Oculodentodigital Dysplasia: A Hypomyelinating Leukodystrophy with a Characteristic MRI Pattern of Brain Stem Involvement.
Oculodentodigital dysplasia, a rare genetic disorder caused by mutations in the gene encoding gap junction protein 1, classically presents with typical facial features, dental and ocular anomalies, and syndactyly. Oligosymptomatic patients are common and difficult to recognize, in particular if syndactyly is absent. Neurologic manifestation occurs in approximately 30% of patients, and leukodystrophy or T2 hypointensity of gray matter structures or both have been noted in individual patients. To investigate MR imaging changes in oculodentodigital dysplasia, we retrospectively and systematically reviewed 12 MRIs from 6 genetically confirmed patients. Diffuse supratentorial hypomyelination, T2-hypointense Rolandic and primary visual cortex, and symmetric involvement of middle cerebellar peduncle, pyramidal tract, and medial lemniscus was present in all, T2-hypointense pallidum and dentate nucleus in 2 patients each. This consistent, characteristic pattern of diffuse supratentorial hypomyelination and brain stem involvement differs from other hypomyelinating and nonhypomyelinating leukodystrophies with brain stem involvement, and its recognition should trigger genetic testing for oculodentodigital dysplasia.


Effectiveness of Web-Based Personalized Nutrition Advice for Adults Using the eNutri Web App: Evidence From the EatWellUK Randomized Controlled Trial.
Evidence suggests that eating behaviors and adherence to dietary guidelines can be improved using nutrition-related apps. Apps delivering personalized nutrition (PN) advice to users can provide individual support at scale with relatively low cost. This study aims to investigate the effectiveness of a mobile web app (eNutri) that delivers automated PN advice for improving diet quality, relative to general population food-based dietary guidelines. Nondiseased UK adults (aged >18 years) were randomized to PN advice or control advice (population-based healthy eating guidelines) in a 12-week controlled, parallel, single-blinded dietary intervention, which was delivered on the web. Dietary intake was assessed using the eNutri Food Frequency Questionnaire (FFQ). An 11-item US modified Alternative Healthy Eating Index (m-AHEI), which aligned with UK dietary and nutritional recommendations, was used to derive the automated PN advice. The primary outcome was a change in diet quality (m-AHEI) at 12 weeks. Participant surveys evaluated the PN report (week 12) and longer-term impact of the PN advice (mean 5.9, SD 0.65 months, after completion of the study). Following the baseline FFQ, 210 participants completed at least 1 additional FFQ, and 23 outliers were excluded for unfeasible dietary intakes. The mean interval between FFQs was 10.8 weeks. A total of 96 participants were included in the PN group (mean age 43.5, SD 15.9 years; mean BMI 24.8, SD 4.4 kg/m2) and 91 in the control group (mean age 42.8, SD 14.0 years; mean BMI 24.2, SD 4.4 kg/m2). Compared with that in the control group, the overall m-AHEI score increased by 3.5 out of 100 (95% CI 1.19-5.78) in the PN group, which was equivalent to an increase of 6.1% (P=.003). Specifically, the m-AHEI components nuts and legumes and red and processed meat showed significant improvements in the PN group (P=.04). At follow-up, 64% (27/42) of PN participants agreed that, compared with baseline, they were still following some (any) of the advice received and 31% (13/42) were still motivated to improve their diet. These findings suggest that the eNutri app is an effective web-based tool for the automated delivery of PN advice. Furthermore, eNutri was demonstrated to improve short-term diet quality and increase engagement in healthy eating behaviors in UK adults, as compared with population-based healthy eating guidelines. This work represents an important landmark in the field of automatically delivered web-based personalized dietary interventions. ClinicalTrials.gov NCT03250858; https://clinicaltrials.gov/ct2/show/NCT03250858.


[Pathomorphological changes in albino mice infected with plague and treated with cefotaxime].
Pathomorphological and bacteriological changes in albino mice infected with plague and treated with cefotaxime were investigated. The control animals which died within 3 days had structural changes characteristic of generalized plague with lesions in the infection site, regional lymph nodes, spleen, liver and lungs. The plague microbe was isolated from the tissues of all the organs and blood. The animals treated with cefotaxime (200 mg/kg for 7 days) survived. The histological examination conclusively demonstrated the absence of the changes characteristic of generalized plague in their internal organs. The infection process was mainly restricted by the primary complex and was strictly localized. The tissue reaction around the focus in the second part of the experiment developed in accordance with the productive type inflammation followed by the organization and cicatrization. In the bacteriological investigation the plague causative agent was detectable during the first days of the treatment in the site of the infection. During the subsequent days the plague microbe was not detected.


Regulation of dendritic spine motility and stability by Rac1 and Rho kinase: evidence for two forms of spine motility.
Dendritic spines are major sites of excitatory synapses in the brain and display rapid motility, which is believed to be important for synapse formation and plasticity. Spine morphology was previously shown to be regulated by the Rho GTPases Rac1 and RhoA. Here, we analyzed the roles of Rac1 and a downstream effector of RhoA, Rho kinase, in controlling spine morphogenesis and their effects on spine motility and stability. Blockade of Rac1 induced long, thin spines and inhibited spine head growth, morphing, and stability. Spine head growth was more severely affected in mature spines. On the other hand, inhibition of Rho kinase induced new, long spines and protrusive motility. These data demonstrate that Rac1 and RhoA/Rho kinase pathways regulate different aspects of spine morphology, motility, and stability and presumably also different aspects of synaptic functions. Moreover, our data show that there are two different types of spine motility: protrusive motility and head morphing, which are differentially regulated by Rac1 and Rho kinase. We propose that these two different types of spine motility serve different functions in synaptogenesis and synapse maturation.


Adolescent depression: Why more girls?
Although there has been evidence for some time of a sex difference in depression, relatively little research has examined the developmental process by which women come to be at greater risk than men for depression. In this paper, the developmental pattern of depressed affect is examined over early and middle adolescence, with a special focus on the patterns of boys as compared to girls. In addition, a developmental model for mental health in adolescence is tested for its power in explaining the emergence of gender differences in depression. Longitudinal data on 335 adolescents randomly selected from two school districts were used to test the hypotheses. Results revealed that girls are at risk for developing depressed affect by 12th grade because they experienced more challenges in early adolescence than did boys. The sex difference in depressed affect at 12th grade disappears once early adolescent challenges are considered.


PU.1 is a suppressor of myeloid leukemia, inactivated in mice by gene deletion and mutation of its DNA binding domain.
In most myeloid leukemias induced in mice by gamma-radiation, one copy of chromosome 2 has suffered a deletion. To search for a potential tumor suppressor gene in that region, we have delineated the deletions in a panel of these tumors. A commonly deleted region of 2 megabase pairs (Mbp) includes the gene encoding the PU.1 transcription factor, a powerful inducer of granulocytic/monocytic differentiation. Significantly, in 87% of these tumors the remaining PU.1 allele exhibited point mutations in the PU.1 DNA binding domain. Surprisingly, 86% of these mutations altered a single CpG, implicating deamination of deoxycytidine, a common mutational mechanism, as the origin of this lesion. The "hot spot" resides in the codon for a contact residue essential for DNA binding by PU.1. In keeping with a tumor suppressor role for PU.1, enforced expression of wild-type PU.1 in the promyelocytic leukemia cells inhibited their clonogenic growth, induced monocytic differentiation, and elicited apoptosis. The mutant PU.1 found in tumors retained only minimal growth suppressive function. The results suggest that PU.1 normally suppresses development of myeloid leukemia by promoting differentiation and that the combination of gene deletion and a point mutation that impairs its ability to bind DNA is particularly leukemogenic.


Metabolism of N-alkyl compounds during the biosynthesis of prostaglandins. N-Dealkylation during prostaglandin biosynthesis.
The microsomal fraction of ram seminal vesicles (RSV), when fortified with arachidonic acid, catalyzed the dealkylation of various N-methyl compounds. These included an analogous series of monomethyl- and dimethyl-substituted anilines as well as the drugs aminopyrine and benzphetamine. In contrast, S-alkyl and O-alkyl compounds were poor substrates for dealkylation by RSV microsomes fortified with fatty acid. RSV microsomal N-dealkylation was completely dependent on enzyme and arachidonic acid and could be inhibited by the prostaglandin synthetase inhibitors indomethacin, phenylbutazone, and flufenamic acid as well as by anaerobic conditions. Butylated hydroxyanisole also inhibited the reaction, whereas SKF-525A and metyrapone, which are inhibitors of cytochrome P-450-dependent N-dealkylation, did not. In addition to arachidonic acid, N-dealkylation was elicited by 15-hydroperoxyarachidonic acid, tert-butyl-hydroperoxide, and hydrogen peroxide; these latter reactions were not inhibited by either prostaglandin synthetase inhibitors or anaerobic conditions but did require the presence of microsomal protein. The time course of RSV N-dealkylation, which paralleled O2 consumption by this tissue (an indicator of prostaglandin biosynthesis) implied arachidonic acid-dependent irreversible self-inactivation of catalytic activity. Apparently, oxidizing agents are formed during the interaction of hydroperoxide intermediates of prostaglandin biosynthesis with prostaglandin synthetase, with the oxidizing agents then causing both substrate N-dealkylation and destruction of the enzyme. The metabolism of N-alkyl compounds during the biosynthesis of prostaglandins may provide an additional xenobiotic oxidation pathway to cytochrome P-450-dependent monooxygenases.


Murine embryonic stem cell-derived pancreatic acinar cells recapitulate features of early pancreatic differentiation.
Acinar cells constitute 90% of the pancreas epithelium, are polarized, and secrete digestive enzymes. These cells play a crucial role in pancreatitis and pancreatic cancer. However, there are limited models to study normal acinar cell differentiation in vitro. The aim of this work was to generate and characterize purified populations of pancreatic acinar cells from embryonic stem (ES) cells. Reporter ES cells (Ela-pur) were generated that stably expressed both beta-galactosidase and puromycin resistance genes under the control of the elastase I promoter. Directed differentiation was achieved by incubation with conditioned media of cultured fetal pancreatic rudiments and adenoviral-mediated co-expression of p48/Ptf1a and Mist1, 2 basic helix-loop-helix transcription factors crucial for normal pancreatic acinar development and differentiation. Selected cells expressed multiple markers of acinar cells, including digestive enzymes and proteins of the secretory pathway, indicating activation of a coordinated differentiation program. The genes coding for digestive enzymes were not regulated as a single module, thus recapitulating what occurs during in vivo pancreatic development. The generated cells displayed transient agonist-induced Ca(2+) mobilization and showed a typical response to physiologic concentrations of secretagogues, including enzyme synthesis and secretion. Importantly, these effects did not imply the acquisition of a mixed acinar-ductal phenotype. These studies allow the generation of almost pure acinar-like cells from ES cells, providing a normal cell-based model for the study of the acinar differentiation program in vitro.


Fondaparinux cross-reactivity in heparin-induced thrombocytopenia successfully treated with high-dose intravenous immunoglobulin and rivaroxaban.
HIT, a prothrombotic disorder caused by heparin-dependent antibodies, is often treated with fondaparinux, usually with good outcomes. A 70-year-old female developed severe HIT (platelet count, 25 × 109/L) post-glioblastoma resection during heparin thromboprophylaxis, complicated by disseminated intravascular coagulation (DIC) and symptomatic lower-limb deep-vein thrombosis (DVT). Despite therapeutic-dose fondaparinux, thrombocytopenia/hypofibrinogenemia persisted, with new symptomatic catheter-associated upper-extremity DVT. This clinical picture could be explained by autoimmune HIT (aHIT) refractory to fondaparinux or by fondaparinux cross-reactivity, so high-dose intravenous immunoglobulin (IVIG) was given (to treat possible aHIT) and fondaparinux switched to rivaroxaban, with subsequent clinical recovery. In vitro studies revealed strong fondaparinux cross-reactivity, without aHIT antibodies. Moreover, the patient's serotonin-release assay became negative post-IVIG, suggesting in-vivo inhibition of HIT antibody-induced platelet activation. Our case illustrates fondaparinux cross-reactivity in HIT manifesting as persisting thrombocytopenia, new thrombosis, and DIC, with successful rivaroxaban treatment, adding to emerging data that oral factor Xa inhibitors are efficacious for treating HIT.


Adolescent accounts of the UK National Lottery and scratchcards: an analysis using Q-sorts.
The study examined adolescents' accounts of the UK National Lottery and scratchcards. Q-sorts were used to examine the views of 62 participants aged between 11 and 15 years of age. Findings identified four distinct accounts in relation to the National Lottery (Moral Opposition, Luck Seeking, Rationalist, & Uncertainty), and four distinct accounts in relation to scratchcards (Scepticism, Thrill-Seeking, Rationalist, & Libertarian). Some of the accounts identified described the UK National Lottery and scratchcards as bona fide forms of gambling. Reports indicated that adolescents were pessimistic about the chances of winning large sums of money, while other accounts demonstrated gambling misperceptions particularly in relation to their belief in luck and the laws of probability. It is argued that to fully understand why adolescents take part in these activities it is important to consider the diverse ways that adolescents represent these activities. These differing representations will have consequences for measures aimed at reducing, preventing, or treating adolescent problem gambling. The utility of Q-sorts as a technique for examining the views of problem and non-problem gamblers is also discussed.


[Detection of the measles virus genome in the peripheral blood lymphocytes of patients with chronic and acute glomerulonephritis].
The presence of the measles (rubeola) virus genome was searched for in the lymphocytes from the peripheral blood of patients suffering from the acute (16 persons) or chronic (164 persons) glomerulonephritis. Dot hybridization technique with the plasmid borne probes to the measles viral genes NP, P and H have been used for the search. The measles viral genome has been detected in 58% of lymphocytes from the patients with the chronic glomerulonephritis and in 50% of lymphocytes from the patients suffering from the acute form of the disease. The genome was not found in the material from the control group including donors and traumatology ward patients. 25 samples of lymphocytes from the patients with the chronic glomerulonephritis contained the RNA that was not hybridizable with the viral genes probes by dot hybridization technique, thus containing no genes homologous to parotitis viral genes. The average titer of anti-measles antibodies in the serum from patients with chronic glomerulonephritis the lymphocytes of which contained the measles viral genome was 1:304, while it was 1:154 for patients with the negative probes. The average anti-measles antibodies titers are the same (1:166 and 1:142) for analogical groups of patients with acute form of disease.


Maximal testosterone suppression in the management of recurrent and metastatic prostate cancer.
Testosterone suppression, or androgen-deprivation therapy (ADT), is an established treatment for recurrent and metastatic prostate cancer (PCa). Based on the accuracy and sensitivity of early assays (c. 1960-1970), the castrate testosterone level was set at ≤1.7 nmol/l. Improved sensitivity of testosterone assays shows that both surgical and medical castration can achieve levels <0.7 nmol/l. However, the clinical implications and importance of maximum testosterone suppression remains a subject of controversy. This evidence-based review assesses prospective and retrospective clinical data, linking maximum suppression of testosterone with improved outcomes from ADT. PubMed and conference proceedings were searched for studies assessing the impact of low testosterone on clinical outcomes from ADT. The key search terms included combinations of prostate cancer and testosterone, predictive/prognostic, and androgen deprivation. Results were limited to studies investigating the relationship between testosterone levels and clinical outcomes. Both prospective and retrospective data support a relationship between testosterone levels below the historical standard of 1.7 nmol/l and improved outcomes. Eight studies showed significant improvements in survival-related outcomes, with the majority of data supporting a testosterone level cutoff of ≤0.7 nmol/l. Tracking both testosterone and prostate-specific antigen (PSA) levels has significant clinical benefits, and the serum testosterone threshold of ≤0.7 nmol/l is a practical goal. The relative levels of testosterone and PSA may indicate continued hormone responsiveness or progression toward castration-resistant prostate cancer (CRPC) and should, therefore, inform treatment strategy. Standardization of assay methods and clinical coordination to facilitate widespread access to state-of the art laboratory equipment is necessary to ensure accurate decision-making.


Glycosidase analysis of large acidic-type glycopeptides from viral and cellular membrane glycoproteins. Evidence for a common oligomannosyl core with branch sugar heterogeneity.
The asparagine-linked oligosaccharides of the complex acidic-type from [3H]mannose-, [3H]glucosamine- or [3H]galactose-labelled membrane glycoproteins of BHK21 cells and Rous-sarcoma virus were analysed by gel filtration combined with extensive digestion with endo- and exo-glycosidases from bacterial and eukaryotic sources. The neutral products from the digestion with a mixture of exoglycosidases and endo-beta-N-acetylglucosaminidase D from Diplococcus pneumoniae included a series of [3H]mannose- and [3H]glucosamine-labelled neutral oligosaccharides that were all converted by digestion with eukaryotic beta-N-acetylglucosaminidases into free N-acetylglucosamine and a small oligomannosyl core containing two alpha-linked mannose residues and a third mannose residue beta-linked to N-acetylglucosamine. These studies suggested that the complex acidic-type oligosaccharides from cellular and viral membrane glycoproteins contained a common oligomannosyl core region (Man2 alpha leads to Man beta leads to GlcNAc2), with heterogeneity in the number and/or linkage of outer branch N-acetylglucosamine residues resulting in partial resistance to beta-N-acetylglucosaminidase from a bacterial source.


Clinical and pathological evidence for a frontal variant of Alzheimer disease.
To evaluate the clinical and pathological features of a subgroup of patients with Alzheimer disease (AD) who exhibited early and disproportionately severe impairments on tests of frontal lobe functioning. We hypothesized that these patients would exhibit a greater degree of either neurofibrillary tangle (NFT) or senile plaque pathology in the frontal lobes than would patients with typical AD. We examined the neuropsychological profiles and senile plaque and NFT accumulation in the frontal, entorhinal, temporal, and parietal cortices in 3 patients with AD who exhibited disproportionate frontal impairments during early stages of dementia (frontal AD) and 3 matched patients with typical AD (typical AD). Compared with the typical AD group, the frontal AD group performed significantly worse on 2 tests of frontal lobe functioning and on the Wechsler Adult Intelligence Scale-Revised Block Design test. No significant group differences were found on other tests. Analysis of brain tissue samples demonstrated that, despite comparable entorhinal, temporal, and parietal NFT loads, the frontal AD group showed a significantly higher NFT load in the frontal cortex than the typical AD group. Senile plaque pathology in the frontal and entorhinal cortices did not differentiate the 2 groups. We identified a subgroup of patients with pathologically confirmed AD who presented in the early stages of dementia with disproportionate impairments on tests of frontal lobe functioning and had a greater-than-expected degree of NFT pathology in the frontal lobes, suggesting the existence of a frontal variant of AD that has distinctive clinical and pathological features.


Characterization of bortezomib-adapted I-45 mesothelioma cells.
Bortezomib, a proteasome-specific inhibitor, has emerged as a promising cancer therapeutic agent. However, development of resistance to bortezomib may pose a challenge to effective anticancer therapy. Therefore, characterization of cellular mechanisms involved in bortezomib resistance and development of effective strategies to overcome this resistance represent important steps in the advancement of bortezomib-mediated cancer therapy. The present study reports the development of I-45-BTZ-R, a bortezomib-resistant cell line, from the bortezomib-sensitive mesothelioma cell line I-45. I-45-BTZ-R cells showed no cross-resistance to the chemotherapeutic drugs cisplatin, 5-fluorouracil, and doxorubicin. Moreover, the bortezomib-adapted I-45-BTZ-R cells had decreased growth kinemics and did not over express proteasome subunit beta5 (PSMB5) as compared to parental I-45 cells. I-45-BTZ-R cells and parental I-45 cells showed similar inhibition of proteasome activity, but I-45-BTZ-R cells exhibited much less accumulation of ubiquitinated proteins following exposure to 40 nm bortezomib. Further studies revealed that relatively low doses of bortezomib did not induce an unfolded protein response (UPR) in the bortezomib-adapted cells, while higher doses induced UPR with concomitant cell death, as evidenced by higher expression of the mitochondrial chaperone protein Bip and the endoplasmic reticulum (ER) stress-related pro-apoptotic protein CHOP. In addition, bortezomib exposure did not induce the accumulation of the pro-apoptotic proteins p53, Mcl-1S, and noxa in the bortezomib-adapted cells. These results suggest that UPR evasion, together with reduced pro-apoptotic gene induction, accounts for bortezomib resistance in the bortezomib-adapted mesothelioma cell line I-45-BTZ-R.


Factors explaining the increase in cost for physician care in Quebec's elderly population.
To examine what role demographic factors and increases in physician fees and utilization played in the rise in costs of physician services provided for elderly people in Quebec between 1982 and 1992, and to investigate changes in patterns of care (type and amount of services) related to utilization. Retrospective study of population-based data. Province of Quebec. Elderly people (65 years of age and over) in Quebec in 1982 (n = 589,800) and in 1992 (n = 803,600). Proportion of the increase in physician care costs attributable to (a) aging (defined as a shift in the age distribution) of the elderly population, (b) the increase in the size of the elderly population, (c) the increase in physician fees and (d) the increase in utilization of physician services; proportion of care provided by general practitioners (GPs) and by specialists; proportion of minor and complete examinations provided by GPs; and rates of hospital admissions and surgery. Aging was responsible for 0.5% of the increase in physician care costs between 1982 and 1992, population growth for 27.0% and the increase in physician fees for 25.5%. The increased utilization accounted for 47.0% of the total cost increase. Analyses of the utilization data revealed a shift toward more costly services, more visits to specialists and higher rates of hospital admissions and surgery in 1992 than in 1982. Aging and population growth had minor effects on the increase in physician care costs between 1982 and 1992. Increased utilization was the most important factor. The appropriateness of this trend needs to be verified.


Genome-wide methylation profiling in decitabine-treated patients with acute myeloid leukemia.
The outcome of older (≥ 60 years) acute myeloid leukemia (AML) patients is poor, and novel treatments are needed. In a phase 2 trial for older AML patients, low-dose (20 mg/m(2) per day for 10 days) decitabine, a DNA hypomethylating azanucleoside, produced 47% complete response rate with an excellent toxicity profile. To assess the genome-wide activity of decitabine, we profiled pretreatment and post treatment (day 25/course 1) methylomes of marrow samples from patients (n = 16) participating in the trial using deep-sequencing analysis of methylated DNA captured by methyl-binding protein (MBD2). Decitabine significantly reduced global methylation compared with pretreatment baseline (P = .001). Percent marrow blasts did not correlate with global methylation levels, suggesting that hypomethylation was related to the activity of decitabine rather than to a mere decrease in leukemia burden. Hypomethylation occurred predominantly in CpG islands and CpG island-associated regions (P ranged from .03 to .04) A significant concentration (P < .001) of the hypomehtylated CpG islands was found in chromosome subtelomeric regions, suggesting a differential activity of decitabine in distinct chromosome regions. Hypermethylation occurred much less frequently than hypomethylation and was associated with low CpG content regions. Decitabine-related methylation changes were concordant with those previously reported in distinct genes. In summary, our study supports the feasibility of methylome analyses as a pharmacodynamic endpoint for hypomethylating therapies.


Use of a simulation laboratory to train radiology residents in the management of acute radiologic emergencies.
Simulation laboratories use realistic clinical scenarios to train physicians in a controlled environment, especially in potentially life-threatening complications that require prompt management. The objective of our study was to develop a comprehensive program using the simulation laboratory to train radiology residents in the management of acute radiologic emergencies. All radiology residents attended a dedicated simulation laboratory course lasting 3 hours, divided over two sessions. Training included basic patient management skills, management of a tension pneumothorax, massive hemorrhage, and contrast agent reactions. Participants were presented with 20 multiple-choice questions before and after the course. Pre- and posttest results were analyzed, and the McNemar test was used to compare correct responses by individual question. Twenty-six radiology residents attended the class. The average pre- and posttest scores and the average difference between the scores for all residents were 13.8, 17.1, and 3.3, respectively (p < 0.0001). Incorrect answers on the pretest examination that were subsequently answered correctly concerned administration of epinephrine for severe reactions, management of a tension pneumothorax, oxygen therapy, ECG placement, cardiopulmonary resuscitation technique, and where to stand during a code situation. Persistent incorrect answers concerned vasovagal reactions and emergency telephone numbers at an off-site imaging center. Simulation laboratories can be used to teach crisis management and crisis resource management for radiology residents and should be part of the education toolbox. Defined objectives lead to a comprehensive course dealing with the management of acute radiologic emergencies. Such programs can improve the role of radiologists as members of the health care team.


Parental cancer and genetic predisposition in malignant pleural mesothelioma: a case-control study.
Familial clustering of pleural mesothelioma (PM) has been previously reported suggesting that genetic factors (predisposition) may be involved in PM. We studied parental cancer history in a cohort of 39 cases of PM and 259 age matched controls to assess the possible influence of family history on PM risk. Cases consisted of 39 patients with PM treated at our institution between 1978 and 1993. An age frequency matched control group (by 5-year age groups) consisted of 259 subjects who were spouses or friends of patients undergoing resection of primary lung cancer. Data were obtained by interview of controls and interview of the patient or next of kin (usually spouse) for cases. The following data were obtained using a standard questionnaire and medical record review; age, sex, date of diagnosis, history of asbestos exposure, smoking history, method of diagnosis, histologic subtype, type of treatment, parental cancer history and tumor type. Cases and control frequency of parental cancer and site specific tumor frequency were compared using chi-square analysis. Twenty-eight (71%) cases reported a parental history of cancer versus 114 (44%) in the control group (P<0.01). Gastrointestinal malignancies were the predominant tumor type among parents of cases, i.e. 11 cases (40%) versus 25% of controls (P<0.01). No other tumor site showed an increased frequency among cases. These data suggest a possible role for family history in the development of PM. Genetic predisposition may be important in the etiology of this tumor.


[Alterations of rheological properties of blood in systemic sclerodermia].
To study hemorheological status in systemic sclerosis (SS) patients. Macro- and microrheology of blood were investigated in 70 SS patients. The rate of spontaneous aggregation of red blood cells [T1(s)], durability of the largest units [Ia2.5(%)], general hydrodynamic durability of units [beta(s-1)], limit of fluidity [tau 0 (mPa)], Casson viscosity K (mPa/s) were determined. The total severity of hemorheological disturbances was 1.90 +/- 0.07 with T1 = 4.98 +/- 1.52s, beta = 62.76 +/- 19.32s, Ia 2.5 = -0.78 +/- 12.83%, tau 0 = 7.00 +/- 0.45 mPa. The Casson viscosity did not differ from normal levels. Plasma viscosity was 1.71 +/- 0.18 rel units, viscosity of sera 1.55 +/- 0.14 rel.units. The severity of hemorheological disturbances did not differ in cute and chronic courses but the parameter beta (72.0 +/- 4.5) was significantly higher (p < 0.05) in the acute course. The severity of hemorheological disturbances was highest in SS patients with cardiac disease (p < 0.05) and in 10 year SS duration. The course of SS is complicated by progressive hyperaggregation syndrome promoting development of visceral pathology. Active correction of hemorheology is pathogenetically validated in SS.


A Novel Mismatched PCR-Restriction Fragment Length Polymorphism Assay for Rapid Detection of gyrA and parC Mutations Associated With Fluoroquinolone Resistance in Acinetobacter baumannii.
Mutations in the quinolone resistance-determining regions (QRDRs) of Acinetobacter baumannii DNA gyrase (gyrA) and topoisomerase IV (parC) are linked to fluoroquinolone (FQ) resistance. We developed a mismatched PCR-restriction fragment length polymorphism (RFLP) assay to detect mutations in the gyrA and parC QRDRs associated with FQ resistance in A. baumannii. Based on the conserved sequences of A. baumannii gyrA and parC, two primer sets were designed for mismatched PCR-RFLP to detect mutations in gyrA (codons 83 and 87) and parC (codons 80 and 84) by introducing an artificial restriction enzyme cleavage site into the PCR products. This assay was evaluated using 58 A. baumannii strains and 37 other Acinetobacter strains that have been identified by RNA polymerase β-subunit gene sequence analysis. PCR amplification of gyrA and parC was successful for all A. baumannii strains. In 11 FQ -susceptible strains, the gyrA and parC PCR products were digested by the selected restriction enzymes at the site containing gyrA (codons 83 and 87) and parC (codons 80 and 84). PCR products from 47 FQ-resistant strains containing mutations in gyrA and parC were not digested by the restriction enzymes at the site containing the mutation. As for the non-baumannii Acinetobacter strains, although amplification products for gyrA were obtained for 28 strains, no parC amplification product was obtained for any strain. This assay specifically amplified gyrA and parC from A. baumannii and detected A. baumannii gyrA and parC mutations with FQ resistance.


The gut-joint axis mediates the TNF-induced RA process and PBMT therapeutic effects through the metabolites of gut microbiota.
The gut-joint axis, one of the mechanisms that mediates the onset and progression of joint and related diseases through gut microbiota, and shows the potential as therapeutic target. A variety of drugs exert therapeutic effects on rheumatoid arthritis (RA) through the gut-joint axis. However, the anti-inflammatory and immunomodulatory effect of novel photobiomodulatory therapy (PBMT) on RA need further validation and the involvement of gut-joint axis in this process remains unknown. The present study demonstrated the beneficial effects of PBMT on RA, where we found the restoration of gut microbiota homeostasis, and the related key pathways and metabolites after PBMT. We also discovered that the therapeutic effects of PBMT on RA mainly through the gut-joint axis, in which the amino acid metabolites (Alanine and N-acetyl aspartate) play the key role and rely on the activity of metabolic enzymes in the target organs. Together, the results prove that the metabolites of amino acid from gut microbiota mediate the regulation effect on the gut-joint axis and the therapeutic effect on rheumatoid arthritis of PBMT.


An enzyme-probe method to detect structural changes in the myosin rod.
The temperature-dependence of local melting within the alpha-helical, coiled-coil structure of rabbit myosin rod has been investigated by following changes in the rate constants of proteolytic digestion. The kinetics of fragmentation of the rod by three different enzymes (alpha-chymotrypsin, trypsin and papain) over the temperature range 5 to 40 degrees C (pH 7, I = 0.5) has been monitored by electrophoresis of the digestion products on sodium dodecyl sulfate/polyacrylamide gels. All rate constants were corrected for the intrinsic temperature-dependence of the enzyme by comparison with model substrates. Results from the three enzyme-probes are similar in showing that local melting within the rod occurs in two distinct stages. At temperatures between 5 and 25 degrees C, melting is confined to a restricted segment of the rod structure near the light meromyosin/heavy meromyosin junction. At temperatures between 25 and 40 degrees C, a wider segment of the rod lysing between the junction and the short subfragment-2 segment (the hinge domain) appears to be melting, judging from the broad spectrum of cleavage sites observed in this region. Results are compared with those from other physicochemical methods that measure the hinging or opening of the coiled-coil structure of the rod.


Vitamin E isoforms differentially regulate intercellular adhesion molecule-1 activation of PKCα in human microvascular endothelial cells.
ICAM-1-dependent leukocyte recruitment in vivo is inhibited by the vitamin E isoform d-α-tocopherol and elevated by d-γ-tocopherol. ICAM-1 is reported to activate endothelial cell signals including protein kinase C (PKC), but the PKC isoform and the mechanism for ICAM-1 activation of PKC are not known. It is also not known whether ICAM-1 signaling in endothelial cells is regulated by tocopherol isoforms. We hypothesized that d-α-tocopherol and d-γ-tocopherol differentially regulate ICAM-1 activation of endothelial cell PKC. ICAM-1 crosslinking activated the PKC isoform PKCα but not PKCβ in TNFα-pretreated human microvascular endothelial cells. ICAM-1 activation of PKCα was blocked by the PLC inhibitor U73122, ERK1/2 inhibitor PD98059, and xanthine oxidase inhibitor allopurinol. ERK1/2 activation was blocked by inhibition of XO and PLC but not by inhibition of PKCα, indicating that ERK1/2 is downstream of XO and upstream of PKCα during ICAM-1 signaling. During ICAM-1 activation of PKCα, the XO-generated ROS did not oxidize PKCα. Interestingly, d-α-tocopherol inhibited ICAM-1 activation of PKCα but not the upstream signal ERK1/2. The d-α-tocopherol inhibition of PKCα was ablated by the addition of d-γ-tocopherol. Crosslinking ICAM-1 stimulated XO/ROS which activated ERK1/2 that then activated PKCα. ICAM-1 activation of PKCα was inhibited by d-α-tocopherol and this inhibition was ablated by the addition of d-γ-tocopherol. These tocopherols regulated ICAM-1 activation of PKCα without altering the upstream signal ERK1/2. Thus, we identified a mechanism for ICAM-1 activation of PKC and determined that d-α-tocopherol and d-γ-tocopherol have opposing regulatory functions for ICAM-1-activated PKCα in endothelial cells.


(De)regulation of key enzyme steps in the shikimate pathway and phenylalanine-specific pathway of the actinomycete Amycolatopsis methanolica.
Prephenate dehydratase (PDT), chorismate mutase (CM) and 3-deoxy-D-arabino-7-heptulosonate 7-phosphate (DAHP) synthase are key regulatory enzymes in aromatic amino acid biosynthesis in the actinomycete Amycolatopsis methanolica. Deregulated, feedback-control-resistant mutants were isolated by incubation of A. methanolica on glucose mineral agar containing the toxic analogue p-fluoro-DL-phenylalanine (pFPhe). Several of these mutants had completely lost PDT sensitivity to Phe inhibition and Tyr activation. Mutant characterization yielded new information about PDT amino acid residues involved in Phe and Tyr effector binding sites. A. methanolica wild-type cells grown on glucose mineral medium normally possess a bifunctional CM/DAHP synthase protein complex (with DS1, a plant-type DAHP synthase). The CM activity of this protein complex is feedback-inhibited by Tyr and Phe, while DS1 activity is mainly inhibited by Trp. Isolation of pFPhe-resistant mutants yielded two feedback-inhibition-resistant CM mutants. These were characterized as regulatory mutants, derepressed in (a) synthesis of CM, now occurring as an abundant, feedback-inhibition-resistant, separate protein, and (b) synthesis of an alternative DAHP synthase (DS2, an E. coli-type DAHP synthase), only inhibited by Tyr and Trp. DS1 and DS2 thus are well integrated in A. methanolica primary metabolism: DS1 and CM form a protein complex, which stimulates CM activity and renders it sensitive to feedback inhibition by Phe and Tyr. Synthesis of CM and DS2 proteins appears to be controlled co-ordinately, sensitive to Phe-mediated feedback repression.


Gastrointestinal parasitosis in cattle: Unveiling the landscape across diverse production systems in Bangladesh.
Factors influencing parasitosis in cattle in Bangladesh remain inadequately explored, necessitating a comprehensive investigation for interventions and sustainable livestock farming. We conducted this study to estimate the prevalence and distribution of gastrointestinal parasites, exploring their intricate relationship with farm management practices across a spectrum of small-, medium-, and large-scale commercial farms. We conducted this study in the Chattogram district of Bangladesh. We collected a total of 189 freshly voided faecal samples from different farms. We recorded the age, breed, milking status, sex, body condition score, and anthelmintic use history of the sampled animals. We processed the samples using the direct smear method, with the identification of one egg per sample being considered positive. We estimated the prevalence of gastrointestinal parasite infection in large-scale (52.1%), medium-scale (54.5%), and small-scale farms (70.0%), with statistically significant differences (p ≤ 0.05). Both pregnant and lactating cows, as well as indigenous cattle, were more likely to have gastrointestinal parasites (p ≤ 0.05). The predominant parasites across farms of all sizes were trematodes (Paramphistomum spp. and Schistosomas spp.) and protozoa (Balantidium coli and Coccidia spp.). Poor farm management practices, such as no pasture management and inadequate deworming regimens, may contribute to the elevated prevalence and infection load observed on small-scale farms. The increased parasitosis in previously dewormed animals can be attributed to the development of anthelmintic resistance against gastrointestinal parasites. Implementing proper and effective deworming strategies is crucial to preventing gastrointestinal parasitosis and mitigating the risk of anthelmintic resistance.


Synergistic effect between NO2 and SO2 in their adsorption and reaction on gamma-alumina.
Field measurements showed that there exists a correlation between nitrate and sulfate on mineral dust. In this work, the synergistic mechanism of adsorption and reaction between SO2 and NO2 on gamma-alumina was studied using in situ diffusion reflectance infrared Fourier spectroscopy (in situ DRIFTS) and temperature programmed desorption (TPD). The results revealed that the reaction pathway of NO2 adsorbed on alumina was altered in the presence of SO2. In the absence of SO2, nitrite was found to be an intermediate in the oxidation of NO2 to surface nitrate species. However, in the presence of SO2, the formation of nitrite was inhibited and a new intermediate, dinitrogen tetraoxide (N2O4), was observed. On the other hand, surface tetravalent sulfur species S(IV), including bisulfite and sulfite, were oxidized to sulfate in air condition when NO2 was present. The atmospheric implication of this synergistic effect was also discussed.


[Living donor nephrectomy for kidney transplantation].
We briefly describe the current two surgical techniques for living donor nephrectomy. The shortage of cadaver donor organs and progressive acceptation of laparoscopic procedures have significantly increased the number of living donor transplants in our environment. Laparoscopic nephrectomy is being rapidly and progressively incorporated to the therapeutic armamentarium in most hospitals. It is a new ally in eliminating reluctante and increasing the number of renal grafts for transplantation. We can say that nowadays most transplant centres perform exclusively laparoscopic donor nephrectomy.


Molecular evolution of the growth hormone-releasing hormone/pituitary adenylate cyclase-activating polypeptide gene family. Functional implication in the regulation of growth hormone secretion.
Growth hormone-releasing hormone (GHRH) and pituitary adenylate cyclase-activating polypeptide (PACAP) belong to the same superfamily of regulatory neuropeptides and have both been characterized on the basis of their hypophysiotropic activities. This review describes the molecular evolution of the GHRH/PACAP gene family from urochordates to mammals and presents the hypothesis that the respective roles of GHRH and PACAP in the control of GH secretion are totally inverted in phylogenetically distant groups of vertebrates. In mammals, GHRH and PACAP originate from distinct precursors whereas, in all submammalian taxa investigated so far, including birds, amphibians and fish, a single precursor encompasses a GHRH-like peptide and PACAP. In mammals, GHRH-containing neurons are confined to the infundibular and dorsomedial nuclei of the hypothalamus while PACAP-producing neurons are widely distributed in hypothalamic and extrahypothalamic areas. In fish, both GHRH- and PACAP-immunoreactive neurons are restricted to the diencephalon and directly innervate the adenohypophysis. In mammals and birds, GHRH plays a predominant role in the control of GH secretion. In amphibians, both GHRH and PACAP are potent stimulators of GH release. In fish, PACAP strongly activates GH release whereas GHRH has little or no effect on GH secretion. The GHRH/PACAP family of peptides thus provides a unique model in which to investigate the structural and functional facets of evolution.


Transplantation tolerance. A complex scenario awaiting clinical applicability.
Organ transplantation is now firmly established as the therapy of choice for end-stage organ failure. Specific immunological tolerance of transplant recipients towards their foreign organ or tissue grafts is a goal that has been sought by transplant biologists for almost 50 years following the original description of the phenomenon in experimental animals by Medawar and colleagues. Since that time, a wealth of experimental data has accumulated relating to strategies for extending allograft survival and function. Recent studies have shed new light on the molecular and cellular basis of transplant rejection and have better defined the mechanisms of allograft tolerance with particular emphasis on a role for regulatory T cells. Still, the question remains of how near we are to the day when long-term tolerance of engrafted organs or tissues will be a clinical reality. Recently, clinical trials to explore pilot tolerance protocols in humans have been initiated under the auspices of the Immune Tolerance Network (www.immunetolerance.org). In this review we will highlight the promise and challenges of making transplantation tolerance a clinical reality.


Intraperitoneal rupture of pancreatic pseudocyst: report of a case and review of the literature.
A case is presented of pancreatic pseudocyst which ruptured as a result of an automobile accident. Sixty-three cases from the literature of ruptured pseudocyst of the pancrease due to a variety of causes are reviewed. Special reference is made of the site of perforation and treatment. It is concluded that each case should be individualized, tailoring the operative procedure to the operative findings. While external drainage may be life saving in some cases and sometimes the only procedure possible, internal drainage is superior and should be considered when it can be done without endangering the patient's life.


An Apple Watch Dashboard for HiGHmed Heart Insufficency Patients.
Wearables are commercially available devices allowing continuous monitoring of users' health parameters. Their easy availability, increasing accuracy and functionality render them relevant for medical practice, specifically for longitudinal monitoring. There are clear benefits for the health care system, such as the opportunity of timely interventions by monitoring a patient during his daily life, resulting in a cost reduction in medical care and improved patient well-being. However, some tools are essential to enable the application of wearables in medical daily practice. For example, there is a need for software solutions that allow clinicians to quickly and easily analyze data from devices of their patients. The goal of this study was to develop a dashboard for physicians, which allows rapid data interpretation of longitudinal data from the Apple Watch. The prototype dashboard is an interactive web-based visualization platform utilizing Plotly. The dashboard displays the most important parameters like heart rate, steps per day, activity, exercise collected by the Apple Watch in a user-friendly and accessible way. Clear visualization makes it easy to identify trends or deviations in the data and see how these changes in daily behaviour affect patients' health. Our software is a key component to monitor patients with heart failure who participate in the HiGHmed use case cardiology project.


Australian prehistory: new aspects of antiquity.
Human occupation of greater Australia occurred by 50,000 years ago, probably through deliberate voyaging by a small group of people. Later migrations, if any, are unlikely to have significantly changed the original genetic and cultural make-up While early Aborigines may have hunted extinct megafauna, the data do not support a rapid "Pleistocene overkill" hypothesis. Finally, aspects of Australian Aboriginal economy, especially plant utilization, and technology-the small tool tradition, ground stone hatchets and boomerangs-are of considerable antiquity and probably originated locally.


[Foodborne disease outbreak in El Huecú community, province of Neuquén].
In the summer of 2006, an epidemic outbreak of acute gastrointestinal illness related to food consumption occurred in a small town in the province of Neuquén, Argentina. During a popular feast, approximately 800 local residents attended lunch held in the facilities of the Municipal Gymnasium. About three hours later, nearly 150 attendees sought medical assistance at the local hospital due to acute gastroenteritis. A case-control epidemiological investigation was conducted using representative non-probability sampling. The epidemiological investigation showed a common-source foodborne disease outbreak with a case-control ratio of 1:1.8. The main symptoms were abdominal cramps (88%), vomiting (73.5%) and diarrhea (60%). The cake was identified as the source of infection (OR 9.79; IC 95%, 2.66-36.00; p = 0.0001), and unsatisfactory hygienic conditions in food production, conservation and handling steps were identified. Coagulase positive, enterotoxigenic Staphylococcus aureus, subspecies aureus was detected in a piece of cake, with a count of 2.4 x 10(6) CFU/g, and in samples from the hands and nostrils of three people involved in food preparation and service. The strains isolated from both the cake and one of the food handlers carried the sea gene, and presented the same Smal-PFGE pattern. The foodborne disease outbreak was considered to be due to contamination in the preparation process of the cake consumed at the feast, which was related to inadequate hygienic conditions, lack of refrigeration and cold chain disruption.


Probiotics for preterm infants - time to end all controversies.
Mortality, necrotising enterocolitis (NEC), late onset sepsis (LOS) and feeding intolerance are significant issues for very preterm (< 32 weeks) and extremely preterm (< 28 weeks) infants. The complications of ≥ Stage II NEC [e.g. Resection of the gangrenous gut, survival with intestinal failure, recurrent infections, prolonged hospital stay, and long-term neurodevelopmental impairment (NDI)] impose a significant health burden. LOS also carries significant burden including long-term NDI due to adverse effects of inflammation on the preterm brain during the critical phase of development. Frequent stopping of feeds due to feeding intolerance is a significant iatrogenic contributor to postnatal growth failure in extremely preterm infants. Over 25 systematic reviews and meta-analyses of RCTs (~12 000 participants) have reported that probiotics significantly reduce the risk of all-cause mortality, NEC ≥ Stage II, LOS and feeding intolerance in preterm infants. Systematic reviews and meta-analysis of non-RCTs have also shown that the benefits after adopting probiotics as a standard prophylaxis for preterm infants are similar to those reported in RCTs. No intervention comes close to probiotics when it comes to significant reduction in death, NEC, LOS and feeding intolerance at a cost of less than a dollar a day irrespective of the setting and baseline incidence of NEC. The common controversies that are preventing the rapid uptake of probiotics for preterm infants are addressed in this paper.


Value and Limitations of Broad Brush Surveys Used in Community-Randomized Trials in Southern Africa.
We describe and reflect on a rapid qualitative survey approach called "Broad Brush Survey" (BBS) used in six community-randomized trials (CRTs)/studies in Zambia and South Africa (2004-2018) to document, compare, classify, and communicate community features systematically for public health and multidisciplinary research ends. BBS is based on a set sequence of participatory qualitative methods and fieldwork carried out prior to a CRT intervention and/or research by social scientists to generate rapid community profiles using four key indicators: physical features, social organization, networks, and community narratives. Profiling makes apparent similarities and differences, enabling comparison across communities and can be facilitated by an ideal model of open-closed systems. Findings have provided practical outputs (e.g., community profiles) and academic opportunities (e.g., community typologies). The BBS approach enables complex social landscapes to be incorporated in CRTs. This method has proven to be useful, adaptable and to have multidisciplinary appeal.


[A critical analysis of research guidelines in Chinese medicine].
The acculturation of Chinese medicine by the West since the 1970s has raised questions about the efficacy, validity, and potential of this form of medicine. Researchers in the field have agreed that studies on Chinese medicine present a methodological challenge. Research conducted in recent decades has focused basically on statistical clinical trials. This article offers a critical analysis of the problems encountered when applying to Chinese medicine the scientific methods common to biomedicine and also suggests new directions for such research guidelines. Relying primarily on the method of text analysis, the issue is approached by applying theoretical references from the social sciences to health.


A knottin scaffold directs the CXC-chemokine-binding specificity of tick evasins.
Tick evasins (EVAs) bind either CC- or CXC-chemokines by a poorly understood promiscuous or "one-to-many" mechanism to neutralize inflammation. Because EVAs potently inhibit inflammation in many preclinical models, highlighting their potential as biological therapeutics for inflammatory diseases, we sought to further unravel the CXC-chemokine-EVA interactions. Using yeast surface display, we identified and characterized 27 novel CXC-chemokine-binding evasins homologous to EVA3 and defined two functional classes. The first, which included EVA3, exclusively bound ELR+ CXC-chemokines, whereas the second class bound both ELR+ and ELR- CXC-chemokines, in several cases including CXC-motif chemokine ligand 10 (CXCL10) but, surprisingly, not CXCL8. The X-ray crystal structure of EVA3 at a resolution of 1.79 Å revealed a single antiparallel β-sheet with six conserved cysteine residues forming a disulfide-bonded knottin scaffold that creates a contiguous solvent-accessible surface. Swapping analyses identified distinct knottin scaffold segments necessary for different CXC-chemokine-binding activities, implying that differential ligand positioning, at least in part, plays a role in promiscuous binding. Swapping segments also transferred chemokine-binding activity, resulting in a hybrid EVA with dual CXCL10- and CXCL8-binding activities. The solvent-accessible surfaces of the knottin scaffold segments have distinctive shape and charge, which we suggest drives chemokine-binding specificity. These studies provide structural and mechanistic insight into how CXC-chemokine-binding tick EVAs achieve class specificity but also engage in promiscuous binding.


Imaging the Neutrophil Phagosome and Cytoplasm Using a Ratiometric pH Indicator.
Neutrophils are crucial to host innate defense and, consequently, constitute an important area of medical research. The phagosome, the intracellular compartment where the killing and digestion of engulfed particles take place, is the main arena for neutrophil pathogen killing that requires tight regulation. Phagosomal pH is one aspect that is carefully controlled, in turn regulating antimicrobial protease activity. Many fluorescent pH-sensitive dyes have been used to visualize the phagosomal environment. S-1 has several advantages over other pH-sensitive dyes, including its dual emission spectra, its resistance to photo-bleaching, and its high pKa. Using this method, we have demonstrated that the neutrophil phagosome is unusually alkaline in comparison to other phagocytes. By using different biochemical conjugations of the dye, the phagosome can be delineated from the cytoplasm so that changes in the size and shape of the phagosome can be assessed. This allows for further monitoring of ionic movement.


Reduced soybean photosynthetic nitrogen use efficiency associated with evolutionary genetic bottlenecks.
Soybean has a narrow genetic base thought to limit future yield genetic gains. However, there is no evidence whether this reduction in genetic diversity correlates with diversity loss for any yield trait. We tested how photosynthetic nitrogen use efficiency (leaf photosynthesis per unit nitrogen, NUEp) evolved from the wild relative Glycine soja Siebold & Zucc. to the current Glycine max (L.) Merr. Five populations resulting from different evolutionary bottlenecks were evaluated under field conditions. Populations were wild ancestors, domesticated Asian landraces, North American ancestors, and modern cultivars. Genotypic differences in photosynthesis and leaf nitrogen were evident, creating a significant 3-fold variation in phenotypic NUEp. There was a parallel reduction in molecular marker and phenotypic NUEp diversity after each evolutionary bottleneck. G. soja had three times more NUEp diversity and 25% more average NUEp compared with the elite modern cultivars. Two strategies for increasing NUEp were identified: (i) increases in light saturated photosynthesis (Pmax), and, alternatively, (ii) reductions in leaf nitrogen. A modelling approach showed that NUEp will increase yield only if based on increased Pmax. Our study quantified the genetic potential of exotic germplasm available for trait-directed breeding. Results antagonise the concept that elite germplasm is always superior for any relevant yield trait when compared with undomesticated germplasm.


Impact of cigarette price increase on health and financing outcomes in Vietnam.
Background: Vietnam had about 15 million male smokers in 2015. To reduce adult tobacco use in Vietnam through an increase in the excise tax of cigarettes, we conducted an extended cost-effectiveness analysis to examine the impact of two scenarios of cigarette price increases. Methods: We estimated, across income quintiles, the life-years gained, treatment cost averted, number of men avoiding catastrophic health expenditure and extreme poverty, and additional tax revenue under a 32% and a 62% increase in cigarette price through increased excise tax. We considered only male smokers as they constitute majority of the smokers. We used the average price elasticity of demand for cigarettes in Vietnam of -0.53. Results: Under both scenarios of price increase, men in the poorest quintile would gain about 2.8 times the life-years and avert 2.5 times the treatment cost averted by the richest quintile. With a 32% price increase, about 285,000 men would avoid catastrophic health expenditure; as a result, about 95,000 men, more than half of whom in the poorest quintile, would avoid falling into extreme poverty. In contrast to the distribution of health benefits, the extra revenue generated from men in the richest quintile would be 1.2 times that from the poorest quintile. With a 62% price increase, about 553,000 men would avoid catastrophic health expenditure, and about 183,000 men, more than half of whom in the poorest quintile, would avoid falling into extreme poverty. The extra revenue generated from men in the richest quintile would be 3.8 times that from the poorest quintile. Conclusions: Higher cigarette prices would particularly benefit the poorest income quintile of Vietnamese, in terms of health and financial outcomes. Thus, tobacco taxes are an effective way to improve health and reduce poverty in Vietnam.


Stable discrete surface light bullets.
We analyze spatiotemporal light localization near the edge of a semi-infinite array of weakly coupled nonlinear optical waveguides and demonstrate the existence of a novel class of continuous-discrete spatiotemporal solitons, the so-called discrete surface light bullets. We show that their properties are strongly affected by the presence of the surface. To this end the crossover between surface and quasi-bulk bullets is studied by analyzing the families of solitons propagating at different distances from the edge of the waveguide array.


Complementarity of delta opioid ligand pharmacophore and receptor models.
The elaboration of a pharmacophore model for the delta opioid receptor selective ligand JOM-13 (Tyr-c[D-Cys-Phe-D-Pen]OH) and the parallel, independent development of a structural model of the delta receptor are summarized. Although the backbone conformation of JOM-13's tripeptide cycle is well defined, considerable conformational lability is evident in the Tyr(1) residue and in the Phe(3) side chain, key pharmacophore elements of the ligand. Replacement of these flexible features of the ligand by more conformationally restricted analogues and subsequent correlation of receptor binding and conformational properties allowed the number of possible binding conformations of JOM-13 to be reduced to two. Of these, one was chosen as more likely, based on its better superposition with other conformationally constrained delta receptor ligands. Our model of the delta opioid receptor, constructed using a general approach that we have developed for all rhodopsin-like G protein-coupled receptors, contains a large cavity within the transmembrane domain that displays excellent complementarity in both shape and polarity to JOM-13 and other delta ligands. This binding pocket, however, cannot accommodate the conformer of JOM-13 preferred from analysis of ligands, alone. Rather, only the "alternate" allowed conformer, identified from analysis of the ligands but "disfavored" because it does not permit simultaneous superposition of all pharmacophore elements of JOM-13 with other delta ligands, fits the binding site. These results argue against a simple view of a single, common fit to a receptor binding site and suggest, instead, that at least some binding site interactions of different ligands may differ.


Temporal patterns of medications dispensed to children and adolescents in a national insured population.
This study aimed to comprehensively describe prevalence and temporal dispensing patterns for medications prescribed to children and adolescents in the United States. Participants were 1.6 million children (49% female) under 18 years old enrolled in a nation-wide, employer-provided insurance plan. All medication claims from 1999-2006 were reviewed retrospectively. Drugs were assigned to 16 broad therapeutic categories. Effects of trend over time, seasonality, age and gender on overall and within category prevalence were examined. Mean monthly prevalence for dispensed medications was 23.5% (range 19.4-27.5), with highest rates in winter and lowest in July. The age group with the highest prevalence was one-year-old children. On average each month, 17.1% of all children were dispensed a single drug and 6.4% were dispensed two or more. Over time, prevalence for two or more drugs did not change, but the proportion of children dispensed a single drug decreased (slope -.02%, p= .001). Overall, boys had higher monthly rates than girls (average difference 0.9%, p= .002). However, differences by gender were greatest during middle childhood, especially for respiratory and central nervous system agents. Contraceptives accounted for a large proportion of dispensed medication to older teenage girls. Rates for the drugs with the highest prevalence in this study were moderately correlated (average Pearson r.66) with those from a previously published national survey. On average, nearly one quarter of a population of insured children in the United States was dispensed medication each month. This rate decreased somewhat over time, primarily because proportionally fewer children were dispensed a single medication. The rate for two or more drugs dispensed simultaneously remained steady.


Biogenesis of mitochondria: DNA sequence analysis of mit- mutations in the mitochondrial oli1 gene coding for mitochondrial ATPase subunit 9 in Saccharomyces cerevisiae.
The nucleotide sequence of the yeast mitochondrial olil gene has been obtained in a series of mit- mutants with mutations in this gene, which codes for subunit 9 of of the mitochondrial ATPase complex. Subunit 9 is the proteolipid, 76 amino acids in length, necessary for the proton translocation function of the membrane Fo-sector. These mutants were classified on the basis of their rescue by a petite strain shown here to retain the entire wild-type olil gene. The mutation in one mit- strain removes a positively charged residue (Arg39----Met) which is likely to be located in a segment of subunit 9 that protrudes from the inner mitochondrial membrane. In a second mit- mutant, a negatively charged residue replaces a conserved glycine residue (Gly18----Asp) in a glycine-rich segment of the protein that is most likely embedded within the membrane. Other mit- mutations result in frameshifts with predicted products 7, 65 and 68 amino acid residues long. In each mit- mutant, there is the loss of one or more of the amino acid residues that are highly conserved among diverse species. The location and nature of specific changes pinpoint amino acid residues in subunit 9 essential to the activity of the mitochondrial ATPase complex.


Pathophysiology of haemorrhagic shock.
Following massive blood loss a number of compensatory mechanisms are activated which are remarkably successful for a limited period. Ultimately the functions of many organs are affected, leading to a vicious circle of impaired cardiac performance and oxygen delivery. The only therapeutic manoeuvre of proven benefit in man is early restoration of circulating volume.


The effects of caldesmon on the ATPase activities of rabbit skeletal-muscle myosin.
We studied the effects of caldesmon, a major actin- and calmodulin-binding protein found in a variety of muscle and non-muscle tissues, on the various ATPase activities of skeletal-muscle myosin. Caldesmon inhibited the actin-activated myosin Mg2+-ATPase, and this inhibition was enhanced by tropomyosin. In the presence of the troponin complex and tropomyosin, caldesmon inhibited the Ca2+-dependent actomyosin Mg2+-ATPase; this inhibition could be partly overcome by Ca2+/calmodulin. Caldesmon, phosphorylated to the extent of approximately 4 mol of Pi/mol of caldesmon, inhibited the actin-activated myosin Mg2+-ATPase to the same extent as did non-phosphorylated caldesmon. Both inhibitions could be overcome by Ca2+/calmodulin. Caldesmon also inhibited the Mg2+-ATPase activity of skeletal-muscle myosin in the absence of actin; this inhibition also could be overcome by Ca2+/calmodulin. Caldesmon inhibited the Ca2+-ATPase activity of skeletal-muscle myosin in the presence or absence of actin, at both low (0.1 M-KCl) and high (0.3 M-KCl) ionic strength. Finally, caldesmon inhibited the skeletal-muscle myosin K+/EDTA-ATPase at 0.1 M-KCl, but not at 0.3 M-KCl. Addition of actin resulted in no inhibition of this ATPase by caldesmon at either 0.1 M- or 0.3 M-KCl. These observations suggest that caldesmon may function in the regulation of actin-myosin interactions in striated muscle and thereby modulate the contractile state of the muscle. The demonstration that caldesmon inhibits a variety of myosin ATPase activities in the absence of actin indicates a direct effect of caldesmon on myosin. The inhibition of the actin-activated Mg2+-ATPase activity of myosin (the physiological activity) may not be due therefore simply to the binding of caldesmon to the actin filament causing blockage of myosin-cross-bridge-actin interaction.


Efficient feeder-free episomal reprogramming with small molecules.
Genetic reprogramming of human somatic cells to induced pluripotent stem cells (iPSCs) could offer replenishable cell sources for transplantation therapies. To fulfill their promises, human iPSCs will ideally be free of exogenous DNA (footprint-free), and be derived and cultured in chemically defined media free of feeder cells. Currently, methods are available to enable efficient derivation of footprint-free human iPSCs. However, each of these methods has its limitations. We have previously derived footprint-free human iPSCs by employing episomal vectors for transgene delivery, but the process was inefficient and required feeder cells. Here, we have greatly improved the episomal reprogramming efficiency using a cocktail containing MEK inhibitor PD0325901, GSK3β inhibitor CHIR99021, TGF-β/Activin/Nodal receptor inhibitor A-83-01, ROCK inhibitor HA-100 and human leukemia inhibitory factor. Moreover, we have successfully established a feeder-free reprogramming condition using chemically defined medium with bFGF and N2B27 supplements and chemically defined human ESC medium mTeSR1 for the derivation of footprint-free human iPSCs. These improvements enabled the routine derivation of footprint-free human iPSCs from skin fibroblasts, adipose tissue-derived cells and cord blood cells. This technology will likely be valuable for the production of clinical-grade human iPSCs.


Zwitterionic oligodeoxyribonucleotide N3'-->P5' phosphoramidates: synthesis and properties.
Zwitterionic, net neutral oligonucleotides containing alternating negatively charged N3'-->P5' phosphoramidate monoester and positively charged phosphoramidate diester groups were synthesized. The ability of zwitterionic phosphoramidates to form complexes with complementary DNA and RNA was evaluated. Stoichiometry and salt dependency of these complexes were determined as a function of the nature of the heterocyclic bases of the zwitterionic compounds. Unlike the melting temperatures of the natural phosphodiester-containing oligomers, the T m of the duplexes formed with the zwitterionic oligothymidylates was salt concentration independent. The thermal stability of these duplexes was much higher with Delta T m values of 20-35 degrees C relatively to phosphodiester counterparts at low salt concentrations. The zwitterionic oligoadenylate formed only 2Py:1Pu triplexes with complementary poly(U) or poly(dT) strands. The thermal stability of these complexes was dependent on salt concentration. Also, the T m values of the complexes formed by the zwitterionic oligoadenylate with poly(U) were 6-41 degrees C higher than for the natural phosphodiester counterpart. Triplexes of this compound with poly(dT) were also more stable with a Delta T m value of 22 degrees C at low salt concentrations. Complexes formed by the zwitterionic oligonucleotides with complementary RNAs were not substrates for RNase H. Surprisingly, the duplex formed by the all anionic alternating N3'-->P5'phosphoramidate-phosphodiester oligothymidylate and poly(A) was a good substrate for RNase H.


Biochemical Basis of CO2-Related Internal Browning Disorders in Pears (Pyrus communis L. cv. Rocha) during Long-Term Storage.
This study aimed at understanding the biochemical basis of internal browning disorders (IBDs) in 'Rocha' pear. For this purpose, the effects of storage under normal controlled atmosphere (CA) (3 kPa of O2 + 0.5 kPa of CO2) and IBD-inducing CA (1 kPa of O2 + 10 kPa of CO2) on the antioxidant and fermentative metabolisms and polyphenol oxidase (PPO) activity and phenolics concentration were studied. The higher IBD incidence in high CO2-stored fruits was positively correlated with fermentative metabolites and negatively with ascorbate and H2O2 concentrations, and it was linked to PPO activation. These results indicate that both the antioxidant and fermentative metabolisms are involved in the occurrence of IBD in 'Rocha' pear. From the integration of the biochemical and enzymatic data, a schematic model illustrating the effects of high CO2 and low O2 in 'Rocha' pears during long-term storage was constructed.


Ultrasound in the selective screening of developmental dysplasia of the hip.
Developmental dysplasia of the hip (DDH) can result in chronic pain, gait abnormalities and degenerative arthritis. Infants with a family history, Breech delivery or unstable/"clicking" of the hip on examination are at higher risk. The goal is to detect cases early enough for normal hip development and function by the end of adolescence, but clinical examination alone is ineffective. All infants born at the West Middlesex University Hospital, Isle-worth, U.K., between 3/3/2005 and 21/10/2006 underwent prospective clinical screening to reveal risk factors of unstable hip on examination, family history of DDH and Breech delivery. Infants with risk factors underwent static and dynamic ultrasound of the hips (Harke's method with Terjesen measurements), performed by a consultant radiologist or sonographer. The infant was then examined by an Orthopaedic Surgeon who was blinded to the ultrasound findings until after creating a management plan. 5772 infants were born during the study period. 200 (3.5%) at-risk infants were identified, resulting in 400 hip ultrasounds. Following review of ultrasound findings, the majority of cases (163/200, 81.5%) lead to no change in management. Change in timing or type of clinical follow up occurred in 31 cases with normal ultrasounds and 20 cases with abnormal (immature hip) ultrasounds. Dysplasia was demonstrated in 6 infants (3%) on ultrasound, who were treated with Parvlik Harness. Of these, only 5 were detected on examination. Therefore, the ultrasound findings lead to 1 intervention with Parvlik Harness which would have otherwise gone undiagnosed from clinical examination. Whereas type and timing of follow up was adjusted in 18.5% of the at-risk infants, targeted screening of at-risk with ultrasound lead to only one intervention. This encourages discussion on the resource implication and viability of ultrasound screening, as only one from two hundred lead to an intervention.


Relations of depressive symptoms and antidepressant use to body mass index and selected biomarkers for diabetes and cardiovascular disease.
We investigated whether depressive symptoms and antidepressant use are associated with biomarkers for glucose dysregulation and inflammation, body mass index (BMI), and waist circumference. Postmenopausal women were recruited into the Women's Health Initiative from 1993 to 1998, and data were collected at regular intervals through 2005. We used multiple linear regression models to examine whether depressive symptoms and antidepressant use are associated with BMI, waist circumference, and biomarkers. Analysis of data from 71, 809 women who completed all relevant baseline and year 3 assessments showed that both elevated depressive symptoms and antidepressant use were significantly associated with higher BMI and waist circumference. Among 1950 women, elevated depressive symptoms were significantly associated with increased insulin levels and measures of insulin resistance. Analyses of baseline data from 2242 women showed that both elevated depressive symptoms and antidepressant use were associated with higher C-reactive protein levels. Monitoring body habitus and other biomarkers among women with elevated depression symptoms or taking antidepressant medication may be prudent to prevent diabetes and cardiovascular disease.


Assessment of conditioning-specific movement tasks and physical fitness measures in talent identified under 16-year-old rugby union players.
Preparedness to train was assessed using a battery of conditioning-specific movement tasks (CSMTs) on a group of talent identified rugby union players (n = 156; age = 15 ± 7 years; stature = 176 ± 7 cm; and mass = 74 ± 14 kg). In addition to explore the link between movement competency and performance, a series of standard fitness tests was conducted. Overall the group's CSMTs competency ratings were low, but task dependent. The proportion of competent players ranged from 14% for a single leg squat to 70% for a double to single leg landing. Players were subsequently grouped based on their CSMTs ratings using cluster analysis. This analysis classified players on features of the CSMT battery that distinguished between groups rather than an arbitrary score. Fitness test scores were then compared between the 3 groups identified. The "general low competency" group jumped 9.1 cm lower (p = 0.0218), sprinted slower across 10, 20 and 40 m (range, p = 0.0126-0.0018) and covered 389 m less (p = 0.0105) Yo-Yo intermittent recovery level 1 distance compared with the "squat competent group." In summary, at this important time before academy selection, most players could not competently perform the CSMTs that underpin rugby conditioning and may not be prepared for the transition into the "training to compete" stage of the suggested long-term athlete development model. For this sample of players, the athlete development process may therefore be unnecessarily inhibited. Moreover, our observations that competency in some CSMTs may explain better running and jumping performances in some players suggest that a focus on monitoring and addressing movement competencies during the training to train stage of player development should be considered.


Analysis of writing inks on paper using direct analysis in real time mass spectrometry.
Ink analysis is central to questioned document examination. We applied direct analysis in real time mass spectrometry (DART MS) to ballpoint, gel, and fluid writing ink analysis. DART MS acquires the mass spectrum of an ink while it is still on a document without altering the appearance of the document. Spectra were acquired from ink on a variety of papers, and the spectrum of the blank paper could be subtracted out to produce a cleanly isolated ink spectrum in most cases. Only certain heavy or heavily processed papers interfered. The time since an ink is written on paper has a large effect on its spectrum. DART spectra change radically during the first few months after an ink is written as the more volatile components evaporate, but the spectra stabilize after that. A library-search study involving 166 well-aged inks assessed the ability to identify inks from their DART spectra. The aggregate success rate was 92%.


Neighborhood social environment and patterns of adherence to oral hypoglycemic agents among patients with type 2 diabetes mellitus.
This study examined whether neighborhood social environment was related to patterns of adherence to oral hypoglycemic agents among primary care patients with type 2 diabetes mellitus. Residents in neighborhoods with high social affluence, high residential stability, and high neighborhood advantage, compared to residents in neighborhoods with one or no high features present, were significantly more likely to have an adherent pattern compared to a nonadherent pattern. Neighborhood social environment may influence patterns of adherence. Reliance on a multilevel contextual framework, extending beyond the individual, to promote diabetic self-management activities may be essential for notable public health improvements.


Role of glucose and insulin loads to the exercising limb in increasing glucose uptake and metabolism.
To assess the contributions of glucose load to the working hindlimb and local contraction-related events (changes related to the microvasculature and/or intrinsic muscle metabolic properties) to the exercise-induced increases in muscle glucose uptake and metabolism in vivo, dogs were studied with somatostatin infused to suppress insulin release, and glucose and insulin were replaced 1) during rest and treadmill exercise at rates that recreate limb glucose and insulin loads evident during exercise (n = 5), 2) at rest to selectively normalize the limb glucose load to rates present during exercise while retaining basal limb insulin loads (GL, n = 5), or 3) at rest to normalize both the limb glucose and insulin loads to those present during exercise (IGL, n = 5). Limb arteriovenous difference and isotopic ([U-14C]glucose) techniques were used to quantify muscle glucose uptake and metabolism. Limb glucose load rose from 819 +/- 141 mumol/min in the basal state to 1,568 +/- 190 mumol/min with exercise. Limb glucose loads were 1,423 +/- 88 and 1,502 +/- 165 mumol/min in GL and IGL. The limb insulin load rose from basal rates of 12.9 +/- 2.3 to 22.9 +/- 5.9 nmol/min during exercise. Limb insulin loads were similar to basal loads in GL (8.8 +/- 1.9 nmol/min) and exercise in IGL (28.2 +/- 5.5 nmol/min).(ABSTRACT TRUNCATED AT 250 WORDS)


Perception of noxious and innocuous heat stimulation among healthy women and women with fibromyalgia: association with mood, somatic focus, and catastrophizing.
Recent studies have demonstrated that persons with fibromyalgia display abnormal processing of different types of painful stimulation, suggesting the disorder is characterized by a central pain-processing deficit not limited specifically to muscle pain. In the present study, 20 women with fibromyalgia and 20 normal, healthy women were compared on measures of pressure pain stimulation and response to contact thermal heat at both noxious and innocuous intensities. Women with fibromyalgia displayed significantly lower pressure pain thresholds at 18 tender point locations as defined by the American College of Rheumatology criteria, as well as lower pressure pain thresholds at five control sites. Women with fibromyalgia had significantly lower heat pain thresholds and tolerances when stimulated on the volar surface of the left forearm. When examining visual analog ratings of intensity and unpleasantness to constant stimuli, a multivariate analysis of variance performed on these ratings indicated that there were significant main effects of level of stimulation and group. Individual analysis of variances at each temperature revealed significant differences between the groups in pain intensity and unpleasantness ratings at both noxious and innocuous temperatures. Multiple regression analyses indicated that greater pain catastrophizing and diagnosis of fibromyalgia were associated with decreased pain thresholds and tolerances in the entire sample, whereas, self-report of depressive symptoms was associated with increased thresholds and tolerances. Self-report of somatic symptoms was not associated with these measures. These findings indicate that persons with fibromyalgia display altered perception of both pressure and thermal stimulation, even at innocuous levels. They also suggest that catastrophic thoughts about pain may play a role in increased pain perception in this population.


Immunoglobulin M and immunoglobulin G responses in BALB/c mice to conjugated outer membrane extracts of four Salmonella serotypes.
Outer membranes (OMs) of Salmonella enteritidis, S. anatum, S. typhimurium, and S. infantis were extracted and cross-linked with glutaraldehyde to form a large macromolecular antigen. The antigen consisted of OM proteins and lipopolysaccharide and was designated 4-OMP-LPS. Polyacrylamide gel electrophoresis of extracted OMs from each serotype revealed differences in protein profiles. S. enteritidis and S. infantis possessed a greater variety of proteins than did S. anatum and S. typhimurium. Immunizations with 4-OMP-LPS in phosphate-buffered saline (4-OMP-LPS-C) and 4-OMP-LPS emulsified with muramyl dipeptide in the oil phase of a hexadecane-water emulsion (4-OMP-LPS-MDP) revealed that BALB/c mice were capable of eliciting specific primary and secondary immunoglobulin M (IgM) and IgG responses. Both antigen preparations were capable of eliciting IgM and IgG specific for the cell surfaces of each live Salmonella serotype. Also, 4-OMP-LPS-MDP and 4-OMP-LPS-C were capable of evoking a substantial anamnestic response. Adsorption studies revealed that the combined serotypes had the antigenic capacity to adsorb up to 94% of the antibodies, but 4-OMP-LPS-MDP antibodies were more effectively adsorbed than were 4-OMP-LPS-C antibodies. Adsorption of pooled antiserum with heterologous bacteria yielded a variety of adsorption profiles.


Serum 25-hydroxyvitamin D concentrations in Mid-adulthood and Parkinson's disease risk.
Low vitamin D levels are common among patients with Parkinson's disease (PD). Experimental evidence further suggests that vitamin D may be protective against PD. The objective of this study was to prospectively assess the association between serum 25-hydroxyvitamin D and PD among 12,762 participants of the Atherosclerosis Risk in Communities Study cohort. Serum samples were collected in 1990-1992, and 25-hydroxyvitamin D was measured by liquid chromatography mass spectrometry. A total of 67 incident PD cases were identified through December 31, 2008. The median length of follow-up was 17 years. We used Cox proportional hazards models to obtain hazard ratios and 95% confidence intervals, adjusting for age, sex, and race. We did not find any association between serum 25-hydroxyvitamin D concentrations and PD risk, regardless of how serum 25-hydroxyvitamin D was modeled. Compared with participants with serum 25-hydroxyvitamin D < 20 ng/mL, the hazards ratio for PD was 1.05 (95% confidence interval, 0.58-1.90) for 20-30 ng/mL and 1.14 (95% confidence interval, 0.59- 2.23) for ≥30 ng/mL. Similar results were obtained in sensitivity analyses that included white participants only and that were stratified by the length of follow-up. This prospective study lends no support to the hypothesis that vitamin D may reduce the risk of PD. © 2016 International Parkinson and Movement Disorder Society.


Investigating the prevalence and impact of device-related problems associated with hearing aid use.
Objective: To explore the prevalence of device-related problems associated with hearing aid use, participants' help-seeking behaviours for these problems, and factors associated with hearing aid problems.Design: A prospective convenience cohort design surveying 413 adult hearing aid users (34-97 years of age) recruited from seven clinics across Australia.Results: Almost all participants (98%) indicated that they were experiencing at least one of the hearing aid problems included on the survey. The number of hearing aid related problems reported by participants ranged from 0 to 25 (of a possible 26), with a mean of 10 problems (SD = 5). The three most reported problems were related to difficulty hearing in noisy environments, hearing in windy environments, and understanding certain voices. Participants had reported less than half (46.33%) of the total problems identified to their clinic (range = 0-100%, mean = 43.40, SD = 13.92). Participants who reported experiencing a greater number of hearing aid problems also reported lower levels of hearing aid benefit, and satisfaction with their hearing aids.Conclusions: The majority of hearing aid owners experience problems with their hearing aids. Addressing these problems would likely contribute to improved hearing aid outcomes.


Supramolecular linear coordination polymers of human serum albumin and haemoglobin.
We describe the synthesis, structure, and functionalities of water-soluble linear coordination polymers of human serum albumin and haemoglobin, which are connected via a bis(terpyridyl)-Fe2+ complex. These protein fibres were self-assembled by lyophilisation and were transformed into single-wall nanotubes. The biological activities of the protein units were perfectly preserved in the long fibres.


Understanding plant stress memory traits can provide a way for sustainable agriculture.
Being sessile, plants encounter a variety of biotic and abiotic threats in their life cycle. To minimize the damages caused by such threats, plants have acquired sophisticated response mechanisms. One major such response includes memorizing the encountered stimuli in the form of a metabolite, hormone, protein, or epigenetic marks. All of these individually as well as together, facilitate effective transcriptional and post-transcriptional responses upon encountering the stress episode for a second time during the life cycle and in some instances even in the future generations. This review attempts to highlight the recent advances in the area of plant memory. A detailed understanding of plant memory has the potential to offer solutions for developing climate-resilient crops for sustainable agriculture.


Contribution of chondroitin-dermatan sulfate-containing proteoglycans to the function of rat mesenteric arteries.
Proteoglycans are an important nonfibrous matrix component of the arterial wall. Direct evidence for their role in resistance-sized arteries is lacking, although they likely have an important role in coordinating and regulating vessel behavior, presumably via interactions of their glycosaminoglycan chains or core proteins with other matrix molecules and/or the smooth muscle cell surface. The purpose of this study was to determine whether the removal of specific glycosaminoglycan chains from proteoglycans in resistance-sized mesenteric arteries would change the mechanical properties of the arterial wall, thereby affecting their functional behavior. The major finding of the study was that 65% removal of chondroitin-dermatan sulfate-containing glycosaminoglycans from the arterial wall increased vascular wall stiffness and altered the myogenic behavior of the artery. The significant alterations in myogenic behavior associated with changes in passive mechanics following partial glycosaminoglycan chain removal support our hypothesis that chondroitin-dermatan sulfate-containing proteoglycans contribute significantly to the functional behavior of resistance arteries. We speculate that these alterations are the result of changes in stress transfer between collagen fibrils and/or stress transfer between cells and collagen fibrils under applied pressure.


Measuring Disease Activity and Damage with Validated Metrics: A Systematic Review on Mortality and Damage in Systemic Lupus Erythematosus.
To identify the effect of disease activity and damage, measured by validated indices, on mortality and damage accrual, in order to inform upcoming Canadian systemic lupus erythematosus (SLE) recommendations. Following GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology to fill in evidence-to-decision tables to create recommendations for "minimal investigations needed to monitor SLE patients at baseline and subsequent visits," a systematic literature review was performed. The effect of disease activity and damage, measured by validated metrics, on mortality and damage was systematically reviewed, with metaanalyses performed when available. A title/abstract screen of 5599 articles identified 816 articles for full paper review, with 102 meeting inclusion criteria and 53 with extractable data. Thirty-three articles describing outcomes related to disease activity and 20 articles related to damage were identified. Mortality was associated with higher SLE Disease Activity Index-2000 scores in 6 studies (HR 1.14, 95% CI 1.06-1.22) and higher Systemic Lupus International Collaborating Clinics/ACR Damage Index scores in 6 studies (HR 1.53, 95% CI 1.28-1.83). Higher SLE Activity Measure scores were associated with increased risk of damage in 3 studies (OR 1.06, 95% CI 1.04-1.08). British Isles Lupus Assessment Group was associated with mortality in 1 study with HR of 1.15. Active SLE disease and damage are associated with and predict greater mortality and damage. The use of validated disease activity and damage metrics is important in the assessment of disease activity and damage and will inform upcoming Canadian recommendations for the assessment of SLE.


Review: allergic contact stomatitis.
Allergic contact stomatitis (ACS) is an oral mucosal immunoinflammatory disorder variably characterized clinically by erythematous plaques, vesiculation, ulceration, and/or hyperkeratosis and by pain, burning sensation, or itchiness. ACS is brought about by a T cell-mediated, delayed hypersensitivity immune reaction generated by a second or subsequent contact exposure of an allergen with the oral mucosa, in a genetically susceptible, sensitized subject. Lichenoid contact reaction is a variant of ACS brought about by direct contact with the oral mucosa of certain metals in dental restorations. The features of ACS are neither clinically nor histopathologically specific, so the diagnosis is usually presumptive and can only be confirmed by resolution of the inflammation after withdrawal or removal of the suspected causative allergen. When ACS is suspected but an allergen cannot be identified, patch testing is necessary. In persistent cases, topical corticosteroids are the treatment of choice, but for severe and extensive lesions, systemic corticosteroid and systemic antihistamines may be indicated. In this short review, we highlight the clinical, immunologic, and histopathological features of ACS, and provide some guidelines for diagnosis and management.


Discounting across generations: necessary, not suspect.
Periodically, ethical objections are raised against the practice of discounting for future effects. Concerns about the potential effects on future generations from long-term nuclear waste disposal and global climate change have caused these ethical objections to recur. This article rebuts the various ethical objections to future discounting on practical, ethical, and analytic grounds. Discounting for future effects is a ubiquitous practice that cannot be practically prevented. In the event that public policy would dictate against future discounting in public decisions, such a constraint could never be successfully imposed on markets. Market values will always reflect the full, discounted streams of future effects even if governments prohibited the practice among individuals. Ethically, there is no basis for choosing an upper-bound time horizon beyond which discounting should be rejected. Any proposed horizon is arbitrary and has no obvious foundation. All decisions are fundamentally irreversible, so opponents of future discounting also must define a degree of irreversibility beyond which normal discounting should not apply, and defend on ethical grounds the basis for this demarcation. This task is further complicated by the likelihood that choices are rarely, if ever, as irreversible as opponents suggest. Typical examples given to prove future discounting is inappropriate overstate the degree of irreversibility actually present and understate subsequent opportunities for modifications. Finally, opposition to distant-future discounting on the ground that burdens are shifted to future generations must face the fact that such shifts are characteristic of intergenerational transfers now practiced widely and with great public support.


Early short-term effects on catecholamine levels and pituitary function in patients with pheochromocytoma or paraganglioma treated with [177Lu]Lu-DOTA-TATE therapy.
While there are reports of treatment-related endocrine disruptions and catecholamine surges in pheochromocytoma/paraganglioma (PPGL) patients treated with [177Lu]Lu-DOTA-TATE therapy, the spectrum of these abnormalities in the immediate post-treatment period (within 48 hours) has not been previously evaluated and is likely underestimated. The study population included patients (≥18 years) enrolled in a phase 2 trial for treatment of somatostatin receptor (SSTR)-2+ inoperable/metastatic pheochromocytoma/paraganglioma with [177Lu]Lu-DOTA-TATE (7.4 GBq per cycle for 1 - 4 cycles). Hormonal measurements [adrenocorticotropic hormone (ACTH), cortisol, thyroid stimulating hormone (TSH), free thyroxine (FT4), follicle stimulating hormone (FSH), luteinizing hormone (LH), testosterone, estradiol, growth hormone, prolactin], catecholamines, and metanephrines were obtained on days-1, 2, 3, 30, and 60 per cycle as per trial protocol, and were retrospectively analyzed. Among the 27 patients (age: 54 ± 12.7 years, 48.1% females) who underwent hormonal evaluation, hypoprolactinemia (14.1%), elevated FSH (13.1%), and elevated LH (12.5%) were the most frequent hormonal abnormalities across all 4 cycles combined. On longitudinal follow-up, significant reductions were noted in i. ACTH without corresponding changes in cortisol, ii. TSH, and FT4, and iii. prolactin at or before day-30 of [177Lu]Lu-DOTA-TATE. No significant changes were observed in the gonadotropic axis and GH levels. Levels of all hormones on day-60 were not significantly different from day-1 values, suggesting the transient nature of these changes. However, two patients developed clinical, persistent endocrinopathies (primary hypothyroidism: n=1 male; early menopause: n=1 female). Compared to day-1, a significant % increase in norepinephrine, dopamine, and normetanephrine levels were noted at 24 hours following [177Lu]Lu-DOTA-TATE dose and peaked within 48 hours. [177Lu]Lu-DOTA-TATE therapy is associated with alterations in endocrine function likely from radiation exposure to SSTR2+ endocrine tissues. However, these changes may sometimes manifest as clinically significant endocrinopathies. It is therefore important to periodically assess endocrine function during [177Lu]Lu-DOTA-TATE therapy, especially among symptomatic patients. https://clinicaltrials.gov/ct2/show/NCT03206060?term=NCT03206060&draw=2&rank=1, identifier NCT03206060.