Assessment of pegylated arginine deiminase and modified FOLFOX6 in patients with advanced hepatocellular carcinoma: Results of an international, single-arm, phase 2 study.
Arginine starvation depletes the micronutrients required for DNA synthesis and interferes with both thymidylate synthetase activity and DNA repair pathways in preclinical models of hepatocellular carcinoma (HCC). Pegylated arginine deiminase (ADI-PEG 20), an arginine degrader, potentiates the cytotoxic activity of platinum and pyrimidine antimetabolites in HCC cellular and murine models. This was a global, multicenter, open-label, single-arm, phase 2 trial of ADI-PEG 20 and modified 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) in patients who had HCC with Child-Pugh A cirrhosis and disease progression on ≥2 prior lines of treatment. The primary objective was the objective response rate assessed according to Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary objectives were to estimate progression-free survival, overall survival, safety, and tolerability. Eligible patients were treated with mFOLFOX6 intravenously biweekly at standard doses and ADI-PEG-20 intramuscularly weekly at 36 mg/m2 . In total, 140 patients with advanced HCC were enrolled. The median patient age was 62 years (range, 30-85 years), 83% of patients were male, 76% were of Asian race, 56% had hepatitis B viremia, 10% had hepatitis C viremia, 100% had received ≥2 prior lines of systemic therapy, and 39% had received ≥3 prior lines of systemic therapy. The objective response rate was 9.3% (95% confidence interval [CI], 5.0%-15.4%), with a median response duration of 10.2 months (95% CI, 5.8 months to not reached). The median progression-free survival was 3.8 months (95% CI, 1.8-6.3 months), and the median overall survival was 14.5 months (95% CI, 13.6-20.9 months). The most common grade ≥3 treatment-related events were neutropenia (32.9%), white blood cell count decrease (20%), platelet count decrease (19.3%), and anemia (9.3%). Concurrent mFOLFOX6 plus ADI-PEG 20 exhibited limited antitumor activity in patients with treatment-refractory HCC. The study was terminated early, and no further evaluation of the combination will be pursued. Arginine is an important nutrient for hepatocellular carcinoma (HCC). The depletion of arginine with pegylated arginine deiminase (ADI-PEG 20), an arginine degrader, appeared to make chemotherapy (FOLFOX) work better in animal models of HCC and in patients with HCC on an early phase clinical trial. To formally test this hypothesis in the clinical setting, a large, global, phase 2 clinical trial was conducted of ADI-PEG 20 and FOLFOX in the treatment of patients with refractory HCC. The study showed limited activity of ADI-PEG 20 and FOLFOX in advanced HCC and was stopped early.


Electrolyte and plasma enzyme analyses during large-volume liposuction.
Substantial fluid shifts occur during liposuction as wetting solution is infiltrated subcutaneously and fat is evacuated, causing potential electrolyte imbalances. In the porcine model for large-volume liposuction, plasma aspartate aminotransferase and alanine transaminase levels were elevated following liposuction. These results raised concerns for possible mechanical injury and/or lidocaine-induced hepatocellular toxicity in a clinical setting. The first objective of this human model study was to explore the effect of the liposuction procedure on electrolyte balance. The second objective was to determine whether elevated plasma aminotransferase levels were observed subsequent to large-volume liposuction. Five female volunteers underwent three-stage, ultrasound-assisted liposuction. Blood samples were collected perioperatively. Plasma levels of sodium, potassium, venous carbon dioxide, blood urea nitrogen, chloride, and creatinine were determined. Liver function analyte levels were measured, including albumin, total protein, aspartate aminotransferase, and alanine transaminase, alkaline phosphatase, gamma-glutamyl transpeptidase, and total bilirubin. To further define intracellular enzyme release, creatine kinase levels were measured. Mild hyponatremia was evident postoperatively (134 to 136 mmol/liter) in four patients. Hypokalemia was evident intraoperatively in all subjects (mean +/- SEM; 3.3 +/- 0.16 mmol/liter; range, 3.0 to 3.4 mmol/liter). Hypoalbuminemia and hypoproteinemia were observed throughout the study (baseline: 2.9 +/- 0.2 g/dl; range, 2.6 to 3.5 g/dl), decreasing to 10 to 40 percent 24 hours postoperatively (2.0 +/- 0.2 g/dl; range, 1.7 to 2.1 g/dl). Aspartate aminotransferase, alanine transaminase, and creatine kinase levels were significantly elevated after the procedure (190 +/- 47.1 U/liter, 50 +/- 7.7 U/liter, and 11,219 +/- 2556.7 U/liter, respectively) (p < 0.01). Release of antidiuretic hormone and even mildly hypotonic intravenous fluid infiltration have long been known to cause hyponatremia postoperatively. Intraoperative hypokalemia is associated with hypocarbia and respiratory alkalosis and the elevated epinephrine levels observed in the concurrent study. Factors having the greatest initial impact on diminished serum albumin and protein levels postoperatively are redistribution and hemodilution. Subsequent diminished viscosity may significantly affect postoperative hemodynamics. Elevated aspartate aminotransferase, alanine transaminase, and creatine kinase levels are associated with skeletal muscle injury, adipocyte lysis, and/or hepatic damage. Therefore, tissue injury is associated with large-volume liposuction as observed in several cellularly released enzymes. Future clinical studies are required to determine the degree of injury and specific tissues that are damaged or sensitive to mechanical trauma and/or drugs used in large-volume liposuction.


Navigating the Cytoplasm: Delivery of the Alphaherpesvirus Genome to the Nucleus.
Herpesviruses virions are large and complex structures that deliver their genetic content to nuclei upon entering cells. This property is not unusual as many other viruses including the adenoviruses, orthomyxoviruses, papillomaviruses, polyomaviruses, and retroviruses, do likewise. However, the means by which viruses in the alphaherpesvirinae subfamily accomplish this fundamental stage of the infectious cycle is tied to their defining ability to efficiently invade the nervous system. Fusion of the viral envelope with a cell membrane results in the deposition of the capsid, along with an assortment of tegument proteins, into the cytosol. Establishment of infection requires that the capsid traverse the cytosol, dock at a nuclear pore, and inject its genome into the nucleoplasm. Accumulating evidence indicates that the capsid is not the effector of this delivery process, but is instead shepherded by tegument proteins that remain capsid bound. At the same time, tegument proteins that are released from the capsid upon entry act to increase the susceptibility of the cell to the ensuing infection. Mucosal epithelial cells and neurons are both susceptible to alphaherpesvirus infection and, together, provide the niche to which these viruses have adapted. Although much has been revealed about the functions of de novo expressed tegument proteins during the late stages of assembly and egress, this review will specifically address the roles of tegument proteins brought into the cell with the incoming virion, and our current understanding of alphaherpesvirus genome delivery to nuclei.


Differential diagnosis of gallbladder ascariasis debris: the added value of contrast enhanced ultrasound with high frequency transducer.
Ascariasis debris of the gallbladder is a very rare incidental or symptomatic presentation. Ascaris debris has a pseudotumorous appearance and may be confused with neoplasia. The aim of the current retrospective study is to investigate the value of contrast enhanced ultrasound (CEUS) for the differential diagnosis of ascariasis debris and neoplasia of the gallbladder. Conventional B-mode ultrasound (BMUS) and CEUS were performed for solitary echo-rich gallbladder lesions. Analysis of the CEUS enhancement pattern of the lesions was conducted according to the current EFSUMB guidelines. Two radiologists assessed the CEUS enhancement patterns in consensus. The final gold standard was surgery with histological examination or imaging follow-up. A total of 9 patients with final diagnoses of gallbladder ascariasis debris were included. As a control group 26 solitary hyperechoic gallbladder lesions without shadowing were included as a control group. The typical zigzag morphology with multiple echogenic parallel lines without shadow were detected inside the lumen of the gallbladder in 6 patients. After injection of 2.4 ml ultrasound contrast agents, all hyperechoic gallbladder ascariasis debris lesions showed no enhancement. All patients in the control group with similar BMUS morphology showed contrast enhancement. Real time visualization of contrast enhancement without radiation exposure is one of the main advantages of CEUS over other diagnostic modalities to differentiate ascariasis debris in the gallbladder from enhancing neoplasia. Thus, surgery and other interventions and their complications could be avoided.


Synthesis and biological evaluation of 1,2,4-triazinylphenylalkylthiazolecarboxylic acid esters as cytokine-inhibiting antedrugs with strong bronchodilating effects in an animal model of asthma.
The influx of leukocytes (eosinophils, lymphocytes, and monocytes) into the airways and their production of proinflammatory cytokines contribute to the severity of allergic asthma. We describe here the synthesis and pharmacological evaluation of a series of triazinylphenylalkylthiazolecarboxylic acid esters that were designed to act as lung-specific antedrugs and inhibitors of the production of interleukin (IL)-5, a primary eosinophil-activating and proinflammatory cytokine. Closer examination of the hydroxypropyl ester, 15, indicated its high metabolic stability (t(1/2) > 240 min) in human lung S9 fraction but rapid conversion (t(1/2) = 15 min) into the pharmacologically inactive carboxylic acid by human liver preparations. In stimulated human whole blood cultures, 15 reduced not only the production of IL-5 (IC(50) = 78 nM) but also the biosynthesis of the monocyte chemotactic proteins MCP-1 (IC(50) = 220 nM), MCP-2 (IC(50) = 580 nM), and MCP-3 (IC(50) = 80 nM). In vivo, intratracheal administration of 15 (6 mg/animal) to allergic sheep, either before (-4 h) or after (+1.5 h) the pulmonary allergen challenge, completely abrogated the late-phase airway response and reduced the bronchial hyperreactivity to inhaled carbachol.


ELANE mutations in cyclic and severe congenital neutropenia: genetics and pathophysiology.
The 2 main forms of hereditary neutropenia are cyclic (CN) and severe congenital (SCN) neutropenia. CN is an autosomal dominant disorder in which neutrophil counts fluctuate with 21-day periodicity. SCN consists of static neutropenia, with promyelocytic maturation arrest in the bone marrow. Unlike CN, SCN displays frequent acquisition of somatic mutations in the gene CSF3R. CN is caused by heterozygous mutations in the gene ELANE, encoding neutrophil elastase. SCN is genetically heterogeneous but is most frequently associated with ELANE mutations. We discuss how the mutations provide clues into the pathogenesis of neutropenia and describe current hypotheses for its molecular mechanisms.


Association between smoking cessation and obstructive spirometry pattern among Korean adults aged 40-79 years.
Smoking cessation aids in restoring lung function. However, whether long-term cessation can fully restore lung function has not been studied thoroughly, especially in Asian countries. This study aimed to evaluate the association between smoking cessation status and obstructive spirometry pattern among Koreans aged 40-79 years. In total, 6298 men and 8088 women aged 40-79 years from the Korea National Health and Nutrition Examination Survey (2015-2019) were analyzed for smoking cessation status, including the duration after quitting. Current-smokers showed a higher likelihood of having an obstructive spirometry pattern than never-smokers among both men (odds ratio [OR]: 3.15, 95% confidence interval [CI]: 2.32-4.29) and women (OR: 2.60, 95% CI: 1.59-4.23). In men, the effect tended to decrease with longer duration after cessation, but male ex-smokers who had quit smoking ≥ 20 years ago still showed a higher likelihood of having an obstructive spirometry pattern than male never-smokers (OR: 1.40, 95% CI: 1.05-1.89). In female ex-smokers, there was no significant association with the obstructive spirometry pattern, compared to that in female never-smokers. This study emphasizes the benefits of smoking cessation, possibility of long-lasting harm to lung function due to tobacco smoking, and importance of smoking prevention.


Comparative chromosome mapping of U2 snRNA and 5S rRNA genes in Gymnotus species (Gymnotiformes, Gymnotidae): evolutionary dynamics and sex chromosome linkage in G . pantanal.
A comparative mapping of U2 small nuclear RNA (snRNA) and 5S ribosomal RNA (rRNA) genes was performed in 6 Gymnotus species. All species analyzed presented the U2 snDNA organized in conspicuous blocks and not co-located with rRNA genes. In addition, 5 species showed the U2 snDNA located in a single pair of chromosomes, which seems to be a conserved trait in this genus. Conversely, G. pantanal was the only species displaying several terminal signals in different chromosome pairs, including the X1 sex chromosome but not the Y chromosome. This is the first report of U2 snRNA genes in sex chromosomes of fishes. The absence of sites in the Y chromosome of G. pantanal indicates a possible loss of terminal segments of the chromosomes involved in the Y formation.


Compartmental analysis and glomerular filtration in chick embryos.
We have developed microtechniques that allow the determination of compartmental fluid distribution and glomerular filtration rate in chick embryos during three significant developmental periods: phase 1, the developmental period when the mesonephros alone is functioning; phase 2, periods of simultaneous meso/metanephric kidney function; and phase 3, the period during late development when the metanephros completely replaces the degenerated mesonephros. Water content of tissues is greater in younger embryos (89.4 +/- 0.2%, day 10) compared with older animals (78.3 +/- 0.5%, day 18). Although all major tissue components show an absolute increase in mass during this period, the embryo proper increases at five times the rate of the extraembryonic tissues. Glomerular filtration rate increases during development from 0.61 +/- 0.08 ml/h at day 10 to 2.31 +/- 0.11 ml/h at day 18. Glomerular filtration rate scales to body mass with an allometric exponent identical to adult birds only if total tissue mass (embryo + membranes) is considered. Our data suggest that significant errors in allometry will be encountered when scaling measurements are made on embryonic or fetal amniotes without taking into consideration the extraembryonic tissues.


Synaptic, intracellular, and neuroprotective mechanisms of anticonvulsants: are they relevant for the treatment and course of bipolar disorders?
Treatment of bipolar disorders has progressed significantly in the last decade due to advances in basic and clinical research. Much of this progress has centered on the development of a new generation of mood stabilizers-anticonvulsants. Valproic acid (VPA) and carbamazepine (CBZ) have clear mood stabilizing properties, while lamotrigine (LTG), topiramate (TPM), and gabapentin (GBP) have been investigated to varying degrees. We provide an overview of mechanisms of these potentially mood-stabilizing anticonvulsants, review their commonalities and dissociations to the gold standard non-anticonvulsant mood stabilizer lithium. Regulations of the glutamate excitatory neurotransmission and/or gamma aminobutyric acid (GABA) inhibitory neurotransmission are mostly studied mechanisms of anticonvulsants. The divergent effects of these agents indicate that this mode of action represents initial effect of anticonvulsants in regulating mood. Similar to lithium, intracellular mechanisms of anticonvulsants, primarily VPA and CBZ, include regulation of several protein kinase signaling pathways, leading to regulation of gene expression. Common genes that can be regulated by mood stabilizers are more likely to be the final normalizing components in bipolar disorders. Several anticonvulsants, such as VPA, LTG, and TPM, show neuronal protective function, a commonality with recently identified neuroprotective function of lithium, although the meaning of neuroprotection in bipolar disorders remains to be identified. Understanding the mechanisms of anticonvulsant mood stabilizers, integrated with clinical observations, may ultimately provide important new insights into the pathophysiology and treatment of bipolar disorders.


Migration and work in postwar Australia: mortality profile comparisons between Australian and Italian workers exposed to blue asbestos at Wittenoom.
Three hundred and thirty thousand Italians arrived in Australia between 1945 and 1966, many on assisted passage schemes where the worker agreed to a 2-year unskilled employment contract. Italians were the largest of 52 migrant groups employed at the Wittenoom blue asbestos mining and milling operation. We compare mortality from asbestos-related diseases among Italian and Australian workers employed at Wittenoom. A cohort of 6500 male workers was established from employment records and followed up at state and national mortality and cancer registries. SMRs were calculated to compare mortality with the Western Australian male population. Time-varying Cox proportional hazards models compared the risk of mesothelioma between Australian and Italian workers. 1031 Italians and 3465 Australians worked at Wittenoom between 1943 and 1966. Duration of employment was longer for the Italian workers, although the concentration of exposure was similar. The mesothelioma mortality rate per 100 000 was higher in Italians (184, 95% CI 148 to 229) than Australians (128, 95% CI 111 to 149). The risk of mesothelioma was greater than twofold (HR 2.27, 95% CI 1.43 to 3.60) in Italians at the lowest asbestos exposure category (<10 fibre years/per mL). A hierarchy in migration, isolation and a shortage of workers led to Italians at Wittenoom incurring higher cumulative exposure to blue asbestos and subsequently a greater rate of malignant mesothelioma than Australian workers. Poor working conditions and disparities between native and foreign-born workers has had a detrimental and differential impact on the long-term health of the workforce.


Cocaine-like subjective effects of nicotine are not blocked by the D1 selective antagonist ecopipam (SCH 39166).
The effects of ecopipam (a D(1) selective antagonist) or triazolam pretreatment on the subjective and physiological effects of intravenously administered nicotine were examined in 10 cigarette-smoking cocaine abusers. Under double-blind, randomized conditions, subjects received oral capsule pretreatment (0, 30 or 100 mg ecopipam, or 0.25 mg/70 kg triazolam), followed 120 min later by an intravenous injection of 2 mg/70 kg nicotine or saline. Subjective ratings, heart rate and blood pressure were assessed before and repeatedly after each intravenous injection. Compared to oral placebo pretreatment, both ecopipam and triazolam pretreatment produced significant elevations in subject-reported capsule effect and observer ratings of sleepiness/sedation. Nicotine increased ratings of 'drug effect', 'rush', 'high', 'stimulated', 'liking', 'good effects' and 'bad effects', and produced modest increases in heart rate and blood pressure. Following both intra-venous saline and nicotine injection, ecopipam tended to reduce heart rate and blood pressure. Although both ecopipam and triazolam lowered several subjective ratings following intravenous saline injection, neither ecopipam nor triazolam affected nicotine subjective effects. In contrast to Romach et al. (Arch Gen Psychiatry 56: 1101-1106, 1999), who showed that pretreatment with ecopipam blocked cocaine subjective effects, the current study found no attenuation of the subjective effects of nicotine, and thus, provides no support for the hypothesis that D(1) receptors mediate the cocaine-like subjective effects of nicotine.


TNF-alpha induced CD38 expression in human airway smooth muscle cells: role of MAP kinases and transcription factors NF-kappaB and AP-1.
In human airway smooth muscle (HASM) cells, the expression of CD38, which synthesizes the calcium-mobilizing molecule cyclic ADP-ribose, is augmented by TNF-alpha, a cytokine implicated in asthma. We determined the role of mitogen-activated protein kinase (MAPK) in the activation of NF-kappaB and AP-1 in the regulation of CD38 expression in HASM cells. In HASM cells exposed to TNF-alpha (40 ng/ml), the inhibitors of extracellular signal-regulated kinase (ERK), p38, or c-Jun NH(2)-terminal kinase (JNK) decreased CD38 expression and ADP-ribosyl cyclase activity. Transfection of HASM cells with a dominant negative MEK decreased while a wild-type ERK increased TNF-alpha-induced CD38 expression. Electrophoretic mobility shift assays (EMSAs) were performed using nuclear proteins and consensus sequences to detect the effect of the MAPKs on NF-kappaB and AP-1 activation. EMSAs confirmed the role of p38 and JNK in mediating NF-kappaB and AP-1 activation. Transfection of a dominant negative c-Jun decreased TNF-alpha-induced CD38 expression indicating involvement of AP-1. Stability of TNF-alpha-induced CD38 transcripts were determined in the presence of MAPK inhibitors after arresting the transcription with actinomycin D. Transcript stability decreased in the presence of ERK and p38 MAPK, but not the JNK, inhibitors. These results indicate that regulation of CD38 expression through p38 and JNK MAPKs involves NF-kappaB and AP-1 activation, and ERK and p38 MAPKs also regulate expression posttranscriptionally through message stability.


Nanodiamonds and gold nanoparticles to obtain a hybrid nanostructure with potential applications in biomedicine.
Using detonation nanodiamonds and fluorescent nitrogen-vacancy center nanodiamonds, linked to gold nanoparticles, we synthesized two hybrid nanostructures (HGDs) that were subsequently conjugated with a fluorophore. An amplification effect induced by the gold nanoparticles increased the emission spectrum of the fluorophore, maximizing the possibilities for imaging applications of these HGDs. The incubation of the nanostructures with HeLa cells produced no alteration of cell viability after 3 h and showed the presence of nanostructures in the cell cytoplasm at 24 h. These observations also indicate the potential biomedical use of the proposed HGDs.


Involvement of kinases in glucose and fructose uptake by Saccharomyces cerevisiae.
Uptake of glucose, fructose, and the nonmetabolizable analog 6-deoxyglucose was measured in wild-type Saccharomyces cerevisiae and two mutant strains, one (hxk1 hxk2) lacking both hexokinase A(P-I) and B(P-II) but containing glucokinase (and hence able to grow on glucose but not fructose) and the other (hxk1 hxk2 glk) also lacking glucokinase (and not able to grow on glucose either). Uptake of the nonmetabolized substances (i.e., 6-deoxyglucose in all three strains, fructose in the two mutants, and glucose in the triple mutant) reached a plateau at or below the external concentration. The kinetic characteristics of uptake were determined from 5-sec incubations by plotting velocity (V) vs. velocity/substrate concentration (V/S) curves. According to such plots, in the wild-type strain uptake had two components, "high affinity uptake" with Km values of ca. 1 mM for glucose and 6 mM for fructose and "low affinity uptake" with Km values of ca. 20 and 50 mM, respectively. The double kinase mutant showed both components for glucose but only the high Km component for fructose, while the triple kinase mutant showed only high Km uptake for both glucose and fructose. Genetic analysis showed that only in strains lacking both hexokinases (hxk1 hxk2) was the low Km system for fructose absent. Low Km uptake was restored to the triple mutant by introduction of the cloned wild-type genes: HXK1 or HXK2, for fructose uptake, and HXK1, HXK2, or GLK1, for glucose uptake. A phosphoglucose isomerase mutant had both low and high Km uptake for glucose. These results indicate the presence of two types of uptake mechanism for glucose and fructose in yeast, the functioning of one of which, the low Km system, is influenced by the cognate kinases.


Infant emmetropization: longitudinal changes in refraction components from nine to twenty months of age.
Rapid emmetropization is described in pediatrically normal infants from 9 months of age during the following year. The infants, obtained from various categories of the Cambridge population screening program, provided a broad range of refractive errors. The large group of 254 nonanisometropic infants studied allowed the mean rate of change and dependence on the initial refraction value to be determined. Refraction was measured by cycloplegic retinoscopy. Rapid emmetropization changes occurred in the following refractive components: mean spherical equivalent (MSE), astigmatism magnitude, the horizontal astigmatism component, the infant's most positive meridian, and the infant's most negative meridian. The MSE and astigmatism rates of change (diopters/year), were highly dependent on their respective initial powers (r = -0.61 and r = -0.76). The percentage weighted mean proportional rate of change for MSE was -30% (SE 4%) and for astigmatism magnitude it was -59% (SE 14%). There was much individual variation, with some exhibiting fast emmetropization and others not. The MSE and astigmatism changes, however, were almost independent of each other. The refractive errors of the most positive and most negative meridians emmetropize because they are both derived from the MSE and half the astigmatism. With-the-rule astigmatism was more prevalent than against-the-rule astigmatism at 9 months of age, and with-the-rule astigmatism exhibited a significantly greater proportional rate of change. The relationship of emmetropization and refractive screening is considered. A new component "MOMS" is introduced, the maximum ocular meridional separation, when both eyes are considered. Thus incorporating astigmatism and anisometropia may be a good single indicator of conditions associated with later amblyopia. The almost independent emmetropization of the MSE and astigmatism components is an important result to consider in theories of emmetropization, refractive screening, clinical prescribing, and the evaluation of infants in treatment trials.


The transcending benefits of physical activity for individuals with schizophrenia: a systematic review and meta-ethnography.
A systematic review and meta-ethnographic synthesis exploring the experiences of people with schizophrenia and healthcare professionals (HCPs) towards physical activity was undertaken. Major electronic databases were searched from inception until January 2014. Studies were eligible if they considered the experiences and perceptions of people with schizophrenia or the perceptions of HCPs towards physical activity. All included studies were synthesised within a meta-ethnographic approach, including completing a methodological quality assessment. The search strategy identified 106 articles, 11 of which were included in the final analysis. Eight articles considered patients׳ experiences and perceptions, and three articles considered the experiences and perceptions of HCPs. A total of 108 patients and 65 HCPs were included. Three main themes were identified: (1) the influence of identity, culture and the environment on physical activity engagement, (2) access and barriers to participation in physical activity, and (3) the benefits of engaging in physical activity. Aspects within the built, social and political environment as well as aspects of social cognition and perceptual biases influence participation in physical activity for individuals with schizophrenia. Specific recommendations for HCPs are given to help promote physical activity in this population group.


Guideline of guidelines: kidney stones.
Several professional organizations have developed evidence-based guidelines for the initial evaluation, diagnostic imaging selection, symptomatic management, surgical treatment, medical therapy, and prevention of recurrence for both ureteric and renal stones. The purpose of this article is to summarize these guidelines with reference to the strength of evidence. All guidelines endorse an initial evaluation to exclude concomitant infection, imaging with a non-contrast computed tomography scan, and consideration of medical expulsive therapy or surgical intervention depending on stone size and location. Recommends for metabolic evaluation vary by guideline, but all endorse increasing fluid intake to reduce the risk of recurrence.


Analysis of factors associated with mortality in major burn patients.
Major burn injury is a type of trauma that still has high morbidity and mortality rates at all age groups. There is no consensus on the provided guidelines regarding the prediction of the severity of the victims. It is sometimes not easy to have sophisticated clinical and blood monitoring for developing countries. It is still a challenge for them. The aim of the present study was to analyze the factors that have an effect on mortality and serve as a guide for burn treatment. Factors affecting mortality in major burn patients with over 30% of burns of the total body surface area who were treated in a burn treatment center of a third step hospital were evaluated, and parameters indicating severity were specifically determined. Medical records and follow-up notes of patients hospitalized in in Ankara Numune Education and Research Hospital Burn Center between 2008 and 2014 were evaluated retrospectively. Data on age, gender, comorbidities, burn percentage, locality, type of burn, process of the burn (suicide or accident), presence of inhalation injury, results of blood hemogram and biochemical tests, length of hospitalization, type of surgical procedures performed, presence of multitrauma, and ventilatory support requirement were analyzed to determine the factors affecting mortality. White blood cell count, hemoglobin count, platelet count, and lactate dehydrogenase level were examined at admission, at the middle of the clinical course, and at the end of treatment (at both exitus date or discharge date). A total of 224 patients were hospitalized with burns ≥30% total body surface area. Of the 224 patients, 81.7% were males, and 18.4% were females. In the mortality group, 41.3% were males, and 58.5% were females. Gender (female, p<0.041), age (p<0.001), age group (0-14/15-59/>60 years, p<0.001), total body surface area (p<0.001), type of burn (flame, p<0.002), presence of inhalation injury (p<0.001), process of the burn (p<0.002), time spent between the event and admission to the hospital (p<0.001), length of hospitalization (p<0.001), presence of comorbidity (p<0.038), diabetes mellitus (p<0.05), ventilation support (p<0.001), lactate dehydrogenase values (lactate dehydrogenaseadmission, p<0.001; lactate dehydrogenasemiddle, p<0.015; lactate dehydrogenaselast, p<0.001), white blood cell count (p<0.001), and platelet count (p<0.043) were found to be significant for univariate analyses. These parameters were further evaluated using multivariate analyses. lactate dehydrogenaselast level (p<0.001), age (p<0.001), length of hospitalization (negative odds ratio), p<0.001), presence of inhalation injury (p<0.029), total body surface area burned (p<0.029), and leukocytosis (p<0.006) were found to be significantly associated with mortality; however, leukocytosis and length of hospitalization did not pose risk for mortality with regard to odds ratios. Early realization of the factors affecting morbidity and mortality in patients and taking preventive measures, in addition to earlier detection and prevention of complications in long-time intensive care unit patients, could reduce complication and mortality rates in major burn trauma patients. Parameters for the indication of severity and mortality are important; however, lactate dehydrogenase is an easily studied parameter and is found to have a predictive value on prognosis.


[Immunotherapy in complex treatment of surgical sepsis].
The results of treatment of 73 patients with confirmed diagnosis of sepsis are analyzed. The most frequent immune disorders in septic patients are: decrease in lymphocyte count, both T (60%) and B (45.7%) populations, decrease of T-helpers and T-suppressors (52.6%) count, increase of C3-complement activator titre (50%) and phagocytic coefficient (52.4%). The more expressed immune depression observed in patients with gram-negative sepsis in comparison with the gram-positive. Standard immunoglobulins were used in the treatment of 38 patients: "Endobulin" (ImmunoAG, Austria)--in 9 cases; "Intraglobin" (Biotest, Germany)--in 14 and "Pentaglobin" (Biotest, Germany)--in 15 cases. Analyze of the control immunogramms showed the reliable improvement of immune indices and normalization of T-cell counts. Lethality among septic patients treated with immunoglobulins was 14.5%.


The structural diversity of ABS₃ compounds with d⁰ electronic configuration for the B-cation.
We use first-principles density functional theory within the local density approximation to ascertain the ground state structure of real and theoretical compounds with the formula ABS3 (A = K, Rb, Cs, Ca, Sr, Ba, Tl, Sn, Pb, and Bi; and B = Sc, Y, Ti, Zr, V, and Nb) under the constraint that B must have a d(0) electronic configuration. Our findings indicate that none of these AB combinations prefer a perovskite ground state with corner-sharing BS6 octahedra, but that they prefer phases with either edge- or face-sharing motifs. Further, a simple two-dimensional structure field map created from A and B ionic radii provides a neat demarcation between combinations preferring face-sharing versus edge-sharing phases for most of these combinations. We then show that by modifying the common Goldschmidt tolerance factor with a multiplicative term based on the electronegativity difference between A and S, the demarcation between predicted edge-sharing and face-sharing ground state phases is enhanced. We also demonstrate that, by calculating the free energy contribution of phonons, some of these compounds may assume multiple phases as synthesis temperatures are altered, or as ambient temperatures rise or fall.


Management of progressive keratoconus with partial topography-guided PRK combined with refractive, customized CXL - a novel technique: the enhanced Athens protocol.
To report a novel application of partial topography-guided photorefractive keratectomy combined with topographically customized, higher fluence, and variable pattern corneal cross-linking applied on the same day of the treatment of keratoconus. A topography-guided partial photorefractive keratectomy treatment of maximum 30 µm over the thinnest cone area was applied initially followed by a 7 mm, 50 µm phototherapeutic keratectomy treatment to address epithelial removal. 0.02% Mitomycin C was applied for 20 seconds and then the exposed stroma was soaked with 0.1% riboflavin solution for 5 minutes. The cornea was then treated with a customized, variable-pattern and 20 mW/cm2 fluence for a total of 5-10 J, and up to 15 J of energy was delivered with the KXL-II device employing an active tracker. The center of the pattern that received the 15 J was topography-matched with the thinnest area of the cone. Visual acuity, refractive error, cornea clarity, keratometry, topography, pachymetry with a multitude of modalities and endothelial cell density were evaluated over 36 months. Keratoconus was stabilized in all cases. The severity of keratoconus stage by Amsler- Krumeich criteria improved from an average of 3.2 (1-4) to 1.8 (0-3). Uncorrected distance visual acuity changed from preoperative 20/80 to 20/25 at 6 months. A maximum astigmatic reduction of 7.8 D (5.3-15.6), and a significant cornea surface normalization (an index of height decentration improvement from 0.155 [±0.065] to 0.045 [±0.042]) were achieved by 1 month and remained relatively stable for 36 months postoperatively. Two cases delayed full reepithelialization for up to 9 days. This paper introduces a novel technique in order to maximize the refractive normalization effect along with ectasia stabilization in young keratoconus patients. This may facilitate the use of less tissue ablation, in comparison to utilizing a homogeneous UV light beam for corneal cross-linking in Athens Protocol cases. It broadens the number of potential candidate cases that would have been limited to employ this technique due to tissue thickness limitations.


25 years of child and adult psychiatric epidemiology studies in Puerto Rico.
A review of the psychiatric epidemiology studies of the adult and child population of Puerto Rico carried out in the last 25 years is presented and discussed. Puerto Rico has experienced a plethora of psychiatric epidemiology studies since the decade of the 80's, with 4 adult and 4 child population based studies. The overall results of these studies showed that island Puerto Ricans are not at greater risk for psychiatric disorders as compared to other US or international populations in spite of the fact that the island is besieged by many of the socio-demographic factors associated with high risk populations. If anything, it appears that important protective factors associated with good family relationships and the importance of the family in Hispanic families may be buffering island families from the development of addictive and antisocial disorders.


Development and validation of safety climate scales for mobile remote workers using utility/electrical workers as exemplar.
The objective of this study was to develop and test the reliability and validity of a new scale designed for measuring safety climate among mobile remote workers, using utility/electrical workers as exemplar. The new scale employs perceived safety priority as the metric of safety climate and a multi-level framework, separating the measurement of organization- and group-level safety climate items into two sub-scales. The question of the emergence of shared perceptions among remote workers was also examined. For the initial survey development, several items were adopted from a generic safety climate scale and new industry-specific items were generated based on an extensive literature review, expert judgment, 15-day field observations, and 38 in-depth individual interviews with subject matter experts (i.e., utility industry electrical workers, trainers and supervisors of electrical workers). The items were revised after 45 cognitive interviews and a pre-test with 139 additional utility/electrical workers. The revised scale was subsequently implemented with a total of 2421 workers at two large US electric utility companies (1560 participants for the pilot company and 861 for the second company). Both exploratory (EFA) and confirmatory factor analyses (CFA) were adopted to finalize the items and to ensure construct validity. Reliability of the scale was tested based on Cronbach's α. Homogeneity tests examined whether utility/electrical workers' safety climate perceptions were shared within the same supervisor group. This was followed by an analysis of the criterion-related validity, which linked the safety climate scores to self-reports of safety behavior and injury outcomes (i.e., recordable incidents, missing days due to work-related injuries, vehicle accidents, and near misses). Six dimensions (Safety pro-activity, General training, Trucks and equipment, Field orientation, Financial Investment, and Schedule flexibility) with 29 items were extracted from the EFA to measure the organization-level safety climate. Three dimensions (Supervisory care, Participation encouragement, and Safety straight talk) with 19 items were extracted to measure the group-level safety climate. Acceptable ranges of internal consistency statistics for the sub-scales were observed. Whether or not to aggregate these multi-dimensions of safety climate into a single higher-order construct (overall safety climate) was discussed. CFAs confirmed the construct validity of the developed safety climate scale for utility/electrical workers. Homogeneity tests showed that utility/electrical workers' safety climate perceptions were shared within the same supervisor group. Both the organization- and group-level safety climate scores showed a statistically significant relationship with workers' self-reported safety behaviors and injury outcomes. A valid and reliable instrument to measure the essential elements of safety climate for utility/electrical workers in the remote working situation has been introduced. The scale can provide an in-depth understanding of safety climate based on its key dimensions and show where improvements can be made at both group and organization levels. As such, it may also offer a valuable starting point for future safety interventions.


Metagenomic analysis of Streptomyces lividans reveals host-dependent functional expression.
Most functional metagenomic studies have been limited by the poor expression of many genes derived from metagenomic DNA in Escherichia coli, which has been the predominant surrogate host to date. To expand the range of expressed genes, we developed tools for construction and functional screening of metagenomic libraries in Streptomyces lividans. We expanded on previously published protocols by constructing a system that enables retrieval and characterization of the metagenomic DNA from biologically active clones. To test the functionality of these methods, we constructed and screened two metagenomic libraries in S. lividans. One was constructed with pooled DNA from 14 bacterial isolates cultured from Alaskan soil and the second with DNA directly extracted from the same soil. Functional screening of these libraries identified numerous clones with hemolytic activity, one clone that produces melanin by a previously unknown mechanism, and one that induces the overproduction of a secondary metabolite native to S. lividans. All bioactive clones were functional in S. lividans but not in E. coli, demonstrating the advantages of screening metagenomic libraries in more than one host.


Two dimensional soft material: new faces of graphene oxide.
Graphite oxide sheets, now called graphene oxide (GO), can be made from chemical exfoliation of graphite by reactions that have been known for 150 years. Because GO is a promising solution-processable precursor for the bulk production of graphene, interest in this old material has resurged. The reactions to produce GO add oxygenated functional groups to the graphene sheets on their basal plane and edges, and this derivatization breaks the π-conjugated network, resulting in electrically insulating but highly water-dispersible sheets. Apart from making graphene, GO itself has many intriguing properties. Like graphene, GO is a two-dimensional (2D) sheet with feature sizes at two abruptly different length scales. The apparent thickness of the functionalized carbon sheet is approximately 1 nm, but the lateral dimensions can range from a few nanometers to hundreds of micrometers. Therefore, researchers can think of GO as either a single molecule or a particle, depending on which length scale is of greater interest. At the same time, GO can be viewed as an unconventional soft material, such as a 2D polymer, highly anisotropic colloid, membrane, liquid crystal, or amphiphile. In this Account, we highlight the soft material characteristics of GO. GO consists of nanographitic patches surrounded by largely disordered, oxygenated domains. Such structural characteristics effectively make GO a 2D amphiphile with a hydrophilic periphery and largely hydrophobic center. This insight has led to better understanding of the solution properties of GO for making thin films and new applications of GO as a surfactant. Changes in pH and sheet size can tune the amphiphilicity of GO, leading to intriguing interfacial activities. In addition, new all-carbon composites made of only graphitic nanostructures using GO as a dispersing agent have potential applications in photovoltaics and energy storage. On the other hand, GO can function as a 2D random diblock copolymer, one block graphitic and the other heavily hydroxylated. Therefore, GO can guide material assembly through π-π stacking and hydrogen bonding. Additionally, the selective etching of the more reactive sp(3) blocks produces a porous GO network, which greatly enhances interactions with gas molecules in chemical sensors. With their high aspect ratio, GO colloids can readily align to form liquid crystalline phases at high concentration. As single-atomic, water-dispersible, soft carbon sheets that can be easily converted to a conductive form, this 2D material should continue to inspire many curiosity-driven discoveries and applications at the interfaces of chemistry, materials science, and other disciplines.


[Creation, development and maintenance of the data-base of a computer-assisted diagnostic system (ADM) (author's transl)].
The creation of the data-base for our ADM system begun in 1972, tests on a high productivity type of procedure which we consider should be explained. In organizing and creating our data-bank our routine procedures are: first, the capture of signs, symptoms and pathological data after the text editing of the description of diseases as prepared by medical students under the direction of the Medical Computing Service; second, the control and coding of the data by the personnel of the Medical Computing Service: third, the machine storage of the data and the automated logical controls by the Medical Computing Service; and fourth, the semantic control of the data as well as the availability of each new version. Other related procedures based on the individual theses and various studies are described as examples. From 1972 to 1980 an impressive data-bank was created holding descriptions of 2200 diseases with 22000 signs and symptoms and 3500 bibliographies. It is now foreseen that between 1980 and 1983, the prototype will be placed in service and adapted. The creation and maintenance of such a data-bank with all the problems that it entails, and developed under such economical conditions justifies our presentation.


[Optimizing conditions for the discontinuous production of unicellular protein using whey].
The cheese whey is one of the most important effluents which is being disposed off in our area. That is why the study for optimizing conditions in the process of recovering whey to produce protein biomass in a batch fermenter was undertaken. A yeast strain (Kluyveromyces marxianus var. lactis) was propagated on a medium based on whey from cheese making plants, the following conditions for cell development being optimized: temperature, pH and initial concentration of lactose. A methodology based on performing several tests ordered according to a "Latin Squares" structure was proposed; this enables the simultaneous study of three variables with a small number of experiences. Such experiences were performed in a cylindrical (air lift type) glass fermenter, obtaining a maximum yield (4.78 g/l by dry weight) when working with an initial lactose concentration equal to 4.8%. For all temperatures (27, 30 and 35 degrees C) and pH (3, 4 and 5) employed, an increase in the cell number occurred with the initial lactose concentration increasing from 2% to 4.8% (Table 2). It is preferable to work at 27 degrees C and pH 4 (since these conditions minimize the bacterial contamination) and with a lactose concentration equal to 4.8%, i.e. the concentration in the residual cheese whey. Thus, an optimum yield in protein biomass is obtained, enabling a good utilization of this effluent, and also diminishing its initial BOD from 60,000 to 15,000 ppm.


[Mexican clinical experience in ocular anti-angiogenic therapy].
Retinal pathological angiogenesis is the leading cause of visual loss in a wide variety of ocular diseases. Some of the examples include: Age-related macular degeneration, diabetic retinopathy and retinopathy associated with prematurity. These last two entities are, in addition, public health problems in developing countries. Recent physiopathological studies, have demonstrated that growth factors play a key role on angiogenesis. Anti-angiogenic therapy came about as an attempt to inhibit the action of growth factors over the process of pathological angiogenesis in order to preserve vision. The objective of this review is to describe Mexico's experience using this therapeutic approach.


Relation between retinal vascular abnormalities and working memory impairment in patients with schizophrenia and bipolar disorder.
Emerging evidence indicates abnormal retinal micro-vasculature in schizophrenia (SCZ) and bipolar disorder (BD) and its relation to cognitive functions. However, the association of these abnormalities with the cognitive deficits in these disorders has not been examined till date. Hence, we explored this aspect in patients with SCZ, BD, and healthy volunteers (HV). We examined 34 with SCZ, 39 with BD, and 45 HV. Retinal images were acquired using nonmydriatic fundus camera. The retinal images were analyzed, and average diameters of retinal arterioles and venules were calculated. Working memory was assessed using computerized one-back test from Cogstate® battery. There was significant difference between groups in retinal venules and arterioles caliber (p < 0.001). Both SCZ and BD patients had wider venules and narrower arterioles. They had significantly lower working memory accuracy (p = 0.008) and higher log mean speed (p < 0.001). There was significant positive correlation between one-back test accuracy and retinal arteriolar caliber (r = 0.22; p = 0.01) and between log mean speed score and retinal venular caliber (r = 0.20; p = 0.02). Findings suggest association between working memory and retinal vascular caliber, a potential pointer towards understanding the vascular pathology in cognitive deficits in SCZ and BD. Future studies need to examine whether retinal vascular could be a biomarker for SCZ and BD.


Posthysterectomy vault prolapse: sacral colpopexy with dura mater graft.
Vaginal vault prolapse is an infrequent complication after abdominal and vaginal hysterectomy. Current surgical methods of repair include transvaginal fixation of the vault to the sacrospinous ligament, repositioning of the vagina over the levator plate by a synchronous abdominoperineal procedure, and transabdominal sacral colpopexy. Because each method results in a durable repair and restores a functional vagina, sacral colpopexy is considered the preferred procedure because of its technical simplicity. The proposed advantages using dura mater as the prosthesis are detailed.


EGCG overcomes gefitinib resistance by inhibiting autophagy and augmenting cell death through targeting ERK phosphorylation in NSCLC.
Several EGFR-tyrosine kinase inhibitors (TKIs), such as gefitinib (Gef), have been used as effective clinical therapies for patients with non-small cell lung cancer (NSCLC). However, due to acquired resistance, the efficacy of Gef treatment is severely blocked. Our preliminary study found that epigallocatechin gallate (EGCG) in combination with Gef could work synergistically to increase the sensitivity to Gef in NSCLC, but the mechanisms responsible for this have not been completely defined. In our present study, we devoted to investigate the synergistic effects of combined EGCG and Gef treatment and the importance of autophagy and ERK signaling pathway in overcoming acquired drug resistance to Gef in NSCLC. We evaluated the synergistic effects of combined EGCG and Gef treatment through in vitro cell proliferation/viability assays and in vivo xenograft studies, respectively. Autophagic flux was assessed by GFP-microtubule-associated protein 1 light chain 3 (LC3) plasmid transfection and western blot detection of autophagy-related proteins. Besides, the role of ERK on acquired resistance was validated with a ERK inhibitor. We discovered that EGCG can synergize with Gef to inhibit the proliferation of Gef-resistant NSCLC cells and suppress tumor growth in a xenograft mouse model. The underlying mechanisms of synergism were investigated, and the results showed that co-treatment with Gef and EGCG could inhibit Gef-induced autophagy and ERK phosphorylation. Consistently, the expression of LC3-II/I and ATG5 were inhibited, whereas the expression of p62 was enhanced in EGCG and Gef combination treatment groups. Further, inhibition of autophagy in Gef-resistant A549 cells could augment cell death. In conclusion, EGCG overcomes Gef resistance by inhibiting autophagy and augmenting cell death through targeting ERK pathway in NSCLC. Gef and EGCG combination therapy may be an effective strategy to overcome acquired resistance in NSCLC.


An illustrated gardener's guide to transgenic Arabidopsis field experiments.
Field studies with transgenic Arabidopsis lines have been performed over 8 yr, to better understand the influence that certain genes have on plant performance. Many (if not most) plant phenotypes cannot be observed under the near constant, low-stress conditions in growth chambers, making field experiments necessary. However, there are challenges in performing such experiments: permission must be obtained and regulations obeyed, the profound influence of uncontrollable biotic and abiotic factors has to be considered, and experimental design has to be strictly controlled. The aim here is to provide inspiration and guidelines for researchers who are not used to setting up such experiments, allowing others to learn from our mistakes. This is believed to be the first example of a 'manual' for field experiments with transgenic Arabidopsis plants. Many of the challenges encountered are common for all field experiments, and many researchers from ecological backgrounds are skilled in such methods. There is huge potential in combining the detailed mechanistic understanding of molecular biologists with ecologists' expertise in examining plant performance under field conditions, and it is suggested that more interdisciplinary collaborations will open up new scientific avenues to aid analyses of the roles of genetic and physiological variation in natural systems.


Preparation of microcapsules with narrow-size distribution by complex coacervation: effect of sodium dodecyl sulphate concentration and agitation rate.
In this paper, microcapsules with narrow-size distribution, in which the core materials are a kind of suspension containing pigment scarlet powders dispersed in dyed tetrachloroethylene with Span-80 as an emulsifier, are prepared by complex coacervation through controlling sodium dodecyl sulphate (SDS) concentration and agitation rate. The microcapsules, formed in optimized process of 0.01 wt% SDS and 800 rpm, are approximately 40 microm in diameter. The phase diagram for the gelatin/SDS/water system indicates that the concentration of SDS in the experiments is outside of the complex formation zone to form a gelatin-SDS complex. Consequently, SDS preferential adsorbs and enriches on the surface of the core droplets due to its higher surface activity. Then, gelatin deposits with SDS at the core droplet/water interface to form a primary layer of complexation. Subsequently, with the pH lower than the isoelectric point of gelatin, complex coacervate of gelatin and gum arabic grows on the primary layer surface and finally deposits on the droplets to form a secondary layer. On the whole, the research indicates that the existence of SDS not only decreases the droplet diameters and centralizes the droplets size distribution, but also accelerates coacervation of gelatin and gum arabic to reach the core droplet/water interface, forming no aggregating microcapsules.


Determination of trans-galactooligosaccharides in selected food products by ion-exchange chromatography: collaborative study.
Eleven collaborating laboratories assayed 7 blind duplicate pairs of food and feed products for tans-galactooligosaccharides. The 7 laboratory sample pairs ranged from low (2%) to high levels (15%). Following the proposed method, the test samples were treated with beta-galactosidase and the released galactose was determined by ion-exchange chromatography. Repeatability standard deviation ranged from 2.9 to 11.6%; reproducibility standard deviation ranged from 4.6 to 11.6%.


Bilateral diaphragmatic paralysis. A case report.
A case of unexplained bilateral diaphragmatic paralysis of sudden onset is described. The striking and characteristic presentation of this disorder and the benign prognosis are emphasized.


Wave Function Based Analysis of Dynamics versus Yield of Free Triplets in Intramolecular Singlet Fission.
Experiments in several intramolecular singlet fission materials have indicated that the triplet-triplet spin biexciton has a much longer lifetime than believed until recently, opening up loss mechanisms that can annihilate the biexciton prior to its dissociation to free triplets. We have performed many-body calculations of excited state wave functions of hypothetical phenylene-linked anthracene molecules to better understand linker-dependent behavior of dimers of larger acenes being investigated as potential singlet fission candidates. The calculations reveal unanticipated features that we show carry over to the real covalently linked pentacene dimers. Dissociation of the correlated triplet-triplet spin biexciton and free triplet generation may be difficult in acene dimers where the formation of the triplet-triplet spin biexciton is truly ultrafast. Conversely, relatively slower biexciton formation may indicate smaller spin biexciton binding energy and greater yield of free triplets. Currently available experimental results appear to support this conclusion. Whether or not the two distinct behaviors are consequences of distinct mechanisms of triplet-triplet generation from the optical singlet is an interesting theoretical question.


Silvopastoral management for lowering trade-offs between beef production and carbon storage in tropical dry woodlands.
Tropical dry woodlands and savannas harbour high levels of biodiversity and carbon, but are also important regions for agricultural production. This generates trade-offs between agriculture and the environment, as agricultural expansion and intensification typically involve the removal of natural woody vegetation. Cattle ranching is an expanding land use in many of these regions, but how different forms of ranching mediate the production/environment trade-off remains weakly understood. Here, we focus on the Argentine Chaco, to evaluate trade-offs between beef production and carbon storage in grazing systems with different levels of woody cover (n = 27). We measured beef productivity and carbon storage during 2018/19 and used a regression framework to quantify the trade-off between both, and to analyze which agroclimatic and management variables explain the observed trade-off. Our main finding was that silvopastures had the lowest trade-off between beef production and carbon storage, as management in these systems seeks to increase herbaceous forage by removing shrubs, while maintaining most of the bigger trees that contain most above-ground carbon. The most important variable explaining the beef production/carbon storage trade-off was pasture management, specifically the number of shrub encroachment control interventions, with a lower trade-off for higher numbers of interventions. Unfortunately, more interventions can also result in woody cover degradation over time, and shrub encroachment management must therefore be improved to become sustainable. Overall, our study highlights the strong environmental trade-offs associated with beef production in dry woodlands and savanna, but also the key role of good management practices in lowering this trade-off. Specifically, silvopastoral systems can increase beef production as much as converting woodlands to tree-less pastures, but silvopastures retain much more carbon in aboveground vegetation. Silvopastoral systems thus represent a promising land-use option to lower production/environment trade-offs in the Dry Chaco and likely many other tropical dry woodlands and savannas.


C-Reactive Protein Stimulates Nicotinic Acetylcholine Receptors to Control ATP-Mediated Monocytic Inflammasome Activation.
Blood levels of the acute phase reactant C-reactive protein (CRP) are frequently measured as a clinical marker for inflammation, but the biological functions of CRP are still controversial. CRP is a phosphocholine (PC)-binding pentraxin, mainly produced in the liver in response to elevated levels of interleukin-1β (IL-1β) and of the IL-1β-dependent cytokine IL-6. While both cytokines play important roles in host defense, excessive systemic IL-1β levels can cause life-threatening diseases such as trauma-associated systemic inflammation. We hypothesized that CRP acts as a negative feedback regulator of monocytic IL-1β maturation and secretion. Here, we demonstrate that CRP, in association with PC, efficiently reduces ATP-induced inflammasome activation and IL-1β release from human peripheral blood mononuclear leukocytes and monocytic U937 cells. Effective concentrations are in the range of marginally pathologic CRP levels (IC50 = 4.9 µg/ml). CRP elicits metabotropic functions at nicotinic acetylcholine (ACh) receptors (nAChRs) containing subunits α7, α9, and α10 and suppresses the function of ATP-sensitive P2X7 receptors in monocytic cells. Of note, CRP does not induce ion currents at conventional nAChRs, suggesting that CRP is a potent nicotinic agonist controlling innate immunity without entailing the risk of adverse effects in the nervous system. In a prospective study on multiple trauma patients, IL-1β plasma concentrations negatively correlated with preceding CRP levels, whereas inflammasome-independent cytokines IL-6, IL-18, and TNF-α positively correlated. In conclusion, PC-laden CRP is an unconventional nicotinic agonist that potently inhibits ATP-induced inflammasome activation and might protect against trauma-associated sterile inflammation.


Protective effect of curcumin on TNBS-induced intestinal inflammation is mediated through the JAK/STAT pathway.
Curcumin displays a protective role in rat models of intestinal inflammation. However, the mechanism of how curcumin affects on intestinal inflammation is less known. The purpose of the current study is to explore the signal pathway in which the curcumin protecting rat from intestinal inflammation. The intestinal inflammation rat models were made by TNBS treatment. Curcumin was added to their diet 5 days before the TNBS instillation. After that, body weight change, score of macroscopic assessment of disease activity and microscopic scoring were utilized to analyse the severity of the induced inflammation. In addition, the level of pro-inflammatory cytokines and anti-inflammatory were detected to determine the effect of curcumin on intestinal inflammation. The JAK/STAT pathway of pro-inflammation response was also evaluated. Finally, the impact of curcumin on apoptosis in intestinal inflammation was assessed by TUNEL staining. Rats pretreated with curcumin significantly reversed the decrease of body weight and increase of colon weight derived from TNBS-induced colitis. Histological improvement was observed in response to curcumin. In addition, curcumin attenuated TNBS-induced secretion of pro-inflammatory cytokines and M1/M2 ratio, while stimulated the secretion of anti-inflammatory cytokines. The inhibition of pro-inflammation response was mediated by SOCS-1, which could efficiently suppress JAK/STAT pathways. Furthermore, curcumin efficiently suppressed the TNBS-induced apoptosis, and reduced the accumulation of cytochrome C in cytosol. The anti-inflammatory effect of curcumin is realized by enhancing SOCS-1 expression and inhibiting JAK/STAT pathways. Curcumin also plays an anti-apoptotic role in TNBS-induced intestinal inflammation. We propose that curcumin may have therapeutic implications for human intestinal inflammation.


Nucleotide variability in the 5-enolpyruvylshikimate-3-phosphate synthase gene from Eleusine indica (L.) Gaertn.
This study reports the results of the partial DNA sequence analysis of the 5-enolpyruvyl-shikimate-3-phosphate synthase (EPSPS) gene in glyphosate-resistant (R) and glyphosate-susceptible (S) biotypes of Eleusine indica (L.) Gaertn from Peninsular Malaysia. Sequencing results revealed point mutation at nucleotide position 875 in the R biotypes of Bidor, Chaah and Temerloh. In the Chaah R population, substitution of cytosine (C) to adenine (A) resulted in the change of threonine (Thr106) to proline (Pro106) and from C to thymidine (T) in the Bidor R population, leading to serine (Ser106) from Pro106. As for the Temerloh R, C was substituted by T resulting in the change of Pro106 to Ser106. A new mutation previously undetected in the Temerloh R was revealed with C being substituted with A, resulting in the change of Pro106 to Thr106 indicating multiple founding events rather than to the spread of a single resistant allele. There was no point mutation recorded at nucleotide position 875 previously demonstrated to play a pivotal role in conferring glyphosate resistance to E. indica for the Lenggeng, Kuala Selangor, Melaka R populations. Thus, there may be another resistance mechanism yet undiscovered in the resistant Lenggeng, Kuala Selangor and Melaka populations.


Medical resource allocation: rationing and ethical considerations, Part II.
The proliferation of medical technology during the past decade has doubtless surpassed that of any other recent period. We have witnessed and are continuing to witness rapid advances in human genetic engineering, reproductive technology, and biomedical intervention in the life process. Our population has benefitted from this technology as a result of its ability to extend the life of individuals, particularly the elderly sector of our society. This technological proliferation has caused philosophers, physicians, engineers, and policy strategists to focus upon questions of ethics and mortality relating to their application. In approaching the ethics of rationing, consideration must be given to both the deontological concepts of the individual and the utilitarian principles of societal preservation. This article continues a discussion of the issues of resource allocation that was begun in the February 1994 issue of Physician Executive.


Generalizability of the effectiveness of a preschool mathematics intervention for low-socioeconomic status Turkish children.
A socioeconomic status (SES)-related achievement gap in mathematics emerges in children from many countries before school entry, persists in primary school, and imposes challenges for education systems worldwide. In response, the United Nations' sustainable development goals include universal access to quality preschool education to support universal numeracy. A generalizability study of the effectiveness of an early mathematics intervention was conducted for low-SES Turkish preschool children (33 boys, 27 girls; Mage = 4.32). Classrooms were randomly assigned to treatment (Pre-K Mathematics) or control conditions. Children's early mathematical knowledge was assessed by the Child Math Assessment. A statistically significant positive impact was found (ES = 1.32). This indicates some generalizability of the intervention and supports the feasibility of using early intervention to achieve UN goals.


Evaluation and management of neonatal onset hyperinsulinemic hypoglycemia: a single neonatal center experience.
To evaluate the clinical characteristics and treatment options of neonates requiring prolonged hospitalization due to persistent hyperinsulinemic hypoglycemia (HH). This retrospective cohort study included infants >34 weeks of gestation at birth who were born in our hospital between 2018 and 2021, diagnosed with HH, and required diazoxide within the first 28 days of life. The baseline clinical characteristics, age at the time of diagnosis and treatment options in diazoxide resistance cases were recorded. Genetic mutation analysis, if performed, was also included. A total of 32 infants diagnosed with neonatal HH were followed up. Among the cohort, 25 infants were classified as having transient form of HH and seven infants were classified as having congenital hyperinsulinemic hypoglycemia (CHI). Thirty-one percent of the infants had no risk factors. The median birth weight was significantly higher in the CHI group, whereas no differences were found in other baseline characteristics. Patients diagnosed with CHI required higher glucose infusion rate, higher doses, and longer duration of diazoxide treatment than those in the transient HH group. Eight patients were resistant to diazoxide, and six of them required treatment with octreotide and finally sirolimus. Sirolimus prevented the need of pancreatectomy in five of six patients without causing major side effects. Homozygous mutations in the ABCC8 gene were found in four patients with CHI. The risk of persistent neonatal hyperinsulinism should be considered in hypoglycemic neonates particularly located in regions with high rates of consanguinity. Our study demonstrated sirolimus as an effective treatment option in avoiding pancreatectomy in severe cases.


[Use of modern technologies in the diagnosis and combined treatment of brain stem tumors].
The latest technologies, introduced into neurosurgery during the last 2 decades of the 20th century, ensured progress in the diagnostics and treatment of brainstem tumors--pathologies that remain until now a most complicated problem in neurooncology. The modern diagnostic tools comprising profound dynamic neurological and neurophysiological examinations (AVP, EEG) visualization techniques (CT, MRT with contrasting, MRT, spectroscopy, PET) provide for detecting not only the initial signs of stem tumors and their sizes but also their topographic interaction with the stem structures; it, in its turn, opens up a possibility to choose between the combined surgical treatment and the radiotherapy or chemotherapy alone. The clinical course, diagnosis and combined treatment of 333 children and adults with tumors bordering on the brainstem are analyzed within the case study.


Engagement of private healthcare providers for case finding of tuberculosis and diabetes mellitus in Pakistan.
The rising co-epidemic of tuberculosis (TB) and diabetes mellitus (DM) is a challenge for constrained health systems in low and middle-income countries. Diabetes is a known risk factor for tuberculosis and associated with poor tuberculosis treatment outcomes, while tuberculosis is associated with worsening glycemic control. We investigated the performance of bi-directional TB and DM case finding approaches through a private-sector engagement model in Karachi, Pakistan. Between July 2016 and July 2018, private health care providers were engaged to generate referrals for bi-directional TB and DM screening at private diagnostic and treatment centers in Karachi, Pakistan. Individuals diagnosed with TB underwent glycated hemoglobin (HbA1c) testing at the time of anti-tuberculous treatment initiation and at three -month follow up stage. All individuals with a history of diabetes or random blood sugar of greater than 200 mg/dl were screened for TB using a chest X-ray and Xpert MTB/RIF. A total of 6312 persons with tuberculosis were tested on HbA1c at treatment initiation, of whom 1516 (24%) were newly diagnosed with DM. About one third of those with HbA1c in the diabetic range (≥ 6.5%) at baseline were found to have a normal HbA1c (< 5.7%) result at 3-month follow-up. A total of 3824 individuals with DM, of whom 2396 (63%) were known cases and 1428 (37%) were newly identified with random blood sugar > 200 mg/dl, underwent chest x-ray and Xpert MTB/RIF testing, with 321 (13.4%) known and 54 (3.8%) new diabetics respectively identified with tuberculosis. This study demonstrates a high yield of TB and DM through bidirectional screening and the feasibility of engagement of private sector in finding missing cases of tuberculosis and diabetes. Given the high prevalence of undiagnosed DM in individuals with TB tuberculosis patients, there is a need to scale-up DM screening within TB programmes. Increased awareness of the high risk of TB among individuals with DM is needed among private health providers and screening for TB among diabetics should be strongly considered.


NMR structure of the natural killer cell receptor 2B4 (CD244): implications for ligand recognition.
2B4, a transmembrane receptor expressed primarily on natural killer (NK) cells and on a subset of CD8(+) T cells, plays an important role in activating NK-mediated cytotoxicity through its interaction with CD48 on target cells. We report here the atomic-resolution structure of the ligand-binding (D1) domain of 2B4 in solution determined by nuclear magnetic resonance (NMR) spectroscopy. The overall main chain structure resembles an immunoglobulin variable (V) domain fold, very similar to that seen previously for domain 1 of CD2 and CD4. The structure contains nine beta-strands assembled into two beta-sheets conventionally labeled DEB and AGFCC'C' '. The six-stranded sheet (AGFCC'C' ') contains structural features that may have implications for ligand recognition and receptor function. A noncanonical disulfide bridge between Cys2 and Cys99 stabilizes a long and parallel beta-structure between strand A (residues 3-12) and strand G (residues 100-108). A beta-bulge at residues Glu45 and Ile46 places a bend in the middle of strand C' that orients two conserved and adjacent hydrophobic residues (Ile46 and Leu47) inside the beta-sandwich as seen in other V domains. Finally, the FG-loop (implicated in ligand recognition in the CD2-CD58 complex) is dynamically disordered in 2B4 in the absence of a ligand. We propose that ligand binding to 2B4 might stabilize the structure of the FG-loop in the ligand complex.


Calcium alters divalent cation modulation of brain benzodiazepine receptors.
Nickel (Ni+2) ions enhance the binding of 3H-diazepam, but decrease the binding of 3H-propyl beta-carboline-3-carboxylate to benzodiazepine receptors in mouse brain. Our experiments were performed to determine the locus for this action. In both control and Ca+2-depleted membranes, Ca+2 blocked the stimulatory effect of Ni+2 on 3H-diazepam binding in a concentration-dependent manner. In Ca+2-depleted membranes, physiological Ca+2 concentrations blocked this effect of Ni+2. In control membranes, Ca+2 did not reverse Ni+2 inhibition of 3H-propyl beta-carboline-3-carboxylate binding, but was effective at physiological concentrations in reversing Ni+2 inhibition in Ca+2-depleted membranes. The effects of Cd+2 ions on 3H-diazepam binding were similar to Ni+2 and were also reversed by Ca+2. The effects of Ni+2 were blocked by La+3 ions but not by Mg+2 ions, and were not due to interactions with the GABA receptor or Cl- ionophore. These data suggest that a Ca+2 binding site is associated with the brain benzodiazepine receptor.


The assessment of mindfulness skills: the "what" and the "how".
Background: The five facets mindfulness questionnaire-short form (FFMQ-SF) is a new, brief measure for the assessment of mindfulness skills in clinical and nonclinical samples. The construct validity of the FFMQ-SF has not been previously assessed in community samples.Aims: The present study investigated the factor structure of the Italian version of the FFMQ-SF.Method: Structured equation modeling was used to test the fit of three alternative models in a sample of highly educated adults (n = 211).Results: A hierarchical model with a single second-order factor loaded by observing, describing, and acting with awareness (i.e. the mindfulness "what" skills) performed slightly better than both a five-factor model with correlated factors and a hierarchical model with a general second-order factor. The FFMQ-SF scores were significantly higher than those reported in both Dutch depressed patients and Australian undergraduate students for all facets (but nonreactivity for the Australian sample).Conclusions: Data support the multifaceted nature of mindfulness skills. Because of its brevity and simplicity of use, the FFMQ-SF is a promising questionnaire in longitudinal and clinical research. This questionnaire can serve as a guideline to help clinicians assess and monitor mindfulness skills acquisition, strengthening, and generalization, and prioritize mindfulness skills that need immediate attention.


The presenilin 1 C92S mutation increases abeta 42 production.
Although wild-type human presenilin 1 (PS1) rescues the C. elegans egg-laying (egl) phenotype that is caused by a loss of function mutation in the C. elegans presenilin homologue sel12, most familial Alzheimer's disease (FAD)-linked PS1 mutants only partially rescue this phenotype. To investigate the effects of the loss of function sel12 mutation on Abeta production in mammalian cells, we analyzed Abeta production in transfected H4 neuroglioma cells expressing the PS1 homologue of the sel12 C60S mutant, PS1 C92S. This analysis revealed that PS1 C92S increased Abeta42 levels in a similar fashion to other pathogenic Alzheimer's disease (AD) PS1 mutations. Significantly, the PS1 C92S mutation has recently been identified as the pathogenic mutation in an Italian family with FAD. Thus, placing a mutation that results in loss of function in C. elegans into a context whereby its effect on mammalian cells can be evaluated suggests that all FAD-linked PS1 mutants result in increased Abeta42 production through a partial loss of function mechanism.


OptMAVEn--a new framework for the de novo design of antibody variable region models targeting specific antigen epitopes.
Antibody-based therapeutics provides novel and efficacious treatments for a number of diseases. Traditional experimental approaches for designing therapeutic antibodies rely on raising antibodies against a target antigen in an immunized animal or directed evolution of antibodies with low affinity for the desired antigen. However, these methods remain time consuming, cannot target a specific epitope and do not lead to broad design principles informing other studies. Computational design methods can overcome some of these limitations by using biophysics models to rationally select antibody parts that maximize affinity for a target antigen epitope. This has been addressed to some extend by OptCDR for the design of complementary determining regions. Here, we extend this earlier contribution by addressing the de novo design of a model of the entire antibody variable region against a given antigen epitope while safeguarding for immunogenicity (Optimal Method for Antibody Variable region Engineering, OptMAVEn). OptMAVEn simulates in silico the in vivo steps of antibody generation and evolution, and is capable of capturing the critical structural features responsible for affinity maturation of antibodies. In addition, a humanization procedure was developed and incorporated into OptMAVEn to minimize the potential immunogenicity of the designed antibody models. As case studies, OptMAVEn was applied to design models of neutralizing antibodies targeting influenza hemagglutinin and HIV gp120. For both HA and gp120, novel computational antibody models with numerous interactions with their target epitopes were generated. The observed rates of mutations and types of amino acid changes during in silico affinity maturation are consistent with what has been observed during in vivo affinity maturation. The results demonstrate that OptMAVEn can efficiently generate diverse computational antibody models with both optimized binding affinity to antigens and reduced immunogenicity.


[Alternative solutions in the treatment of patients with combined benign endometrial and myometrial pathology].
The study included 96 women with combined benign hyperplastic uterine conditions. Half of them underwent a radical uterine resection and were examined at 3.1 +/- 0.2 years following the operation. The rest were randomly selected as matched pairs and were evaluated at 4.3 +/- 0.13 years following multicomponent treatment including hormones (n-26) and cryohormonal treatment (n-22). Analysis of results revealed a complex pathogenesis of this disease of the reproductive tract, presenting as severe postoperative vegetoneurotic disorders. Potential of an adequate conservative treatment in preserving specific female functions was determined.


The Prostate Cancer Prevention Trial and European Randomized Study of Screening for Prostate Cancer risk calculators indicating a positive prostate biopsy: a comparison.
To assess the potential problem that different tools for predicting a positive outcome of prostate biopsy can produce divergent outcomes in the same man, by comparing the risk calculators based on the Prostate Cancer Prevention Trial (PCPT) and the European Randomized Study of Screening for Prostate Cancer (ERSPC). In the prostate-specific antigen (PSA) range of 0.2-30.0 ng/mL, the prediction curves of 'virtual' standard study participants were evaluated using both prediction tools. The effects of prostate volume, digital rectal examination, transrectal ultrasonography (TRUS), previous negative biopsy, family history, race, and age were also assessed. Important differences in underlying study design and populations between the PCPT and ERSPC cause an essential discrepancy between the risk calculators. In the PCPT there were few biopsies in the higher PSA ranges, and in the ERSPC in the lower PSA ranges. Both risk indicators have incorporated some variables that are not used in the other, because they were insignificant in multivariate analysis. TRUS and especially prostate volume (not available in the PCPT) have a considerably larger effect on predictions in comparable PSA ranges than race, age, family history of prostate cancer, and previous negative biopsy (indicators that were excluded in ERSPC). Before using risk calculators users must consider the properties of the underlying populations and what are the included or unavailable risk factors, and compare these to the patient. When these prerequisites are disregarded, dissimilarities will result in grossly inaccurate predictions for individual patients.


Twice as Nice: How Doubling Otolaryngology Rotation Time Affects the Intern Experience Nationwide.
Describe the current state of otolaryngologic residency training with recent changes to the program requirements by the Accreditation Council for Graduate Medical Education (ACGME) which increased the amount of time on intern year otolaryngology rotations from 3 to 6 months. A cross-sectional study was performed and recruitment was done via personalized email sent to program coordinators of 113 ACGME-accredited otolaryngology training programs within the Unites States. The message requested a breakdown of the amount of time and specialty in which first year otolaryngologic residents rotated. Interval follow ups were sent at 3 and 6 months for coordinators who had not responded. Response rate was 79.7% (90/113). General surgery and surgical intensive care unit were the two most common non-otolaryngologic rotations (92.2% and 96.6% respectively) while ophthalmology and radiation oncology were the least common at 7.8% each. All first year residents spend time on an inpatient otolaryngologic rotation, while 30.7% spend time on outpatient rotations. The most common subspecialties were head and neck oncology (40.0%) followed by pediatric otolaryngology (36.0%). Otolaryngologic training continues to become more slanted towards specialty-specific training and a concurrent reduction in "off-service" rotations. General inpatient services still predominate the intern year both inter- and intra-departmentally. These data provide insight into the training environment of the otolaryngologic trainees set to graduate residency for the first time this year.


Evidence of inflammatory immune signaling in chronic fatigue syndrome: A pilot study of gene expression in peripheral blood.
Genomic profiling of peripheral blood reveals altered immunity in chronic fatigue syndrome (CFS) however interpretation remains challenging without immune demographic context. The object of this work is to identify modulation of specific immune functional components and restructuring of co-expression networks characteristic of CFS using the quantitative genomics of peripheral blood. Gene sets were constructed a priori for CD4+ T cells, CD8+ T cells, CD19+ B cells, CD14+ monocytes and CD16+ neutrophils from published data. A group of 111 women were classified using empiric case definition (U.S. Centers for Disease Control and Prevention) and unsupervised latent cluster analysis (LCA). Microarray profiles of peripheral blood were analyzed for expression of leukocyte-specific gene sets and characteristic changes in co-expression identified from topological evaluation of linear correlation networks. Median expression for a set of 6 genes preferentially up-regulated in CD19+ B cells was significantly lower in CFS (p = 0.01) due mainly to PTPRK and TSPAN3 expression. Although no other gene set was differentially expressed at p < 0.05, patterns of co-expression in each group differed markedly. Significant co-expression of CD14+ monocyte with CD16+ neutrophil (p = 0.01) and CD19+ B cell sets (p = 0.00) characterized CFS and fatigue phenotype groups. Also in CFS was a significant negative correlation between CD8+ and both CD19+ up-regulated (p = 0.02) and NK gene sets (p = 0.08). These patterns were absent in controls. Dissection of blood microarray profiles points to B cell dysfunction with coordinated immune activation supporting persistent inflammation and antibody-mediated NK cell modulation of T cell activity. This has clinical implications as the CD19+ genes identified could provide robust and biologically meaningful basis for the early detection and unambiguous phenotyping of CFS.


Self micro-emulsifying drug delivery system: formulation development and biopharmaceutical evaluation of lipophilic drugs.
Several methods are being employed to improve the oral bioavailability of lipophilic drugs like using inert lipid vehicles such as Oils, Surfactant dispersions, Self Microemulsifying Drug Delivery Systems (SMEDDS) and Liposomes. SMEDDS is formulated with the help of oil or suitable lipid materials, Surfactants and hydrophilic Co-surfactants. Mixture of above ingredients can be filled in a soft capsule and ingested. When the mixture comes in contact with gastrointestinal fluid it forms a stable O/W Microemulsion. A pseudo ternary phase diagram is used for identifying the efficient Self micro-emulsification region. SMEDDS can be formulated to give sustained release by use of inert polymers. When this polymer comes in contact with GI fluids, it forms gelled polymeric matrix, which releases the micro-emulsified active principle in a continuous and prolonged manner. Physical characterization of SMEDDS should be carried out by droplet size analysis and spontaneity of emulsification. The purpose of this review is to provide a brief out line of the formulation of SMEDDS, possible mode for improving bioavailability, fate and evaluation of the same.


Perceived social support and psychosocial distress among children affected by AIDS in china.
The psychosocial wellbeing of the children affected by Acquired Immune Deficiency Syndrome (AIDS) receives growing international attention. However, limited data in this area are available in China, which hosts an estimate of 100,000 AIDS-orphaned children. The study aims to examine the relationship between perceived social support (PSS) and psychosocial wellbeing among children affected by AIDS. A cross-sectional survey was administered to 1,625 children (aged 6-18 years) in Henan Province, an area with a large number of HIV cases due to unhygienic commercial blood/plasma collection. Our sample included 296 double orphans (i.e., children who lost both parents to AIDS), 459 single orphans (children who lost one parent to AIDS), 466 vulnerable children (children living with HIV-infected parents) and 404 comparison children (children who did not experience HIV-related illness and death in family). Data suggest that vulnerable children reported the lowest level of PSS compared to AIDS orphans and comparison children. Level of PSS was significantly and positively associated with psychosocial wellbeing even after controlling for potential confounders. The study underscores the importance of providing social support and mental health services for children affected by AIDS in China.


Inhibition of Diacylglycerol Lipase Impairs Fear Extinction in Mice.
Elucidating the underlying molecular mechanisms regulating fear and extinction learning may offer insights that can lead to novel treatments for debilitating anxiety and trauma-related disorders including posttraumatic stress disorder. The endocannabinoid (eCB) system is a retrograde inhibitory signaling pathway involved in regulating central responses to stress. The eCB 2-arachidonoylglycerol (2-AG) has recently been proposed to serve as a homeostatic signal mitigating adverse effects of stress exposure, however, less well understood is 2-AG's role in fear learning and fear extinction. In this study, we have sought to explore 2-AG's role in fear conditioning and fear extinction by disrupting 2-AG synthesis utilizing the DAGL inhibitor (DO34) and DAGLα knock-out mice (DAGLα-/-). We found that DAGLα-/- mice, and male and female C57B6/J mice treated with DO34, exhibited impairment in extinction learning in an auditory cue fear-conditioning paradigm. DO34 did not increase unconditioned freezing. Interestingly, inhibition of fatty-acid amide hydrolase was not able to restore normal fear extinction in DO34-treated mice suggesting increased Anandamide cannot compensate for deficient 2-AG signaling in the regulation of fear extinction. Moreover, augmentation of CB1R signaling with tetrahydrocannabinol also failed to restore normal fear extinction in DO34-treated mice. Overall, these data support the hypothesis that DAGLα plays an important role in fear extinction learning. Although genetic and pharmacological disruption of DAGL activity causes widespread lipidomic remodeling, these data combined with previous studies putatively suggest that deficient 2-AG signaling could be a susceptibility endophenotype for the development of trauma-related psychiatric disorders.


Plasticity of functional traits varies clinally along a rainfall gradient in Eucalyptus tricarpa.
Widespread species often occur across a range of climatic conditions, through a combination of local genetic adaptations and phenotypic plasticity. Species with greater phenotypic plasticity are likely to be better positioned to cope with rapid anthropogenic climate changes, while those displaying strong local adaptations might benefit from translocations to assist the movement of adaptive genes as the climate changes. Eucalyptus tricarpa occurs across a climatic gradient in south-eastern Australia, a region of increasing aridity, and we hypothesized that this species would display local adaptation to climate. We measured morphological and physiological traits reflecting climate responses in nine provenances from sites of 460 to 1040 mm annual rainfall, in their natural habitat and in common gardens near each end of the gradient. Local adaptation was evident in functional traits and differential growth rates in the common gardens. Some traits displayed complex combinations of plasticity and genetic divergence among provenances, including clinal variation in plasticity itself. Provenances from drier locations were more plastic in leaf thickness, whereas leaf size was more plastic in provenances from higher rainfall locations. Leaf density and stomatal physiology (as indicated by δ(13)C and δ(18)O) were highly and uniformly plastic. In addition to variation in mean trait values, genetic variation in trait plasticity may play a role in climate adaptation.


[Clinical and pathological study on early diagnosis of Parkinson's disease and dementia with Lewy bodies].
Cardiac uptake of meta-iodobenzylguanidine (MIBG) is specifically reduced in Lewy body disease (LBD). To see pathological basis of the reduced cardiac uptake of MIBG in LBD, we immunohistichemically examined cardiac tissues from patients with LBD, related movement disorders and Alzheimer's disease (AD). In LBD, cardiac sympathetic denervation occurs, which accounts for the reduced cardiac uptake of MIBG. Patients with LBD have Lewy bodies (LBs) in the nervous system, whereas patients with the other neurodegenerative parkinsonism, parkin-associated Parkinson's disease (PD) and AD and have no LBs. Therefore, cardiac sympathetic denervation is closely related to the presence of LBs in a wide range of neurodegenerative processes. We further investigate how a-synuclein aggregates are involved in degeneration of the cardiac sympathetic nerve in PD. Accumulation of alpha-synuclein aggregates in the distal axons of the cardiac sympathetic nervous system precedes that of neuronal somata or neurites in the paravertebral sympathetic ganglia and that it heralds centripetal degeneration of the cardiac sympathetic nerve in PD. This chronological and dynamic relationship between alpha-synuclein aggregates and degeneration of the cardiac sympathetic nervous system may represent the pathological mechanism underlying a common degenerative process in PD.


Hepatitis A virus 3C protease cleaves NEMO to impair induction of beta interferon.
NEMO (NF-κB essential modulator) is a bridging adaptor indispensable for viral activation of interferon (IFN) antiviral response. Herein, we show that hepatitis A virus (HAV) 3C protease (3Cpro) cleaves NEMO at the Q304 residue, negating its signaling adaptor function and abrogating viral induction of IFN-β synthesis via the retinoic acid-inducible gene I/melanoma differentiation-associated protein 5 (RIG-I/MDA5) and Toll-like receptor 3 (TLR3) pathways. NEMO cleavage and IFN antagonism, however, were lost upon ablation of the catalytic activity of 3Cpro. These data describe a novel immune evasion mechanism of HAV.


Computer-aided tumor detection based on multi-scale blob detection algorithm in automated breast ultrasound images.
Automated whole breast ultrasound (ABUS) is an emerging screening tool for detecting breast abnormalities. In this study, a computer-aided detection (CADe) system based on multi-scale blob detection was developed for analyzing ABUS images. The performance of the proposed CADe system was tested using a database composed of 136 breast lesions (58 benign lesions and 78 malignant lesions) and 37 normal cases. After speckle noise reduction, Hessian analysis with multi-scale blob detection was applied for the detection of tumors. This method detected every tumor, but some nontumors were also detected. The tumor like lihoods for the remaining candidates were estimated using a logistic regression model based on blobness, internal echo, and morphology features. The tumor candidates with tumor likelihoods higher than a specific threshold (0.4) were considered tumors. By using the combination of blobness, internal echo, and morphology features with 10-fold cross-validation, the proposed CAD system showed sensitivities of 100%, 90%, and 70% with false positives per pass of 17.4, 8.8, and 2.7, respectively. Our results suggest that CADe systems based on multi-scale blob detection can be used to detect breast tumors in ABUS images.


False-Negative Rate of Papanicolaou Testing: A National Survey from the Thai Society of Cytology.
To evaluate the performance of Papanicolaou smear screening in Thailand at the national level, and to propose recommendations for continuing quality control. This study was conducted by The Thai Society of Cytology and involved 124 laboratories in 76 provinces during 2010-2014. Random sampling suggested recalling of 10% of slides defined as negative at routine screenings (10% random rescreening [R10] model) directly from the reading unit. Out of 330,075 smears covered by the rescreening project throughout its 5-year duration, the rates of abnormal, unsatisfactory, and normal results were 0.63, 1.82, and 97.55%, respectively. Abnormal findings were largely represented by ASC-US (54%) and L-SIL (21%). The average false-negative rate (FNR) measured at the level of L-SIL and higher was 13.8%. The national project was developed to address the accuracy of cervical cancer screening and to promote internal quality assurance based on the R10, on-site surveys, and education. The major output parameters of this study (FNR and number and distribution of abnormal cases on rescreening) improved significantly in the main phase of the project (2012-2014), after revising substantial logistics issues encountered during the first 2 years of this study. This project provided objective measurable evidence related to the quality of cytology-based cervical cancer screening in Thailand.