A cohort and database study of airway management in patients undergoing thyroidectomy for retrosternal goitre.
Patients undergoing thyroid surgery with retrosternal goitre may raise concerns for the anaesthetist, especially airway management. We reviewed a multicentre prospective thyroid surgery database and extracted data for those patients with retrosternal goitre. Additionally, we reviewed the anaesthetic charts of patients with retrosternal goitre at our institution to identify the anaesthetic induction technique and airway management. Of 4572 patients in the database, 919 (20%) had a retrosternal goitre. Two cases of early postoperative tracheomalacia were reported, one in the retrosternal group. Despite some very large goitres, no patient required tracheostomy or cardiopulmonary bypass and there were no perioperative deaths. In the subset of 133 patients managed at our institution over six years, there were no major adverse anaesthetic outcomes and no patient had a failed airway or tracheomalacia. In the latter cohort, of 32 (24%) patients identified as having a potentially difficult airway, 17 underwent awake fibreoptic tracheal intubation, but two of these were abandoned and converted to intravenous induction and general anaesthesia. Eleven had inhalational induction; two of these were also abandoned and converted to intravenous induction and general anaesthesia. Of those suspected as having a difficult airway, 28 (87.5%) subsequently had direct laryngoscopy where the laryngeal inlet was clearly visible. We found no good evidence that thyroid surgery patients with retrosternal goitre, with or without symptoms and signs of tracheal compression, present the experienced anaesthetist with an airway that cannot be managed using conventional techniques. This does not preclude the need for multidisciplinary discussion and planning.


Requirement of the bacteriopahge T7 0.7 gene for phage growth in the presence of the Col 1b factor.
A variety of colicinogenic factors were examined for their effect on the growth of phages related to T7. Col B1 and Col B4 inhibited the growth of every phage tested. Col B2, however, did not interfere with T3 and H. Col E2 interfered only with growth of T3, while Col Ib produced abortive infection with some T7 mutants. The abortive infection associated with Col Ib seems to be correlated with the absence of the virus phosphokinase; mixed infection with T7 wild type and a phosphokinase deficient mutant was productive but the phage yield was depressed. The abortively infected cells lysed.


Leaf Vein-Inspired Hierarchical Wedge-Shaped Tracks on Flexible Substrate for Enhanced Directional Water Collection.
Water collection has been extensively researched due to its potential for mitigating the water scarcity in arid and semiarid regions. Numerous structures mimicking the fog-harvesting strategy of organisms have been fabricated for improving water-collecting efficiency. In this contribution, we demonstrate four-level wedge-shaped tracks inspired by leaf vein for enhancing directional water collection. Superhydrophilic Cu(OH)2 nanowires are introduced and prepared on flexible hydrophobic polyethylene terephthalate (PET) substrates by alkali-assisted surface oxidation at room temperature. They provide abundant capillary paths for promoting droplet absorption and forming water film tracks. Then, the hierarchical wedge-shaped tracks enable the water to be transported to a certain accumulation region spontaneously owing to the continuous Young-Laplace pressure difference. As a result, the four-level wedge-shaped tracks on PET substrate achieve the highest water-collecting efficiency, increasing by nearly 1150 and 510% compared to the bare PET and Cu(OH)2 nanowires on PET, respectively. After being bent for 105 cycles at a radius of 10 mm, the samples can still preserve high efficiency, indicating that the synthetic structures possess outstanding durability. Our approach provides a novel strategy for water collection and paves ways for directional liquid transportation and microfluidic devices.


A new insight on the role of zinc in the regulation of altered thyroid functions during lithium treatment.
Lithium salts are widely used for the treatment of mental disorders but cause thyroid dysfunctions while zinc is an essential trace element and is required for a broad range of biological activities. The present study was designed to explore the potential of zinc in regulating 131I biokinetics and thyroid functions following lithium therapy. To carry out the investigations, 40 female sprague dawley rats weighing 110-140g were segregated into four groups viz. Group I animals served as untreated controls, group II animals were given lithium (Li2CO31.1 g/kg diet), group III animals were supplemented with zinc (227 mg ZnSO4/L drinking water) and animals in group IV were given a combined treatment of lithium and zinc. The treatments were given for durations of 1, 2 and 4 months. Following intraperitoneal administration of 0.37 MBq carrier- free-131I, a significant depression in the thyroidal 131I uptake both at 2 and 24 hrs was observed following lithium treatment for all the durations which however was brought to within normal levels following zinc supplementation. Lithium treatment caused a significant elevation in the thyroidal biological half lives of 131I which was appreciably attenuated following 2 and 4 months of zinc supplementation. Lithium administration for 2 and 4 months significantly decreased serum T3 and T4 levels which however were increased following zinc supplementation. Lithium treatment for 4 months caused a significant decrease in the thyroidal activities of Na+ K+ ATPase and monoamine oxidase which were brought to near normal levels by zinc. Further, lithium treatment for 4 months raised thyroidal levels of lipid peroxidation and catalase which however were normalized by zinc supplementation. On the contrary, thyroidal levels of reduced glutathione and glutathione S transferase decreased significantly following 2 and 4 months of lithium treatment but were significantly increased following zinc treatment. The present study concludes that zinc supplementation is helpful in attenuating the adverse effects caused by lithium on thyroid functions and can effectively regulate the biokinetics of 131I.


Arf gene loss enhances oncogenicity and limits imatinib response in mouse models of Bcr-Abl-induced acute lymphoblastic leukemia.
Mouse bone marrow cells transduced with retroviral vectors encoding either of two oncogenic Bcr-Abl isoforms (p210(Bcr-Abl) and p185(Bcr-Abl)) induce B cell lympholeukemias when transplanted into lethally irradiated mice. If the activity of the Arf tumor suppressor is compromised, these donor cells initiate a much more highly aggressive and rapidly fatal disease. When mouse bone marrow cells expressing Bcr-Abl are placed in short-term cultures selectively designed to support the outgrowth of pre-B cells, only those lacking one or two Arf alleles can initiate lympholeukemias when inoculated into immunocompetent, syngeneic recipient mice. Although the ABL kinase inhibitor imatinib mesylate (Gleevec) provides highly effective treatment for BCR-ABL-positive chronic myelogenous leukemia, it has proven far less efficacious in the treatment of BCR-ABL-positive acute lymphoblastic leukemias (ALLs), many of which sustain deletions of the INK4A-ARF (CDKN2A) tumor suppressor locus. Mice receiving Arf-/- or Arf+/- p210(Bcr-Abl)-positive pre-B cells do not achieve remission when maintained on high doses of oral imatinib therapy and rapidly succumb to lympholeukemia. Although cells expressing the Bcr-Abl kinase can proliferate in the absence of IL-7, they remain responsive to this cytokine, which can reduce their sensitivity to imatinib. Treatment of Arf-/-, p210(Bcr-Abl)-positive pre-B cells with imatinib together with an inhibitor of JAK kinases abrogates this resistance, suggesting that this combination may prove beneficial in the treatment of BCR-ABL-positive acute lymphoblastic leukemia.


Laparoscopic and endoscopic cooperative surgery as palliative treatment for elderly patients with gastric cancer.
Oncological gastrectomy, despite remaining a mainstay of gastric cancer treatment, is reportedly associated with high morbidity and mortality in elderly patients. Less invasive modalities suitable for senior gastric cancer patients with insufficient surgical tolerance are thus needed. We adopted laparoscopic and endoscopic cooperative surgery as an alternative for elderly gastric cancer cases unsuitable for aggressive gastrectomy. To date, we have experienced three cases (80-86 years old) undergoing palliative laparoscopic and endoscopic cooperative surgery. Postoperative courses were uneventful in two cases, while sutural leakage occurred in the other, which was managed conservatively. Postoperative loss of body weight and skeletal muscle mass appeared to be minimal according to bioelectrical impedance analyses. No gastric cancer recurrence was detected in any of our three cases. As to the balance between radicality and safety, laparoscopic and endoscopic cooperative surgery is potentially a viable option for geriatric gastric cancer patients in whom conventional gastrectomy is contraindicated.


Anterior ankle dislocation with associated trigonal process fracture. A case report and literature review.
Anterior ankle dislocations without concomitant malleolar fractures are rare injuries. Review of the English-language literature disclosed only three previously reported cases. A 21-year-old man sustained an isolated anterior ankle dislocation with an associated fracture of the trigonal process, which was reduced without difficulty. At follow-up examination 33 months later, the patient's major complaint was chronic, posttraumatic peroneal tendon dislocation. The proposed mechanism of injury suggested in this case is forced plantar flexion.


Current status and problems in development of molecular target agents for gastrointestinal malignancy in Japan.
Since late 1990s, many molecular target agents have been introduced to clinical trials for various kinds of tumors, and some of them showing significant benefits have been approved. However, these global trials were mainly conducted outside Japan, and the 'drag lag' has been a serious problem in Japan recently. Nowadays, Japanese institutions have been participating in some global trials, and the drug lags are getting shorter. For colorectal cancer, molecular target agents such as bevacizumab and cetuximab have been approved in Japan, resulting in improved clinical outcomes. For gastric cancer, Japanese institutions not only contribute to the global Phase III trials of trastuzumab and bevacizumab but also show leadership in the early development of other new agents. For pancreatic cancer, only erlotinib has shown a survival benefit in these 10 years. Worldwide approach including Japan is warranted to achieve better clinical outcomes. For liver cancer, although Japanese institutions did not participate even in the Asian trial of sorafenib, it has been approved in Japan. For esophageal cancer, because there has been no new molecular target agents developed by pharmaceutical companies, investigator-initiated registration trial will play an important role. For all gastrointestinal malignancies, molecular target agents have made a progress in their treatments. In the near future, Japanese institutions will participate in more and more global trials and should play a specific role in worldwide drug development. Furthermore, the optimal use of these new drugs, molecular target agents, based on the daily practice should also be explored in Japan.


Leaf onset in the northern hemisphere triggered by daytime temperature.
Recent warming significantly advanced leaf onset in the northern hemisphere. This signal cannot be accurately reproduced by current models parameterized by daily mean temperature (T(mean)). Here using in situ observations of leaf unfolding dates (LUDs) in Europe and the United States, we show that the interannual anomalies of LUD during 1982-2011 are triggered by daytime (Tmax) more than by nighttime temperature (T(min)). Furthermore, an increase of 1 °C in Tmax would advance LUD by 4.7 days in Europe and 4.3 days in the United States, more than the conventional temperature sensitivity estimated from T(mean). The triggering role of Tmax, rather than the T(min) or T(mean) variable, is also supported by analysis of the large-scale patterns of satellite-derived vegetation green-up in spring in the northern hemisphere (>30 °N). Our results suggest a new conceptual framework of leaf onset using daytime temperature to improve the performance of phenology modules in current Earth system models.


Functional capacity, physical activity and muscle strength assessment of individuals with non-small cell lung cancer: a systematic review of instruments and their measurement properties.
The measurement properties of instruments used to assess functional capacity, physical activity and muscle strength in participants with non-small cell lung cancer (NSCLC) have not been systematically reviewed. To identify outcome measures used to assess these outcomes in participants with NSCLC; and to evaluate, synthesise and compare the measurement properties of the outcome measures identified. A systematic review of articles using electronic databases MEDLINE (1950-2012), CINAHL (1982-2012), EMBASE (1980-2012), Cochrane Library (2012), Expanded Academic ASAP (1994-2012), Health Collection Informit (1995-2012) and PEDRO (1999-2012). Additional studies were identified by searching personal files and cross referencing. Eligibility Criteria for Study Selection: Search one: studies which assessed functional capacity, physical activity or muscle strength in participants with NSCLC using non-laboratory objective tests were included. Search two: studies which evaluated a measurement property (inter- or intra-rater reliability; measurement error; criterion or construct validity; or responsiveness) in NSCLC for one of the outcome measures identified in search one. Studies published in English from 1980 were eligible. Data Extraction and Methodological Quality Assessment: data collection form was developed and data extracted. Methodological quality of studies was assessed by two independent reviewers using the 4-point COSMIN checklist. Thirteen outcome measures were identified. Thirty-one studies evaluating measurement properties of the outcome measures in participants with NSCLC were included. Functional capacity was assessed using the six- and twelve-minute walk tests; incremental- and endurance-shuttle walk tests; and the stair-climbing test. Criterion validity for three of these measures was established in NSCLC but not the reliability or responsiveness. Physical activity was measured using accelerometers and pedometers. Only the construct validity for accelerometers and pedometers was reported. Muscle strength was measured using hand-held dynamometry, hand-grip dynamometry, manual muscle test, one-repetition maximum and the chair-stand test, however only two studies reported reliability and measurement error and one study reported construct validity. Currently there is a gap in the literature regarding the measurement properties of commonly used outcome measures in NSCLC participants, particularly reliability, measurement error and responsiveness. Further research needs to be conducted to determine the most suitable outcome measures for use in trials involving NSCLC participants.


Child Diet and Household Characteristics Relate Differently to Child Development at the Beginning and the End of the Second "1000 Days" in Rural Nepal.
The "second 1000 days" is a period of rapid brain growth which consolidates developmental foundations and establishes school readiness. Understanding the relation between household characteristics, child diet, and child development remains incomplete, especially in resource-poor settings where >250 million children risk not achieving their full developmental potential. Child developmental performance was assessed (Ages & Stages Questionnaire [ASQ]) at ages 2 and 5 years in a cohort of Nepali children (n = 207) whose families participated in a nutrition/livestock management+community development intervention trial. Relationships between child developmental performance and mother's education, family wealth, child diet (animal source food [ASF] consumption, dietary diversity score [DDS]), school attendance, and intervention group were examined by adjusted linear regressions. These relationships varied at the 2 ages. At age 2 years, ASQ scores related positively to "Full Package Intervention" and negatively to "Partial Package Intervention" membership. At age 5 years, intervention group did not relate to ASQ scores. Mother's education did not relate to developmental findings for 2-year-olds. Mother's education, wealth, and school attendance positively predicted ASQ scores for these same children as 5-year-olds. Animal source food consumption was related to child development more strongly at age 5 than at 2 years. DDS had a less pronounced relationship to development than ASF consumption at both ages. Over this time span bracketing the second 1000 days, household characteristics and child diet related differentially to developmental performance depending on child age. Better understanding of the timing and mechanisms of these relationships is needed to effectively design interventions targeting improved child development in resource-poor settings.


Transanal Total Mesorectal Excision: Why, When, and How.
Transanal total mesorectal excision (taTME) has evolved over the past decade fueled by advances in minimally invasive surgery. The technique aims to overcome the constraints posed by a narrow rigid pelvis and poor TME visualization that are encountered during "top-down" rectal surgery. A more accurate pelvic dissection should subsequently result in safer oncological resections and better preservation of pelvic autonomic nerves. taTME is an advanced complex technique that requires dedicated training and experience in TME surgery. Initial results from small cohorts are promising and confirmation by randomized controlled trials is eagerly awaited.


Neural modelling of the semantic predictability gain under challenging listening conditions.
When speech intelligibility is reduced, listeners exploit constraints posed by semantic context to facilitate comprehension. The left angular gyrus (AG) has been argued to drive this semantic predictability gain. Taking a network perspective, we ask how the connectivity within language-specific and domain-general networks flexibly adapts to the predictability and intelligibility of speech. During continuous functional magnetic resonance imaging (fMRI), participants repeated sentences, which varied in semantic predictability of the final word and in acoustic intelligibility. At the neural level, highly predictable sentences led to stronger activation of left-hemispheric semantic regions including subregions of the AG (PGa, PGp) and posterior middle temporal gyrus when speech became more intelligible. The behavioural predictability gain of single participants mapped onto the same regions but was complemented by increased activity in frontal and medial regions. Effective connectivity from PGa to PGp increased for more intelligible sentences. In contrast, inhibitory influence from pre-supplementary motor area to left insula was strongest when predictability and intelligibility of sentences were either lowest or highest. This interactive effect was negatively correlated with the behavioural predictability gain. Together, these results suggest that successful comprehension in noisy listening conditions relies on an interplay of semantic regions and concurrent inhibition of cognitive control regions when semantic cues are available.


Glutamate protects against Ca(2+) paradox-induced injury and inhibits calpain activity in isolated rat hearts.
This study determined the effects of glutamate on the Ca(2+) paradoxical heart, which is a model for Ca(2+) overload-induced injury during myocardial ischaemia and reperfusion, and evaluated its effect on a known mediator of injury, calpain. An isolated rat heart was retrogradely perfused in a Langendorff apparatus. Ca(2+) paradox was elicited via perfusion with a Ca(2+) -free Krebs-Henseleit (KH) solution for 3 minutes followed by Ca(2+) -containing normal KH solution for 30 minutes. The Ca(2+) paradoxical heart exhibited almost no viable tissue on triphenyltetrazolium chloride staining and markedly increased LDH release, caspase-3 activity, cytosolic cytochrome c content, and apoptotic index. These hearts also displayed significantly increased LVEDP and a disappearance of LVDP. Glutamate (5 and 20 mmol/L) significantly alleviated Ca(2+) paradox-induced injury. In contrast, 20 mmol/L mannitol had no effect on Ca(2+) paradox. Ca(2+) paradox significantly increased the extent of the translocation of μ-calpain to the sarcolemmal membrane and the proteolysis of α-fodrin, which suggests calpain activation. Glutamate also blocked these effects. A non-selective inhibitor of glutamate transporters, dl-TBOA (10 μmol/L), had no effect on control hearts, but it reversed glutamate-induced cardioprotection and reduction in calpain activity. Glutamate treatment significantly increased intracellular glutamate content in the Ca(2+) paradoxical heart, which was also blocked by dl-TBOA. We conclude that glutamate protects the heart against Ca(2+) overload-induced injury via glutamate transporters, and the inhibition of calpain activity is involved in this process.


Neuromuscular control in landing from supra-maximal dropping height.
The present study utilized high-impact supra-maximal landings to examine the influence of the pre-impact force level on the post-impact electromyographic (EMG) activity and, in particular, on the short latency EMG reflex (SLR) component. Unilateral-leg landings were performed in a sitting position on a sledge apparatus after release from high, but individually constant dropping height. A lower limb guiding device fixed to the front of the sledge seat allowed the subjects to sustain a given pre-set force level up to impact. This force level was either freely chosen or set at 20, 35, and 50% of maximal isometric plantarflexion force. EMG activity was recorded from eight major lower limb muscles. It was expected that the increase in the pre-impact force level would require the intervention of a protective neural strategy during the post-impact phase that would attenuate the SLR amplitude. The ultrasonography recordings confirmed that the soleus fascicles were stretched to induce SLR. The main finding was the similarity across all tested conditions of the impact peak force and post-impact EMG activity, including the SLR response. Both observations are mostly attributed to the similar EMG levels and close force levels reached toward impact. The instruction to maintain a given pre-set force level was indeed overruled when getting close to impact. It is suggested that, in the present supra-maximal landing condition, a protective central neural strategy did occur that took into account the pre-set force level to secure similar impact loads.


A randomized trial of nicotine-replacement therapy patches in pregnancy.
Nicotine-replacement therapy is effective for smoking cessation outside pregnancy and its use is widely recommended during pregnancy. We investigated the efficacy and safety of nicotine patches during pregnancy. We recruited participants from seven hospitals in England who were 16 to 50 years of age with pregnancies of 12 to 24 weeks' gestation and who smoked five or more cigarettes per day. Participants received behavioral cessation support and were randomly assigned to 8 weeks of treatment with active nicotine patches (15 mg per 16 hours) or matched placebo patches. The primary outcome was abstinence from the date of smoking cessation until delivery, as validated by measurement of exhaled carbon monoxide or salivary cotinine. Safety was assessed by monitoring for adverse pregnancy and birth outcomes. Of 1050 participants, 521 were randomly assigned to nicotine-replacement therapy and 529 to placebo. There was no significant difference in the rate of abstinence from the quit date until delivery between the nicotine-replacement and placebo groups (9.4% and 7.6%, respectively; unadjusted odds ratio with nicotine-replacement therapy, 1.26; 95% confidence interval, 0.82 to 1.96), although the rate was higher at 1 month in the nicotine-replacement group than in the placebo group (21.3% vs. 11.7%). Compliance was low; only 7.2% of women assigned to nicotine-replacement therapy and 2.8% assigned to placebo used patches for more than 1 month. Rates of adverse pregnancy and birth outcomes were similar in the two groups. Adding a nicotine patch (15 mg per 16 hours) to behavioral cessation support for women who smoked during pregnancy did not significantly increase the rate of abstinence from smoking until delivery or the risk of adverse pregnancy or birth outcomes. However, low compliance rates substantially limited the assessment of safety. (Funded by the National Institute for Health Research Health Technology Assessment Programme; Current Controlled Trials number, ISRCTN07249128.).


Positive FNR-like control of anaerobic arginine degradation and nitrate respiration in Pseudomonas aeruginosa.
A mutant of Pseudomonas aeruginosa was characterized which could not grow anaerobically with nitrate as the terminal electron acceptor or with arginine as the sole energy source. In this anr mutant, nitrate reductase and arginine deiminase were not induced by oxygen limitation. The anr mutation was mapped in the 60-min region of the P. aeruginosa chromosome. A 1.3-kb chromosomal fragment from P. aeruginosa complemented the anr mutation and also restored anaerobic growth of an Escherichia coli fnr deletion mutant on nitrate medium, indicating that the 1.3-kb fragment specifies an FNR-like regulatory protein. The arcDABC operon, which encodes the arginine deiminase pathway enzymes of P. aeruginosa, was rendered virtually noninducible by a deletion or an insertion in the -40 region of the arc promoter. This -40 sequence (TTGAC....ATCAG) strongly resembled the consensus FNR-binding site (TTGAT....ATCAA) of E. coli. The cloned arc operon was expressed at low levels in E. coli; nevertheless, some FNR-dependent anaerobic induction could be observed. An FNR-dependent E. coli promoter containing the consensus FNR-binding site was expressed well in P. aeruginosa and was regulated by oxygen limitation. These findings suggest that P. aeruginosa and E. coli have similar mechanisms of anaerobic control.


A Cross-sectional Analysis of Facebook Comments to Study Public Perception of the Mass Drug Administration Program in the Philippines.
Mass Drug Administration (MDA) of albendazole is being implemented in the Philippines to eliminate soil-transmitted helminthiasis (STH) among school-age children (SAC). The first round of MDA for the school year 2019-2020 was suspended in the province of Surigao del Norte due to a reported death of a student after deworming. It was broadcasted on a national television and the story was then posted on Facebook. We used structured and simple nature of social media research to study public perception of the MDA program after the controversial issue in the Philippines. The news story was assessed, and the Facebook comments were analyzed. A large portion of the Facebook comments expressed a declining trust of the Filipinos toward MDA. The negative impact could be attributed to the public-initiated discussion and sharing of comments with no solid evidence in Facebook. This study showed a possible threat to the successful implementation of the program if not properly managed. The Department of Health (DOH) should be able to cope with the developing landscape of public perception during the era of social media.


Improving accuracy and reproducibility of vibrational spectra for diluted solutions.
In what appears to be a trivial operation in which the averaged spectrum of solvent is subtracted from the spectra of solutions, can be a misleading step in improving reproducibility of vibrational spectra. Near-infrared spectra of pure water and glycine solutions were used to quantify instrumental and spectral variations, and examine its influence on the reproducibility of difference spectra over a wide concentration range. Significant improvements were observed (fourfold), in comparison with the most commonly applied technique that uses an averaged spectrum of solvent. We propose a new technique, in which subtraction of the closest spectrum of solvent involves calculating the smallest area under the subtracted curve, to extract the optimal outcome. These results reveal that, contrary to common practice, reproducibility for spectra of diluted solutions can bypass even instrumental baseline shifts and render results that are limited only by the noise originating from the instrument's sensor.


SIRT1 regulates hepatocyte lipid metabolism through activating AMP-activated protein kinase.
Resveratrol may protect against metabolic disease through activating SIRT1 deacetylase. Because we have recently defined AMPK activation as a key mechanism for the beneficial effects of polyphenols on hepatic lipid accumulation, hyperlipidemia, and atherosclerosis in type 1 diabetic mice, we hypothesize that polyphenol-activated SIRT1 acts upstream of AMPK signaling and hepatocellular lipid metabolism. Here we show that polyphenols, including resveratrol and the synthetic polyphenol S17834, increase SIRT1 deacetylase activity, LKB1 phosphorylation at Ser(428), and AMPK activity. Polyphenols substantially prevent the impairment in phosphorylation of AMPK and its downstream target, ACC (acetyl-CoA carboxylase), elevation in expression of FAS (fatty acid synthase), and lipid accumulation in human HepG2 hepatocytes exposed to high glucose. These effects of polyphenols are largely abolished by pharmacological and genetic inhibition of SIRT1, suggesting that the stimulation of AMPK and lipid-lowering effect of polyphenols depend on SIRT1 activity. Furthermore, adenoviral overexpression of SIRT1 stimulates the basal AMPK signaling in HepG2 cells and in the mouse liver. AMPK activation by SIRT1 also protects against FAS induction and lipid accumulation caused by high glucose. Moreover, LKB1, but not CaMKKbeta, is required for activation of AMPK by polyphenols and SIRT1. These findings suggest that SIRT1 functions as a novel upstream regulator for LKB1/AMPK signaling and plays an essential role in the regulation of hepatocyte lipid metabolism. Targeting SIRT1/LKB1/AMPK signaling by polyphenols may have potential therapeutic implications for dyslipidemia and accelerated atherosclerosis in diabetes and age-related diseases.


[A chronic destructive non-suppurative cholangitis-like disease picture with antinuclear antibodies (immunocholangitis)].
Three females had suffered, two for many years, from bouts of a liver disease of unknown origin, which clinically, histologically and biochemically fulfills the criteria of chronic destructive non-suppurative cholangitis. None of the patients had antimitochondrial antibodies, but all had antinuclear antibodies at high titres. Two of them are mother and daughter; the latter has two daughters (aged 10 and 12 years), both of whom have antinuclear antibodies at low titres but no abnormal liver function tests. The female family members of the third patient also had antinuclear antibodies in their serum with normal liver enzyme tests. None of the patients was taking any drugs. Contrary to true chronic destructive nonsuppurative cholangitis (primary biliary cirrhosis), in the three patients immunosuppressive treatment with azathioprine (Imurek) and prednisone (Decortin) was successful. It is suggested that the described disease be called immunocholangitis.


Novel Cyanobacterial Diversity Found in Costa Rican Thermal Springs Associated with Rincon de la Vieja and Miravalles Volcanoes: A Polyphasic Approach.
Central America is one of the most important biodiversity hot spots in the world, and Costa Rican microbial communities from thermal springs are the best characterized in the isthmus. Miravalles is an inactive quaternary stratovolcano, and the Rincón de la Vieja is a unique active volcano, in whose slopes diverse hydrothermal springs, such as Las Lilas, are located. These springs harbor extensive microbial mats, whose diversity has been studied. Based on their importance as primary producers, in this study we focused on cultured cyanobacterial diversity from two geothermal environments of northern Costa Rica. Several cultural, molecular and taxonomic techniques were employed to maximize the results of a polyphasic approach. Sample collection sites were physicochemically described, and strains were isolated and characterized by light and electron microscopy. Phylogenetic analysis was performed using 16S rRNA gene sequences and amplified ribosomal DNA restriction analysis (ARDRA). Fifty-six phylotypes were isolated and classified into 21 morphotypes and identified in 14 genera, some of them might be new species within these genera. Furthermore, according to phylogenetic analysis, there are three possible new genera in our collection. Miravalles and Las Lilas thermal springs are reservoirs of novel phylogeographic lineages of phototrophic microorganisms. This study is the first report of strains that belong to the genera Gloeocapsa, Stanieria, Microseira, Klisinema and Oculatella isolated from thermal springs and growing at temperatures above 50°C. We also obtained isolates assigned to Synechococcus, Leptolyngbya spp., and Fischerella, which are considered typical strains in these environments.


Treadmill walking reduces pre-frontal activation in patients with Parkinson's disease.
Among patients with Parkinson's disease (PD), gait is typically disturbed and less automatic. These gait changes are associated with impaired rhythmicity and increased prefrontal activation, presumably in an attempt to compensate for reduced automaticity. We investigated whether during treadmill walking, when the pace is determined and fixed, prefrontal activation in patients with PD is lower, as compared to over-ground walking. Twenty patients with PD (age: 69.8 ± 6.5 yrs.; MoCA: 26.9 ± 2.4; disease duration: 7.9 ± 4.2 yrs) walked at a self-selected walking speed over-ground and on a treadmill. A wireless functional near infrared spectroscopy (fNIRS) system measured prefrontal lobe activation, i.e., oxygenated hemoglobin (Hb02) in the pre-frontal area. Gait was evaluated using 3D-accelerometers attached to the lower back and ankles (Opal™, APDM). Dynamic gait stability was assessed using the maximum Lyapunov exponent to investigate automaticity of the walking pattern. Hb02 was lower during treadmill walking than during over-ground walking (p = 0.001). Gait stability was greater on the treadmill, compared to over-ground walking, in both the anteroposterior and medio-lateral axes (p < 0.001). These findings support the notion that when gait is externally paced, prefrontal lobe activation is reduced in patients with PD, perhaps reflecting a reduced need for compensatory cognitive mechanisms.


Inhibition of ornithine decarboxylase alters the roscovitine-induced mitochondrial-mediated apoptosis in MCF-7 breast cancer cells.
Polyamines (PAs) are small aliphatic amines that play a major role in multicellular functions. The PA levels are controlled by ornithine decarboxylase (ODC), the rate limiting enzyme of PA biosynthesis. α-difluoromethylornithine (DFMO) is the ODC inhibitor, which has been shown to act as an antiproliferative agent in human cancer cells by irreversibly inhibiting ODC, which is overexpressed in breast cancer cells. Roscovitine (ROSC; CYC202), a selective cyclin-dependent kinase inhibitor, induces cell cycle arrest and concomitantly apoptosis in tumor cells. In this study, we aimed to investigate the possible role of PAs in ROSC-induced apoptosis in estrogen-dependent MCF-7 breast cancer cells. Cell viability was assessed following the exposure of MCF-7 cells to DFMO and/or ROSC by MTT cell viability assay. To evaluate the drug-induced apoptotic events, DNA fragmentation by Cell Death ELISA assay and 4,6-diamidino-2-phenylindole staining, were utilized. The disruption of mitochondrial membrane potential, caspase-9 and PARP cleavage was also determined in order to investigate the role of mitochondrial-mediated apoptosis. The modulation of Bcl-2 family members was also evaluated using the immunoblotting technique. Drug-induced reactive oxygen species was determined by a fluorometer following 2',7'-dichlorofluorescein diacetate staining. We found that ROSC induced apoptosis in a dose- and caspase-dependent manner. The ODC specific inhibitor, DFMO, altered the apoptotic effects of ROSC by increasing the generation of reactive oxygen species, decreasing the PA intracellular pool and modulating pro-apoptotic and anti-apoptotic Bcl-2 family members. All these findings suggest that ODC may be a critical target for evaluating the PA metabolic pathway as a therapeutic target in ROSC-induced mitochondrial-mediated apoptosis in estrogen-dependent MCF-7 breast cancer cells.


Diarylmethyloxime and hydrazone derivatives with 5-indolyl moieties as potent inhibitors of tubulin polymerization.
We describe the synthesis and biological evaluation of a series of diarylmethyloxime and diarylmethylhydrazone analogues that contain an indole ring and different modifications on the nitrogen of the bridge. Several compounds showed potent tubulin polymerization inhibitory action as well as cytotoxic activity against cancer cell lines. The N-methyl-5-indolyl substituted analogues are more potent than ethyl substituted ones. The most potent inhibitors of tubulin polymerization are the diarylketones and the diaryloximes. The cytotoxicity against several cancer cell lines is lower for the oximes than for the ketones. Other substitutions on the imine nitrogen greatly reduce the tubulin inhibitory and/or cytotoxic potencies.


Do Smoking and Socioeconomic Factors Influence Imaging Outcomes in Axial Spondyloarthritis? Five-Year Data From the DESIR Cohort.
To investigate the relationship between smoking and imaging outcomes over 5 years in axial spondyloarthritis (SpA) and to assess whether socioeconomic factors influence these relationships. Axial SpA patients from the Devenir des Spondylarthropathies Indifferérenciées Récentes cohort were included. The following 4 imaging outcomes were assessed by 3 central readers at baseline, 2 years, and 5 years: spine radiographs (using the modified Stoke Ankylosing Spondylitis Spine Score [mSASSS]), sacroiliac (SI) joint radiographs (using the modified New York criteria), magnetic resonance imaging (MRI) of the spine (using the Spondyloarthritis Research Consortium of Canada [SPARCC] score), and MRI of the SI joint (using the SPARCC score). The explanatory variable of interest was smoking status at baseline. Interactions between smoking and socioeconomic factors (i.e., job type [blue-collar or manual work versus white-collar or nonmanual work] and education [low versus high]) were first tested, and if significant, analyses were run using separate strata. Generalized estimating equations models were used, with adjustments for confounders. In total, 406 axial SpA patients were included (52% male, 40% smokers, and 18% blue collar). Smoking was independently associated with more MRI-detected SI joint inflammation at each visit over the 5 years, an effect that was seen only in patients with blue-collar professions (β = 5.41 [95% confidence interval (95% CI) 1.35, 9.48]) and in patients with low education levels (β = 2.65 [95% CI 0.42,4.88]), using separate models. Smoking was also significantly associated with spinal inflammation (β = 1.69 [95% CI 0.45, 2.93]) and SI joint damage (β = 0.57 [95% CI 0.18, 0.96]) across all patients, irrespective of socioeconomic factors and other potential confounders. Strong associations were found between smoking at baseline and MRI-detected SI joint inflammation at each visit over a time period of 5 years in axial SpA patients with a blue-collar job or low education level. These findings suggest a possible role for mechanical stress amplifying the effect of smoking on axial inflammation in axial SpA.


[Cytogenetic studies on 334 myelodysplastic syndrome (MDS), aplastic anemia (AA) and other hematological diseases].
In order to distinguish various types of MDS, such as RA/AA, RA/ITP or RA/HA, from AA, ITP or HA, bone marrow (BM) cells were studied by using cytogenetic techniques including R-banding karyotypic analysis and sister chromatid differentiation (SCD) assay in 334 cases of hematological diseases (160 MDS, 54 RA/AA, RA/ITP or RA/HA; 60 AA, 3 other known anemias, 38 PNH and 19 ITP). The results showed: (1) karyotypes and SCD values were both normal in more than 90% of AA, PNH, ITP and other known anemias, but they were both abnormal in about 35.6% of MDS and only 13.0% of RA/AA, RA/ITP or RA/HA. These results indicated that cytogenetic techniques were useful in hematological clinic and that RA/AA, or RA/ITP or RA/HA might be pre-RA or atypic RA. This was supported by the results of following up on some RA/AA, RA/ITP or RA/HA cases, (2) clonal abnormal karyotypes were found in 64.4% of MDS. The recurrent chromosomal alterations were +8, 20q-, -5/5q-, -7/7q-, similar to those reported in literatures. (3) 16 MDS cases were followed up and 15 MDS with SCD negative, but one with SCD positive developed leukemia in our hospital. It is suggested that change from SCD positive to negative was indicative of malignant transformation of BM cells. This was supported by the results of cytogenetic analysis in RA/AA, RA/ITP, RA, RAEB, RAEBT and leukemias. (4) Because more structural chromosome alterations occur in SCD negative than SCD positive MDS, the numerous chromosome alterations (monosomy) might occur in earliest development of MDS into leukemias.


[The system of natural physiologically active peptides].
The system of natural physiologically (endocrino-, immuno-) active peptides was shown to have a special amino acid content of peptides as the basis of their polyfunctionality, and the amino acid sequence as the basis of the specificity. The approach to the quantitative definition of oligopeptides was based on a notation system and made it possible to study the correlation between the structure and the activity. The findings can be used for the synthesis of new active peptide compounds.


The burden of stillbirths in low resource settings in Latin America: Evidence from a network using an electronic surveillance system.
To determine stillbirth ratio and its association with maternal, perinatal, and delivery characteristics, as well as geographic differences in Latin American countries (LAC). We analysed data from the Perinatal Information System of the Latin American Center for Perinatology and Human Development (CLAP) between January 2018 and June 2021 in 8 health facilities from five LAC countries (Bolivia, Guatemala, Honduras, Nicaragua, and the Dominican Republic). Maternal, pregnancy, and delivery characteristics, in addition to pregnancy outcomes were reported. Estimates of association were tested using chi-square tests, and P < 0.05 was regarded as significant. Bivariate analysis was conducted to estimate stillbirth risk. Prevalence ratios (PR) with their 95% confidence intervals (CI) for each predictor were reported. In total, 101,852 childbirths comprised the SIP database. For this analysis, we included 99,712 childbirths. There were 762 stillbirths during the study period; the Stillbirth ratio of 7.7/1,000 live births (ranged from 3.8 to 18.2/1,000 live births across the different maternities); 586 (76.9%) were antepartum stillbirths, 150 (19.7%) were intrapartum stillbirths and 26 (3.4%) with an ignored time of death. Stillbirth was significantly associated with women with diabetes (PRadj 2.36; 95%CI [1.25-4.46]), preeclampsia (PRadj 2.01; 95%CI [1.26-3.19]), maternal age (PRadj 1.04; 95%CI [1.02-1.05]), any medical condition (PRadj 1.48; 95%CI [1.24-1.76, and severe maternal outcome (PRadj 3.27; 95%CI [3.27-11.66]). Pregnancy complications and maternal morbidity were significantly associated with stillbirths. The stillbirth ratios varied across the maternity hospitals, which highlights the importance for individual surveillance. Specialized antenatal and intrapartum care remains a priority, particularly for women who are at a higher risk of stillbirth.


Impact of Socioeconomic Disadvantage and Diabetic Retinopathy Severity on Poor Ophthalmic Follow-Up in a Rural Vermont and New York Population.
To investigate the impact of socioeconomic disadvantage and diabetic retinopathy severity on follow-up for vision care among people with diabetes mellitus (DM) residing in rural Vermont and northern New York State. A retrospective chart review of people with DM who visited our academic eye clinic at least once between October 1, 2015, and March 31, 2016, was done. Of 1,466 unique patient visits, 500 were chosen for full chart review by simple random sampling. DM follow-up within 1 year was recommended for 331 adults. Data about prescribed and actual follow-up intervals were extracted. Regression models were used to identify factors associated with poor attendance at follow-up appointments. Sixty-eight [20.5%] patients had poor follow-up, defined as no ophthalmology visit within double the prescribed interval. Of these, 57 were not seen in follow-up by the end of study observation. Poor follow-up was greatest among socioeconomically disadvantaged patients, as defined by Medicaid enrollment (odds ratio [OR], 1.95; 95% CI, 1.07-3.56) in comparison to non-disadvantaged patients. Follow-up was better among those with moderate or worse diabetic retinopathy (OR, 0.38 95% CI, 0.20-0.70), and those with macular edema (OR, 0.19; 95% CI, 0.057-0.62). Medicaid insurance and better diabetic retinopathy status were associated with worse follow-up among our predominantly rural population of patients. Patients who did not follow-up within double the recommended interval were unlikely to follow-up at all. Interventions are needed to target those at highest risk for poor follow-up.


Segmental anatomy of the vastus lateralis: guidelines for muscle-sparing flap harvest.
The vastus lateralis muscle is a versatile donor site for pedicled and free flaps that, despite great potential, remains unpopular. Although the muscle is classically described as a single belly, evidence exists for a more complex morphology. The aim of this study was to investigate the segmental anatomy of the vastus lateralis muscle and the feasibility of selective flap harvest. Ten cadaveric lower limbs were investigated. Muscular partitions were identified according to morphologic architecture, vascular supply, and nerve supply; guidelines for selective flap harvest were described. Twenty-three segmental vastus lateralis (n = 14) or chimeric anterolateral thigh-vastus lateralis flaps (n = 9) were raised based on neurovascular segmental supply, and used as noninnervated free flaps for reconstruction of moderate and large defects of the head and neck, trunk, or lower limbs. Intraoperative electrostimulation was used to confirm segmental innervation. Lower limb function was evaluated through the Lower Extremity Functional Scale. The authors clearly identified three anatomical partitions, which receive a constant segmental neurovascular supply, and two aponeuroses. The authors successfully applied the proposed guidelines for flap harvesting to all 23 patients. Intraoperative electrostimulation confirmed functional integrity of both the flap and the spared partitions. All muscle flaps survived. Donor-site morbidity was negligible, with comparable mean preoperative and postoperative Lower Extremity Functional Scale values (67.7 versus 67.4; p > 0.05). This study provides detailed knowledge on the morphologic and neurovascular anatomy of the vastus lateralis muscle, which supports the authors' guidelines for selective flap harvesting. The technique described is safe and minimizes surgical damage.


Which factors predict placebo response in anxiety disorders and major depression? An analysis of placebo-controlled studies of escitalopram.
The placebo response rate has increased in several psychiatric disorders and is a major issue in the design and interpretation of clinical trials. The current investigation attempted to identify potential predictors of placebo response through examination of the placebo-controlled clinical trial database for escitalopram in 3 anxiety disorders and in major depressive disorder (MDD). Raw data from placebo-controlled studies (conducted from 2002 through the end of 2004) of escitalopram in patients meeting DSM-IV criteria for MDD and anxiety disorders (generalized anxiety disorder [GAD], social anxiety disorder [SAD], panic disorder) were used. Potential predictors examined were type of disorder, location of study, dosing regimen, number of treatment arms, gender of patients, and duration and severity of disorder. Placebo response (defined as the percent decrease from baseline in the reference scale) was higher in GAD and MDD studies conducted in Europe (p < .0001 and p = .0006, respectively) and was not associated with gender or duration of episode. In GAD, the placebo response rate was higher in a European fixed-dose study, which also had more treatment arms. In SAD and in U.S. specialist-treated MDD, a higher placebo response rate was predicted by decreased baseline disorder severity. Additional work is needed before definitive recommendations can be made about whether standard exclusion criteria in clinical trials of antidepressants, such as mild severity of illness, maximize medication-to-placebo differences. This analysis in a range of anxiety disorders and MDD suggests that there may be instances in which the predictors of placebo response rate themselves vary across different conditions.


Feasibility of promoting smoking cessation in small worksites: an exploratory study.
The workplace is recognized as an appropriate site for smoking cessation efforts, but little is known about promoting cessation at smaller worksites. The goal of the present study was to identify strategies for promoting smoking cessation in worksites employing 10-100 workers. Qualitative interviews were conducted with 22 employers in small businesses in the manufacturing-labor and hospitality-service sectors; and eight focus groups were conducted with 59 smokers employed in these sectors. Employers mentioned practical barriers to implementing cessation activities and reluctance to intervene in employees' personal health decisions. Nevertheless, both employers and smokers thought it was desirable and appropriate for employers to promote cessation resources to people who want to quit. Discrepancies existed between the worksite activities favored by employers and those endorsed as potentially useful by smokers. Smokers expressed interest in incentive programs, contests, and nicotine replacement products; employers favored providing information. Both groups were generally unaware of smoking cessation resources available through health plans or in the community. Results suggest that interventions should attempt to increase knowledge about available cessation resources and support for cessation at the workplace. Contests, incentives, and free samples of nicotine replacement products might be feasible and effective for promoting cessation.


Reduction by tetrahydrobiopterin of H2O2-induced endothelial cell injury.
The purpose of this study was to examine the effect of tetrahydrobiopterin, a co-factor of nitric oxide synthase, on H2O2-induced endothelial cell injury. Pretreatment with sepiapterin, a precursor of tetrahydrobiopterin biosynthesis, increased tetrahydrobiopterin content of endothelial cells, and reduced H2O2-induced endothelial cell injury, which was measured by leakage of lactate dehydrogenase. Both the increase in tetrahydrobiopterin content and the protective effect of sepiapterin were prevented by co-pretreatment with N-acetylserotonin, an inhibitor of sepiapterin reductase. Although Ca2+ ionophore ionomycin-induced nitric oxide synthesis was increased by pretreatment with sepiapterin, the protective effect of sepiapterin was not affected by an inhibitor of nitric oxide synthesis. On the other hand, pretreatment with sepiapterin also reduced H2O2-induced rat foetal lung fibroblast cell injury via an increase in tetrahydrobiopterin content, despite rat foetal lung fibroblast cells lacking nitric oxide synthase. Moreover, increase in tetrahydrobiopterin strongly reduced H2O2-induced intracellular oxidative stress. These findings indicate that sepiapterin reduces H2O2-induced endothelial cell injury via an increase in tetrahydrobiopterin content. Although increase in endothelial tetrahydrobiopterin content stimulated nitric oxide production, the protective effect of tetrahydrobiopterin against H2O2-induced endothelial cell injury is unlikely to be related to the stimulation of nitric oxide release from nitric oxide synthase. The protective effect of tetrahydrobiopterin may involve reactive oxygen species-scavenging activity.


Risk Governance of Nanomaterials: Review of Criteria and Tools for Risk Communication, Evaluation, and Mitigation.
Nanotechnologies have been increasingly used in industrial applications and consumer products across several sectors, including construction, transportation, energy, and healthcare. The widespread application of these technologies has raised concerns regarding their environmental, health, societal, and economic impacts. This has led to the investment of enormous resources in Europe and beyond into the development of tools to facilitate the risk assessment and management of nanomaterials, and to inform more robust risk governance process. In this context, several risk governance frameworks have been developed. In our study, we present and review those, and identify a set of criteria and tools for risk evaluation, mitigation, and communication, the implementation of which can inform better risk management decision-making by various stakeholders from e.g., industry, regulators, and the civil society. Based on our analysis, we recommend specific methods from decision science and information technologies that can improve the existing risk governance tools so that they can communicate, evaluate, and mitigate risks more transparently, taking stakeholder perspectives and expert opinion into account, and considering all relevant criteria in establishing the risk-benefit balance of these emerging technologies to enable more robust decisions about the governance of their risks.


Dysnatremia in COVID-19 Patients-An Analysis of the COLOS Study.
Sodium imbalance is one of the most common electrolyte disturbances encountered in the medical practice, and it may present with either hyponatremia or hypernatremia. Both sodium abnormalities are related with unfavorable outcomes. Elucidation of the prevalence of dysnatremia among COVID-19 patients and its impact on 30- and 90-day mortality and need for ICU admission was the goal. A single-center, retrospective, observational study was conducted. A total of 2026 adult, SARS-CoV-2 positive patients, admitted to Wroclaw University Hospital between 02.2020 and 06.2021, were included. On admission, patients were divided into groups: normonatremic (N), hyponatremic (L), and hypernatremic (H). Acquired data was processed, and Cox hazards regression and logistic regression were implemented. Hyponatremia on admission occurred in 17.47% (n = 354) of patients and hypernatremia occurred in 5.03% (n = 102). Dysnatremic patients presented with more comorbidities, used more drugs, and were statistically more often admitted to the ICU. Level of consciousness was the strongest predictor of ICU admission (OR = 1.21, CI: 1.16-1.27, p < 0.001). Thirty-day mortality was significantly higher in both the L and H groups (28.52%, p = 0.0001 and 47.95%, p < 0.0001, respectively), in comparison to 17.67% in the N group. Ninety-day mortality showed a similar trend in all study groups: 34.37% in the L group (p = 0.0001), 60.27% (p < 0.0001) in the H group, and 23.32% in the N group. In multivariable analyses, hypo- and hypernatremia were found to be independent predictors of 30- and 90-day mortality. Both hypo- and hypernatremia are strong predictors of mortality and disease severity in COVID-19 patients. Extraordinary care should be taken when dealing with hypernatremic, COVID-positive patients, as this group exhibits the highest mortality rates.


Lipid-polymer hybrid nanoparticles: Development & statistical optimization of norfloxacin for topical drug delivery system.
Poly lactic acid is a biodegradable, biocompatible, and non-toxic polymer, widely used in many pharmaceutical preparations such as controlled release formulations, parenteral preparations, surgical treatment applications, and tissue engineering. In this study, we prepared lipid-polymer hybrid nanoparticles for topical and site targeting delivery of Norfloxacin by emulsification solvent evaporation method (ESE). The design of experiment (DOE) was done by using software to optimize the result, and then a surface plot was generated to compare with the practical results. The surface morphology, particle size, zeta potential and composition of the lipid-polymer hybrid nanoparticles were characterized by SEM, TEM, AFM, and FTIR. The thermal behavior of the lipid-polymer hybrid nanoparticles was characterized by DSC and TGA. The prepared lipid-polymer hybrid nanoparticles of Norfloxacin exhibited an average particle size from 178.6 ± 3.7 nm to 220.8 ± 2.3 nm, and showed very narrow distribution with polydispersity index ranging from 0.206 ± 0.36 to 0.383 ± 0.66. The surface charge on the lipid-polymer hybrid nanoparticles were confirmed by zeta potential, showed the value from +23.4 ± 1.5 mV to +41.5 ± 3.4 mV. An Antimicrobial study was done against Staphylococcus aureus and Pseudomonas aeruginosa, and the lipid-polymer hybrid nanoparticles showed potential activity against these two. Lipid-polymer hybrid nanoparticles of Norfloxacin showed the %cumulative drug release of 89.72% in 24 h. A stability study of the optimized formulation showed the suitable condition for the storage of lipid-polymer hybrid nanoparticles was at 4 ± 2 °C/60 ± 5% RH. These results illustrated high potential of lipid-polymer hybrid nanoparticles Norfloxacin for usage as a topical antibiotic drug carriers.


Coffee reduces SULT1E1 expression in human colon carcinoma Caco-2 cells.
Recent epidemiological studies have shown that moderate coffee consumption is associated with a lower risk of certain types of cancers, particularly colon cancer in postmenopausal women. To elucidate the molecular basis for the preventive action of coffee, we investigated the effect of coffee on estrogen sulfotransferase (SULT) because sulfation is the major pathway involved in the inactivation of estrogens. We found that coffee reduced SULT1E1 gene expression in human colon carcinoma Caco-2 cells. Treatment with 2.5% (v/v) coffee for 24 h resulted in a 60% reduction of the expression of the SULT1E1 gene in Caco-2 cells. Corresponding to reduced SULT1E1 gene expression, cytosolic estrogen SULT activity toward E(2) (20 nM) decreased by 25%. In addition, an accumulation of E(2) sulfates in the medium, which reflects cellular activity of estrogen SULT, decreased after the cells were treated with coffee. Major bioactive constituents in coffee such as caffeine, chlorogenic acid and caffeic acid did not show any effect. The inhibitory activity was extractable by using ethyl acetate. We also found that the inhibitory activity was produced by roasting the coffee beans. Mithramycin, an inhibitor of the transcription factor stimulating protein 1 (Sp1), was able to restore coffee-reduced SULT1E1 gene expression. Our data suggest that daily coffee consumption may reduce estrogen SULT activity, thereby enhancing estrogenic activity in the colon.


Photoreceptor responses to light in the pathogenesis of diabetic retinopathy.
Vision loss, among the most feared complications of diabetes, is primarily caused by diabetic retinopathy, a disease that manifests in well-recognized, characteristic microvascular lesions. The reasons for retinal susceptibility to damage in diabetes are unclear, especially considering that microvascular networks are found in all tissues. However, the unique metabolic demands of retinal neurons could account for their vulnerability in diabetes. Photoreceptors are the first neurons in the visual circuit and are also the most energy-demanding cells of the retina. Here, we review experimental and clinical evidence linking photoreceptors to the development of diabetic retinopathy. We then describe the influence of retinal illumination on photoreceptor metabolism, effects of light modulation on the severity of diabetic retinopathy, and recent clinical trials testing the treatment of diabetic retinopathy with interventions that impact photoreceptor metabolism. Finally, we introduce several possible mechanisms that could link photoreceptor responses to light and the development of retinal vascular disease in diabetes. Collectively, these concepts form the basis for a growing body of investigative efforts aimed at developing novel pharmacologic and nonpharmacologic tools that target photoreceptor physiology to treat a very common cause of blindness across the world.


Soy milk consumption and blood pressure among type 2 diabetic patients with nephropathy.
The purpose of this study was to determine the effects of soy milk consumption cardiovascular risk and biomarkers of renal function in type 2 diabetic patients with nephropathy. This randomized, crossover, controlled clinical trial was conducted in 29 type 2 diabetic patients with nephropathy. Participants were randomly assigned to consume a diet containing soy milk, or a diet containing cow's milk, each for 4 weeks. There was a 2-week washout between the two intervention periods. Anthropometric and biochemical measurements were performed according to standard protocols. The mean age and body mass index of patients were 51 ± 10 years and 28 ± 4 kg/m(2), respectively. Consumption of soy milk resulted in a significant reduction in systolic blood pressure compared with consumption of cow's milk (percent change: -4.50 vs. 5.89%; P = .03). Serum triglyceride levels decreased significantly after soy milk consumption (percent change: -15.22 vs. 2.37%; P = .02). After adjustment for carbohydrate intake, the effect of soy milk on triglyceride level was not significant. There were no significant differences between soy milk and cow's milk consumption in terms of their effect on cardiovascular risks and markers of kidney function. Soy milk consumption was associated with better blood pressure control among diabetic patients with nephropathy.


Small RNA populations for two unrelated viruses exhibit different biases in strand polarity and proximity to terminal sequences in the insect host Homalodisca vitripennis.
Next generation sequence analyses were used to assess virus-derived small RNA (vsRNA) profiles for Homalodisca coagulata virus-1 (HoCV-1), family Dicistroviridae, and Homalodisca vitripennis reovirus (HoVRV), family Reoviridae, from virus-infected H. vitripennis, the glassy-winged sharpshooter. The vsRNA reads were mapped against the monopartite genome of HoCV-1 and all 12 genome segments of HoVRV, and 21nt vsRNAs were most common. However, strikingly contrasting patterns for the HoCV-1 and HoVRV genomic RNAs were observed. The majority of HoCV-1 vsRNAs mapped to the genomic positive-strand RNA and, although minor hotspots were observed, vsRNAs mapped across the entire genomic RNA. In contrast, HoVRV vsRNAs mapped to both positive and negative-sense strands for all genome segments, but different genomic segments showed distinct hotspots. The HoVRV vsRNAs were more common for 5' and 3' regions of HoVRV regions of all segments. These data suggest that taxonomically different viruses in the same host offer different targets for RNA-antiviral defense.


A phase II trial of fixed-dose rate gemcitabine plus capecitabine in metastatic/advanced biliary tract cancer patients.
This phase II trial was conducted to determine the activity and safety of the combination of fixed-dose rate (FDR) gemcitabine and capecitabine in metastatic biliary tract cancer (BTC) patients. Patients with unresectable BTC who had pathologically confirmed adenocarcinoma, no prior chemotherapy, Eastern Cooperative Oncology Group (ECOG) performance status ≤1 and measurable disease were enrolled. Treatment consisted of FDR gemcitabine at 800 mg/m(2) on days 1 and 8 every 21 days with capecitabine administered orally b.i.d. in equal doses (650 mg/m(2) b.i.d.) for 14 days (28 doses). Between May 2005 and February 2009, 30 patients were enrolled. The median age was 67 years (45-76) and there were 14 males. Thirty patients were evaluable for response and toxicity. A total of 221 cycles were administered (median 7, range 2-16). One patient achieved complete response and 7 patients achieved partial response, giving an overall response rate of 26.7% in the intention-to-treat population. Twelve patients (40.0%) had stable disease. The median progression-free survival was 6.33 months. The median overall survival was 10.8 months. Grade 3/4 neutropenia and thrombocytopenia were noted in 13 and 7% of the patients, respectively. Grade 2/3 nonhematologic toxicities were asthenia (54% of patients), diarrhea (17%), stomatitis (23%) and hand-foot syndrome (7%). There was no treatment-related death. The drugs taken were skipped at least once in 45% of the patients and the dose was reduced in 26% of them. The combination of FDR gemcitabine and capecitabine in this 3-week cycle is safe and seems to have a good activity in advanced biliary cancer.


Effect of natalizumab treatment on the rate of No Evidence of Disease Activity in young adults with multiple sclerosis in relation to pubertal stage.
Approximately 40% of young-onset multiple sclerosis (MS) patients experience breakthrough disease, which carries a high risk for long-term disability, and requires using therapies beyond traditional first-line agents. Despite the increasing use of newer disease-modifying treatments (DMTs) in this population, data are not available to guide the need for escalating DMTs and there is a scarcity of data on the effects of natalizumab in children and young adults with active disease. We performed a retrospective analysis of the rate of No Evidence of Disease Activity (NEDA), tolerability, and safety of natalizumab in a multi-center cohort of 36 children and young adults with highly active MS. All patients had active disease and initiated treatment with natalizumab. The primary endpoint was the rate of achieving NEDA-3 status, within two years of natalizumab treatment. To examine a possible effect of age on the outcome of treatment, outcomes were also analyzed by pre-pubertal (n = 13 children aged 9-13 years) and pubertal subgroups (n = 23 young adolescents aged 14-20 years). The NEDA-3 status of the pre-pubertal group was 92% in the first and second year and in the pubertal group - 96% in the first year and 92% in the second year. Natalizumab reduced the number and volume of brain lesions in both pre-pubertal and pubertal groups. Treatment was well-tolerated, only 8 patients (22.2%) had adverse events during the 2-year study period. Our analysis shows that natalizumab is effective and well-tolerated in pre-pubertal and pubertal MS patients.


Effects of medical therapies on retinopathy progression in type 2 diabetes.
We investigated whether intensive glycemic control, combination therapy for dyslipidemia, and intensive blood-pressure control would limit the progression of diabetic retinopathy in persons with type 2 diabetes. Previous data suggest that these systemic factors may be important in the development and progression of diabetic retinopathy. In a randomized trial, we enrolled 10,251 participants with type 2 diabetes who were at high risk for cardiovascular disease to receive either intensive or standard treatment for glycemia (target glycated hemoglobin level, <6.0% or 7.0 to 7.9%, respectively) and also for dyslipidemia (160 mg daily of fenofibrate plus simvastatin or placebo plus simvastatin) or for systolic blood-pressure control (target, <120 or <140 mm Hg). A subgroup of 2856 participants was evaluated for the effects of these interventions at 4 years on the progression of diabetic retinopathy by 3 or more steps on the Early Treatment Diabetic Retinopathy Study Severity Scale (as assessed from seven-field stereoscopic fundus photographs, with 17 possible steps and a higher number of steps indicating greater severity) or the development of diabetic retinopathy necessitating laser photocoagulation or vitrectomy. At 4 years, the rates of progression of diabetic retinopathy were 7.3% with intensive glycemia treatment, versus 10.4% with standard therapy (adjusted odds ratio, 0.67; 95% confidence interval [CI], 0.51 to 0.87; P=0.003); 6.5% with fenofibrate for intensive dyslipidemia therapy, versus 10.2% with placebo (adjusted odds ratio, 0.60; 95% CI, 0.42 to 0.87; P=0.006); and 10.4% with intensive blood-pressure therapy, versus 8.8% with standard therapy (adjusted odds ratio, 1.23; 95% CI, 0.84 to 1.79; P=0.29). Intensive glycemic control and intensive combination treatment of dyslipidemia, but not intensive blood-pressure control, reduced the rate of progression of diabetic retinopathy. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov numbers, NCT00000620 for the ACCORD study and NCT00542178 for the ACCORD Eye study.)


Reconciling experimental catalytic data stemming from structure sensitivity.
Experimental data have long served as a valuable resource for model validation and identification of the active site. Yet, literature kinetics data often exhibit significant differences among laboratories for the same catalyst and reaction, but the reasons have remained elusive. Here, we exploit if we can rationalize (most of) this variation through catalyst structure sensitivity. We introduce a methodology to build a structure-descriptor-based microkinetic model and investigate the relations between nanoparticle structure and reaction kinetics using the complete methane oxidation on Pt as a model reaction and literature data mining. A volcano-like rate is observed with an optimum coordination number. Unlike common expectations, smaller particles have very low reactivity because of carbon poisoning. Interestingly, most of the data variation can be successfully traced to structure sensitivity. This methodology also enables rapid prediction of kinetic performance and active site determination for designing optimal catalyst structures. It can also serve as a data quality tool to assess experimental outliers. Additional reasons for data variability are discussed.


Potent In Vitro Antiproliferative Synergism of Combinations of Ergosterol Biosynthesis Inhibitors against Leishmania amazonensis.
Leishmaniases comprise a spectrum of diseases caused by protozoan parasites of the Leishmania genus. Treatments available have limited safety and efficacy, high costs, and difficult administration. Thus, there is an urgent need for safer and more-effective therapies. Most trypanosomatids have an essential requirement for ergosterol and other 24-alkyl sterols, which are absent in mammalian cells. In previous studies, we showed that Leishmania amazonensis is highly susceptible to aryl-quinuclidines, such as E5700, which inhibit squalene synthase, and to the azoles itraconazole (ITZ) and posaconazole (POSA), which inhibit C-14α-demethylase. Herein, we investigated the antiproliferative, ultrastructural, and biochemical effects of combinations of E5700 with ITZ and POSA against L. amazonensis. Potent synergistic antiproliferative effects were observed against promastigotes, with fractional inhibitory concentration (FIC) ratios of 0.0525 and 0.0162 for combinations of E5700 plus ITZ and of E5700 plus POSA, respectively. Against intracellular amastigotes, FIC values were 0.175 and 0.1125 for combinations of E5700 plus ITZ and E5700 plus POSA, respectively. Marked alterations of the ultrastructure of promastigotes treated with the combinations were observed, in particular mitochondrial swelling, which was consistent with a reduction of the mitochondrial transmembrane potential, and an increase in the production of reactive oxygen species. We also observed the presence of vacuoles similar to autophagosomes in close association with mitochondria and an increase in the number of lipid bodies. Both growth arrest and ultrastructural/biochemical alterations were strictly associated with the depletion of the 14-desmethyl endogenous sterol pool. These results suggest the possibility of a novel combination therapy for the treatment of leishmaniasis.


Autonomic Nervous System Function in Newly Diagnosed Multiple Sclerosis: Association With Lipid Levels and Insulin Resistance.
Autonomic nervous system (ANS) disorders are common in multiple sclerosis (MS). Previous studies showed differences in insulin resistance (IR) and lipoprotein levels in MS subjects compared to controls. Lipolysis caused by increased sympathetic activity could be one of the possible linking mechanisms leading to dyslipidemia in MS. Our study aimed to evaluate ANS activity in the context of glucose and lipid metabolism in people with MS. We prospectively measured short-term heart rate variability (HRV), fasting lipoprotein concentrations, and calculated IR indices based on plasma glucose and insulin levels during oral glucose tolerance test (oGTT) in 32 patients with MS and 29 healthy controls matched for age, sex and body mass index in our study. There was no significant difference in HRV parameters and lipoprotein levels between MS and controls. A significant positive correlation was found between low/high-frequency power ratio (LF/HF) and triglycerides (r=0.413, p=0.021) in MS subjects but not in controls. A significantly lower whole-body insulin sensitivity index (ISIMat) was found in patients with MS compared to the control group (7.3±3.7 vs. 9.8±5.6, p=0.041). No significant correlations were found between LF/HF and IR parameters. In MS subjects, the positive correlation of LF/HF with triglycerides could reflect the effects of sympathetic activity on lipolysis. Positive correlations of sympathetic activity with increased lipoprotein levels could rather reflect processes associated with immune system activation/inflammation, than processes involved in glucose homeostasis maintenance.


Utility of the caput succedaneum in the forensic investigation of neonaticide: a case report.
Suspicion of neonaticide often leads to a request for a forensic autopsy. In that setting, it is important to correlate autopsy findings with the history given by the mother. So far, caput succedaneum has not raised interest in forensic pathology. A caput succedaneum is a haemorrhagic oedema involving the skin and superficial fascia of the head that results from circulatory stasis caused by compression exerted by the uterus or cervix on the presenting part. It is usually seen with prolonged labour. We report a case of caput succedaneum in a forensic autopsy that overturned the mother's history of giving birth suddenly, consequently increasing the evidence of neonaticide.


Occupational noise-induced hearing loss surveillance in Michigan.
Occupational noise-induced hearing loss (NIHL) is an important yet often overlooked illness that can affect an individual's safety and performance at work. This article describes a state-based surveillance system for occupational NIHL. The Michigan surveillance system enables us to describe the magnitude of occupational NIHL among Michigan workers and direct public health interventions in the form of enforcement workplace inspections. The data presented are based on interviews of individuals with occupational NIHL reported to the Michigan Department of Consumer and Industry Services (MDCIS) by Michigan's audiologists and otolaryngologists from 1992-1997. From 1992-1997, 1378 individuals with occupational NIHL were reported to the MDCIS and interviewed about their exposures to noise at work. Over 70% of the workplace noise exposure were in manufacturing. At the most recent company where these individuals were exposed to noise, approximately 46% were not provided regular hearing testing. Regular hearing testing was more likely to occur in the larger companies and in industries covered by regulations requiring such testing to be performed. There were improvements over time in the percentages of companies providing regular hearing testing and hearing protection. Construction workers are employees among a group of industries that are not adequately protected from excessive noise exposures by occupational regulations. Regular hearing testing was not provided for over 90% of construction jobs, although hearing protection such as earplugs or earmuffs was provided for approximately half of these jobs. Forty-three state enforcement inspections were conducted at the companies reported by the patients interviewed, because these companies were reported to provide no regular hearing testing or no hearing protection despite exposures to excessive levels of noise. During the 43 inspections, 23 companies had noise levels above dBA, and 17 of those had either no hearing conservation program (HCP) or had one that was cited as being incomplete. The inspections potentially protected 758 similarly exposed workers in the companies with the high noise levels that lacked an HCP or that had a deficient HCP. The number of patients with occupational NIHL is likely a gross underestimate of the true magnitude of the disease. However, the surveillance system has identified workplaces with hazardous levels of noise and no HCP, thereby protecting similarly exposed coworkers of the index patients from further exposures to noise and hearing loss.


Genomic and metabolic disposition of non-obese type 2 diabetic rats to increased myocardial fatty acid metabolism.
Lipotoxicity of the heart has been implicated as a leading cause of morbidity in Type 2 Diabetes Mellitus (T2DM). While numerous reports have demonstrated increased myocardial fatty acid (FA) utilization in obese T2DM animal models, this diabetic phenotype has yet to be demonstrated in non-obese animal models of T2DM. Therefore, the present study investigates functional, metabolic, and genomic differences in myocardial FA metabolism in non-obese type 2 diabetic rats. The study utilized Goto-Kakizaki (GK) rats at the age of 24 weeks. Each rat was imaged with small animal positron emission tomography (PET) to estimate myocardial blood flow (MBF) and myocardial FA metabolism. Echocardiograms (ECHOs) were performed to assess cardiac function. Levels of triglycerides (TG) and non-esterified fatty acids (NEFA) were measured in both plasma and cardiac tissues. Finally, expression profiles for 168 genes that have been implicated in diabetes and FA metabolism were measured using quantitative PCR (qPCR) arrays. GK rats exhibited increased NEFA and TG in both plasma and cardiac tissue. Quantitative PET imaging suggests that GK rats have increased FA metabolism. ECHO data indicates that GK rats have a significant increase in left ventricle mass index (LVMI) and decrease in peak early diastolic mitral annular velocity (E') compared to Wistar rats, suggesting structural remodeling and impaired diastolic function. Of the 84 genes in each the diabetes and FA metabolism arrays, 17 genes in the diabetes array and 41 genes in the FA metabolism array were significantly up-regulated in GK rats. Our data suggest that GK rats' exhibit increased genomic disposition to FA and TG metabolism independent of obesity.


Direct carotid-cavernous sinus fistulas.
1. Direct carotid-cavernous sinus fistulas usually result from multi-trauma or head injuries. These patients are more likely to be seen at trauma based hospitals. 2. Ocular manifestations of direct carotid-cavernous sinus fistulas include exophthalmos, swollen eyelids, ocular pulsation, pulsating exophthalmos, conjunctival chemosis, arterialization of conjunctival vessels, exposure keratopathy, a bruit over the affected eye (heard by the patient as a swishing sound), diplopia, visual loss, and ophthalmoscopic abnormalities that include moderate dilation of retinal veins, optic disc swelling, and intraretinal hemorrhage. 3. The ultimate diagnostic test for direct carotid-cavernous sinus fistulas is cerebral arteriography of both the internal and external carotid arteries. 4. The optimal treatment of a direct carotid-cavernous sinus fistula is closure of the abnormal arteriovenous communication with preservation of internal carotid artery patency. Detachable, flow-guided balloons are presently used to close most direct carotid-cavernous sinus fistulas.


Maternal near-miss and death incidences - Frequencies, causes and the referral chain in Somaliland: A pilot study using the WHO near-miss approach.
Background Somaliland is a self-declared country with a population of 3.5 million. Most of its population reside in rural areas. The objective of this pilot near-miss study was to monitor the frequency and causes of maternal near-miss and deaths and the referral chain for women to access Skilled Birth Attendants (SBA). A facility-based study of all maternal near-miss and mortality cases over 5months using the WHO near-miss tool in a main referral hospital. Reasons for bypassing the Antenatal Care facility (ANC) and late arrival to the referral hospital were investigated through verbal autopsy. One hundred and thirty-eight (138) women with severe maternal complications were identified: 120 maternal near-miss, 18 maternal deaths. There were more near-miss cases on arrival (74.2%) compared with events that developed inside the hospital (25.8%). Likewise, there were more maternal deaths (77.8%) on arrival than was the case during hospitalization (22.2%). The most common mode of referral among maternal near-miss events was family referrals (66.7%). Of 18 maternal deaths, 15 were family referrals. Reasons for bypassing ANC were as follows: lack of confidence in the service provided; lack of financial resources; and lack of time to visit ANC. Reasons for late arrival to the referral hospital were as follows: lack of knowledge and transportation; and poor communication. Conclusion and clinical implication: To increase the utilization of ANC might indirectly lower the number of near-miss and death events. Collaboration between ANC staff and referral hospital staff and a more comprehensive near-miss project are proposed.


[A cytogenetic study of the functions of the variable regions in human C heterochromatin. II. C heterochromatin in families with hereditary short stature].
The C heterochromatin in chromosomes 1, 9, 16, and Y was studied for 12 families of patients with inherited short stature. A comparison of the results of cytogenetic and genealogical analysis has revealed a correlation between the growth retardation in children and the short stature in parents, and the accumulation of the small C segment in chromosomes 1, 9, and 16 in their karyotypes. These data are entirely consistent with our results obtained for the families having children with gene syndromes (Russell-Silver, Dubowitz etc.) and obligate growth retardation. Obviously, there is a type of narrow height in man associated with the presence of a small amount of C heterochromatin. This appears to be an additional proof of a great importance of C heterochromatin in embryonal and postnatal development. Differential diagnostics of such a type of short stature is important for children endocrinology, since the hormonal growth-stimulated therapy does not have a desirable effect on these patients.


Isolation and characterization of chromatin replication bands and macronuclei from Euplotes eurystomus.
A method is described for isolating replication bands (RBs) from Euplotes eurystomus in quantities sufficient for biochemical analysis. The method involves the disruption of whole cells in a low ionic strength buffer that maintains RB integrity while dispersing macronuclear chromatin. The RBs are then stabilized with MgCl2 and spermidine phosphate and isolated by gradient centrifugation. Staining with silver nitrate and thiol-specific coumarin maleimide has been demonstrated in the RBs of Euplotes and other hypotrichs; both of these properties were maintained in isolated RBs. A method is also described in this study for isolating highly purified macronuclei. Examination of isolated macronuclei and RBs with electron microscopy (EM) indicates that the morphology of both structures remain essentially intact during purification. We also observe with EM an increase in the number of replicating molecules in RBs compared to macronuclei. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) demonstrates a consistent but minor enrichment of a 55 kilodalton protein in RBs when compared to macronuclear proteins.


Ovulation induction in normogonadotropic anovulation (PCOS).
Treatment of normogonadotropic anovulatory infertility (World Health Organization class 2, or WHO2) is by induction of ovulation using clomiphene citrate (CC), followed by follicle-stimulating hormone (FSH) in cases of treatment failure. Not all patients will become ovulatory or will conceive with this treatment. Others, exhibiting multifollicular instead of monofollicular development, may encounter complications such as ovarian hyperstimulation and multiple pregnancy. Recently introduced alternative treatment interventions-such as insulin-sensitizing drugs, aromatase inhibitors, or laparoscopic electrocautery of the ovaries-may offer the possibility of improving the efficacy of the classical ovulation induction algorithm. Based on initial patient characteristics, it may be possible to identify specific patient subgroups with altered chances of success or complications while using one of these interventions. Regarding CC and FSH ovulation induction, this has been performed using multivariate prediction models. This approach may enable us to improve safety, cost-effectiveness, and patient convenience in future ovulation induction.


Integrating X-ray fluorescence and infrared imaging microspectroscopies for comprehensive characterization of an acetaminophen model pharmaceutical.
The integration of full spectral images using the complementary microspectroscopic imaging techniques X-ray fluorescence and Fourier transform infrared is demonstrated. This effort surpasses previous work in that a single chemometric software package is used to elicit chemical information from the integrated spectroscopic images. Integrating these two complementary spectroscopic methods provides both elemental and molecular spatial distribution within a specimen. The critical aspect in this work is using full spectral maps from each pixel within the image and subsequent processing with chemometric tools to provide integrated chemical information. This integration enables a powerful approach to more comprehensive materials characterization. Issues addressed include sample registration and beam penetration depth and how each affects post-processing. An inorganic salt and an acetaminophen pharmaceutical model mixture demonstrate the power of integrating these techniques with chemometric software.


Middle-Aged Men With HIV Have Diminished Accelerometry-Based Activity Profiles Despite Similar Lab-Measured Gait Speed: Pilot Study.
People aging with HIV are living with increased risk for functional decline compared with uninfected adults of the same age. Early preclinical changes in biomarkers in middle-aged individuals at risk for mobility and functional decline are needed. This pilot study aims to compare measures of free-living activity with lab-based measures. In addition, we aim to examine differences in the activity level and patterns by HIV status. Forty-six men (23 HIV+, 23 HIV-) currently in the MATCH (Muscle and Aging Treated Chronic HIV) cohort study wore a consumer-grade wristband accelerometer continuously for 3 weeks. We used free-living activity to calculate the gait speed and time spent at different activity intensities. Accelerometer data were compared with lab-based gait speed using the 6-minute walk test (6-MWT). Plasma biomarkers were measured and biobehavioral questionnaires were administered. HIV+ men more often lived alone (P=.02), reported more pain (P=.02), and fatigue (P=.048). In addition, HIV+ men had lower blood CD4/CD8 ratios (P<.001) and higher Veterans Aging Cohort Study Index scores (P=.04) and T-cell activation (P<.001) but did not differ in levels of inflammation (P=.30) or testosterone (P=.83). For all participants, accelerometer-based gait speed was significantly lower than the lab-based 6-MWT gait speed (P<.001). Moreover, accelerometer-based gait speed was significantly lower in HIV+ participants (P=.04) despite the absence of differences in the lab-based 6-MWT (P=.39). HIV+ participants spent more time in the lowest quartile of activity compared with uninfected (P=.01), who spent more time in the middle quartiles of activity (P=.02). Accelerometer-based assessment of gait speed and activity patterns are lower for asymptomatic men living with HIV compared with uninfected controls and may be useful as preclinical digital biomarkers that precede differences captured in lab-based measures.


Glycolytic Enzymes Localize to Synapses under Energy Stress to Support Synaptic Function.
Changes in neuronal activity create local and transient changes in energy demands at synapses. Here we discover a metabolic compartment that forms in vivo near synapses to meet local energy demands and support synaptic function in Caenorhabditis elegans neurons. Under conditions of energy stress, glycolytic enzymes redistribute from a diffuse localization in the cytoplasm to a punctate localization adjacent to synapses. Glycolytic enzymes colocalize, suggesting the ad hoc formation of a glycolysis compartment, or a "glycolytic metabolon," that can maintain local levels of ATP. Local formation of the glycolytic metabolon is dependent on presynaptic scaffolding proteins, and disruption of the glycolytic metabolon blocks the synaptic vesicle cycle, impairs synaptic recovery, and affects locomotion. Our studies indicate that under energy stress conditions, energy demands in C. elegans synapses are met locally through the assembly of a glycolytic metabolon to sustain synaptic function and behavior. VIDEO ABSTRACT.


[Effect of the economic activity of man on natural foci of plague].
Under the effect of human economic activity in the natural plague foci there occurred changes in the structures of local biocenoses. The extent and the direction of these changes were determined by the character and the scale of the economic activity. The final outcome of ploughing up, irrigation and supply with water of the vast areas is elimination of the focus or of its autonomic areas, but excessive exploitation of the desert pastures not infrequently leads to the opposite result. Large industrial construction and building of means of communications decreased the territories of the natural foci of plague only slightly, although no significant action was produced by them on the structure of biocenoses and the state of the foci.


Single muscle fiber discharge transformations: fibrillation potential to positive sharp wave.
It is presently believed that a fibrillation potential (FP) can transform into a positive sharp wave (PSW) by displaying a number of individual transitional potentials with a high degree of morphological variation between different sets of independent transformations. Clinically obtained examples of FP-to-PSW transformations and a myotonic discharge transformation are simulated by a finite fiber computer model. The simulations demonstrate that the two clinical FP-to-PSW examples may well be the result of two independent muscle fibers synchronously firing for a short period of time such that their separate waveforms summate at the electrode to create a false impression of one potential changing into another through a specific series of transitional waveforms. The transition characterized by the myotonic discharge is substantiated through modeling to define the most reasonable transitional series of waveform morphologies for a single muscle fiber. The combination of clinical examples, histological needle electrode muscle penetration studies, and simulations of single muscle fiber discharge transitions support the hypothesis that a needle recording electrode is capable of inducing a variable degree of mechanical compression with a commensurate amount of action potential blockade. The degree of action potential blockade directly contributes to the clinically observed configuration for the single muscle fiber discharge in both innervated and denervated tissues.


Tablet-Based Automatic Assessment for Early Detection of Alzheimer's Disease Using Speech Responses to Daily Life Questions.
Health-monitoring technologies for automatically detecting the early signs of Alzheimer's disease (AD) have become increasingly important. Speech responses to neuropsychological tasks have been used for quantifying changes resulting from AD and differentiating AD and mild cognitive impairment (MCI) from cognitively normal (CN). However, whether and how other types of speech tasks with less burden on older adults could be used for detecting early signs of AD remains unexplored. In this study, we developed a tablet-based application and compared speech responses to daily life questions with those to neuropsychological tasks in terms of differentiating MCI from CN. We found that in daily life questions, around 80% of speech features showing significant differences between CN and MCI overlapped those showing significant differences in both our study and other studies using neuropsychological tasks, but the number of significantly different features as well as their effect sizes from life questions decreased compared with those from neuropsychological tasks. On the other hand, the results of classification models for detecting MCI by using the speech features showed that daily life questions could achieve high accuracy, i.e., 86.4%, comparable to neuropsychological tasks by using eight questions against all five neuropsychological tasks. Our results indicate that, while daily life questions may elicit weaker but statistically discernable differences in speech responses resulting from MCI than neuropsychological tasks, combining them could be useful for detecting MCI with comparable performance to using neuropsychological tasks, which could help develop health-monitoring technologies for early detection of AD in a less burdensome manner.


[Effect of medical and social factors on quality of life of elderly inhabitants of St. Petersburg].
The study of health and social well-being of elderly inhabitants was carried out in St. Petersburg in 2004. The original questionnaire was developed and approved by the specialists of St. Petersburg City geriatric medical and social center. Using this questionnaire enables to evaluate an influence of medical and social factors on quality of life of elderly people living in mega polls. There has been discovered that the reduction of quality of life is connected not only with aged-related social and physical dependencies but with insufficient quality of healthcare and social protection system and also with reduction of availability of healthcare for elderly people in general.


Structure, function, and phylogeny of [Arg8]vasotocin receptors from teleost fish and toad.
[Arg8]Vasotocin (AVT) is considered to be the most primitive known vertebrate neurohypophyseal peptide of the vasopressin/oxytocin hormone family and may thus be ancestral to all the other vertebrate peptide hormones. The molecular evolution of the corresponding receptor family has now been studied by cloning an AVT receptor, consisting of 435 amino acid residues, from the teleost fish, the white sucker Catostomus commersoni. Frog oocytes injected with the AVT receptor-encoding cRNA respond to the application of AVT, but not to its structural and functional counterpart isotocin, by an induction of membrane chloride currents indicating the coupling of the AVT receptor to the inositol phosphate/calcium pathway. The pharmacological properties of the expressed AVT receptor show that it represents, or is closely related to, an ancestral nonapeptide receptor: oxytocin, aspargtocin, mesotocin, and vasopressin activated the receptor, but other members of the vasopressin/oxytocin family tested showed little or no potency; antagonists of the mammalian vasopressin V1 and oxytocin receptors blocked the AVT response. Comparison of AVT receptor sequences spanning transmembrane domains two to five, deduced by cloning cDNAs from the Pacific salmon Oncorhynchus kisutch, the cave-dwelling fish Astyanax fasciatus, and the anuran Xenopus laevis, with those of their mammalian counterparts emphasizes amino acid residues that are involved in hormone binding. The presence of a 5.0-kb transcript in various teleost tissues (pituitary, liver, gills, swim bladder, and lateral line) points to a physiological role for the fish AVT receptor in metabolic, osmoregulatory, and sensory processes.