Matrix metalloproteinase 9 activity in patients before and after endovascular or surgical repair of abdominal aortic aneurysms.
The objective of this prospective study was to assess matrix metalloproteinase 9 (MMP-9) activity in patients undergoing open surgery or endovascular repair of abdominal aortic aneurysms (AAAs), comparing changes in plasma levels in the two groups. We studied 12 patients after conventional open surgery and 9 patients after endovascular aneurysm repair. MMP-9 was assayed in plasma at baseline and 1 week and 1 month thereafter. Preoperative MMP-9 levels were similar in the two groups (41.7 +/- 19.1 vs 44.4 +/- 24.6 ng/mL; p = not significant). Assessment 1 week later showed that MMP levels in both repair groups had increased. In the open surgery group, they increased significantly (59.7 +/- 16.8 ng/mL; p < .05) but not in the endovascular group (49.3 +/- 32.4 ng/mL). One month later, MMP-9 levels decreased in both groups but not significantly (to 32.6 +/- 24.6 ng/mL for open surgery repair and to 34.7 +/- 23.5 ng/mL for endovascular repair). At 1 month after repair, MMP-9 levels decreased significantly only in smokers, whereas in nonsmokers, they did not (from 46.9 +/- 22.1 to 31.7 +/- 21.5 ng/mL in smokers [p < .05] vs from 34.7 +/- 17.4 to 37.1 +/- 28.9 ng/mL in nonsmokers). This study confirms that enzyme secretion changes during the postoperative course. The differing patterns of MMP-9 expression prevent us from reaching definitive conclusions about the use of MMP-9 as a marker during early postprocedural follow-up. An important matter to clarify is the role of MMP-9 in long-term follow-up, especially after endovascular AAA repairs.


Renewable energy transition to sustainable tourism: extrapolating from core density and non-parametric approaches.
The globe has faced severe challenges recently, and environmental deterioration has become more prominent. Therefore, the world has taken several initiatives to deal with environmental issues while the problem remains intact. Interestingly, the OECD economies are the leading example to understand the accurate picture of sustainability across the near regions. This study makes an effort to introduce the core factors such as economic development, renewable energy, tourism, natural resources, and innovations in OECD economies over the period of 2000-2021. Similarly, to investigate the study's objectives, this study employs the quantile autoregressive distributed lag model (Q-ARDL). The analyzed results show the significant contribution of renewable energy, tourism, and natural resources to environmental sustainability. In contrast, income and innovations contribute to ecological deterioration. Moreover, the quantile causality is being used by this empirical study to investigate the causal association among studied variables. However, using green energy in sustainable tourism is highly recommended for specified economies. In order to deal with environmental pressure, this research proposes green implications to attain the desired sustainability level.


Pharmaceutical Benefit-Risk Perception and Older Age: A Pilot Study.
Older age plays an important role in pharmaceutical benefit-risk perception. This creates challenges and opportunities, especially for regulatory authorities and advocacy groups seeking to communicate with patients of all ages. This study explored the pharmaceutical benefit-risk perceptions of older versus younger adults to identify age-related effects for further study. 80 face-to-face surveys were conducted with samples of older and younger respondents from Boulder, Colorado (USA), and Dublin (Ireland). Older adults were more likely than their younger counterparts to view greater risk today than 20 years ago for 14 out of 16 items ranging from diabetes and Alzheimer disease, to patients taking prescription medicines. Both older and younger respondents perceived most medical treatments as high in benefit and low in risk. Older adults construed "risk" variably as (1) side effects, (2) dangers of inappropriate use, and (3) wider issues. Crucially, older adults' quantitative benefit-risk judgments were strongly influenced by personal experiences and the positive/negative feelings they most associated with different medicines, medical procedures and tests. While positive associations influenced high benefit perceptions, negative associations influenced high risk perceptions. Age-related effects on risk perception should be further explored to help improve the effectiveness of benefit-risk communication for adults of all ages.


Small molecule-mediated directed differentiation of human embryonic stem cells toward ventricular cardiomyocytes.
The generation of human ventricular cardiomyocytes from human embryonic stem cells and/or induced pluripotent stem cells could fulfill the demand for therapeutic applications and in vitro pharmacological research; however, the production of a homogeneous population of ventricular cardiomyocytes remains a major limitation. By combining small molecules and growth factors, we developed a fully chemically defined, directed differentiation system to generate ventricular-like cardiomyocytes (VCMs) from human embryonic stem cells and induced pluripotent stem cells with high efficiency and reproducibility. Molecular characterization revealed that the differentiation recapitulated the developmental steps of cardiovascular fate specification. Electrophysiological analyses further illustrated the generation of a highly enriched population of VCMs. These chemically induced VCMs exhibited the expected cardiac electrophysiological and calcium handling properties as well as the appropriate chronotropic responses to cardioactive compounds. In addition, using an integrated computational and experimental systems biology approach, we demonstrated that the modulation of the canonical Wnt pathway by the small molecule IWR-1 plays a key role in cardiomyocyte subtype specification. In summary, we developed a reproducible and efficient experimental platform that facilitates a chemical genetics-based interrogation of signaling pathways during cardiogenesis that bypasses the limitations of genetic approaches and provides a valuable source of ventricular cardiomyocytes for pharmacological screenings as well as cell replacement therapies.


3-Bromopyruvate induces endoplasmic reticulum stress, overcomes autophagy and causes apoptosis in human HCC cell lines.
Autophagy, a cellular response to stress, plays a role in resistance to chemotherapy in cancer cells. Resistance renders systemic chemotherapy generally ineffective against human hepatocellular carcinoma (HCC). Recently, we reported that the pyruvate analog 3-bromopyruvate (3-BrPA) promoted tumor cell death by targeting GAPDH. In continuance, we investigated the intracellular response of two human HCC cell lines (Hep3B and SK-Hep1) that differ in their status of key apoptotic regulators, p53 and Fas. 3-BrPA treatment induced endoplasmic reticulum (ER) stress, translation inhibition and apoptosis based on Western blot and qPCR, pulse labeling, Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and active caspase-3 in both the cell lines. However, electron microscopy revealed that 3-BrPA treated SK-Hep1 cells underwent classical apoptotic cell death while Hep3B cells initially responded with the protective autophagy that failed to prevent eventual apoptosis. 3-BrPA treatment promotes apoptosis in human HCC cell lines, irrespective of the intracellular response.


[Amylase-producing extramedullary plasmacytoma with multiple cutaneous metastasis following a solitary plasmacytoma of bone].
A 65-year-old woman was admitted because of multiple cutaneous tumors in the left lumbar area in March 1983. In 1979, she had been diagnosed as solitary plasmacytoma (IgG, kappa) of the left femur and amputation of the left leg had been performed. In 1981, the tumor relapsed in the left ilium in association with an increased level of serum IgG with M-component and normal activity of serum amylase. The serum M-protein had been disappeared after resection of the tumor. On admission laboratory examinations showed a slightly high level of serum IgG and elevated activities of serum and urine amylase. Amylase isoenzyme analysis revealed a predominance of the S-isozyme. Bone marrow aspiration revealed no atypical plasma cells. The supernate of cultured plasma cells obtained from the cutaneous tumor contained high amylase activity consisting exclusively of S-type. Thereafter serum amylase activities changed approximately in parallel with serum M-protein levels and total tumor volumes after chemotherapy or radiotherapy. At the terminal phase in 1986, however, serum amylase activities became extraordinarily high compared with serum M-protein levels, suggesting a clonal change of the plasmacytoma cells.


Interfacial and Electronic Modulation of M-Bridged Heterostructures with L-Tryptophan and Transition Metallic Oxides: Enhancing Corrosion Resistance and Photocatalytic Activity.
Despite remarkable advancements in multilayer composite materials, achieving controlled growth on stationary platforms for optimal corrosion protection and photocatalytic capabilities remains a challenge. In this study, we introduce an innovative approach by integrating bifunctional metal-organic frameworks (MOFs) into plasma-electrolyzed layers made on AZ31 Mg alloy. Metallic oxides of Zr, Ti, and W serve as new pivotal centers for MOF formation, while L-tryptophan (Trp) acts as an organic linker. This innovative approach establishes an efficient electron transport system that acts as a functional pathway for creating highly effective and versatile materials. The tunable structure of the MOF/plasma electrolyzed layer enables it to concurrently display electrochemical stability and photocatalytic activity for the photodegradation of organic pollutants. Remarkably, the WOF complex emerges as a standout performer, effectively shielding the substrate from corrosive anion attacks. This sample showcases exceptional photocatalytic efficiency of 99.61% for crystal violet solution, with sustained performance after five cycles and a 72 h corrosion test (96.55% and 98.39% degradation, respectively). Moreover, DFT calculations elucidate the fundamental bonding modes between MOFs and inorganic constituents, delivering comprehensive insights into their structural formation. Our research addresses the critical challenge of achieving controlled growth for enhanced corrosion resistance and photocatalytic activity, demonstrating a novel pathway for creating multifunctional materials with practical applications across various fields.


Dinuclear Ruthenium Complex Based on a π-Extended Bridging Ligand with Redox-Active Tetrathiafulvalene and 1,10-Phenanthroline Units.
The synthesis of a π-extended bridging ligand with both redox-active tetrathiafulvalene (TTF) and 1,10-phenanthroline (phen) units, namely, bis(1,10-phenanthro[5,6-b])tetrathiafulvalene (BPTTF), was realized via a self-coupling reaction. Using this ligand and Ru(tbbpy)2Cl2 (tbbpy = 4,4'-di-tert-butyl-2,2'-bipyridine), the dinuclear ruthenium(II) compound [{Ru(tbbpy)2}2(BPTTF)](PF6)4 (1) has been obtained by microwave-assisted synthesis. Structural characterization of 1 revealed a crossed arrangement of the TTF moieties on adjacent dimers within the crystal structure. The optical and redox properties of 1 were investigated using electrochemical, spectroelectrochemical, electron paramagnetic resonance (EPR), and absorption spectroscopic studies combined with theoretical calculations. One exhibits a rich electrochemical behavior owing to the multiple redox-active centers. Interestingly, both the ligand BPTTF and the ruthenium compound 1 are EPR-active in the solid state owing to intramolecular charge-transfer processes. The results demonstrate that the TTF-annulated bis(phen) ligand is a promising bridging ligand to construct oligomeric or polymeric metal complexes with multiple redox-active centers.


Comparison of performance with frequency transposition hearing aids and conventional hearing aids.
Four experienced hearing aid users were evaluated using a frequency transposition (TranSonic) hearing system. Following a trial period, the Abbreviated Profile of Hearing Aid Performance (APHAB) and a variety of speech audiometric measures were used to compare the frequency transposition fitting with each subject's conventional hearing aids. A single-subject study design with a series of repeated measures permitted statistical analysis of differences in performance with the various amplification strategies. Two of the four subjects demonstrated statistically significant benefit with the frequency transposition device. Results show the efficacy of frequency transposition in improving speech understanding and quality of life in some individuals with severe-to-profound hearing loss. Overall, results suggest the need for evaluating the benefit of frequency transposition on an individual basis.


Calvarial deformity and remodeling following prolonged scalp expansion in a child.
A main concern in the use of scalp tissue expansion in the pediatric population has been the risk of skull deformation. Little is known about the long-term effects of tissue expansion on the skull and the ability of the skull to remodel following removal of the tissue expander. We report a recent case in which a 5-year-old boy had a fully inflated tissue expander retained under the scalp for a 15-month period. At surgery for removal of the implant the patient was noted to have a profound skull deformity characterized by severe calvarial depression and ridging. The patient underwent scalp reconstruction. Follow-up at 6 months revealed nearly complete remodeling of the skull with minimal visual deformity. This case demonstrates not only the profound bony deformity that can result from tissue expansion, but also the striking ability of the pediatric skull to remodel.


Maternal obesity programs reduced leptin signaling in the pituitary and altered GH/IGF1 axis function leading to increased adiposity in adult sheep offspring.
Studies in rodents highlight a role for leptin in stimulation of pituitary growth hormone (GH) secretion, with an impact on body composition regulation. We have reported that maternal obesity (MO) during ovine pregnancy results in hyperphagia, glucose-insulin dysregulation, increased adiposity, hypercortisolemia and hyperleptinemia in mature offspring subjected to a bout of ad libitum feeding. We hypothesized that MO reduces leptin signaling in the pituitary and down regulates the GH/IGF1 axis and increases circulating cortisol leading to increased adiposity in their adult offspring. Male lambs born to MO (n = 6) or control (CON, n = 6) ewes were fed only to requirements until placed on a 12 week ad libitum feeding trial at maturity. The pituitary, hypothalamic arcuate nucleus, and liver were collected at necropsy and mRNA and protein expression determined. Plasma cortisol concentrations were increased (P<0.05) in MO vs. CON offspring at the end of the feeding trial. Further, serum concentrations of IGF1 decreased (P<0.01) and GH tended to decrease (P<0.08) in MO vs. CON offspring. Pituitary mRNA and leptin receptor protein expression were decreased in MO vs. CON offspring in association with decreased GH mRNA expression, and decreased IGF1 mRNA and protein expression in liver. Liver 11β-hydroxysteroid dehydrogenase 1 (11βHSD1) expression was increased (P<0.01) and its cofactor hexose-6-phosphate dehydrogenase tended to increase (P<0.06) in MO vs. CON offspring. 11βHSD2 expression remained unchanged. These data indicate that MO induced an increase in liver conversion of cortisone to cortisol in adult offspring and support a role for leptin signaling in the pituitary in mediating offspring adiposity.


PHYSICAL HEALTH OF FEMALES FROM THE MOUNTAIN DISTRICTS OF ZAKARPATTIA ACCORDING TO THE METABOLIC LEVEL OF AEROBIC AND ANAEROBIC ENERGY SUPPLY DEPENDING ON THE COMPONENT BODY COMPOSITION.
Aim: To determine the aerobic and anaerobic productivity of females from the mountain districts of Zakarpattia region, depending on the component composition of body weight. Materials and Methods: A comparative analysis of physical health status of females in the post-pubertal period of ontogenesis, was carried out. Physical health status was assessed by indicators of aerobic and anaerobic productivity depending on the component composition of the body, which was determined by impedance measurement. Results: Physical health of females from the mountain districts depends on the component composition of the body, namely: an excellent level of aerobic productivity is observed in females who have a insufficient body weight with a normal relative fat content and a high relative content of skeletal muscles, VО2 max rel > 38 ml·min-1·kg-1; as a result, their physical health exceeds the "critical level" according to H.L. Apanasenko and corresponds to "excellent" according to Ya.P. Pyarnat's criteria. Females from the mountain districts with normal body weight, high relative fat and normal relative skeletal muscle have average level of aerobic performance., i.e., VО2 max rel. is within 28-33 ml∙min-1∙kg-1. As a result, their physical health is below the "critical level". Conclusions: "Excellent" and "good" level of aerobic productivity of females from the mountain districts of the Zakarpattia region guarantees "safe health level". Females from mountain districts with a high content of fat component have an "average" level of aerobic performance, which does not provide a "safe health level".


Interaction of social role functioning and coping in people with recent-onset attenuated psychotic symptoms: a case study of three Chinese women at clinical high risk for psychosis.
Clinical high risk of psychosis is defined as the period in which the first signs of psychotic symptoms begin to appear. During this period, there is an increased probability of developing frank psychosis. It is crucial to investigate the interaction between psychotic symptoms and the individual's personality and life experiences in order to effectively prevent, or delay the development of psychosis. This paper presents case reports of three Chinese female subjects with attenuated positive symptoms, attending their initial outpatient assessment in a mental health service, and their longitudinal clinical outcomes. Information regarding each subject's symptoms and life stressors was collected at 2-month intervals over a 6-month period. The assessments indicated that these women were suffering from the recent onset of symptoms in different ways. However, all three hid their symptoms from others in their school or workplace, and experienced a decline in performance related to their social roles and in their daily functioning. They were often excluded from the social groups to which they had previously belonged. A decline in social activities may be a risk factor in the development of psychosis and a mediator of functional sequelae in psychosis. Effective treatment strategies may include those that teach individuals to gain insights related to their symptoms and a service that provides a context in which individuals can discuss their psychotic symptoms.


[Which tools should be used to identify educational objectives? The experience of the Tuscany Region].
The tools used by the Tuscany Region to identify its training objectives show the Region's training network. Continuing education is planned, delivered, and evaluated by an "educational networking". This means that people involved in the educational process are not alone but are part of a network constituting a system, which is linked at three interconnected levels: Regional, sub-Regional (consortia of local health units linked together according to their geographical position), and "Area Aziendale". The three levels contribute to outline strategies, to bring into focus the information needs, to match them and to evaluate the effectiveness of the CME.


Strength comparison of mitral annuloplasty ring and suturing combinations: an in-vitro study.
While mattress sutures are commonly used to secure annuloplasty rings during mitral valve repair, the use of a flexible ring secured with a running polypropylene suture has recently been advocated. The study aim was to assess the separation tensions of semi-rigid and flexible rings using mattress and running suture techniques in an in-vitro static load model. Semi-rigid and flexible annuloplasty rings were sutured with either mattress or running sutures (RM, RR, FM, FR) in four groups, of eight hearts each. Twelve additional sutures were passed through the surfaces of each ring to fix the preparation to a testing machine. In a fifth (control) group the mattress sutures securing a flexible ring (FMS) were connected directly to the machine. Each preparation was subjected to progressive axially directed (base-apex) tension until ring-tissue separation occurred. The first major decrease in tension (defined as > or = 10 N in < or = 1.5 s) typically occurred with the separation of at least three adjacent sutures. These starting tensions (N) were: FMS 117 +/- 32.6, RR 131.7 +/- 30.5, RM 137.4 +/- 35.3, FM 152.1 +/- 32.3, and FR 213.2 +/- 30.5. The magnitudes of tension decrease with separation (and percentage of starting tensions) were: FMS 25.4 (21.2%), RR 26.8 (17.6%), RM 28.9 (21.6%), FM 24.6 (17.6%), and FR 22.5 (10.8%). The FR group required more tension to separate than the other groups (p < 0.001), but had a lower magnitude of force drop at dehiscence. Flexible rings secured with a running suture required more force to separate than other ring-suture combinations. The lower magnitude of force drop in this group indicated a better tension distribution than in the other groups. Semi-rigid rings separated with a lower force, and had larger drops in tension, regardless of the suture technique used.


Temperature-pulse-induced "memory" in Bacillus subtilis macrofibers and a role for protein(s) in the left-handed-twist state.
Macrofibers in steady-state growth at one temperature were subjected to pulses of various durations at a temperature at which the opposite helix hand would form and then returned to the initial temperature. In an upshift pulse (20 to 48 degrees C), at least 3 min of incubation was required to induce a transient inversion that occurred later after return to 20 degrees C. Longer pulses resulted in shorter delays in onset of the transient inversion. This "memory" of a brief high-temperature pulse suggests that even a small amount of material can influence the twist of the entire macrofiber. Similar results were found for temperature downshift pulses corresponding to the opposite inversion. Adding chloramphenicol during the temperature pulse blocked the establishment of memory associated with the right-to-left inversion but not that associated with left-to-right inversion. In contrast, inhibiting peptidoglycan synthesis with D-cycloserine during the temperature pulse did not prevent establishment of memory. Inhibiting protein synthesis in mutants fixed as left-handed structures over the entire temperature range induced conversion to right-handedness but did not affect mutants fixed as right-handed structures. Adding protease to either live or formaldehyde-killed macrofibers always induced rotations of right-handed orientation. Steady-state growth in the presence of protease was found to shift the initial macrofiber twist towards the right-hand end of the twist spectrum. The phenomenon was observed in several mutants with different initial twists.


In situ pulsed-field gradient NMR determination of the size of oil bodies in vegetable seeds. Analysis of the effect of the gradient pulse length.
We report a pulsed-field gradient NMR study of the size of the oil bodies in lettuce seeds. The pulsed-field gradient spin-echo method (PFGSE) was applied to measure the self-diffusion coefficient of triacylglycerol molecules (TAG) inside the oil bodies. The confined nature of TAG diffusion is used to determine the size dispersion of the oil bodies. At long diffusion time, we measure a spin-echo attenuation that is related to the form factor of the confining volumes in the reciprocal q space, where q is proportional to the product of the gradient intensity and the length of the pulse gradient. Specific care was taken in analyzing the influence of the gradient pulse length delta on the shape of the PFGSE decay in order to construct the function corresponding to the short gradient pulse approximation (SGP). The SGP model gives an analytical framework for the PFGSE signal that enables the size distribution of the oil bodies to be determined. The SGP function was unambiguously obtained by varying the gradient pulse length delta in order to linearly extrapolate at delta = 0 the SGP limit. In this work, we also consider the Gaussian phase distribution (GPD) assumption that is often used to analyze confined diffusion experiments. Although the GPD assumption is known to be inaccurate in predicting the fine structure of the PFGSE function in q space, we point out that in the present case it can be used to take into account the finite value of delta. A log-normal distribution of the radius values was assumed in simulating the PFGNMR experiments since this type of distribution is observed in vegetable seeds by transmission electronic microscopy. From a practical and experimental standpoint, the NMR measurements reported here require no specific treatment of the seeds and the size of oil bodies is determined "in situ" on seeds poured into the NMR tube.


Experiences with Regional Anesthesia for Analgesia During Prolonged Aeromedical Evacuation.
There is much debate regarding the appropriate analgesic management of patients undergoing medical evacuation following combat trauma. Our primary objective was to review the utility of regional anesthetic techniques in patients undergoing aeromedical evacuation following surgical limb amputation as treatment for combat trauma. This study was conducted as an observational retrospective cohort whereby acutely injured amputee patients were identified via the U.S. Transportation Command's patient movement database. The Theater Medical Data Store was cross-referenced for additional patient care data including opioid consumption, duration of regional technique, pain scores, and rates of intubation. Eighty-four records were retrieved from the Theater Medical Data Store. All 84 patients were victims of improvised explosive device detonation requiring limb amputation and subsequent transport from Kandahar Airfield or Camp Bastion, Afghanistan, to the United States. The majority of interventions remained in place throughout the evacuation process. A significant decrease in opioid consumption in patients receiving regional anesthesia was identified at each leg of the medical evacuation process. Pain scores were sporadically reported and not statistically different. Higher rates of intubation were identified in the nonregional anesthetic group. Our analysis demonstrates the feasibility and effectiveness of applying regional anesthetic techniques for pain management to our combat wounded trauma patients throughout multiple stages of aeromedical evacuation. Benefits include the potential for less sedation and less opioid consumption while potentially foregoing the requirement for intubation during transport.Carness JM, Wilson MA, Lenart MJ, Smith DE, Dukes SF. Experiences with regional anesthesia for analgesia during prolonged aeromedical evacuation. Aerosp Med Hum Perform. 2017; 88(8):768-772.


The temporal coherence improvement of the two-dimensional negative-index slab image.
In this letter, we investigate the image field of the quasi-monochromatic random source in the two-dimensional negative-index slab. The prominent temporal-coherence gain of the image is observed in the numerical simulations even when the frequency-filtering effects are very weak. We find that the signals originating from the source will take the different time-"group" retarded time to reach the image location along the different optical paths. Based on the new physical picture, a simple phenomenological theory is constructed to obtain the image field and demonstrate that the temporal-coherence gain is from different "group" retarded time. The phenomenological theory agrees well with the FDTD simulation and the strict Green's function method. These results should have important impacts on the study of coherence mechanism and the design of novel devices.


Radiation-induced up-regulation of adhesion molecules in brain microvasculature and their modulation by dexamethasone.
Little is known about the time course and magnitude of the up-regulation of endothelial cell adhesion molecules (ECAMs) in irradiated brain vasculature and the mechanisms by which dexamethasone modulates this up-regulation. We used antibody-conjugated microspheres and a rat closed cranial window model to determine the time course of functional up-regulation of radiation (20 Gy)-induced ICAM1, E-selectin and P-selectin in the pial vasculature of the rat brain and to determine the relationship between suppression of inflammation by dexamethasone and the expression of these ECAMs. The results indicate that ICAM1, E-selectin and P-selectin were up-regulated to a functional level in the microvasculature with distinct time-course patterns. The number of adherent anti-E-selectin and anti-P-selectin microspheres was 5- 12 times greater than that of IgG microspheres 3-6 h postirradiation, and their expression returned to normal at 48 h. The number of adherent anti-ICAM1 microspheres was five and nine times greater than that of IgG at 24 and 48 h, respectively, and returned to baseline by 7 days. Dexamethasone significantly reduced the number of adhering leukocytes and the number of adhering anti-ICAM1, anti-E-selectin and anti-P-selectin microspheres to background levels. Our findings partially identify a key sequence in radiation-induced inflammatory response and provide a potential means to limit radiation-induced inflammatory responses and their potential side effects in the brain.


Salivary secretion, mucin concentrations and Candida carriage in HIV-infected patients.
To test whether the submandibular/sublingual (SMSL) salivary secretion, mucin concentration and candida carriage status were altered in human immunodeficiency virus-positive (HIV+) patients. SMSL saliva collected from 48 HIV-infected and 31 HIV-negative men were analyzed for flow rates, total protein and mucin concentrations. Salivary cultures were performed for Candida assessment. The salivary flow rate and protein secretion of the HIV+ patients was 37% and 32% less than that of the controls (P < 0.0001, P = 0.0087). The mucin concentrations (MG1 and MG2) were higher in the HIV+ subjects compared with controls (P = 0.0186, P = 0.0014); however, the mucin secretions were not different. The frequency of Candida-positive cultures was higher in the HIV+ subjects than in the controls (61.4%vs 24.1%, P = 0.0018). In the HIV-infected group, the unstimulated SMSL flow rates were lower in Candida-positive than in Candida-negative patients (P = 0.0158). The salivary secretion of the SMSL glands was reduced in HIV infection. Although the mucin concentration increased in HIV+ subjects, mucin secretion was not altered. Highly active antiviral therapy had no effect on salivary function. We found an association between the level of candida carriage and salivary flow rate in HIV-infected patients.


Biomechanical vibration of the abdominal region during running and bicycling.
The incidence of gastrointestinal (GI) distress reported among long distance runners and not in practitioners of other sports with more gliding movements, such as bicycling, leads one to speculate that there is a difference in concussions and vibration of the GI region and that this may possibly be associated with the disparity in GI disorders. The present experiment was conducted to quantify the difference in vibration (accelerations/decelerations) of the GI region during running as compared to bicycling. An actometer was used which included a piezoelectric sensor. The sensor was placed on the abdomen of six subjects during identical trials of bicycling and running. Movement in three planes was detected by the sensor and recorded. The accelerometer output (AO) is an integral of these measurements. AO was used in making comparisons of the two types of movement, expressed as counts per minute. Mean AO was more than doubled in running, 859.5 +/- 130.1 (SD), versus bicycling, 425.8 +/- 149.5 (SD) (p less than .0001). The common assumption that running results in more body vibrations than bicycling has been substantiated and quantified. Although the differences are large, it can only be speculated that these differences explain the high frequency of GI symptoms among runners.


The emerging threat of artemisinin resistance in malaria: focus on artemether-lumefantrine.
The development of artemisinin resistance in the Greater Mekong Subregion poses a significant threat to malaria elimination. Artemisinin-based combination therapies including artemether-lumefantrine (AL) are recommended by WHO as first-line treatment for uncomplicated Plasmodium falciparum malaria. This article provides a comprehensive review of the existing and latest data as a basis for interpretation of observed variability in parasite sensitivity to AL over the last 5 years. Clinical efficacy and preclinical data from a range of endemic countries are summarized, including potential molecular markers of resistance. Overall, AL remains effective in the treatment of uncomplicated P. falciparum malaria in most regions. Establishing validated molecular markers for resistance and strict efficacy monitoring will reinforce timely updates of treatment policies.


A Comparative Analysis of Preemptive Versus Targeted Sedation on Cardiovascular Stability After High-Risk Cardiac Surgery in Infants.
To compare the effect of two sedation practices on cardiovascular stability during the early postoperative period in young infants following cardiac surgery: the routine early use of midazolam infusion (preemptive sedation) and the discretionary use of sedatives tailored to the patient's clinical condition (targeted sedation). Retrospective cohort study with matched controls. A 15-bedded pediatric cardiac ICU. Sedation strategies were compared by matching patients before and after the introduction of a targeted sedation guideline, replacing the existing practice of preemptive sedation. Inclusion criteria were age less than 6 months and cardiopulmonary bypass time greater than 150 minutes. Matching criteria were surgical procedure, age, and duration of cardiopulmonary bypass and cross-clamp. The main outcome was cardiovascular instability, defined by the presence of one of the following criteria in the first 12 hours after PICU admission: 1) simultaneous administration of greater than or equal to two inotropic or vasopressor drugs; 2) administration of greater than 60 mL/kg fluid boluses. Secondary outcomes were: 1) markers of cardiac output adequacy (heart rate, blood pressure, vasoactive inotropic score, urine output, volume of fluid boluses, central venous oxygen saturation, lactate); 2) occurrence of adverse events (cardiac arrest, extracorporeal membrane oxygenation, death); 3) sedatives administered and depth of sedation. Introduction of a guideline of targeted sedation. Thirty-three patients with preemptive sedation were matched to 33 patients with targeted sedation. Targeted sedation resulted in less frequent oversedation, without compromising cardiovascular stability, as indicated by similar occurrence of cardiovascular instability (68.8% with preemptive sedation vs 62.5% with targeted sedation; p = 0.53) and adverse events, and similar markers of cardiac output adequacy. Although all preemptively sedated patients received an infusion of midazolam in the first 12 hours after surgery, only 19.4% of patients in the targeted sedation group received a sedative infusion (p < 0.001). Our data suggest that after high-risk cardiac surgery in young infants, routine sedation with midazolam may not prevent low cardiac output syndrome. When accompanied by a careful assessment of level of sedation, routine sedation of infants after high-risk cardiac surgery can be avoided without compromising hemodynamic stability or patient safety. The potential benefit of this approach is reduced exposure to sedative.


MultitaskProtDB: a database of multitasking proteins.
We have compiled MultitaskProtDB, available online at http://wallace.uab.es/multitask, to provide a repository where the many multitasking proteins found in the literature can be stored. Multitasking or moonlighting is the capability of some proteins to execute two or more biological functions. Usually, multitasking proteins are experimentally revealed by serendipity. This ability of proteins to perform multitasking functions helps us to understand one of the ways used by cells to perform many complex functions with a limited number of genes. Even so, the study of this phenomenon is complex because, among other things, there is no database of moonlighting proteins. The existence of such a tool facilitates the collection and dissemination of these important data. This work reports the database, MultitaskProtDB, which is designed as a friendly user web page containing >288 multitasking proteins with their NCBI and UniProt accession numbers, canonical and additional biological functions, monomeric/oligomeric states, PDB codes when available and bibliographic references. This database also serves to gain insight into some characteristics of multitasking proteins such as frequencies of the different pairs of functions, phylogenetic conservation and so forth.


Not all emotions are created equal: the negativity bias in social-emotional development.
There is ample empirical evidence for an asymmetry in the way that adults use positive versus negative information to make sense of their world; specifically, across an array of psychological situations and tasks, adults display a negativity bias, or the propensity to attend to, learn from, and use negative information far more than positive information. This bias is argued to serve critical evolutionarily adaptive functions, but its developmental presence and ontogenetic emergence have never been seriously considered. The authors argue for the existence of the negativity bias in early development and that it is evident especially in research on infant social referencing but also in other developmental domains. They discuss ontogenetic mechanisms underlying the emergence of this bias and explore not only its evolutionary but also its developmental functions and consequences. Throughout, the authors suggest ways to further examine the negativity bias in infants and older children, and they make testable predictions that would help clarify the nature of the negativity bias during early development.


Tai Chi can prevent cardiovascular disease and improve cardiopulmonary function of adults with obesity aged 50 years and older: A long-term follow-up study.
To research the possible role of Tai Chi in preventing cardiovascular disease and improving cardiopulmonary function in adults with obesity aged 50 years and older.Between 2007 and 2012, 120 adults with obesity, aged 50 years and older, were divided into a Tai Chi group and a control group, with 60 participants in each group. The 2 groups were evaluated for weight, waist circumference, hip circumference, blood pressure (BP), body mass index, and incidence of chronic disease during follow-up monitoring.Two- and 6-year follow-up showed that the average BP in the Tai Chi group along with either the systolic or diastolic pressure decreased significantly compared to those in the control group (P < .001). Waist and hip circumference, weight, and body mass index in the Tai Chi group were significantly reduced compared to those in the control group (P < .001). The cardiopulmonary function of the control group and the Tai Chi group changed, with the cardiac index significantly higher in the Tai Chi group than in the control group (P < .05). The Tai Chi group had significantly higher levels of lung function, including vital capacity, maximal oxygen uptake, and total expiratory time, than the control group. The total incidence of complications and mortality in the Tai Chi group were much lower than those in the control group (P < .001). The incidence of cardiovascular and cerebrovascular disease in the Tai Chi group (16.67%) was lower than that in the control group (38.33%).Tai Chi is not only a suitable exercise for elderly people with obesity, but it can also help to regulate BP, improve heart and lung function in these individuals, as well as reduce the incidence of cardiovascular disease and other chronic diseases, helping to improve their quality of life.


A sol-gel method using acetic anhydride in the presence of cholesterol in organic solution media: preparation of silicas that recognize steroid hormones.
Silicas were prepared by a sol-gel method from tetraethoxysilane and acetic anhydride in the presence of cholesterol in organic solution media. Some silicas had higher pore volumes than silicas obtained in the absence of cholesterol. The adsorption abilities by these silicas were compared using various compounds in benzene solution. Although no clear difference among their adsorptions of cholesterol was observed, progesterone and other analogous steroid hormones were well adsorbed by silicas prepared in the presence of cholesterol, especially, prepared with n-heptane as an additional solvent. This silica adsorbed steroid hormones more selectively than other analogous compounds such as bisphenol A and hexestrol. On the other hand, a silica prepared by the usual aqueous sol-gel method with cholesterol had no clear adsorption selectivity to steroid hormones. Furthermore, no selective adsorption of steroid hormones was observed in the case of a common silica gel for column chromatography. This unique property of adsorption observed in silicas prepared using acetic anhydride in the presence of cholesterol is likely to be induced by the imprinting effect of the steroid skeleton part of cholesterol in silica matrix.


Activation of CD4+ and CD8+ T-lymphocytes by insulin and GAD in patients with type 1 or 2 diabetes mellitus.
The origin of autoimmune disease type 1 diabetes is still unknown. This study assessed the activation of CD4+ and CD8+ T-lymphocytes by human insulin and human glutamate decarboxylase (GAD) in patients with type 1 or type 2 diabetes mellitus (DM) and healthy volunteers. The expression of CD69, a marker of T-lymphocyte activity, was determined in whole blood samples by flow cytometry after 12 h of incubation with or without insulin or GAD. The analysis included samples from 12 type 1 DM patients, 14 type 2 DM patients and 12 healthy volunteers. Significant increases in the number of activated CD4+ and CD8+ T-lymphocytes following pre-incubation of whole blood samples with human insulin or GAD were observed in samples from patients with type 1 DM, whereas no activation of these cells was detected in samples from either type 2 DM patients or healthy subjects. These results indicated that latent pre-activation of CD4+ and CD8+ T-lymphocytes in response to insulin or GAD epitopes occurred in type 1 DM patients. These findings suggest that pre-immunization against insulin and/or GAD might be associated with the development of type 1 DM. Alternatively, these results might reflect a non-specific, bystander autoimmune response.


The methods and advances of adaptive immune receptors repertoire sequencing.
The adaptive immune response is a powerful tool, capable of recognizing, binding to, and neutralizing a vast number of internal and external threats via T or B lymphatic receptors with widespread sets of antigen specificities. The emergence of high-throughput sequencing technology and bioinformatics provides opportunities for research in the fields of life sciences and medicine. The analysis and annotation for immune repertoire data can reveal biologically meaningful information, including immune prediction, target antigens, and effective evaluation. Continuous improvements of the immunological repertoire sequencing methods and analysis tools will help to minimize the experimental and calculation errors and realize the immunological information to meet the clinical requirements. That said, the clinical application of adaptive immune repertoire sequencing requires appropriate experimental methods and standard analytical tools. At the population cell level, we can acquire the overview of cell groups, but the information about a single cell is not obtained accurately. The information that is ignored may be crucial for understanding the heterogeneity of each cell, gene expression and drug response. The combination of high-throughput sequencing and single-cell technology allows us to obtain single-cell information with low-cost and high-throughput. In this review, we summarized the current methods and progress in this area.


The SARS epidemic in mainland China: bringing together all epidemiological data.
To document and verify the number of cases of severe acute respiratory syndrome (SARS) during the 2002-2003 epidemic in mainland China. All existing Chinese SARS data sources were integrated in one final database. This involved removing non-probable and duplicate cases, adding cases at the final stage of the outbreak, and collecting missing information. The resulting database contains a total of 5327 probable SARS cases, of whom 343 died, giving a case fatality ratio (CFR) of 6.4%. While the total number of cases happens to be equal to the original official reports, there are 5 cases overall which did not result in death. When compared with Hong Kong Special Administrative Region of China, China Taiwan, and Singapore, the SARS epidemic in mainland China resulted in a considerably lower CFR, involved relatively younger cases and included fewer health care workers. To optimise future data collection during large-scale outbreaks of emerging or re-emerging infectious disease, China must further improve the infectious diseases reporting system, enhance collaboration between all levels of disease control, health departments, hospitals and institutes nationally and globally, and train specialized staff working at county centres of disease control.


Family structure and multiple domains of child well-being in the United States: a cross-sectional study.
We examine the association between family structure and children's health care utilization, barriers to health care access, health, and schooling and cognitive outcomes and assess whether socioeconomic status (SES) accounts for those family structure differences. We advance prior research by focusing on understudied but increasingly common family structures including single father families and five different family structures that include grandparents. Our data on United States children aged birth through 17 (unweighted N = 198,864) come from the 1997-2013 waves of the National Health Interview Survey, a nationally representative, publicly available, household-based sample. We examine 17 outcomes across nine family structures, including married couple, cohabiting couple, single mother, and single father families, with and without grandparents, and skipped-generation families that include children and grandparents but not parents. The SES measures include family income, home ownership, and parents' or grandparents' (depending on who is in the household) employment and education. Compared to children living with married couples, children in single mother, extended single mother, and cohabiting couple families average poorer outcomes, but children in single father families sometimes average better health outcomes. The presence of grandparents in single parent, cohabiting, or married couple families does not buffer children from adverse outcomes. SES only partially explains family structure disparities in children's well-being. All non-married couple family structures are associated with some adverse outcomes among children, but the degree of disadvantage varies across family structures. Efforts to understand and improve child well-being might be most effective if they recognize the increasing diversity in children's living arrangements.


Correlation of tumour response with starting tumour size and dose of tamoxifen in an N-methyl-N-nitrosourea (NMU)-induced rat mammary cancer model.
The aim of this preliminary study was to address variations of responses observed with different starting tumor sizes of 10 and 15 mm, and the effects of different doses of tamoxifen (TAM) on experimental rat mammary tumors. Thirty-five inbred female Sprague Dawley rats aged 43 days were administered with three weekly doses of N-methyl-N-nitrosourea (NMU) intraperitoneally (ip) at 50 mg/kg body weight. Animals were randomized (beginning from 10 mm tumor size) into four TAM-treated (50, 100, 200 and 500 μg/day) groups of six animals each, and another group (n=6) treated with TAM 100 μg/day at starting tumour size of 15 mm. The animals were treated by oral gavage daily for 8 weeks before sacrifice. Serum urea and creatinine, and overall physical tumor burden were significantly modulated in animals treated with variable doses of TAM compared to the untreated controls (n=5). Final body weight and tumor number were significantly different in the 10 mm-treated animals compared to those treated at 15 mm. There were no significant differences in histopathological features among all the groups. Our findings suggest the importance of standardizing tumour size and drug doses before initiation of treatment, particularly in the direct comparison of basic end-tumour physical parameters.


Final analysis of a randomised trial comparing pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory advanced melanoma.
To evaluate the protocol-specified final analysis of overall survival (OS) in the KEYNOTE-002 study (NCT01704287) of pembrolizumab versus chemotherapy in patients with ipilimumab-refractory, advanced melanoma. In this randomised, phase II study, eligible patients had advanced melanoma with documented progression after two or more ipilimumab doses, previous BRAF or MEK inhibitor or both, if BRAFV600 mutant-positive. Patients were randomised to pembrolizumab 2 mg/kg or 10 mg/kg every 3 weeks or investigator-choice chemotherapy. Crossover to pembrolizumab was allowed following progression on chemotherapy. The protocol-specified final OS was performed in the intent-to-treat population. Survival was positive if p < 0.01 in one pembrolizumab arm. A total of 180 patients were randomised to pembrolizumab 2 mg/kg, 181 to pembrolizumab 10 mg/kg and 179 to chemotherapy. At a median follow-up of 28 months (range 24.1-35.5), 368 patients died and 98 (55%) crossed over to pembrolizumab. Pembrolizumab 2 mg/kg (hazard ratio [HR] 0.86, 95% confidence interval [CI] 0.67-1.10, p = 0.117) and 10 mg/kg (0.74, 0.57-0.96, p = 0.011) resulted in a non-statistically significant improvement in OS versus chemotherapy; median OS was 13.4 (95% CI 11.0-16.4) and 14.7 (95% CI 11.3-19.5), respectively, versus 11.0 months (95% CI 8.9-13.8), with limited improvement after censoring for crossover. Two-year survival rates were 36% and 38%, versus 30%. Progression-free survival, objective response rate and duration of response improved with pembrolizumab versus chemotherapy, regardless of dose. Grade III-V treatment-related adverse events occurred in 24 (13.5%), 30 (16.8%) and 45 (26.3%) patients, respectively. Improvement in OS with pembrolizumab was not statistically significant at either dose versus chemotherapy.


Complications of gastroesophageal reflux.
An edited summary of an Interdepartmental Conference arranged by the Department of Medicine of the UCLA School of Medicine, Los Angeles. The Director of Conferences is William M. Pardridge, MD, Professor of Medicine. Several specialists have recently recognized that gastrointestinal reflux causes complications resulting in significant disease. It causes discomfort, indigestion, esophagitis, Barrett's esophagus, and carcinoma of the esophagus. Pediatricians attribute many early pulmonary problems, and even some sudden deaths in infants, to the reflux of gastric contents. Otolaryngologists now recognize that many cases of nonbacterial, nonspecific pharyngitis and laryngitis are due to the reflux of gastrc acid secretions. Contact granuloma and cancer of the larynx may, in some instances, be secondary to nocturnal reflux. Thoracic surgeons and pulmonologists believe chronic tracheobronchitis and some cases of pulmonary disease are attributable to recurrent bathing of the respiratory epithelium by aspirated gastric contents. An awareness of the many complications of gastrointestinal reflux should lead to a multidisciplined attack on the factors responsible for these diseases.


Design Principles for Rapid Prototyping Forces Sensors using 3D Printing.
Force sensors provide critical information for robot manipulators, manufacturing processes, and haptic interfaces. Commercial force sensors, however, are generally not adapted to specific system requirements, resulting in sensors with excess size, cost, and fragility. To overcome these issues, 3D printers can be used to create components for the quick and inexpensive development of force sensors. Limitations of this rapid prototyping technology, however, require specialized design principles. In this paper, we discuss techniques for rapidly developing simple force sensors, including selecting and attaching metal flexures, using inexpensive and simple displacement transducers, and 3D printing features to aid in assembly. These design methods are illustrated through the design and fabrication of a miniature force sensor for the tip of a robotic catheter system. The resulting force sensor prototype can measure forces with an accuracy of as low as 2% of the 10 N measurement range.


Impact of digital finance on enterprise green innovation: From the perspective of information asymmetry, consumer demand and factor market distortions.
The study endeavors to empirically assess the influence of digital finance on promoting enterprise green innovation, while simultaneously probing its underlying mechanisms, by leveraging panel data from a sample of 2071 China A-share listed firms over an extensive time frame spanning from 2011 to 2021. The findings demonstrate that digital finance plays a crucial role in promoting enterprise green innovation, and that both the coverage breadth and usage depth of digital finance have a significant effect on enterprise green innovation, but the digitization level of digital finance also has a non-significant effect on enterprise green innovation, and the conclusions hold even after multiple robustness tests and consideration of endogeneity issues. Furthermore, heterogeneity analysis reveals that digital finance is only has a significant promoting effect on green innovation of SMEs, and high-tech enterprises. After conducting the mechanism analysis, it has been noted that digital finance serves as a facilitator in promoting green innovation in enterprises by reducing information asymmetry, stimulating consumer demand, and attenuating the distortion of regional factor markets. Intellectual property protection and environmental governance will strengthen the positive impact of digital finance on enterprises' green innovation. The research results provide policy implications for the green development of digital finance enabling enterprises.


Motivation and incentive preferences of community health officers in Ghana: an economic behavioral experiment approach.
Health worker shortage in rural areas is one of the biggest problems of the health sector in Ghana and many developing countries. This may be due to fewer incentives and support systems available to attract and retain health workers at the rural level. This study explored the willingness of community health officers (CHOs) to accept and hold rural and community job postings in Ghana. A discrete choice experiment was used to estimate the motivation and incentive preferences of CHOs in Ghana. All CHOs working in three Health and Demographic Surveillance System sites in Ghana, 200 in total, were interviewed between December 2012 and January 2013. Respondents were asked to choose from choice sets of job preferences. Four mixed logit models were used for the estimation. The first model considered (a) only the main effect. The other models included interaction terms for (b) gender, (c) number of children under 5 in the household, and (d) years worked at the same community. Moreover, a choice probability simulation was performed. Mixed logit analyses of the data project a shorter time frame before study leave as the most important motivation for most CHOs (β 2.03; 95 % CI 1.69 to 2.36). This is also confirmed by the largest simulated choice probability (29.1 %). The interaction effect of the number of children was significant for education allowance for children (β 0.58; 95 % CI 0.24 to 0.93), salary increase (β 0.35; 95 % CI 0.03 to 0.67), and housing provision (β 0.16; 95 % CI -0.02 to 0.60). Male CHOs had a high affinity for early opportunity to go on study leave (β 0.78; 95 % CI -0.06 to 1.62). CHOs who had worked at the same place for a long time greatly valued salary increase (β 0.28; 95 % CI 0.09 to 0.47). To reduce health worker shortage in rural settings, policymakers could provide "needs-specific" motivational packages. They should include career development opportunities such as shorter period of work before study leave and financial policy in the form of salary increase to recruit and retain them.


CT perfusion for the monitoring of neoadjuvant chemotherapy and radiation therapy in rectal carcinoma: initial experience.
To prospectively monitor changes in rectal cancer perfusion after combined neoadjuvant chemotherapy and radiation therapy with perfusion computed tomography (CT) and to evaluate whether perfusion CT findings correlate with response to therapy. The study was approved by the institutional ethics committee of the European Institute of Oncology; written informed consent was obtained from all participants before the study. Twenty-five patients with rectal adenocarcinoma (18 men, seven women; age range, 42-72 years; mean age, 61.3 years) underwent perfusion CT; all of them underwent neoadjuvant chemotherapy and radiation therapy, followed by surgery. In 19 patients, perfusion CT was repeated after chemotherapy and radiation therapy. Dynamic perfusion CT was performed for 50 seconds after intravenous injection of contrast medium (40 mL, 370 mg iodine per milliliter, 4 mL/sec). Blood flow (BF), blood volume (BV), mean transit time, and permeability-surface area product (PS) were computed in the tumor and in normal rectal wall by two independent blinded radiologists. Microvessel density was evaluated in pretreatment biopsy specimens in nine patients and in surgical specimens in seven patients. Wilcoxon signed-rank and rank sum tests were used for paired and independent comparisons, respectively. BF, BV, and PS were significantly higher in rectal cancer than in normal rectal wall (P < .001). BF, BV, and PS significantly decreased after combined chemotherapy and radiation therapy (P < .009). No correlation was found between perfusion parameters and microvessel density, neither in baseline values nor in posttherapy changes. Baseline BF and BV in the seven patients who failed to respond to treatment were significantly lower than in the 17 responders (P = .02 for BF and < .001 for BV). Perfusion CT has potential for monitoring the effects of combined neoadjuvant chemotherapy and radiation therapy and predicting the response of rectal cancer to such therapy.


Creutzfeldt-Jakob disease in Austria.
Between 1969 and 30 September 1995, 79 Austrian patients had Creutzfeldt-Jakob disease (CJD) diagnosed neuropathologically by necropsy or biopsy. The annual incidence has significantly increased in recent years (average 0.18 per million in 1969-85, and 0.67 per million in 1986-94; estimate for 1995: 1.5 per million). Also, the percentage of patients with CJD over 70 years at death increased significantly until 1989 but is since in decline. There is no regional clustering, familial occurrence, or recognised iatrogenic risk. One patient had a 10 year history of intramuscular injection of purified bovine RNA preparation (Regeneresen) from various organs including the brian. The ages at death are symmetrically distributed around the median of 64 years. The median duration of disease is four months. Most patients (76%) died within six months of onset. Retrospectively, 86% of patients fulfilled clinical criteria of probable or possible CJD. Neuropathology showed the classic triad of spongiform change, astrogliosis, and neuronal loss in most cases. Two cases did not show unequivocal tissue alterations, but anti-PrP immunocytochemistry detected PrP deposits also in these cases. It is concluded that the recent rise in incidence of CJD in Austria most likely reflects increased awareness and diagnosis of CJD rather than a real increase. As bovine spongiform encephalopathy (BSE) has not been reported in Austria, the data do not support a link between a rise in incidence of sporadic CJD and BSE.


In vitro assessment of chelating agents with regard to their abstraction efficiency of Cd(2+) bound to plasma proteins.
The exposure of various human populations to Cd(2+) is of increasing health concern. After its gastrointestinal absorption into the bloodstream, Cd(2+) binds to α(2)-macroglobulin and serum albumin. Although animal studies have demonstrated that meso-2,3-dimercaptosuccinic acid (DMSA) and diethylenetriamine pentaacetic acid (DTPA) can effectively mobilize Cd(2+) to urine and decrease the Cd concentrations of the kidneys, the liver and the brain, not much is known about the abstraction of Cd(2+) from blood plasma proteins. We prepared a stock of Cd(2+) spiked rabbit plasma (2.0 μg of Cd(2+)/mL) and analyzed aliquots by size exclusion chromatography coupled on-line to an inductively coupled plasma atomic emission spectrometer (SEC-ICP-AES) while simultaneously monitoring the emission lines of Ca, Cd, Cu, Fe, and Zn. After the addition of 0.33 mM, 0.66 mM or 0.99 mM of DMSA, DTPA, 2,3-dimercapto-1-propanesulfonic acid (DMPS) or N-acetyl-l-cysteine (NAC) to plasma aliquots, the obtained mixtures were analyzed by SEC-ICP-AES after 5 min and 30 min. None of the investigated compounds adversely affected the plasma distribution of Fe at all investigated doses. At 0.33 mM, DTPA was most effective at mobilizing plasma protein bound Cd(2+) to a ~5 kDa Cd-species (100% removal), followed by DMPS (94%), DMSA (83%) and NAC (3%). All investigated compounds also mobilized Zn(2+) from plasma proteins to ~5 kDa Zn-species (DTPA: 80% removal; DMPS: 63%; DMSA: 29% and NAC: 3%). The addition of DTPA resulted in the dose-dependent elution of a [Ca-DTPA](3-) complex. Based on these results, 0.33 mM DMSA represents the best compromise that can be achieved between maximizing the abstraction of Cd(2+) from plasma proteins (83%), while minimizing the mobilization of Zn(2+) from plasma proteins (29%), and avoiding the complexation of Ca(2+).


Wolbachia do not live by reproductive manipulation alone: infection polymorphism in Drosophila suzukii and D. subpulchrella.
Drosophila suzukii recently invaded North America and Europe. Populations in Hawaii, California, New York and Nova Scotia are polymorphic for Wolbachia, typically with <20% infection frequency. The Wolbachia in D. suzukii, denoted wSuz, is closely related to wRi, the variant prevalent in continental populations of D. simulans. wSuz is also nearly identical to Wolbachia found in D. subpulchrella, plausibly D. suzukii's sister species. This suggests vertical Wolbachia transmission through cladogenesis ('cladogenic transmission'). The widespread occurrence of 7-20% infection frequencies indicates a stable polymorphism. wSuz is imperfectly maternally transmitted, with wild infected females producing on average 5-10% uninfected progeny. As expected from its low frequency, wSuz produces no cytoplasmic incompatibility (CI), that is, no increased embryo mortality when infected males mate with uninfected females, and no appreciable sex-ratio distortion. The persistence of wSuz despite imperfect maternal transmission suggests positive fitness effects. Assuming a balance between selection and imperfect transmission, we expect a fitness advantage on the order of 20%. Unexpectedly, Wolbachia-infected females produce fewer progeny than do uninfected females. We do not yet understand the maintenance of wSuz in D. suzukii. The absence of detectable CI in D. suzukii and D. subpulchrella makes it unlikely that CI-based mechanisms could be used to control this species without transinfection using novel Wolbachia. Contrary to their reputation as horizontally transmitted reproductive parasites, many Wolbachia infections are acquired through introgression or cladogenesis and many cause no appreciable reproductive manipulation. Such infections, likely to be mutualistic, may be central to understanding the pervasiveness of Wolbachia among arthropods.


Chemical Looping Technology in Mild-Condition Ammonia Production: A Comprehensive Review and Analysis.
Ammonia is an efficient and clean hydrogen carrier that promises to tackle the increasing energy and environmental problems. However, more than 90% of ammonia is produced by the Haber-Bosch process, and its enormous energy consumption and CO2 emissions require the development of novel alternatives. Chemical looping technology can decouple the one-step ammonia synthesis reaction into separated nitridation and hydrogenation processes at atmospheric pressure, thereby achieving the mild ammonia synthesis based on renewable energy. The strategy of stepwise reactions circumvents the problem of competing adsorption of N2 and H2 /H2 O at the active sites and provides additive freedom for optimal regulation of sub-reactions. This review introduces the concept and mechanism of chemical looping ammonia production (CLAP), and comprehensively summarizes the state-of-art research from the perspective of reaction pathways and nitrogen carriers. The challenges faced by CLAP and strategies to address them in terms of nitrogen carriers, methods, equipment, and technological processes are also proposed.


Daily blood feeding rhythms of laboratory-reared North American Culex pipiens.
Blood feeding by free-living insect vectors of disease is rhythmic and can be used to predict when infectious bites will occur. These daily rhythms can also be targeted by control measures, as in insecticide-treated nets. Culex pipiens form pipiens and C.p. f. molestus are two members of the Culex pipiens assemblage and vectors of West Nile Virus throughout North America. Although Culex species vector human pathogens and parasites, the daily blood feeding rhythms of C.p. f. molestus, to our knowledge, have not been studied. We described and compared the daily blood feeding rhythms of three laboratory-reared populations of Culex pipiens, one of which has confirmed molestus ancestry. We also examined the plasticity of blood feeding time for these three populations. For most (>70%) C.p. f. pipiens and C.p. f. molestus collected from metropolitan Chicago, IL, blood feeding took place during scotophase. Peak blood feeding occurred in mid-scotophase, 3-6 hours after lights off. For C.p. f. pipiens originating from Pennsylvania, most mosquitoes (> 90%) blood fed during late photophase and early scotophase. C.p. f. molestus denied a blood meal during scotophase were less likely to blood feed during early photophase (< 20%) than were C.p. f. pipiens from Chicago (> 50%). C.p. f. pipiens from Pennsylvania were capable of feeding readily at any hour of photo- or scotophase. Daily blood feeding rhythms of C.p. f. molestus are similar to those of C.p. f. pipiens, particularly when populations originate from the same geographic region. However, the timing of blood feeding is more flexible for C.p. f. pipiens populations relative to C.p. f. molestus.


Genomic features shaping the landscape of meiotic double-strand-break hotspots in maize.
Meiotic recombination is the most important source of genetic variation in higher eukaryotes. It is initiated by formation of double-strand breaks (DSBs) in chromosomal DNA in early meiotic prophase. The DSBs are subsequently repaired, resulting in crossovers (COs) and noncrossovers (NCOs). Recombination events are not distributed evenly along chromosomes but cluster at recombination hotspots. How specific sites become hotspots is poorly understood. Studies in yeast and mammals linked initiation of meiotic recombination to active chromatin features present upstream from genes, such as absence of nucleosomes and presence of trimethylation of lysine 4 in histone H3 (H3K4me3). Core recombination components are conserved among eukaryotes, but it is unclear whether this conservation results in universal characteristics of recombination landscapes shared by a wide range of species. To address this question, we mapped meiotic DSBs in maize, a higher eukaryote with a large genome that is rich in repetitive DNA. We found DSBs in maize to be frequent in all chromosome regions, including sites lacking COs, such as centromeres and pericentromeric regions. Furthermore, most DSBs are formed in repetitive DNA, predominantly Gypsy retrotransposons, and only one-quarter of DSB hotspots are near genes. Genic and nongenic hotspots differ in several characteristics, and only genic DSBs contribute to crossover formation. Maize hotspots overlap regions of low nucleosome occupancy but show only limited association with H3K4me3 sites. Overall, maize DSB hotspots exhibit distribution patterns and characteristics not reported previously in other species. Understanding recombination patterns in maize will shed light on mechanisms affecting dynamics of the plant genome.


RNA editing of the serotonin 5HT2C receptor and its effects on cell signalling, pharmacology and brain function.
The process of RNA editing involves the modification of mRNA at specific sites by adenosine deaminases that act on RNA (ADAR) enzymes. By catalyzing the conversion of adenosine to inosine, these enzymes alter the way in which the mRNA is translated, and consequently alter the primary structure of the resultant proteins. The serotonin (5HT) 2C receptor (5HT2CR) is currently the only known member of the superfamily of seven transmembrane domain receptors (7TMRs) to undergo this modification, and provides a fascinating case study in the effects of such changes. Here we review the current state of knowledge surrounding the editing of the 5HT2CR, the stark differences in signalling arising due to this process, and the potential for (and difficulties in) exploiting the phenomenon for improved therapeutic intervention in various neurological disorders.


In vivo hyperoxic preconditioning prevents myocardial infarction by expressing bcl-2.
Preconditioning with oxidative stress has been demonstrated in vitro to stimulate the cellular adaptation to subsequent severe oxidative stress. However, it is uncertain whether this preconditioning works in vivo. In the present study, we examined in vivo the beneficial effect of oxidative preconditioning. After rats were pretreated with whole-body hyperoxygenation (100% O(2) at 3 atmosphere for 20 mins, four cycles with 20-min intermission), isolated hearts were subjected to 45-min ischemia followed by 90-min reperfusion. This hyperoxic preconditioning significantly reduced infarct size, cytochrome-c release, DNA fragmentation, and terminal deoxynucleotidyl transferase-mediated dUTD nick-end labeling-positive cell frequency in the left ventricle, biphasically with an early (30-min) and a delayed (48-hr) effect after the hyperoxygenation. Mechanistically, the NF-kappaB activity and Bcl-2 expression were enhanced in the hearts, and a NF-kappaB inhibitor, pyrrolidine dithiocarbamate, abolished the Bcl-2 induction as well as the infarct-limiting effect. An antioxidant, N-acetylcysteine, and protein kinase C (PKC) inhibitors chelerythrine and Gö 6983 also blocked the preconditioning effects. These results indicate that hyperoxia induces myocardial tolerance against ischemia-reperfusion injury in association with Bcl-2 induction by NF-kappaB activation through reactive oxygen species and PKC-dependent signaling pathway.


Patellar dislocation in Rubenstein-Taybi syndrome.
This report describes 11 patients with Rubinstein-Taybi syndrome (RTS) and patellar dislocation. The age at diagnosis of patellar dislocation ranged from birth to 16 years. Ten patients had chronic dislocations and 8 of 11 had bilateral patellar dislocations. Eight patients required surgical stabilization of the patella; most achieved a good outcome with surgical repair. All families reported that the patellar dislocations impaired developmental skills which improved after surgery. Seven of the 11 patients were described as having other joint abnormalities including congenital dislocations and laxity of the joints. Patients with RTS should undergo regular thorough joint examinations, including the knees, because abnormalities may result in delay of attainment of motor skills.


The effects of myasthenic immunoglobulins on neuromuscular transmission and thymus histology in mice.
An autoimmune reaction to the endplate acetylcholine receptor (AChR) is thought to be responsible for the muscular weakness of myasthenia gravis (MG). However, the significance of antithymic antibodies and the thymic AChR-like protein is still uncertain. We transferred immunoglobulins (Igs) from patients with MG to mice. Thymitis was observed in 12 of 14 mice, and miniature endplate potential amplitudes were reduced in 8. Control mice showed none of these abnormalities. Immunofluorescence examination failed to reveal the binding of human IgG, IgM, or IgA to the thymic tissue. Our findings support the hypothesis that antithymic antibodies may alter thymic histology.


Skin exposure to UVB light induces a skin-brain-gonad axis and sexual behavior.
Ultraviolet (UV) light affects endocrinological and behavioral aspects of sexuality via an unknown mechanism. Here we discover that ultraviolet B (UVB) exposure enhances the levels of sex-steroid hormones and sexual behavior, which are mediated by the skin. In female mice, UVB exposure increases hypothalamus-pituitary-gonadal axis hormone levels, resulting in larger ovaries; extends estrus days; and increases anti-Mullerian hormone (AMH) expression. UVB exposure also enhances the sexual responsiveness and attractiveness of females and male-female interactions. Conditional knockout of p53 specifically in skin keratinocytes abolishes the effects of UVB. Thus, UVB triggers a skin-brain-gonadal axis through skin p53 activation. In humans, solar exposure enhances romantic passion in both genders and aggressiveness in men, as seen in analysis of individual questionaries, and positively correlates with testosterone level. Our findings suggest opportunities for treatment of sex-steroid-related dysfunctions.


Pharmacophore discovery--lessons learned.
Pharmacophore discovery is one of the major elements of molecular modeling in the absence of X-ray structural data. While pharmacophores initially made their debut as a means for lead discovery, more recent refinements have brought them into the domain of lead optimization, e.g. as a means to define the molecular alignment in 3D-QSAR. In this review, the experiences of over a decade of confronting and solving the challenges of pharmacophore discovery applied to actual drug discovery are summarized. Also, practical tips are described for using the author's methodology for pharmacophore discovery, DANTE.


MicroRNA hsa-miR-1301-3p Regulates Human ADH6, ALDH5A1 and ALDH8A1 in the Ethanol-Acetaldehyde-Acetate Metabolic Pathway.
Alcohol dehydrogenases (ADHs) and aldehyde dehydrogenases (ALDHs) are vital enzymes involved in the metabolism of a variety of alcohols. Differences in the expression and enzymatic activity of human ADHs and ALDHs correlate with individual variability in metabolizing alcohols and drugs and in the susceptibility to alcoholic liver disease. MicroRNAs (miRNAs) function as epigenetic modulators to regulate the expression of drug-metabolizing enzymes. To characterize miRNAs that target ADHs and ALDHs in human liver cells, we carried out a systematic bioinformatics analysis to analyze free energies of the interaction between miRNAs and their cognate sequences in ADH and ALDH transcripts and then calculated expression correlations between miRNAs and their targeting ADH and ALDH genes using a public data base. Candidate miRNAs were selected to evaluate bioinformatic predictions using a series of biochemical assays. Our results showed that 11 miRNAs have the potential to modulate the expression of two ADH and seven ALDH genes in the human liver. We found that hsa-miR-1301-3p suppressed the expression of ADH6, ALDH5A1, and ALDH8A1 in liver cells and blocked their induction by ethanol. In summary, our results revealed that hsa-miR-1301-3p plays an important role in ethanol metabolism by regulating ADH and ALDH gene expression. SIGNIFICANCE STATEMENT: Systematic bioinformatics analysis showed that 11 microRNAs might play regulatory roles in the expression of two alcohol dehydrogenase (ADH) and seven aldehyde dehydrogenase (ALDH) genes in the human liver. Experimental evidences proved that hsa-miR-1301-3p suppressed the expression of ADH6, ALDH5A1, and ALDH8A1 in liver cells and decreased their inducibility by ethanol.


Some methodologic criteria for studies in developmental neuropsychiatry.
Studies which have sought to address the question of how brain dysfunction might be an etiological factor in the development of psychiatric disorders in childhood are reviewed from the point of view of the methodological issues which arise. It is argued that common forms of behavioral disturbance are more likely to have a psychosocial rather than a neurological origin, whereas epidemiologically unusual conditions are more likely to have neuro-developmental causal factors. Possible study designs are reviewed with the recommendation that cohort studies most closely approximate the ideal of the randomized control trial, whereas case control studies are weakest. The assessment of the reliability and validity of measures of brain dysfunction is discussed. Criteria for attributing causation after an association has been identified include temporal sequence, a 'dose-response' relationship, and the specificity of the cause. The clinical as opposed to the statistical significance of the association must be assessed. Confounding variables in such studies, variables which account in part for the association identified, but which undermine the etiological significance which can be attributed, are discussed. The particular importance of psychosocial disadvantage in this field is stressed as a factor to be taken into account in the critical evaluation of studies.


RNA-sequencing analysis reveals the co-biodegradation performance of crude oil by marine Chlorella vulgaris under norfloxacin stress.
In this study, the microalgal growth and crude oil (CRO) biodegradation by marine Chlorella vulgaris (C. vulgaris) were assessed under norfloxacin (NFX) stress. The presence of NFX negatively affected the bio-removal of CRO within 5 days, as the NFX concentration increased from 100 to 1600 μg/L, due to its toxicity as an antibiotic. However, its negative impact on the final degradation capabilities of C. vulgaris was less significant (P-value <0.05). After 9 days of cultivation, CRO bio-removal efficiencies still exceeded 90 %, while NFX bio-removal efficiencies maintained over 47 %. RNA-seq analysis revealed that the degradation of CRO and NFX was attributed to the combined action of functional genes involved in scavenging reactive oxygen species. The production of pigments and the bio-removal performance of C. vulgaris in CRO, NFX, and CRO & NFX coexistence media were consistent with the changes in the number of differentially expressed genes in these samples.


Best practices in coronary revascularization procedures: are we where we should be?
To address the most recent evidence bases for coronary artery bypass grafting (CABG) and stenting in patients with multivessel and left main coronary artery disease (CAD) and for optimizing the performance of CABG with particular reference to multiple arterial grafts, off-pump and less invasive CABG, graft flow measurements and external stenting of vein grafts. Current evidence confirms that CABG results in markedly superior survival to stenting for most patients with multivessel and/or left main stem CAD, as well as a significant reduction in subsequent myocardial infarction and repeat revascularization. Whereas there is strong circumstantial evidence of important survival benefits with bilateral internal mammary arteries, there is no evidence for clinical benefits of off-pump CABG, except perhaps in higher-risk patients. There appears to be increasing justification for routine graft flow measurements, while minimally invasive and robotic CABG remains as a niche specialty. CABG remains the most effective revascularization strategy in terms of survival and freedom from myocardial infarction and repeat revascularization in most patients with multivessel and/or left main stem CAD. There is a strong case for much wider use of bilateral internal mammary arteries during CABG, and off-pump CABG may be beneficial in higher-risk patients with particular reference to reducing neurologic injury. There is a strong rationale for the routine use of graft flow measurement, and particularly when using composite arterial grafts. There is a potential role for the development of an external stent to reduce the development of intimal hyperplasia in vein grafts.


A golden age of clinical chemistry: 1948-1960.
This segment of history aims to inform the new, and remind the not-so-new, members of the profession about the relatively recent period that initiated the dominant role played by technological innovation in the modern investigation of disease. The 12 years from 1948 to 1960 were notable for introduction of the Vacutainer tube, electrophoresis, radioimmunoassay, and the AutoAnalyzer. Also appearing during this interval were new organizations, publications, programs, and services that established a firm foundation for the professional status of clinical chemists. It was a golden age.


Modulation of the fluorescence yield in heliobacterial cells by induction of charge recombination in the photosynthetic reaction center.
Heliobacteria contain a very simple photosynthetic apparatus, consisting of a homodimeric type I reaction center (RC) without a peripheral antenna system and using the unique pigment bacteriochlorophyll (BChl) g. They are thought to use a light-driven cyclic electron transport pathway to pump protons, and thereby phosphorylate ADP, although some of the details of this cycle are yet to be worked out. We previously reported that the fluorescence emission from the heliobacterial RC in vivo was increased by exposure to actinic light, although this variable fluorescence phenomenon exhibited very different characteristics to that in oxygenic phototrophs (Collins et al. 2010). Here, we describe the underlying mechanism behind the variable fluorescence in heliobacterial cells. We find that the ability to stably photobleach P800, the primary donor of the RC, using brief flashes is inversely correlated to the variable fluorescence. Using pump-probe spectroscopy in the nanosecond timescale, we found that illumination of cells with bright light for a few seconds put them in a state in which a significant fraction of the RCs underwent charge recombination from P800 (+)A0 (-) with a time constant of ~20 ns. The fraction of RCs in the rapidly back-reacting state correlated very well with the variable fluorescence, indicating that nearly all of the increase in fluorescence could be explained by charge recombination of P800 (+)A0 (-), some of which regenerated the singlet excited state. This hypothesis was tested directly by time-resolved fluorescence studies in the ps and ns timescales. The major decay component in whole cells had a 20-ps decay time, representing trapping by the RC. Treatment of cells with dithionite resulted in the appearance of a ~18-ns decay component, which accounted for ~0.6 % of the decay, but was almost undetectable in the untreated cells. We conclude that strong illumination of heliobacterial cells can result in saturation of the electron acceptor pool, leading to reduction of the acceptor side of the RC and the creation of a back-reacting RC state that gives rise to delayed fluorescence.


Single-dose Live Oral Cholera Vaccine CVD 103-HgR Protects Against Human Experimental Infection With Vibrio cholerae O1 El Tor.
No licensed cholera vaccine is presently available in the United States. Cholera vaccines available in other countries require 2 spaced doses. A single-dose cholera vaccine that can rapidly protect short-notice travelers to high-risk areas and help control explosive outbreaks where logistics render 2-dose immunization regimens impractical would be a major advance.PXVX0200, based on live attenuated Vibrio cholerae O1 classical Inaba vaccine strain CVD 103-HgR, elicits seroconversion of vibriocidal antibodies (a correlate of protection) within 10 days of a single oral dose. We investigated the protection conferred by this vaccine in a human cholera challenge model. Consenting healthy adult volunteers, 18-45 years old, were randomly allocated 1:1 to receive 1 oral dose of vaccine (approximately 5 × 10(8) colony-forming units [CFU]) or placebo in double-blind fashion. Volunteers ingested approximately 1 × 10(5) CFU of wild-type V. cholerae O1 El Tor Inaba strain N16961 10 days or 3 months after vaccination and were observed on an inpatient research ward for stool output measurement and management of hydration. The vaccine was well tolerated, with no difference in adverse event frequency among 95 vaccinees vs 102 placebo recipients. The primary endpoint, moderate (≥3.0 L) to severe (≥5.0 L) diarrheal purge, occurred in 39 of 66 (59.1%) placebo controls but only 2 of 35 (5.7%) vaccinees at 10 days (vaccine efficacy, 90.3%; P < .0001) and 4 of 33 (12.1%) vaccinees at 3 months (vaccine efficacy, 79.5%; P < .0001). The significant vaccine efficacy documented 10 days and 3 months after 1 oral dose of PXVX0200 supports further development as a single-dose cholera vaccine. NCT01895855.


The effects of chromium propionate supplementation to yearling steers in a commercial feedyard on growth performance, carcass characteristics, and health.
British crossbred steers (n = 3,072; initial body weight [BW] = 358 ± 37 kg) were used to evaluate the effects of chromium propionate supplementation to yearling steers in a commercial feedyard on growth performance, carcass characteristics, and health. Steers were blocked by initial BW; pens were assigned randomly to one of two dietary treatments within block. Treatments, replicated in 15 pens per treatment with 75 to 135 heads per pen, included 1) control, 0 mg supplemental Cr/kg dietary dry matter (DM) (CTL); 2) 0.50 mg supplemental Cr/kg diet DM (chromium propionate; KemTRACE Chromium 0.4%, Kemin Industries, Des Moines, IA) (chromium propionate, CR). Final BW (638 vs. 641 kg), average daily gain (1.81 vs. 1.82 kg), DM intake (11.02 vs. 11.02 kg), and gain efficiency (0.164 vs. 0.165) did not differ between CTL and CR, respectively (P ≥ 0.75). No differences among treatments for hot carcass weight (407 vs. 408 kg, CTL and CR, respectively), dressing percentage, longissimus muscle area, or yield grade were observed (P ≥ 0.15). Twelfth-rib fat thickness tended (P = 0.10) to be greater for CR vs. CTL (1.55 vs. 1.29 cm, respectively). A trend (P = 0.10) for marbling score to be higher for CR vs. CTL was detected (452 vs. 440, respectively). Distribution of quality grade was similar between CR and CTL; 1.52% of carcasses graded prime (P = 0.68), and 87.2% of carcasses graded choice (P = 0.68). Respiratory morbidity was low (1.93%) and not different among treatments (P = 0.20); likewise, there was no difference in respiratory treatment rates between treatments (P ≥ 0.18). Supplementing Cr to high-performing yearling steers did not alter growth performance, carcass characteristics, or health outcomes.


Circumstances and implications of conversion from minimally invasive to open liver resection: a multi-center analysis from the AMILES registry.
Minimally invasive approaches to liver resection (MILR) are associated with favorable outcomes. The aim of this study was to determine the implications of conversion to an open procedure on perioperative outcomes. Patients who underwent MILR at 10 North American institutions were identified from the Americas Minimally Invasive Liver Resection (AMILES) database. Outcomes of patients who required conversion were compared to those who did not. Additionally, outcomes after conversion due to unfavorable findings (poor visualization/access, lack of progress, disease extent) versus intraoperative events (bleeding, injury, cardiopulmonary instability) were compared. Of 1675 patients who underwent MILR, 102 (6.1%) required conversion. Conversion rate ranged from 4.4% for left lateral sectionectomy to 10% for right hepatectomy. The primary reason for conversion was unfavorable findings in 67 patients (66%) and intraoperative adverse events in 35 patients (34%). By multivariable analysis, major resection, cirrhosis, prior liver surgery, and tumor proximity to major vessels were identified as risk factors for conversion (p < 0.05). Patients who required conversion had higher blood loss, transfusion requirements, operative time, and length of stay, (p < 0.05). They also had higher major complication rates (23% vs. 5.2%, p < 0.001) and 30-day mortality (8.8% vs. 1.3%, p < 0.001). When compared to those who required conversion due to unfavorable findings, patients who required conversion due to intraoperative adverse events had significantly higher major complication rates (43% vs. 14%, p = 0.012) and 30-day mortality (20% vs. 3.0%, p = 0.007). Conversion from MILR to open surgery is associated with increased perioperative morbidity and mortality. Conversion due to intraoperative adverse events is rare but associated with significantly higher complication and mortality rates, while conversion due to unfavorable findings is associated with similar outcomes as planned open resection. High-risk patients may benefit from early conversion in a controlled fashion if difficulties are encountered or anticipated.


Methotrexate, vinblastine, adriamycin and cisplatin versus methotrexate and cisplatin in advanced urothelial cancer. A randomized study.
From September 1984 to December 1988, 28 consecutive patients with metastatic urothelial cancer entered a randomized study to compare 4 courses of modified methotrexate, vinblastine, adriamycin and cisplatin (M-VAC) to 4 courses of methotrexate followed by folinic acid rescue and cisplatin (MP). Non-responders or relapsing patients were to be crossed to the other therapy. Hematological toxicity was more frequent (85%), but less severe, in patients treated with M-VAC than in patients treated with MP (21%, with 1 septic death). Complete plus partial remissions were achieved in 10 (71.4%) of 14 patients treated with M-VAC and in 6 (50%) of the 12 evaluable patients treated with MP. The 20% difference lay only on complete remissions, which were 8.3% in the MP versus 28.5% in the M-VAC group. At cross-over, however, only 1 of 5 patients resistant to MP responded to M-VAC, while 3 of 5 patients resistant to M-VAC responded to MP. It seems that M-VAC should be considered as the first-line therapy of choice in metastatic urothelial cancer, while MP, or high-dose methotrexate, could be considered for salvage.


Cellular resolution in clinical MALDI mass spectrometry imaging: the latest advancements and current challenges.
Mass spectrometry (MS) is the workhorse of metabolomics, proteomics and lipidomics. Mass spectrometry imaging (MSI), its extension to spatially resolved analysis of tissues, is a powerful tool for visualizing molecular information within the histological context of tissue. This review summarizes recent developments in MSI and highlights current challenges that remain to achieve molecular imaging at the cellular level of clinical specimens. We focus on matrix-assisted laser desorption/ionization (MALDI)-MSI. We discuss the current status of each of the analysis steps and remaining challenges to reach the desired level of cellular imaging. Currently, analyte delocalization and degradation, matrix crystal size, laser focus restrictions and detector sensitivity are factors that are limiting spatial resolution. New sample preparation devices and laser optic systems are being developed to push the boundaries of these limitations. Furthermore, we review the processing of cellular MSI data and images, and the systematic integration of these data in the light of available algorithms and databases. We discuss roadblocks in the data analysis pipeline and show how technology from other fields can be used to overcome these. Finally, we conclude with curative and community efforts that are needed to enable contextualization of the information obtained.


PVA-PEG physically cross-linked hydrogel film as a wound dressing: experimental design and optimization.
The development of hydrogel films as wound healing dressings is of a great interest owing to their biological tissue-like nature. Polyvinyl alcohol/polyethylene glycol (PVA/PEG) hydrogels loaded with asiaticoside, a standardized rich fraction of Centella asiatica, were successfully developed using the freeze-thaw method. Response surface methodology with Box-Behnken experimental design was employed to optimize the hydrogels. The hydrogels were characterized and optimized by gel fraction, swelling behavior, water vapor transmission rate and mechanical strength. The formulation with 8% PVA, 5% PEG 400 and five consecutive freeze-thaw cycles was selected as the optimized formulation and was further characterized by its drug release, rheological study, morphology, cytotoxicity and microbial studies. The optimized formulation showed more than 90% drug release at 12 hours. The rheological properties exhibited that the formulation has viscoelastic behavior and remains stable upon storage. Cell culture studies confirmed the biocompatible nature of the optimized hydrogel formulation. In the microbial limit tests, the optimized hydrogel showed no microbial growth. The developed optimized PVA/PEG hydrogel using freeze-thaw method was swellable, elastic, safe, and it can be considered as a promising new wound dressing formulation.


Technical Note: Machine learning approaches for range and dose verification in proton therapy using proton-induced positron emitters.
Online proton range/dose verification based on measurements of proton-induced positron emitters is a promising strategy for quality assurance in proton therapy. Because of the nonlinear correlation between the dose distribution and the activity distribution of positron emitters in addition to the presence of noise, machine learning approaches were proposed to establish their relationship. Simulations were carried out with a spot-scanning proton system using GATE-8.0 and Geant4-10.3 toolkit with a computed tomography (CT)-based patient phantom. The one-dimensional (1D) distributions of positron emitters and radiation dose were obtained. A feedforward neural network classification model comprising two hidden layers, was developed to estimate whether the range is within a preset threshold. A recurrent neural network (RNN) regression model comprising three layers and ten neurons in each hidden layer was developed to estimate dose distribution. The performance was quantitatively studied in terms of mean squared error (MSE) and mean absolute error (MAE) under different signal-to-noise ratio (SNR) values. The feasibility of proton range and dose verification using the proposed neural network framework was demonstrated. The feedforward NN model achieves high classification accuracy close to 100% for individual classes without bias. The RNN model is able to accurately predict the 1D dose distribution for different energies and irradiation positions. When the SNR of the input activity profiles is above 4, the framework is able to predict with an MAE of ~0.60 mm and an MSE of ~0.066. Moreover, the model demonstrates a good capability of generalization. The RNN model is found to be effective in identifying the relationship between the distributions of dose and positron emitters. The machine learning-based framework and RNN models may be a useful tool to allow for accurate online range and dose verification based on proton-induced positron emitters.


Job sharing for women pharmacists in academia.
The pharmacist shortage, increasing numbers of female pharmacy graduates, more pharmacy schools requiring faculty members, and a lower percentage of female faculty in academia are reasons to develop unique arrangements for female academic pharmacists who wish to work part-time. Job sharing is an example of a flexible alternative work arrangement that can be successful for academic pharmacists who wish to continue in a part-time capacity. Such partnerships have worked for other professionals but have not been widely adopted in pharmacy academia. Job sharing can benefit the employer through retention of experienced employees who collectively offer a wider range of skills than a single employee. Benefits to the employee include balanced work and family lives with the ability to maintain their knowledge and skills by remaining in the workforce. We discuss the additional benefits of job-sharing as well as our experience in a non-tenure track job-sharing position at the University of Tennessee College of Pharmacy.