescription drug abuse, and guidelines on safe practices in prescribing opioids in chronic pain have subsequently emerged from professional organizations and governmental agencies, limited guidance exists for prescribers of opioids to treat pain in patients with cancer or terminal illness. Patients with active cancer or terminal illness often have pain and are frequently prescribed opioids and other controlled substances. Current studies suggest that patients with cancer have similar rates of risk for misuse, abuse, and addiction as the general public. Moreover, palliative care and hospice programs appear poorly prepared for assessing or managing patients with aberrant behaviors or evidence of drug abuse. Further research and professional consensus are needed to help address the challenges associated with misuse, abuse, and addiction in patients with cancer and terminal illness.


Treatment of Alzheimer's disease: current status and new perspectives.
Alzheimer's disease (AD) is the most common neurodegenerative disorder and the most prevalent cause of dementia with ageing. Pharmacological treatment of AD is based on the use of acetylcholinesterase inhibitors, which have beneficial effects on cognitive, functional, and behavioural symptoms of the disease, but their role in AD pathogenesis is unknown. Other pharmacological therapies are becoming available--including the recently approved drug memantine, an NMDA channel blocker indicated for advanced AD. Here, we review clinical features of the available cholinesterase inhibitors (donepezil, rivastigmine, and galantamine) including their pharmacological properties, the evidence for switching from one agent to another, "head to head" studies, and the emerging evidence for the use of memantine in AD. New therapeutic approaches--including those more closely targeted to the pathogenesis of the disease--will also be reviewed. These potentially disease modifying treatments include amyloid-beta-peptide vaccination, secretase inhibitors, cholesterol-lowering drugs, metal chelators, and anti-inflammatory agents.


Biomarkers Can't Bypass the Mouth of a Wound.
This article critiques the idealization of a biomarker-based "objective pain scale" in order to argue for increased investment in communication-centric approaches to chronic pain diagnosis and treatment. Although new technological advances and the rise of big data have revived old fantasies of objective pain measures, scholars have long affirmed the dangers of converting human experience into numbers, as well as the fundamental impossibility of reducing pain to physiology. Biomarkers can certainly be useful tools, but investments must also be made in fostering the "strong objectivity" that feminist scholars have advocated for and that the incorporation of narrative-driven initiatives can provide. Because expressing pain is notoriously difficult, doing this creative, communication-driven work well requires substantial effort, time, and training. Engaging with chronic pain from a feminist standpoint-one that affirms individuals' situated experiences as valuable data and that attends to the rich multi-modal vocabularies emerging on social media-can pave the way to a more equitable, ethical, and effective future of pain care.


High-efficiency semi-external-cavity-structured periodically poled MgLN-based optical parametric oscillator with output power exceeding 9.2 W at 3.82 microm.
We report a high-efficiency and high-power mid-IR laser generation by a periodically poled (PP) MgLN-based optical parametric oscillator (OPO) working at room temperature, from which 9.23 W of output was obtained at 3.82 microm when pumped by a linearly polarized acousto-optic Q-switched Nd:YVO(4) laser of 48.2 W output. A semi-external-cavity structure was applied in the OPO system to avoid the conversion saturation caused by the thermal lens effect of the PPMgLN crystal and thus to maintain the high conversion efficiency and the high beam quality under the high power level. It was computed that 29.4% slope efficiency and 19.2% total efficiency were realized for the 1.063-3.82 microm conversion.


Transcutaneous Vagal Nerve Stimulation Alone or in Combination With Radiotherapy Stimulates Lung Tumor Infiltrating Lymphocytes But Fails to Suppress Tumor Growth.
The combination of radiotherapy (RT) with immunotherapy represents a promising treatment modality for non-small cell lung cancer (NSCLC) patients. As only a minority of patients shows a persistent response today, a spacious optimization window remains to be explored. Previously we showed that fractionated RT can induce a local immunosuppressive profile. Based on the evolving concept of an immunomodulatory role for vagal nerve stimulation (VNS), we tested its therapeutic and immunological effects alone and in combination with fractionated RT in a preclinical-translational study. Lewis lung carcinoma-bearing C57Bl/6 mice were treated with VNS, fractionated RT or the combination while a patient cohort with locally advanced NSCLC receiving concurrent radiochemotherapy (ccRTCT) was enrolled in a clinical trial to receive either sham or effective VNS daily during their 6 weeks of ccRTCT treatment. Preclinically, VNS alone or with RT showed no therapeutic effect yet VNS alone significantly enhanced the activation profile of intratumoral CD8+ T cells by upregulating their IFN-γ and CD137 expression. In the periphery, VNS reduced the RT-mediated rise of splenic, but not blood-derived, regulatory T cells (Treg) and monocytes. In accordance, the serological levels of protumoral CXCL5 next to two Treg-attracting chemokines CCL1 and CCL22 were reduced upon VNS monotherapy. In line with our preclinical findings on the lack of immunological changes in blood circulating immune cells upon VNS, immune monitoring of the peripheral blood of VNS treated NSCLC patients (n=7) did not show any significant changes compared to ccRTCT alone. As our preclinical data do suggest that VNS intensifies the stimulatory profile of the tumor infiltrated CD8+ T cells, this favors further research into non-invasive VNS to optimize current response rates to RT-immunotherapy in lung cancer patients.


MPDZ is associated with immune infiltration and regulates migration and invasion by switching YAP1 phosphorylation in colorectal cancer.
Multiple PDZ Domain Crumbs Cell Polarity Complex Component (MPDZ) is involved in a few human cancers. However, the features and potential mechanisms of MPDZ in progression of colorectal cancer (CRC) remains unknown. The prognostic role of MPDZ in CRC was determined by Kaplan-Meier and univariate regression analysis. Enrichment analysis was performed to characterize crucial pathways of MPDZ. Immune infiltration and immunotherapeutic outcome were further evaluated. CCK8, EDU, transwell, and wound healing assay were used to assess the influence of MPDZ on pernicious performance of CRC cells. CD8+ T cells and CRC cells were co-cultured to explore the effect of MPDZ on the tumor microenvironment. qRT-PCR, western blot, immunoprecipitation (IP), and methylated RNA immunoprecipitation (me-RIP) were implemented in seeking for the potential mechanisms of MPDZ in CRC. CRC patients with elevated MPDZ expression suffered from significantly worse prognosis. Enrichment analysis revealed that MPDZ involved in pathways related to metastasis and cell cycle in CRC. In addition, MPDZ expression were related to several immunoinhibitors and had the ability to predict immunotherapy response. Finally, in vitro assays demonstrated that MPDZ knockdown inhibited migration, invasion and immune evasion of CRC cells. Mechanistically, MPDZ knockdown enhanced YAP1 phosphorylation by increased LATS1 expression. Moreover, m6A-MPDZ mRNA may be recognized and degraded by m6A recognition protein YTHDF2. MPDZ was critical for CRC development and could be a promising candidate for the treatment of CRC patients.


Surface-Modified Polypyrrole-Coated PLCL and PLGA Nerve Guide Conduits Fabricated by 3D Printing and Electrospinning.
The efficiency of nerve guide conduits (NGCs) in repairing peripheral nerve injury is not high enough yet to be a substitute for autografts and is still insufficient for clinical use. To improve this efficiency, 3D electrospun scaffolds (3D/E) of poly(l-lactide-co-ε-caprolactone) (PLCL) and poly(l-lactide-co-glycolide) (PLGA) were designed and fabricated by the combination of 3D printing and electrospinning techniques, resulting in an ideal porous architecture for NGCs. Polypyrrole (PPy) was deposited on PLCL and PLGA scaffolds to enhance biocompatibility for nerve recovery. The designed pore architecture of these "PLCL-3D/E" and "PLGA-3D/E" scaffolds exhibited a combination of nano- and microscale structures. The mean pore size of PLCL-3D/E and PLGA-3D/E scaffolds were 289 ± 79 and 287 ± 95 nm, respectively, which meets the required pore size for NGCs. Furthermore, the addition of PPy on the surfaces of both PLCL-3D/E (PLCL-3D/E/PPy) and PLGA-3D/E (PLGA-3D/E/PPy) led to an increase in their hydrophilicity, conductivity, and noncytotoxicity compared to noncoated PPy scaffolds. Both PLCL-3D/E/PPy and PLGA-3D/E/PPy showed conductivity maintained at 12.40 ± 0.12 and 10.50 ± 0.08 Scm-1 for up to 15 and 9 weeks, respectively, which are adequate for the electroconduction of neuron cells. Notably, the PLGA-3D/E/PPy scaffold showed superior cytocompatibility when compared with PLCL-3D/E/PPy, as evident via the viability assay, proliferation, and attachment of L929 and SC cells. Furthermore, analysis of cell health through membrane leakage and apoptotic indices showed that the 3D/E/PPy scaffolds displayed significant decreases in membrane leakage and reductions in necrotic tissue. Our finding suggests that these 3D/E/PPy scaffolds have a favorable design architecture and biocompatibility with potential for use in peripheral nerve regeneration applications.


Binder-free V2O5/CNT paper electrode for high rate performance zinc ion battery.
Organic compounds, such as polyvinylidene fluoride (PVDF), have been widely used as a binder in battery electrode preparations. While such an approach does not have a significant impact on the performance of the batteries that utilize low valence ions, such as the Li ion battery (LIB), the diffusion of high valence ions (such as Zn2+) will be severely impaired. This will be especially pronounced if the polymeric binder contains highly electronegative atoms, such as fluorine. The high charge density ions, such as Zn2+, tend to adsorb onto these electronegative atoms, thus the mobility of these ions across the material is inevitably affected. As such, it becomes highly necessary to consider the binder-free electrode architecture when designing a high rate performing and cycling-stable zinc ion battery (ZIB) cathode. Herein, this work demonstrates an improved Zn ion battery by adopting a freestanding electrode. The obtained V2O5/CNT paper electrode delivers a specific capacity of 312 mA h g-1, while achieving a respectable 75% retention in capacity after increasing the current density by 10-fold. Furthermore, excellent cycling stability is recorded with 81% capacity retention after 2000 cycles at 1.0 A g-1. Thus, this work clearly demonstrated that the freestanding electrode is a promising approach for high valence ion batteries.


The choline-methionine interrelationship for growth of the chick.
Three experiments involving 1230 battery-reared crossbred chicks were conducted to evaluate the potential sparing effect of choline on methionine and vice versa. Experiment 1 employed a crystalline amino acid diet to establish the sulfur-amino acid (SAA) and choline requirement for maximal feed efficiency of chicks during the period 8 to 18 days posthatching. Six graded levels of DL-methionine (.20 to .45% in the presence of .20% L-cystine) and five of choline (0 to 1216 mg/kg) were employed in a 6 X 5 factorial treatment arrangement. Gain/feed ratio was maximized at 608 mg/kg choline at all levels of methionine and at .30 to .35% methionine at all levels of choline. Two identical experiments (8 to 25 days posthatching) with a corn-soybean meal diet were carried out to explore the relationship between supplemental methionine (0 to .20% in five equal increments) and supplemental choline (0, 217, and 434 mg/kg). Optimal performance occurred at .10% supplemental methionine regardless of choline level and at 217 mg/kg choline at supplemental methionine levels of 0 and .05%. At .10, .15, and .20% supplemental methionine, no gain or gain/feed response to supplemental choline was observed. It was thus apparent that excess levels of choline had minimal capacity to reduce the dietary requirement for methionine. Excess levels of methionine, however, seemed to have a consistent, although small, effect on the chick's dietary need for choline.


Aberrantly flattened responsivity to emotional pictures in paranoid schizophrenia.
To investigate the nature of emotional experience in schizophrenia, we examined emotional responses to affective stimuli. Twenty-one outpatients with schizophrenia (9 paranoid, 12 nonparanoid) and 20 normal controls rated the arousal and valence that they experienced from the presentation of 60 pictures. Schizophrenia patients displayed less emotional responsivity to the positive stimuli and they displayed diverse responsivity to the negative stimuli, which depended upon arousal level. Further analysis, using schizophrenia subtype, indicated that nonparanoid patients reported increased negative responsivity and decreased positive responsivity, regardless of arousal level. However, paranoid schizophrenia patients showed enhanced self-reported experiences of emotion to the low arousing stimuli and diminished responsivity to the high arousing stimuli. This pattern was robust to the negative stimuli. These findings suggest that paranoid schizophrenia patients might suffer from aberrantly flattened responses to negative emotional stimuli, and that this may account for paranoid tendency and secondary social isolation in paranoid schizophrenia.


A Tunable, Three-Dimensional In Vitro Culture Model of Growth Plate Cartilage Using Alginate Hydrogel Scaffolds.
Defining the final size and geometry of engineered tissues through precise control of the scalar and vector components of tissue growth is a necessary benchmark for regenerative medicine, but it has proved to be a significant challenge for tissue engineers. The growth plate cartilage that promotes elongation of the long bones is a good model system for studying morphogenetic mechanisms because cartilage is composed of a single cell type, the chondrocyte; chondrocytes are readily maintained in culture; and growth trajectory is predominately in a single vector. In this cartilage, growth is generated via a differentiation program that is spatially and temporally regulated by an interconnected network composed of long- and short-range signaling mechanisms that together result in the formation of functionally distinct cellular zones. To facilitate investigation of the mechanisms underlying anisotropic growth, we developed an in vitro model of the growth plate cartilage by using neonatal mouse growth plate chondrocytes encapsulated in alginate hydrogel beads. In bead cultures, encapsulated chondrocytes showed high viability, cartilage matrix deposition, low levels of chondrocyte hypertrophy, and a progressive increase in cell proliferation over 7 days in culture. Exogenous factors were used to test functionality of the parathyroid-related protein-Indian hedgehog (PTHrP-IHH) signaling interaction, which is a crucial feedback loop for regulation of growth. Consistent with in vivo observations, exogenous PTHrP stimulated cell proliferation and inhibited hypertrophy, whereas IHH signaling stimulated chondrocyte hypertrophy. Importantly, the treatment of alginate bead cultures with IHH or thyroxine resulted in formation of a discrete domain of hypertrophic cells that mimics tissue architecture of native growth plate cartilage. Together, these studies are the first demonstration of a tunable in vitro system to model the signaling network interactions that are required to induce zonal architecture in growth plate chondrocytes, which could also potentially be used to grow cartilage cultures of specific geometries to meet personalized patient needs.


Ventricular septal defect: the three-dimensional point of view.
This case highlights the clinical usefulness of three-dimensional (3D) echocardiography. The diagnosis of inter-ventricular septal defect associated with aortic regurgitation has been performed in a 50-year-old man using 3D echocardiography. This advanced echocardiography could accurately reproduce the anatomy of the defect and provide further insights in the mechanisms of aortic regurgitation showing an unusual non-coronary cusp prolapse. The routinely use of 3D echocardiography in clinics might allow a better characterization of cardiac anatomy, especially of aortic valve disorders.


Traffic crash involvement: experiential driving knowledge and stressful contextual antecedents.
Researchers have rarely examined stressful environments and psychological characteristics as predictors of driving behavior in the same study. The authors hypothesized that (a) safer drivers more accurately assess physical and emotional traffic hazards and (b) stress and emotional states elevate crash risk. The hypotheses were evaluated with procedural and declarative tacit driving knowledge tests requiring assessment of emotional and contextual hazards and with accident reports describing crash antecedents, including stressful events and environmental conditions. Analyses identified separate driving knowledge factors corresponding to emotional and contextual hazards that were significantly related to the crash criteria. Accident report analyses show that stress significantly elevates at-fault crash risk. The results demonstrate the importance of experiential knowledge acquired without instruction (procedural or tacit knowledge) and provide safety recommendations.


Comparison of benefit-to-risk ratios of aspirin and fenoprofen: controlled multicentre study in rheumatoid arthritis.
The benefit-to-risk ratios of fenoprofen (2.4 gm/day) and aspirin (3.9 gm/day) were compared in a randomized, double-blind, 26-week parallel study involving 216 patients. Criteria for inclusion, exclusion, subjective, and objective evaluations were based on the PMA-FDA Nonsteroidal Anti-Inflammatory Drug Clinical Testing Guidelines. Thirty-four of 109 aspirin-treated patients and 23 of 107 patients on fenoprofen dropped out of the study. Both fenoprofen and aspirin brought about improvement in most efficacy parameters measured, but fenoprofen was superior to aspirin (p less than 0.05) in reduction of swollen joints, grip strength, activity index, and patients' preference of medication. The number and frequency of complaints and the incidence of abnormal SGOT levels, were greater with aspirin than with fenoprofen. The study suggests that fenoprofen has a better benefit-to-risk ratio than aspirin, when given in equally effective doses.


Psychometric properties of infant electroencephalography: Developmental stability, reliability, and construct validity of frontal alpha asymmetry and delta-beta coupling.
Resting-state electroencephalography (EEG) provides developmental neuroscientists a noninvasive view into the neural underpinnings of cognition and emotion. Recently, the psychometric properties of two widely used neural measures in early childhood-frontal alpha asymmetry and delta-beta coupling-have come under scrutiny. Despite their growing use, additional work examining how the psychometric properties of these neural signatures may change across infancy is needed. The current study examined the developmental stability, split-half reliability, and construct validity of infant frontal alpha asymmetry and delta-beta coupling. Infants provided resting-state EEG data at 8, 12, and 18 months of age (N = 213). Frontal alpha asymmetry and delta-beta coupling showed significant developmental change from 8 to 18 months. Reliability for alpha asymmetry, and alpha, delta, and beta power, individually, was generally good. In contrast, the reliability of delta-beta coupling scores was poor. Associations between frontal alpha asymmetry and approach tendencies generally emerged, whereas stronger (over-coupled) delta-beta coupling scores were associated with profiles of dysregulation and low inhibition. However, the individual associations varied across time and specific measures of interest. We discuss these findings with a developmental lens, highlighting the importance of repeated measures to better understand links between neural signatures and typical and atypical development.


Feasibility of the fetal anatomic and maternal pelvic survey by magnetic resonance imaging at term.
This study was undertaken to determine which nonbiometric components of the American College of Obstetricians and Gynecologists recommended ultrasound fetal anatomic and maternal pelvic survey can be evaluated by fast acquisition magnetic resonance (MR) imaging in the term fetus. Nonbiometric components of the fetal survey were retrospectively evaluated by fast acquisition MR images. Thirteen components were assessed, including fetal number, presentation, placental location, qualitative assessment of amniotic fluid, and the maternal pelvis (n=5). The fetal anatomy included bilateral cerebral ventricles, spine, bilateral kidneys, stomach, bladder, cord insertion, sex, and four-chamber view of the heart (n=8). Studies were performed before delivery and neonatal outcomes were reviewed. All 50 neonates were normal at follow-up. A total of 94% (702 of 750) of the components were assessed by MR imaging. Fetal MR imaging can assess 94% of the American College of Obstetricians and Gynecologists recommended ultrasound fetal and pelvic anatomic survey. If the heart is excluded, this increases to 99%.


Relationship between radiation therapy and bullous pemphigoid.
Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease. To review the literature on radiation therapy (RT)-associated BP. A review of the English language literature on patients who developed BP during and up to 10 years post RT was performed. 29 patients were reported. 25 (86.2%) were women, 84% of whom had received RT for breast cancer. Three patients were male (10.3%). Gender was not mentioned in 1 (3.4%). 72% developed BP post RT; 28% developed BP while undergoing RT. BP was initially localized to irradiated sites in 25 patients and to non-irradiated sites in 2 patients. Two patients presented with generalized disease. Disease control was reported in 12 patients, partial remission in 7 and complete remission in 5. The clinical profile, response to therapy and clinical outcome may indicate that RT-associated BP may be a specific subset of BP with a relatively benign course.


ESR investigations of gamma irradiated medical devices.
Guided tissue regeneration (GTR) and guided bone regeneration (GBR) biomaterials have been employed in recent years for periodontal procedures. In the present study, widely used dental GTR/GBR biomaterials (grafts: G1, G2, G3 and membranes: M1, M2, M3, M4) were exposed to gamma irradiation at an absorbed dose range of 0-50kGy and the radiolytic intermediates that have been created in the samples upon irradiation were characterized in detail by Electron Spin Resonance (ESR) spectroscopy. We aimed to standardize the measurement conditions for practical applications of gamma radiation sterilization of GTR/GBR biomaterials. We investigated the characteristic features of free radicals in gamma irradiated GTR/GBR biomaterials and examined the stability of the induced radicals at room temperature and accelerated stability conditions with ESR spectroscopy including dose-response curves, microwave power studies, dosimetric features of the biomaterials, variations of the peak heights with temperature, and long term stabilities of the radical species. Long-term stability studies have shown that G1 is quite stable even in accelerated storage conditions. The signal intensities of graft-type GTR/GBR biomaterials stored in normal and stability conditions have decreased very rapidly even only a few days after gamma irradiation sterilization. Thus, those samples indicating relatively low stability features can be very good candidates for the radiosterilization process. The beta-tricalcium phosphate and PLGA containing G1 and M1 respectively have found to be the most gamma stable bone substitute biomaterials and be safely sterilized by gamma radiation. ESR spectroscopy is an appropriate technique in giving important detailed spectroscopic findings in the gamma radiation sterilization studies of GTR/GBR biomaterials.


Vapocoolants (cold spray) for pain treatment during intravenous cannulation.
Intravenous cannulation is a painful procedure that can provoke anxiety and stress. Injecting local anaesthetic can provide analgesia at the time of cannulation, but it is a painful procedure. Topical anaesthetic creams take between 30 and 90 minutes to produce an effect. A quicker acting analgesic allows more timely investigation and treatment. Vapocoolants have been used in this setting, but studies have reported mixed results. To determine effects of vapocoolants on pain associated with intravenous cannulation in adults and children. To explore variables that might affect the performance of vapocoolants, including time required for application, distance from the skin when applied and time to cannulation. To look at adverse effects associated with the use of vapocoolants. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Latin American Caribbean Health Sciences Literature (LILACS), the Cumulative Index to Nursing and Allied Health Literature (CINAHL), the Institute for Scientific Information (ISI) Web of Science and the http://clinicaltrials.gov/, http://www.controlled-trials.com/ and http://www.trialscentral.org/ databases to 1 May 2015. We applied no language restrictions. We also scanned the reference lists of included papers. We included all blinded and unblinded randomized controlled trials (RTCs) comparing any vapocoolant with placebo or control to reduce pain during intravenous cannulation in adults and children. Three review authors independently assessed trial quality and extracted data, contacted study authors for additional information and assessed included studies for risk of bias. We collected and analysed data for the primary outcome of pain during cannulation, and for the secondary outcomes of pain associated with application of the vapocoolant, first attempt success rate of intravenous cannulation, adverse events and participant satisfaction. We performed subgroup analyses for the primary outcome to examine differences based on age of participant, type of vapocoolant used, application time of vapocoolant and clinical situation (emergency vs elective). We used random-effects model meta-analysis in RevMan 5.3 and assessed heterogeneity between trial results by examining forest plots and calculating the I(2) statistic. We found nine suitable studies of 1070 participants and included them in the qualitative analyses. We included eight studies of 848 participants in the meta-analysis for the primary outcome (pain during intravenous cannulation). Use of vapocoolants resulted in a reduction in pain scores as measured by a linear 100 mm visual analogue scale (VAS 100) compared with controls (difference between means -12.5 mm, 95% confidence interval (CI) -18.7 to -6.4 mm; moderate-quality evidence). We could not include in the meta-analysis one study, which showed no effects of the intervention.Use of vapocoolants resulted in increased pain scores at the time of application as measured by a VAS 100 compared with controls (difference between means 6.3 mm, 95% CI 2.2 to 10.3 mm; four studies, 461 participants; high-quality evidence) and led to no difference in first attempt success compared with controls (risk ratio (RR) 1.00, 95% CI 0.94 to 1.06; six studies, 812 participants; moderate-quality evidence). We documented eight minor adverse events reported in 279 vapocoolant participants (risk difference (RD) 0.03, 95% CI 0 to 0.05; five studies, 551 participants; low quality-evidence).The overall risk of bias of individual studies ranged from low to high, with high risk of bias for performance and detection bias in four studies. Sensitivity analysis showed that exclusion of studies at high or unclear risk of bias did not materially alter the results of this review. Moderate-quality evidence indicates that use of a vapocoolant immediately before intravenous cannulation reduces pain during the procedure. Use of vapocoolant does not increase the difficulty of cannulation nor cause serious adverse effects but is associated with mild discomfort during application.


Cancer of unknown primary.
Cancers of unknown primary (CUPs) are histologically confirmed, metastatic malignancies with a primary tumor site that is unidentifiable on the basis of standard evaluation and imaging studies. CUP comprises 2-5% of all diagnosed cancers worldwide and is characterized by early and aggressive metastasis. Current standard evaluation of CUP requires histopathologic evaluation and identification of favorable risk subtypes that can be more definitively treated or have superior outcomes. Current standard treatment of the unfavorable risk subtype requires assessment of prognosis and consideration of empiric chemotherapy. The use of molecular tissue of origin tests to identify the likely primary tumor site has been extensively studied, and here we review the rationale and the evidence for and against the use of such tests in the assessment of CUPs. The expanding use of next generation sequencing in advanced cancers offers the potential to identify a subgroup of patients who have actionable genomic aberrations and may allow for further personalization of therapy.


Advances in catecholamine and metabolite measurements for diagnosis of pheochromocytoma.
Assessment of catecholamine production and excretion is important in the laboratory detection of pheochromocytoma, a rare but curable cause of hypertension. Advances in catecholamine and metabolite methodologies have enhanced the diagnostic acumen by increasing analytical sensitivity and eliminating many of the interferences observed with earlier methods. Estimation of urinary catecholamines metanephrine and vanillylmandelic acid is routinely used in the biochemical detection of pheochromocytoma and in monitoring the completeness of tumor excision as well as the possibility of recurrence. Traditional spectrophotometric and fluorometric methods for urinary catecholamines and their metabolites are being replaced by highly sensitive and selective chromatographic methods. The ability to quantify individual catecholamines and metanephrines by high-performance liquid chromatography is of particular value for detecting familial forms of the tumor that may secrete epinephrine. Plasma norepinephrine and epinephrine measurements are of additional diagnostic value in determining recent catecholamine release and response to clonidine suppression. For either urine or plasma measurements, appropriate patient preparation, sample collection, and method validation along with an understanding of the variable pattern of catecholamine secretion and metabolism in pheochromocytoma are essential. Advances in laboratory methodology and reference intervals for catecholamines for clinical interpretation are reviewed.


Bacterial behavior in human blood reveals complement evaders with some persister-like features.
Bacterial bloodstream infections (BSI) are a major health concern and can cause up to 40% mortality. Pseudomonas aeruginosa BSI is often of nosocomial origin and is associated with a particularly poor prognosis. The mechanism of bacterial persistence in blood is still largely unknown. Here, we analyzed the behavior of a cohort of clinical and laboratory Pseudomonas aeruginosa strains in human blood. In this specific environment, complement was the main defensive mechanism, acting either by direct bacterial lysis or by opsonophagocytosis, which required recognition by immune cells. We found highly variable survival rates for different strains in blood, whatever their origin, serotype, or the nature of their secreted toxins (ExoS, ExoU or ExlA) and despite their detection by immune cells. We identified and characterized a complement-tolerant subpopulation of bacterial cells that we named "evaders". Evaders shared some features with bacterial persisters, which tolerate antibiotic treatment. Notably, in bi-phasic killing curves, the evaders represented 0.1-0.001% of the initial bacterial load and displayed transient tolerance. However, the evaders are not dormant and require active metabolism to persist in blood. We detected the evaders for five other major human pathogens: Acinetobacter baumannii, Burkholderia multivorans, enteroaggregative Escherichia coli, Klebsiella pneumoniae, and Yersinia enterocolitica. Thus, the evaders could allow the pathogen to persist within the bloodstream, and may be the cause of fatal bacteremia or dissemination, in particular in the absence of effective antibiotic treatments.


Rapid diagnosis of pulmonary coccidioidomycosis. Cytologic v potassium hydroxide preparations.
In 26 patients with culture-proved pulmonary coccidioidomycosis, cytologic preparations of respiratory secretions were significantly more sensitive (38.5%) than potassium hydroxide (KOH) preparations (15.4%) in identifying spherules of Coccidioides immitis. Those patients able to produce sputum or having multiple-lobe pneumonitis on chest roentgenogram appeared to be more likely to have spherules identified in the sputum by either technique. In the absence of sputum production or multiple-lobe pneumonitis, neither cytologic nor KOH preparations were likely to disclose spherules. Because of its greater sensitivity, a cytologic preparation should be examined in addition to a KOH preparation when pulmonary coccidioidomycosis is a clinical consideration.


The neural basis of implicit learning and memory: a review of neuropsychological and neuroimaging research.
Memory systems research has typically described the different types of long-term memory in the brain as either declarative versus non-declarative or implicit versus explicit. These descriptions reflect the difference between declarative, conscious, and explicit memory that is dependent on the medial temporal lobe (MTL) memory system, and all other expressions of learning and memory. The other type of memory is generally defined by an absence: either the lack of dependence on the MTL memory system (nondeclarative) or the lack of conscious awareness of the information acquired (implicit). However, definition by absence is inherently underspecified and leaves open questions of how this type of memory operates, its neural basis, and how it differs from explicit, declarative memory. Drawing on a variety of studies of implicit learning that have attempted to identify the neural correlates of implicit learning using functional neuroimaging and neuropsychology, a theory of implicit memory is presented that describes it as a form of general plasticity within processing networks that adaptively improve function via experience. Under this model, implicit memory will not appear as a single, coherent, alternative memory system but will instead be manifested as a principle of improvement from experience based on widespread mechanisms of cortical plasticity. The implications of this characterization for understanding the role of implicit learning in complex cognitive processes and the effects of interactions between types of memory will be discussed for examples within and outside the psychology laboratory.


Socio-economic and environmental factors in the global spread of COVID-19 outbreak.
COVID-19 is a virus with a very fast spread rate in the world. Therefore, knowledge of factors that may explain such spread is paramount. The main objective of this research was to analyze the determinants of the virus spread worldwide. Unlike previous studies that were limited to traditional factors, this research extends the analysis to government measures (quarantine, containment, and response budget) against the spread of the virus. Thus, an econometric model relating the variable of interest to a number of variables was carried out using the Ordinary Least Squares (OLS) and the Two Steps Least Squares (2SLS) methods on a sample of 163 countries. The main findings indicate that economic factors such as the level of development, the degree of trade openness and the response budget to the COVID-19 pandemic, have a positive effect on the spread of the virus. With regard to social factors, the population density and confinement are major causes of the spread of the virus. Finally, temperature contributes to reduce the spread of the virus. These findings are robust to the estimation technique and to the measurement of the spread of the virus considered. In the light to these findings, implications for economic policies have been drawn.


Alginate encapsulation of chitosan nanoparticles: a viable alternative to soluble chemical signaling in definitive endoderm induction of human embryonic stem cells.
Human embryonic stem cells (hESCs) are characterized by both their pluripotency and ability to self-renew, rendering them attractive for treatment of degenerative diseases. The cues necessary to induce hESC differentiation to a desired lineage can be categorized as either chemical or biophysical in nature. While chemical cues are used as primary inducers of differentiation, biophysical cues have been found to augment the process. In this regard, we have designed a novel chitosan nanoparticle augmented encapsulated alginate (CNPEA) platform which can not only augment, but induce differentiation of hESCs into the definitive endoderm (DE) lineage in the absence of specific soluble chemical inducers. These endoderm cells were comparable in phenotype with chemically driven DE cells and remained amenable to further maturation into pancreatic lineages. This study demonstrates the feasibility of carefully designed and tailored nanomaterials inducing differentiation, and moreover demonstrating the possibility of replacing growth factors by material cues.


A fast dose calculation method based on table lookup for IMRT optimization.
This note describes a fast dose calculation method that can be used to speed up the optimization process in intensity-modulated radiotherapy (IMRT). Most iterative optimization algorithms in IMRT require a large number of dose calculations to achieve convergence and therefore the total amount of time needed for the IMRT planning can be substantially reduced by using a faster dose calculation method. The method that is described in this note relies on an accurate dose calculation engine that is used to calculate an approximate dose kernel for each beam used in the treatment plan. Once the kernel is computed and saved, subsequent dose calculations can be done rapidly by looking up this kernel. Inaccuracies due to the approximate nature of the kernel in this method can be reduced by performing scheduled kernel updates. This fast dose calculation method can be performed more than two orders of magnitude faster than the typical superposition/convolution methods and therefore is suitable for applications in which speed is critical, e.g., in an IMRT optimization that requires a simulated annealing optimization algorithm or in a practical IMRT beam-angle optimization system.


PALB2: research reaching to clinical outcomes for women with breast cancer.
PALB2 has taken its place with bona fide breast cancer susceptibility genes. It is now well established that women who carry loss-of-function mutations in the PALB2 gene are at similarly elevated breast cancer risks to those who carry mutations in BRCA2. Information about PALB2 is now being used in breast cancer clinical genetics practice and is routinely included in breast cancer predisposition gene panel tests. Tens of thousands of women worldwide have now had genetic tests for PALB2 mutations in the context of breast cancer susceptibility. However, prospective data related to the clinical outcomes of PALB2 mutation carriers is lacking and very little information (beyond mutation penetrance) is available to guide current clinical management for carriers (affected and unaffected by cancer). In addition, clinical classification of the vast array of non-loss-of-function genetic variants identified in PALB2 is in its infancy. These are key areas of current research efforts and are important foundations on which to move information about PALB2 into the precision public health arena.


Evidence for ethnic tropism of Helicobacter pylori.
Helicobacter pylori infection in humans is linked to gastritis, gastric and duodenal ulcers, and gastric cancer. Peptic ulcer disease, as distinct from chronic asymptomatic infection, is strongly associated with expression of bacterial virulence markers, including a major antigen, CagA, and the vacuolating cytotoxin VacA. We have previously described significant differences in colonization rates, independent of socioeconomic status, among ethnic groups in New Zealand. To evaluate relative risks for peptic ulcer disease, we examined the frequency of two virulence markers in H. pylori strains infecting these ethnic groups. Although these markers occurred significantly more frequently in strains isolated from Polynesians than in strains from Europeans, this frequency was not reflected in the incidence of peptic ulcer disease in the two groups. DNA fingerprinting of the urease gene showed that Polynesians are more frequently infected by a group of strains which are genetically distinct from those affecting European New Zealanders. Our data suggest that separate bacterial lineages may have evolved in parallel with race-specific specialization.