Stereodivergent Biocatalytic Formal Reduction of α-Angelica Lactone to (R)- and (S)-γ-Valerolactone in a One-Pot Cascade.
The formal asymmetric and stereodivergent enzymatic reduction of α-angelica lactone to both enantiomers of γ-valerolactone was achieved in a one-pot cascade by uniting the promiscuous stereoselective isomerization activity of Old Yellow Enzymes with their native reductase activity. In addition to running the cascade with one enzyme for each catalytic step, a bifunctional isomerase-reductase biocatalyst was designed by fusing two Old Yellow Enzymes, thereby generating an unprecedented case of an artificial enzyme catalyzing the reduction of nonactivated C=C bonds to access (R)-valerolactone in overall 41 % conversion and up to 91 % ee. The enzyme BfOYE4 could be used as single biocatalyst for both steps and delivered (S)-valerolactone in up to 84 % ee and 41 % overall conversion. The reducing equivalents were provided by a nicotinamide recycling system based on formate and formate dehydrogenase, added in a second step. This enzymatic system provides an asymmetric route to valuable chiral building blocks from an abundant bio-based chemical.


Development and comprehensive evaluation of a new spring-steel-driven glove for grasping assistance during activities of daily living.
Millions of people suffer from a decline in grip strength and hand function due to conditions such as chronic disease, injuries, and aging. Hand function decline results in difficulties with performing activities of daily living, where grasping, lifting, and releasing objects are essential. There is an increasing demand for assistive gloves to enhance users' hand function and improve their independence. This paper presents the design of a new bidirectional lightweight assistive glove and demonstrates its capabilities through comprehensive experiments using human subjects. The developed glove can provide adequate power augmentation for grasping and releasing objects due to its simple yet effective design using spring steel strips and linear actuators. The glove directly transfers assistive forces to users' fingertips without any complex intermediate mechanism, and its low weight of 196 g promotes its usability. The rigorous experiment design provided a thorough assessment of the developed glove by accounting for both parameters of size and weight of objects and by including subjects with different hand sizes. To quantify the glove's performance, the subjects' muscle activity, their finger and thumb joints' trajectories, and their grasping forces while using the glove were investigated. The glove could generate the necessary grasping forces to assist with lifting common-household objects. The subjects' muscle activity significantly decreased when using the glove for object manipulation. The trajectories of the index finger and thumb joints when using the glove were dependent on the size of objects similar to natural unassisted grasping. The obtained results demonstrate the glove's ability for grip power augmentation of individuals with declining hand strength.


Orbital pseudotumour presenting as orbital cellulitis.
A 33-year-old woman presented to a community emergency department with a 4-day history of monocular orbital pain, photophobia and pain on extraocular movement. Findings included chemosis, conjunctival injection and restricted extraocular movements causing strabismus. She was diagnosed with orbital cellulitis during her initial emergency department visit and treated with intravenous antibiotics. On her second ED visit later the same day, a diagnosis of orbital pseudotumour was made after computed tomography revealed inflammation of the sclera, optic nerve, muscle and adipose tissue within the orbit. Antibiotics were discontinued and tapering steroids were initiated, with prompt resolution of symptoms.


Heme oxygenase in pregnancy and preeclampsia.
Emerging evidence supports an important role for the heme oxygenase system in the maintenance of a healthy pregnancy. This review attempts to collect these wide-ranging data and summarize the recent progress in the field. New studies looking at heme oxygenase depletion in a variety of animal models have demonstrated that the heme oxygenase system is an important regulator of placental development, particularly in vascular structure. Furthermore, emerging studies demonstrate a role for heme oxygenase in the maintenance of pregnancy, especially during pathological challenge. Intriguingly, it now appears that the heme oxygenase system can be dramatically altered by pathological disorders of pregnancy, in particular preeclampsia, perhaps functionally in the symptomatic phase of the disorder. Promisingly, however, recent data suggest that induction of the heme oxygenase system, or administration of its bioactive metabolites, could provide a promising novel therapeutic approach to the management of this currently untreatable disease. Long considered a molecular housekeeping system, the heme oxygenase system is now known to be an important stress response pathway. New evidence suggests that it is also an important player in pregnancy and preeclampsia. However, the evidence now also suggests that it may provide a therapeutic approach for this common disease with few management options.


Systematic review of cadaveric studies on anatomic posterior cruciate ligament reconstruction: the landmarks in anatomic posterior cruciate ligament reconstruction.
Recently, several new techniques for anatomic posterior cruciate ligament reconstruction (PCLR) have emerged and are believed to restore the normal anatomy of the posterior cruciate ligament more accurately. Despite the latest trend, the optimal methods for anatomic PCLR remain controversial. The purpose of this research is to review surgical techniques for PCLR in cadaver studies and suggest consistent and reproducible technical criteria. For the review of the literature, MEDLINE and EMBASE were screened for articles on anatomic PCLR. Only basic science studies on PCLR performed on human cadavers and written in English were included. Seventeen studies were included in this systematic review. Only the tunnel positions, graft types, and surgical techniques were reported in the majority of the studies. There were many variations of the reported tunnel positions, graft types, and surgical techniques among the studies. In most studies, surgical techniques for consistent and reproducible anatomic PCLR were not explained clearly. Therefore, high level medical research should be encouraged in order to establish standard surgical techniques for anatomic PCLR.


Physical activity, maternal metabolic measures, and the incidence of gallbladder sludge or stones during pregnancy: a randomized trial.
To evaluate the effect of a physical activity intervention upon the incidence of gallbladder sludge or stones during pregnancy. Pregnant women without gallstones were randomized to an intervention to increase moderate to vigorous physical activity or control. Intervention group women received motivational materials and small-group instruction to increase physical activity. Gallbladder ultrasound and blood draws were obtained at entry, 18 weeks' gestation, and 36 weeks' gestation. In all, 591 were randomized to the intervention and 605 women to control groups. Women in the intervention group reported modestly higher levels of physical activity compared with control women, and fewer women in the intervention group reported no physical activity during pregnancy. The incidence of gallbladder sludge or stones was similar in intervention and control groups at 18 weeks (4.8% versus 5.4%; relative risk 0.89; 95% confidence interval 0.53, 1.47) and 36 weeks (4.3% versus 3.3%; relative risk 1.31; 95% confidence interval 0.70, 2.54). Fasting glucose, lipid, insulin, leptin, and adiponectin levels were similar in the two groups, as was insulin sensitivity and the incidence of gestational diabetes. An intervention to increase moderate to vigorous physical activity did not decrease the incidence of gallbladder sludge or stones during pregnancy and did not result in improvement in maternal metabolic measures.


Methods to Study Mrp4-containing Macromolecular Complexes in the Regulation of Fibroblast Migration.
Multidrug resistance protein 4 (MRP4) is a member of the ATP-binding cassette family of membrane transporters and is an endogenous efflux transporter of cyclic nucleotides. By modulating intracellular cyclic nucleotide concentration, MRP4 can regulate multiple cyclic nucleotide-dependent cellular events including cell migration. Previously, we demonstrated that in the absence of MRP4, fibroblast cells contain higher levels of intracellular cyclic nucleotides and can migrate faster. To understand the underlying mechanisms of this finding, we adopted a direct yet multifaceted approach. First, we isolated potential interacting protein complexes of MRP4 from a MRP4 over-expression cell system using immunoprecipitation followed by mass-spectrometry. After identifying unique proteins in the MRP4 interactome, we utilized Ingenuity Pathway Analysis (IPA) to explore the role of these protein-protein interactions in the context of signal transduction. We elucidated the potential role of the MRP4 protein complex in cell migration and identified F-actin as a major mediator of the effect of MRP4 on cell migration. This study also emphasized the role of cAMP and cGMP as key players in the migratory phenomena. Using high-content microscopy, we performed cell-migration assays and observed that the effect of MRP4 on fibroblast migration is completely abolished by disruption of the actin cytoskeleton or inhibition of cAMP-dependent kinase A (PKA). To visualize signaling modulations in a migrating cell in real time, we utilized a FRET-based sensor for measuring PKA activity and found, the presence of more polarized PKA activity near the leading edge of migrating Mrp4(-/-) fibroblast, compared to Mrp4(+/+)fibroblasts. This in turn increased cortical actin formation and augmented the process of migration. Our approach enables identification of the proteins acting downstream to MRP4 and provides us with an overview of the mechanism involved in MRP4-dependent regulation of fibroblast migration.


[Bacteraemia due to Campylobacter fetus in an immune suppressed patient].
We report a case of bacteraemia by Campylobacter fetus subsp. fetus in a 77 year-old woman with immunosuppression secondary to steroid use. Diagnosis was suspected by finding Gram negative curved rods in blood cultures taken after 4 days of a febrile illness without local findings. Diarrhea was not present. There was no consumption of undercooked meat or non-pasteurized milk and no contact with pets. The patient was treated with sulbactam-cefoperazone due to the coexistence of urinary tract infection by multiresistant E. coli. The outcome was favorable and albeit susceptibility was not assessed, quinolone resistance was presumed because illness appeared during ciprofloxacin prophylaxis for urinary tract infection. In contrast to C. jejuni infections, C. fetus infections are associated to debilitated or immunosuppressed patients, bacteraemia is predominant, diarrhea is rarely observed and disease is not self-limited.


[Vapor extraction technology in oil contaminated soil remediation].
In order to study the Vapor Extraction Technology that can be applied to China, on the basis of mechanism analysis of Vapor Extraction Technology for oil-contaminated soil, a simplified and practical contaminant removal model to simulate the soil remediation time was presented. With the typical unsaturated soils in North of China, the effects of the vapor flow rate, soil water content and quality on the remediation process were studied. The results showed that the best value of flow velocity was existed, and water content had different influence on different kinds of soil, for silty soil, the efficiency of remediation enhanced with water content increase, but there was a reverse result for clayey soil. Through one-dimension soil column experiments, the results showed that these factors had different effects on remediation time. The research using the soil column apparatus show that the predicted results were validated and the applied conditions of this model were qualified.


Effect of brevetoxin-B on the neuromuscular transmission of the mouse diaphragm.
The effects of brevetoxin-B, a polyether toxin isolated from Gymnodinium breve Davis, on neuromuscular transmission were studied on the mouse hemidiaphragm using general pharmacological and electrophysiological methods. Brevetoxin-B initially induced spontaneous muscle twitching followed by complete paralysis of the indirectly elicited twitch tension of the mouse diaphragm. The directly elicited muscle twitch tension was not affected and the compound action potential of the phrenic nerve could still be recorded when neuromuscular transmission was completely blocked by the toxin. Brevetoxin-B initially increased, but then decreased, the antidromic activity of the phrenic nerve. Brevetoxin-B increased the frequency of miniature endplate potentials (MEPP), while it decreased the muscle membrane potential. Application of tetrodotoxin (TTX) completely abolished the increase in MEPP frequency and the depolarization of the muscle membrane potential. The results suggested that brevetoxin-B may affect the sodium channels in the nerve terminal and muscle membrane.


Antecedents of elderly home residency in cognitive healthy elders: a qualitative study.
Admission to elderly homes brings with itself fear of losing home and many other mental consequences to both the elder and family members. The aim of this study was to explore the experiences of elders about factors influencing living in the elderly home. Using a qualitative design, 14 elder people living in elderly homes were chosen through purposive sampling based on defined criteria. Semi-structured interviews were held with the participants and field noting was taken during the interviews. Collected data was analyzed using thematic analysis, which resulted in the development of three main themes: "basic Predictors", "self-care crisis", and "role crisis", which were consisted of a couple of subthemes. We conclude that nurses to better care in community and elderly homes, need to know that living in elderly homes has universal predictors; Of course their weight and position are different on different contexts.


Draft Genome Resource for Forest Pathogen Coniferiporia weirii - A Facultative Pathogen of Thuja plicata and Callitropsis nootkatensis.
In North America, Coniferiporia weirii causes root and butt rot of western redcedar (Thuja plicata) and yellow-cedar (Callitropsis nootkatensis). There is currently no draft genome for C. weirii. As a result, C. weirii isolate 30910 originally isolated from a Thuja plicata in Idaho, U.S.A., was sequenced using an Illumina HiSeq 3000 sequencing system. The genome was assembled into 24,918 scaffolds with a scaffold N50 length of 53,821 bp. The total size of the genome was estimated to be 42.2 Mb. This included 96% and 95% recovery of basidiomycete complete and single-copy BUSCO genes, respectively. A total of 3.2% of the assessed BUSCO genes were missing and were not recovered. The assembly contained 10,351 predicted protein-coding genes. The estimated mean gene length of the predicted genes was 1,911 bp. While much is known about the biology of this fungus, little is known about its genome. This draft genome provides a baseline resource that will help further understand the population structure, reproductive mode, and evolutionary history of this important forest pathogen.


Perilymphatic fistula--the value of diagnostic tests.
Perilymphatic fistula (PLF) remains one of the most challenging problems in otological practice. Fifty-two consecutive patients (53 ears) who underwent explorative tympanotomy for suspected PLF between 1985-1992 were included in this study. The clinical picture, history, patients' complaints and laboratory tests were analysed and compared with the operative findings. The conclusions of our work are that the diagnosis of PLF is based mostly on the clinical picture and a battery of laboratory diagnostic tests, but no one test is truly diagnostic for PLF.


Delayed cutaneous hypersensitivity: epidemiologic factors affecting and usefulness in predicting diarrheal incidence in young Peruvian children.
Cell-mediated immunity, as assessed by delayed cutaneous hypersensitivity, can be diminished by malnutrition and viral infections. In turn, decreased immune functioning might lead to more frequent or more severe infectious diseases. Delayed cutaneous hypersensitivity was assessed in young Peruvian children by simultaneous application of seven standardized antigens and a negative control (Multitest CMI). Response to tuberculin was frequent and was higher in children vaccinated with Bacillus Calmette-Guérin, response to tetanus or diphtheria toxoids was also good, especially in children who had received at least two doses of diphtheria-tetanus toxoids-pertussis vaccine. Two summary assessments, the number of positive responses and the sum of indurations of all positive responses provided useful measures of delayed cutaneous hypersensitivity. Responsiveness, as assessed by these summary measures, was inversely related to the incidence of diarrhea, identified by household surveillance for the 6 months after the skin test. Undernutrition, as assessed by weight for age or length for age, was also a significant determinant of the incidence of diarrhea, but not the duration of episodes, in this group of study children. Depressed cell-mediated immunity and malnutrition may be important risk factors for diarrhea in developing country children.


Reduction of pertechnetate by acetohydroxamic acid: formation of [TcII(NO)(AHA)2(H2O)]+ and implications for the UREX process.
Reductive nitrosylation and complexation of ammonium pertechnetate by acetohydroxamic acid has been achieved in aqueous nitric and perchloric acid solutions. The kinetics of the reaction depend on the relative concentrations of the reaction components and are accelerated at higher temperatures. The reaction does not occur unless conditions are acidic. Analysis of the X-ray absorption fine structure spectroscopic data is consistent with a pseudo-octahedral geometry and the linear Tc-N-O bond typical of technetium nitrosyl compounds, and electron spin resonance spectroscopy is consistent with a d (5) Tc(II) nitrosyl complex. The nitrosyl source is generally AHA, but it may be augmented by some products of the reaction with nitric acid. The resulting low-valency trans-aquonitrosyl(diacetohydroxamic)-technetium(II) complex ([Tc (II)(NO)(AHA) 2H 2O] (+), 1) is highly soluble in water, extremely hydrophilic, and is not extracted by tri- n-butylphosphate in a dodecane diluent. Its extraction properties are not pH-dependent: potentiometric-spectrophotometric titration studies indicate a single species from pH 4 down to -0.6 (calculated). This molecule is resistant to oxidation by H 2O 2, even at high pH, and can undergo substitution to form other technetium nitrosyl complexes. The potential formation of 1 during reprocessing may strongly impact the fate of technetium in the nuclear fuel cycle.


Long-term effect of exercise training in patients after transcatheter aortic valve implantation: Follow-up of the SPORT:TAVI randomised pilot study.
Background Increased exercise capacity favourably influences clinical outcomes after transcatheter aortic valve implantation. In our SPORT:TAVI randomised pilot trial, eight weeks of endurance and resistance training (training group, TG) shortly after transcatheter aortic valve implantation resulted in significantly improved exercise capacity, muscular strength and quality of life compared to usual care (UC). However, the long-term clinical benefits of such an intervention are unknown. Design A randomised controlled trial. Methods SPORT:TAVI participants underwent reassessment of trial endpoints 24 ± 6 months after baseline: maximal oxygen uptake (VO2peak) and anaerobic threshold (VO2AT) were assessed with cardiopulmonary exercise testing, muscular strength with one-repetition maximum testing, quality of life with the Kansas City cardiomyopathy and medical outcomes study 12-item short-form health survey questionnaires, and prosthetic aortic valve function with echocardiography. Results Of 27 original participants (TG 13; UC 14; age 81 ± 6 years), more patients had died during follow-up in UC ( n = 5) than in TG ( n = 2; P = 0.165); three further patients (TG 1; UC 2) were unavailable for other reasons. In the remaining patients (TG 10; UC 7), a significant between-group difference in favour of TG was observed for change in VO2AT from baseline (2.7 ml/min/kg (95% confidence interval 0.8-4.6); P = 0.008), but not for change in VO2peak (2.1 ml/min/kg (-1.1-5.4); P = 0.178). Changes in muscular strength and quality of life did not differ between groups over time. Overall, prosthetic valve function remained intact in both groups. Conclusions Eight weeks of exercise training shortly after transcatheter aortic valve implantation resulted in preserved long-term improvements in VO2AT, but not VO2peak, muscular strength or quality of life compared to usual care. The findings emphasise the importance of ongoing exercise interventions following transcatheter aortic valve implantation to maintain initial improvements long term. Clinical Trial Registration (original trial): Clinicaltrials.gov NCT01935297.


Perioperative Challenges in Repeat Bladder Exstrophy Repair - Case Report.
Bladder exstrophy is a rare congenital malformation. It presents as leakage of urine in the anterior abdominal wall following defects in midline anterior abdominal wall skin and bladder. We report the use of combined general anaesthesia and caudal epidural analgesia in a 4yr old boy for repeat bladder exstrophy repair. Problems of prolonged surgery and the challenges of pain and sedation management in the post operative period are discussed.


Possible involvement of nitric oxide synthase in oxidative stress-induced endothelial cell injury.
The purpose of this study was to characterize the protective effect of NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase, on oxidative stress-induced endothelial cell injury. Intracellular oxidative stress was induced by 1-chloro-2,4-dinitrobenzene, a glutathione (GSH) depleting agent, and the leakage of intracellular lactate dehydrogenase was measured as a marker of cell injury. Addition of 1-chloro-2,4-dinitrobenzene (100-500 microM) induced leakage of lactate dehydrogenase from endothelial cells, and the leakage of lactate dehydrogenase was strongly attenuated by L-NAME, but not by NG-methyl-L-arginine, also an inhibitor of nitric oxide synthase. However, cell injury induced by the Ca2+ ionophore ionomycin was not affected by L-NAME or NG-methyl-L-arginine. Moreover, neither L-NAME nor NG-methyl-L-arginine affected GSH depleting agent-induced or H2O2-induced cell injury in a rat foetal lung fibroblast cell line which lacks nitric oxide synthase. These results suggest that the protective effect of L-NAME is likely to be related to nitric oxide synthase, while the inhibition of nitric oxide production may not be involved in the protective effect of L-NAME, since NG-methyl-L-arginine did not affect endothelial cell injury.


[A cross-sectional survey of blindness and low vision among adults aged 60 years and above in Xinchengqiao Blocks, Nantong].
To investigate the prevalence and causes of blindness and low vision among adults aged > or = 60 years in the urban population of Nantong. Cluster sampling was used to select 8 from 14 communities in Xinchengqiao Blocks, in which all individuals aged > or = 60 years were visited. The visual acuity without correction and the presenting acuity with the participants' habitual distance correction were measured separately for each eye. In individuals with visual acuity less than 0.6, pinhole visual acuity was tested with pinhole spectacle. External eye, anterior segment and ocular fundus were examined by the ophthalmologist using a slit lamp-microscope and direct ophthalmoscopy. The survey was preceded by a pilot study. Of 3352 enumerated subjects, 3040 individuals participated in this survey (90.69% response rate). According to pinhole visual acuity and World Health Organization (WHO) visual impairment criterion (blindness: less than 0.05 in the better eye; low vision: less than 0.3 to 0.05 in the better eye), the prevalence of blindness and low vision was 1.35% and 1.84% respectively. The prevalence of blindness and low vision for females were 1.92% and 2.33%, respectively, which were differenced from that in males (0.66% and 1.24%, respectively). The prevalence of blindness and low vision increased with age. The survey showed that the most important cause leading to blindness and low vision was cataract. According to the presenting visual acuity and visual impairment criterion (blindness: less than 0.1 in both eyes), the prevalence of blindness and visual impairment was 1.58% and 13.59%, respectively, 2.10% and 15.98% in females and 0.95% and 10.66% in males, respectively. The prevalence of blindness and visual impairment was raised with increasing age. Cataract was also the leading cause for blindness. The prevalence of blindness in the Nantong area was lower than that in northern, southern and western China. Females and illiteracy were more likely to have blindness and low vision than that of males and literate. The leading causes of blindness in Nantong are, in descending sequence, cataract, ocular fundus diseases, ametropia and corneal scar/opacity.


Regulation of equine infectious anemia virus expression.
Equine infectious anemia virus (EIAV) is an ungulate lentivirus that is related to human immunodeficiency virus (HIV). Much of the understanding of lentiviral gene regulation comes from studies using HIV. HIV studies have provided insights into molecular regulation of EIAV expression; however, much of the regulation of EIAV expression stands in stark contrast to that of HIV. This review provides an overview of the current state of knowledge of EIAV regulation by comparing and contrasting EIAV gene regulation to HIV. The role of EIAV gene regulation is discussed in relation to EIAV pathogenesis.


[A Case of Pathological Complete Response Induced by Preoperative Gemcitabine plus S-1 with Concurrent Radiation Therapy Followed by Gemcitabine plus S-1 Therapy in Borderline Resectable Pancreatic Cancer].
The patient was a 69-year-old man. He visited our hospital with a complaint of right back pain. An abdominal CT scan confirmed a hypovascular mass 35 mm in diameter in the pancreatic head. He was diagnosed with pancreatic head cancer (cT3, cN0, cM0, cStage ⅡA, borderline resectable-A). Gemcitabine plus S-1(GS)-based chemoradiation therapy(CRT) was performed, followed by 6 courses of GS therapy. Tumor markers were almost normalized, and subtotal stomach-preserving pancreaticoduodenectomy was performed. Histopathological examination of the resected specimen revealed highly atrophic pancreatic tissue with fibrosis and no evidence of residual cancer cells (pathological complete response). The patient remains disease-free 36 months after surgery. There are few reports of pancreatic cancer with pCR after GS-based chemoradiation therapy and subsequent GS therapy. We therefore report this case together with a review of the literature.


Hepatitis B and C virus infections in patients with hemophilia in Zahedan, southeast Iran.
To determine the prevalence of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections in patients with hemophilia in Zahedan, Iran. From March 2003 to January 2006, we evaluated 81 hemophiliac patients in Zahedan Hemophilia Center, southeast Iran, for hepatitis C virus antibody (HCV-Ab) and hepatitis B surface antigen (HBsAg), and evaluated the prevalence of HBV/HCV co-infection. The seroprevalence of HCV was 29.6%, and the HBsAg was positive in 4.9%. Four cases had HCV and HBV co-infection. All of the infected patients were unknowingly treated with contaminated plasma products before the middle of 1996. All hemophiliacs, especially patients who have been treated with unheated clotting factor concentrates, should be evaluated for HCV and HBV infections.


Small molecules keep mitotic kinases in check.
The remarkable progress in the discovery of small molecules that target protein kinases continues, and two recent reports have described alternative approaches to this task: homology modeling and phenotype-based screening. Compounds targeting the nucleotide binding pockets of polo-like kinases in particular provide significant new insights into the molecular mechanisms controlling cell-division phenotypes.


Elevated glucose increases genomic instability by inhibiting nucleotide excision repair.
We investigated potential mechanisms by which elevated glucose may promote genomic instability. Gene expression studies, protein measurements, mass spectroscopic analyses, and functional assays revealed that elevated glucose inhibited the nucleotide excision repair (NER) pathway, promoted DNA strand breaks, and increased levels of the DNA glycation adduct N 2 -(1-carboxyethyl)-2'-deoxyguanosine (CEdG). Glycation stress in NER-competent cells yielded single-strand breaks accompanied by ATR activation, γH2AX induction, and enhanced non-homologous end-joining and homology-directed repair. In NER-deficient cells, glycation stress activated ATM/ATR/H2AX, consistent with double-strand break formation. Elevated glucose inhibited DNA repair by attenuating hypoxia-inducible factor-1α-mediated transcription of NER genes via enhanced 2-ketoglutarate-dependent prolyl hydroxylase (PHD) activity. PHD inhibition enhanced transcription of NER genes and facilitated CEdG repair. These results are consistent with a role for hyperglycemia in promoting genomic instability as a potential mechanism for increasing cancer risk in metabolic disease. Because of the pleiotropic functions of many NER genes beyond DNA repair, these results may have broader implications for cellular pathophysiology.


Effectiveness of patching traumatic eardrum perforations with lens cleaning paper via an otoscope.
To study the clinical effect of lens cleaning paper patching on traumatic eardrum perforations. A total of 122 patients were divided into 2 groups, of which 56 patients were treated with lens cleaning paper patching and 66 acted as controls. The closure rate and healing time were compared between the two groups. The healing rate of small perforations was 96.4 per cent (27 out of 28) in the patching group and 90 per cent (27 out of 30) in the control group. The difference was not statistically significant (p > 0.05). The healing rate of large perforations was 89.3 per cent (25 out of 28) and 80.6 per cent (29 out of 36) in the two groups, respectively. The difference was statistically significant (p < 0.05). The healing time of large perforations was shorter in the patching group than in the control group (p < 0.01). Patching with lens cleaning paper under an endoscope can accelerate the closure of large traumatic eardrum perforations.


Futility Risk Model for Predicting Outcome After Transcatheter Aortic Valve Implantation.
Risk-benefit assessment for transcatheter aortic valve implantation (TAVI) is still a matter of debate. We aimed to identify patients with a bad outcome within 1 year after TAVI, and to develop a Futile TAVI Simple score (FTS). Based on the administrative hospital-discharge database, all consecutive patients treated with percutaneous TAVI in France between 2010 and 2018 were included. A prediction model was derived and validated for 1-year all-cause death after TAVI (considered as futility) by using split-sample validation: 20,443 patients were included in the analysis (mean age 83 ± 7 years). 7,039 deaths were recorded (yearly incidence rate 15.5%), among which 3,702 (53%) occurred in first year after TAVI procedure. In the derivation cohort (n = 10,221), the final logistic regression model included male sex, history of hospital stay with heart failure, history of pulmonary oedema, atrial fibrillation, previous stroke, vascular disease, renal disease, liver disease, pulmonary disease, anaemia, history of cancer, metastasis, depression and denutrition. The area under the curve (AUC) for the FTS was 0.674 (95%CI 0.660 to 0.687) in the derivation cohort and 0.651 (95%CI 0.637 to 0.665) in the validation cohort (n = 10,222). The Hosmer-Lemeshow test had a p-value of 0.87 suggesting an accurate calibration. The FTS score outperformed EuroSCORE II, Charlson comorbidity index and frailty index for identifying futility. Based on FTS score, 7% of these patients were categorized at high risk with a 1-year mortality at 43%. In conclusion, the FTS score, established from a large nationwide cohort of patients treated with TAVI, may provide a relevant tool for optimizing healthcare decision.


An evaluation of REACTMH mental health training for healthcare supervisors.
Healthcare workers (HCWs) are vulnerable to developing mental ill-health. Prior research has shown those in managerial or supervisory positions have pivotal roles in creating a healthy work environment, as well as recognizing and supporting HCWs with mental health symptoms to improve occupational outcomes and reduce sickness absence. To evaluate the effectiveness of active listening skills training (REACTMH) for UK healthcare managers. Managers of HCWs were voluntarily enrolled on a REACTMH active listening skills training package. Attendees anonymously completed questionnaires before and immediately after attending the 1-h remote training session and again 1 month later. The questionnaire asked about confidence in recognizing, conversing with and supporting distressed colleagues as well as perceived usefulness and importance of the training and how often they had used the taught active listening skills. Fifty-eight healthcare managers enrolled onto the REACTMH programme in July 2020 and 32 (55%) completed the 1-month follow-up. Just less than half reported feeling confident in being able to identify, speak to and support potentially distressed staff before the training; significantly more (>80%) reported feeling confident 1 month afterwards (P < 0.001). Around three-quarters of attendees reported the REACTMH programme as highly useful, highly important and said they had frequently used the learned skills. A brief active listening skills training package was associated with significant improvements healthcare manager's confidence in recognizing, speaking with and supporting HCWs with suspected mental health conditions. Further research is needed to investigate the longer term effectiveness and acceptability of REACTMH training.


Combination of ferric ammonium citrate with cytokines involved in apoptosis and insulin secretion of human pancreatic beta cells related to diabetes in thalassemia.
Diabetes mellitus (DM) is a common complication found in β-thalassemia patients. The mechanism of DM in β-thalassemia patients is still unclear, but it could be from an iron overload and increase of some cytokines, such as interleukin1-β (IL-1β) and tumor necrosis factor-α (TNF-α). The objective of this study was to study the effect of interaction between ferric ammonium citrate (FAC) and cytokines, IL-1β and TNF-α, on 1.1B4 human pancreatic β-cell line. The effect of the combination of FAC and cytokines on cell viability was studied by MTT assay. Insulin secretion was assessed by the enzyme-linked immunosorbent assay (ELISA). The reactive oxygen species (ROS) and cell apoptosis in normal and high glucose condition were determined by flow cytometer. In addition, gene expression of apoptosis, antioxidant; glutathione peroxidase 1 (GPX1) and superoxide dismutase 2 (SOD2), and insulin secretory function were studied by real-time polymerase chain reaction (Real-time PCR). The findings revealed that FAC exposure resulted in the decrease of cell viability and insulin-release, and the induction of ROS and apoptosis in pancreatic cells. Interestingly, a combination of FAC and cytokines had an additive effect on SOD2 antioxidants' genes expression and endoplasmic reticulum (ER) stress. In addition, it reduced the insulin secretion genes expression; insulin (INS), glucose kinase (GCK), protein convertase 1 (PSCK1), and protein convertase 2 (PSCK2). Moreover, the highest ROS and the lowest insulin secretion were found in FAC combined with IL-1β and TNF-α in the high-glucose condition of human pancreatic beta cell, which could be involved in the mechanism of DM development in β-thalassemia patients.


Effect of orally administered tramadol alone or with an intravenously administered opioid on minimum alveolar concentration of sevoflurane in cats.
OBJECTIVE-To compare the effect of oral administration of tramadol alone and with IV administration of butorphanol or hydromorphone on the minimum alveolar concentration (MAC) of sevoflurane in cats. DESIGN-Crossover study. ANIMALS-8 Healthy 3-year-old cats. PROCEDURES-Cats were anesthetized with sevoflurane in 100% oxygen. A standard tail clamp method was used to determine the MAC of sevoflurane following administration of tramadol (8.6 to 11.6 mg/kg [3.6 to 5.3 mg/lb], PO, 5 minutes before induction of anesthesia), butorphanol (0.4 mg/kg [0.18 mg/lb], IV, 30 minutes after induction), hydromorphone (0.1 mg/kg [0.04 mg/lb], IV, 30 minutes after induction), saline (0.9% NaCl) solution (0.05 mL/kg [0.023 mL/lb], IV, 30 minutes after induction), or tramadol with butorphanol or with hydromorphone (same doses and routes of administration). Naloxone (0.02 mg/kg [0.009 mg/lb], IV) was used to reverse the effects of treatments, and MACs were redetermined. RESULTS-Mean +/- SEM MACs for sevoflurane after administration of tramadol (1.48 +/- 0.20%), butorphanol (1.20 +/- 0.16%), hydromorphone (1.76 +/- 0.15%), tramadol and butorphanol (1.48 +/- 0.20%), and tramadol and hydromorphone (1.85 +/- 0.20%) were significantly less than those after administration of saline solution (2.45 +/- 0.22%). Naloxone reversed the reductions in MACs. CONCLUSIONS AND CLINICAL RELEVANCE-Administration of tramadol, butorphanol, or hydromorphone reduced the MAC of sevoflurane in cats, compared with that in cats treated with saline solution. The reductions detected were likely mediated by effects of the drugs on opioid receptors. An additional reduction in MAC was not detected when tramadol was administered with butorphanol or hydromorphone.


Isolation and characterization of a cysteine protease of freesia corms.
A protease, freesia protease (FP)-A, was purified to electrophoretic homogeneity from regular freesia (Freesia reflacta) corms in harvest time. The Mr of FP-A was estimated to be 24 k by SDS-PAGE. The optimum pH of the enzyme was 8.0 using a casein substrate. These enzymes were strongly inhibited by p-chloromercuribenzoic acid but not by phenylmethane-sulfonylfluoride and EDTA. These results indicate that FP-A belongs to the cysteine proteases. The amino terminal sequence of FP-A was similar to that of papain, and the sequences was regarded to the conservative residues of cysteine protease. From the hydrolysis of peptidyl-p-NAs, the specificity of FP-A was found to be broad. It was thought that FP-A was a new protease from freesia corms.


Toxinotyping of necrotic enteritis-producing and commensal isolates of Clostridium perfringens from chickens fed organic diets.
The present study determined the effect of Clostridium perfringens isolates taken from necrotic enteritis (NE) outbreaks on organic farms in a NE virulence testing model. Thirteen strains were isolated in the course of the study. Six C. perfringens field isolates were taken from a naturally occurring NE outbreak on an organic farm. Polymerase chain reaction toxinotyping was used to establish C. perfringens strains, as well as to create a toxin profile. All field isolates were found to be type A and positive for alpha, beta-2 and netB toxin genes. During the NE virulence model, digesta samples were collected before oral inoculation to define the C. perfringens found as part of the natural flora. Three of the five natural flora isolates were found to be C. perfringens type E while the other two isolates were type A; only four of five isolates were positive for either netB or beta-2 toxin genes. Two isolates collected after inoculation were C. perfringens type A positive for cpb2 and netB. All isolates were tested positive for the quorum-sensing-related gene luxS, regardless of the strain source. The presence of luxS, alpha, netB and beta-2 toxin genes seems not to be a determinant of the disease as they were present in isolates from both outbreak birds as well as healthy and pre-inoculated birds. The C. perfringens field isolates induced mild NE lesions in one-half of the birds during the challenge study. Other mechanisms must play a role in the development of the disease beyond toxinotype, potentially including intestinal ecology and health, which would account for acute disease as seen in the field outbreak.


Venlafaxine ER as a treatment for generalized anxiety disorder in older adults: pooled analysis of five randomized placebo-controlled clinical trials.
Concerns about the safety of benzodiazepines in older adults may have led investigators and clinicians to underestimate the importance of adequately treating generalized anxiety disorder (GAD) in later life. To evaluate the safety and efficacy profile of an alternative treatment in older patients, we conducted a secondary analysis of five randomized, placebo-controlled clinical trials of extended release venlafaxine (venlafaxine ER, Effexor XR) for adult patients with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) diagnosis of GAD. The five multicenter, parallel-group, double-blind, prospectively randomized, placebo-controlled clinical trials used similar designs to evaluate short-term efficacy after 8 weeks. In addition, two studies evaluated efficacy and safety over 24 weeks under double-blind conditions. Outpatients from both primary care and specialty mental healthcare settings were included. Three studies were conducted in the United States and two in Europe. Intention-to-treat analyses included 1,839 adult outpatients with a DSM-IV diagnosis of GAD and total scores of > or =18 on the Hamilton Rating Scale for Anxiety (HAMA). Ten percent of the patients were aged 60 and older and 5.0% were aged 65 and older. Fixed or flexible doses of venlafaxine ER in the dose range of 37.5 to 225 mg/day or matched placebo were used for 8 weeks in all studies and for 24 weeks in two studies. Primary efficacy variables included the HAMA total score and psychic anxiety factor, the anxiety subscale of the Hospital Anxiety and Depression (HAD) Scale, and the Clinical Global Impression of Improvement (CGI-I). Secondary efficacy variables included the HAMA somatic anxiety factor, the depression subscale of the HAD, CGI-3 severity, the Covi Scale for Anxiety, and the Raskin Scale for Depression. On the CGI, 66% of older patients (> or =60 years) responded to venlafaxine ER, compared with 41% for placebo (P <.01 by logistic regression). For younger patients (<60 years), comparable figures were 67% and 44%, respectively (P <.001). Analysis of variance showed no main effects for age and no age-by-treatment interactions for any of the primary or secondary efficacy outcome measures for either the 8- or 24-week analyses. Within the older adults subgroup, increasing age did not influence responses. In this cohort of GAD patients, higher levels of depression were associated with decreased responses of anxiety symptoms. In older adults, 23% of venlafaxine ER patients discontinued treatment prematurely versus 31% of those who received placebo; comparable figures for younger adult patients were 27% and 28%, respectively. Discontinuations due to adverse events were 15% versus 14% for venlafaxine ER and placebo, respectively, in older adults compared with 15% versus 8%, respectively, for younger adults. Venlafaxine ER is equally safe and well tolerated by and shows similar efficacy in younger and older patients in the treatment of GAD.


[Determination and status quo survey of phathalic acid esters in air of plastic production logistics by GC-MS].
To establish GC-MS method for the determination of phathalic acid esters (PAEs) in the air of plastic production logistics, and conduct a status quo survey of PAEs pollution in occupational environments basing on it. The determination method was established according to the Monitor Investigating Guidelines on Poisons in Workplace Air, and then used to determine samples collected to carry out an on-the-spot investigation. Calibration curves of the six PAEs were proved to be all linear in the range of 2-1000 ng/ml, equivalent to 0.67-333 microg/m3 in the air considering 3 L air sample was collected. The sensitivities were high with all limits of detection lower than 1 ng/ml, i.e., the minimum detectable concentrations of the six PAEs were all lower than 0.33 microg/m3. Intra-day precision and accuracies were all good, with relative standard deviation in the range of 3.0%-7.8% and recoveries in the range of 93.1%-105.1% respectively. And inter-day precision and accuracies were 3.4%-9.9% and 93.4%-106.4% correspondingly. The eluting efficiency was 92.9%-97.9%, and the sampling efficiencies were nearly 100%. The breakthrough capacities were all larger than 1.4 mg. And samples could be stored stably at room temperature for 7 days. The selectivity of this method was good. Results of status quo survey indicated that the PAEs pollution in the air of plastic production logistics was not serious, and no obvious clinical symptoms and signs were found in those occupationally-exposed workers. This method meets the demand of the Monitor Investigating Guidelines on Poisons in Workplace Air, and thus then could be applied to determine PAEs in the air of plastic production logistics.


High precision measurement of the superallowed 0+ --> 0+ beta decay of 22Mg.
The half-life, 3.8755(12) s, and superallowed branching ratio, 0.5315(12), for 22Mg beta decay have been measured with high precision. The latter depended on gamma-ray intensities being measured with an HPGe detector calibrated for relative efficiencies to an unprecedented 0.15%. Previous precise measurements of 0+ --> 0+ transitions have been restricted to the nine that populate stable daughter nuclei. No more such cases exist, and any improvement in a critical Cabibbo-Kobayashi-Maskawa unitarity test must depend on precise measurements of more exotic nuclei. With this branching-ratio measurement, we show those to be possible for T(z)=-1 parents. We obtain a corrected Ft value of 3071(9) s, in good agreement with expectations.


Lessons from management of syphilis in Nunavut, Canada, 2012-2020.
Nunavut, part of Inuit Nunangat, is a geographically vast territory in northern Canada, with a population of over 38,000 people. Most (85%) of the population identify as Inuit. Nunavut has experienced a significant rise in heterosexual infectious syphilis cases since 2012. Management of communicable diseases, including syphilis, is challenging due to high staff turnover and long delays in specimen transport times. Social determinants of health are also an important contributor. The aim of this study is to describe the epidemiology and program elements for infectious syphilis from 2012-2020 and to highlight beneficial interventions. Syphilis is a notifiable disease in Nunavut with all cases reported to the Territorial Department of Health. Cases were staged by a medical consultant. Data were analyzed and released in public reports as part of the public health program. From 2012 to 2020, 655 infectious syphilis cases were reported, with 53% of reported cases among females. Infection rates were highest in 20 to 39-year-olds. There was significant variability in reported cases over this time period by geographic region, with the majority of infectious cases reported from the Kivalliq region. Despite 48 reported cases in pregnancy, no confirmed congenital syphilis cases were identified. Program staff identified strengths of the response as well as ongoing needs, such as plain language resources available in multiple languages. Despite the logistical challenges with syphilis management in the territory, the overall outcomes have been positive, with no confirmed congenital cases identified. We attribute this to a coordinated effort by multiple partners including key actions by public health nurses and community health representatives.


Recent Advances in Ring-Opening Functionalization of Cycloalkanols by C-C σ-Bond Cleavage.
Cycloalkanols prove to be privileged precursors for the synthesis of distally substituted alkyl ketones and polycyclic aromatic hydrocarbons (PAHs) by virtue of cleavage of their cyclic C-C bonds. Direct functionalization of cyclobutanols to build up other chemical bonds (e. g., C-F, C-Cl, C-Br, C-N, C-S, C-Se, C-C, etc.) has been achieved by using the ring-opening strategy. Mechanistically, the C-C cleavage of cyclobutanols can be involved in two pathways: (a) transition-metal catalyzed β-carbon elimination; (b) radical-mediated 'radical clock'-type ring opening. The recent advances of our group for the ring-opening functionalization of tertiary cycloalkanols are described in this account.


[The general methodological approaches identifying strategic positions in developing healthy lifestyle of population].
The article deals with analysis of national and international publications concerning methodological aspects of elaborating systematic approach to healthy life-style of population. This scope of inquiry plays a key role in development of human capital. The costs related to healthy life-style are to be considered as personal investment into future income due to physical incrementation of human capital. The definitions of healthy life-style, its categories and supportive factors are to be considered in the process of development of strategies and programs of healthy lifestyle. The implementation of particular strategies entails application of comprehensive information and educational programs meant for various categories of population. Therefore, different motivation techniques are to be considered for children, adolescents, able-bodied population, the elderly. This approach is to be resulted in establishing particular responsibility for national government, territorial administrations, health care administrations, employers and population itself. The necessity of complex legislative measures is emphasized. The recent social hygienic studies were focused mostly on particular aspects of development of healthy life-style of population. Hence, the demand for long term exploration of development of organizational and functional models implementing medical preventive measures on the basis of comprehensive information analysis using statistical, sociological and professional expertise.


Toluene diisocyanate exposures in the flexible polyurethane foam industry.
A 3-year survey of toluene diisocyanate exposure in two flexible polyurethane foam manufacturing facilities has been conducted. The geometric mean time-weighted average exposures were 2.36 ppb, 1.10 ppb, and 1.50 ppb for the foam line workers, finishing workers, and maintenance personnel, respectively. The OSHA ceiling standard of 20 ppb was exceeded by 1.3% of the short-term (12 min) exposure measurements taken. Exposures were shown to be predominantly to the 2,6 isomer of TDI.


Heterochronic Pellet Assay to Test Cell-cell Communication in the Mouse Retina.
All seven retinal cell types that make up the mature retina are generated from a common, multipotent pool of retinal progenitor cells (RPCs) (Wallace, 2011). One way that RPCs know when sufficient numbers of particular cell-types have been generated is through negative feedback signals, which are emitted by differentiated cells and must reach threshold levels to block additional differentiation of that cell type. A key assay to assess whether negative feedback signals are emitted by differentiated cells is a heterochronic pellet assay in which early stage RPCs are dissociated and labeled with BrdU, then mixed with a 20-fold excess of dissociated differentiated cells. The combined cells are then re-aggregated and cultured as a pellet on a membrane for 7-10 days in vitro. During this time frame, RPCs will differentiate, and the fate of the BrdU+ RPCs can be assessed using cell type-specific markers. Investigators who developed this pellet assay initially demonstrated that neonatal RPCs give rise to rods on an accelerated schedule compared to embryonic RPCs when the two cell types are mixed together (Watanabe and Raff, 1990; Watanabe et al., 1997). We have used this assay to demonstrate that sonic hedgehog (Shh), which we found acts as a negative regulator of retinal ganglion cell (RGC) differentiation, promotes RPC proliferation (Jensen and Wallace, 1997; Ringuette et al., 2014). More recently we modified the heterochronic pellet assay to assess the role of feedback signals for retinal amacrine cells, identifying transforming growth factor β2 (Tgfβ2) as a negative feedback signal, and Pten as a modulator of the Tgfβ2 response (Ma et al., 2007; Tachibana et al., 2016). This assay can be adapted to other lineages and tissues to assess cell-cell interactions between two different cell-types (heterotypic) in either an isochronic or heterochronic manner.


1-D simulation of a novel nonvolatile resistive random access memory device.
The operation of a novel, nonvolatile memory device based on a conductive ferroelectric/semiconductor thin film multilayer stack is simulated numerically. The simulation involves the self-consistent steady-state solution of the transport equation for electrons assuming a drift-diffusion transport mechanism and the Poisson equation. Special emphasis is put on the screening of the spontaneous polarization by conduction electrons as a function of the applied voltage. Depending on the orientation of the polarization in the ferroelectric layer, a high and a low resistive state are found, giving rise to a hysteretic I-V characteristic. The switching ratio, ranging from > 50% to several orders of magnitude, is calculated as a function of the dopant content. The suggested model provides one possible physical explanation of the I-V hysteresis observed for single-layer ferroelectric devices, if interfacial layers are taken into consideration. The approach will allow one to develop guidelines to improve the performance of these devices.


Assuming the mantle of leadership: issues and challenges for directors of nursing.
This ethnographic study investigated leadership from the perspective of directors of nursing (DONs) in proprietary nursing homes. Data from interviews and extensive participant observation with 10 DONs were analyzed using open coding and content analysis. The study drew on a priori concepts from transformational leadership theory to describe the role, DON approaches to leadership, and factors that facilitate or impede leadership in nursing homes. This article reports findings from a larger study related to conditions existing when participants entered the DON position. Antecedent conditions influenced organizational expectations of incoming DONs and shaped participants' leadership experiences. DONs filling long-standing vacancies had to reestablish the influence and authority of the role. Those replacing unsuccessful DONs confronted serious regulatory, care, and morale issues. In contrast, DONs with successful predecessors experienced organizational support and had confidence in their abilities to lead.


Noncollinear paramagnetism of a GaAs two-dimensional hole system.
We have performed transport measurements in tilted magnetic fields in a two-dimensional hole system grown on the surface of a (311)A GaAs crystal. A striking asymmetry of Shubnikov-de Haas oscillations occurs upon reversing the in-plane component of the magnetic field along the low-symmetry [2[over ¯]33] axis. As usual, the magnetoconductance oscillations are symmetric with respect to reversal of the in-plane field component aligned with the high-symmetry [011[over ¯]] axis. Our observations demonstrate that an in-plane magnetic field can generate an out-of-plane component of magnetization in a low-symmetry hole system, creating new possibilities for spin manipulation.


Protein-tyrosine phosphorylation by IgG1 subclass CD38 monoclonal antibodies is mediated through stimulation of the FcgammaII receptors in human myeloid cell lines.
The human surface Ag CD38 is a 46-kDa type II transmembrane glycoprotein, and its expression is dependent on the cell differentiation and activation of lymphocytes. Our previous work in human myeloid cells showed that ligation of CD38 with mAbs (HB-7 and T-16; IgG1 subclass) not only induced protein-tyrosine phosphorylation but also potentiated superoxide generation stimulated by G protein-coupled receptors. In the present study we analyzed the mechanisms of action of the agonistic mAbs. HB-7-induced tyrosine phosphorylation could be still observed in human myeloid cells expressing CD38 mutants, of which cytoplasmic and transmembrane domains had been deleted or replaced by those of another type II glycoprotein (PC-1). Moreover, N-linked glycosylation on the cell surface CD38 was not required for the HB-7-induced cell signaling. The profile of tyrosine-phosphorylated proteins by HB-7 was exactly the same as that induced by cross-linking of FcgammaII receptors (FcgammaRII/CD32), and FcgammaRII itself was tyrosine phosphorylated in the two stimulated cells. The HB-7-induced tyrosine phosphorylation was completely abolished after masking of FcgammaRII with its mAb. Finally, F(ab')2 of HB-7 failed to mimic the actions of the whole form of mAb. These results indicate that anti-CD38 mAb-induced tyrosine phosphorylation and its associated cell response are entirely mediated through the FcgammaRII-induced signaling pathway, possibly resulting from stimulation of the cell surface human FcgammaRII with the mouse Fc region (IgG1 subclass) of CD38-ligated mAbs.


Human T-lymphoid progenitors generated in a feeder-cell-free Delta-like-4 culture system promote T-cell reconstitution in NOD/SCID/γc(-/-) mice.
Slow T-cell reconstitution is a major clinical concern after transplantation of cord blood (CB)-derived hematopoietic stem cells. Adoptive transfer of in vitro-generated T-cell progenitors has emerged as a promising strategy for promoting de novo thymopoiesis and thus accelerating T-cell reconstitution. Here, we describe the development of a new culture system based on the immobilized Notch ligand Delta-like-4 (DL-4). Culture of human CD34(+) CB cells in this new DL-4 system enabled the in vitro generation of large amounts of T-cell progenitor cells that (a) displayed the phenotypic and molecular signatures of early thymic progenitors and (b) had high T lymphopoietic potential. When transferred into NOD/SCID/γc(-/-) (NSG) mice, DL-4 primed T-cell progenitors migrated to the thymus and developed into functional, mature, polyclonal αβ T cells that subsequently left the thymus and accelerated T-cell reconstitution. T-cell reconstitution was even faster and more robust when ex vivo-manipulated and nonmanipulated CB samples were simultaneously injected into NSG mice (i.e., a situation reminiscent of the double CB transplant setting). This work provides further evidence of the ability of in vitro-generated human T-cell progenitors to accelerate T-cell reconstitution and also introduces a feeder-cell-free culture technique with the potential for rapid, safe transfer to a clinical setting.


Diagnosis of acute and chronic cardiac rejection by magnetic resonance imaging: a non-invasive in-vivo study.
To evaluate the potential usefulness for characterization of tissue and anatomical changes associated with cardiac transplantation rejection by nuclear magnetic resonance imaging (MRI), sixteen dogs underwent heterotropic cardiac transplantation with six not immunosuppressed serving as controls. Myocardial biopsy and MRI were obtained and compared on a weekly basis. Untreated allografts showed a significant increase in T2 and intensity values by MRI compared to the native heart as early as one week after transplantation. The MRI findings corresponded to the histological progression of acute rejection process in both treated and untreated groups. The linear relationship between histology and MRI was 0.72 while the correlation between T2 and the water content was 0.92. Serial gated MRI correlated with chronic anatomical changes of transplant rejection with evidence of progressive or increasing myocardial wall thickness and decrease in ventricular chamber size.


Manipulating the sulfur amino acid content of the early diet and its implications for long-term health.
Epidemiological studies of human populations show that poor growth in utero predisposes an individual to the later development of type 2 (non-insulin-dependent) diabetes mellitus and hypertension in adulthood. This phenomenon is not confined to man; feeding pregnant rats diets moderately deficient in protein has a similar effect, programming the adult blood pressure and glucose metabolism of the offspring. A restriction in the amino acid supply was thought to cause poor fetal growth. However, recent experiments have shown that this is not the case and instead have implicated the metabolism of the S-containing amino acids. Many semi-synthetic experimental diets contain an imbalance in S-containing amino acids, forcing the animal to synthesise a sizeable part of its cysteine requirement from methionine. Unfortunately, when the diet is low in protein, the oxidation of amino acids is reduced, perturbing methionine metabolism and increasing levels of homocysteine. It is this interaction between protein content and composition of the diet which influences neonatal viability and may also determine the long-term health of the offspring. An excess of homocysteine is known to affect levels of two of the main mediators of cellular methylation reactions, S-adenosyl methionine and methylene tetrahydrofolate. S-adenosyl methionine is the methyl donor for the methylation of newly-synthesised DNA, regulating chromatin assembly and gene expression. The balance between S-adenosyl methionine and the methylated derivatives of folic acid may be critical for the development of differentiating cells and the long-term regulation of gene expression.


Branching, segmentation and the metapterygial axis: pattern versus process in the vertebrate limb.
Explanations of the patterns of vertebrate fin and limb evolution are improving as specific hypotheses based on molecular and developmental data are proposed and tested. Comparative analyses of gene expression patterns and functions in developing limbs, and morphological patterns in embryonic, adult and fossil limbs point to digit specification as a key developmental innovation associated with the origin of tetrapods. Digit development during the fin-to-limb transition involved sustained proximodistal outgrowth and a new phase of Hox gene expression in the distal fin bud. These patterning changes in the distal limb have been explained by the linked concepts of the metapterygial axis and the digital arch. These have been proposed to account for the generation of limb pattern by sequential branching and segmentation of precartilagenous elements along the proximodistal axis of the limb. While these ideas have been very fruitful, they have become increasingly difficult to reconcile with experimental and comparative studies of fin and limb development. Here we argue that limb development does not involve a branching mechanism, and reassess the concept of a metapterygial axis in limb development and evolution.


Oscillatory behaviors and hierarchical assembly of contractile structures in intercalating cells.
Fluctuations in the size of the apical cell surface have been associated with apical constriction and tissue invagination. However, it is currently not known if apical oscillatory behaviors are a unique property of constricting cells or if they constitute a universal feature of the force balance between cells in multicellular tissues. Here, we set out to determine whether oscillatory cell behaviors occur in parallel with cell intercalation during the morphogenetic process of axis elongation in the Drosophila embryo. We applied multi-color, time-lapse imaging of living embryos and SIESTA, an integrated tool for automated and semi-automated cell segmentation, tracking, and analysis of image sequences. Using SIESTA, we identified cycles of contraction and expansion of the apical surface in intercalating cells and characterized them at the molecular, cellular, and tissue scales. We demonstrate that apical oscillations are anisotropic, and this anisotropy depends on the presence of intact cell-cell junctions and spatial cues provided by the anterior-posterior patterning system. Oscillatory cell behaviors during axis elongation are associated with the hierarchical assembly and disassembly of contractile actomyosin structures at the medial cortex of the cell, with actin localization preceding myosin II and with the localization of both proteins preceding changes in cell shape. We discuss models to explain how the architecture of cytoskeletal networks regulates their contractile behavior and the mechanisms that give rise to oscillatory cell behaviors in intercalating cells.


Human macrophage-derived chemokine (MDC), a novel chemoattractant for monocytes, monocyte-derived dendritic cells, and natural killer cells.
A cDNA encoding a novel human chemokine was isolated by random sequencing of cDNA clones from human monocyte-derived macrophages. This protein has been termed macrophage-derived chemokine (MDC) because it appears to be synthesized specifically by cells of the macrophage lineage. MDC has the four-cysteine motif and other highly conserved residues characteristic of CC chemokines, but it shares <35% identity with any of the known chemokines. Recombinant MDC was expressed in Chinese hamster ovary cells and purified by heparin-Sepharose chromatography. NH2-terminal sequencing and mass spectrophotometry were used to verify the NH2 terminus and molecular mass of recombinant MDC (8,081 dalton). In microchamber migration assays, monocyte-derived dendritic cells and IL-2-activated natural killer cells migrated to MDC in a dose-dependent manner, with a maximal chemotactic response at 1 ng/ml. Freshly isolated monocytes also migrated toward MDC, but with a peak response at 100 ng/ml MDC. Northern analyses indicated MDC is highly expressed in macrophages and in monocyte-derived dendritic cells, but not in monocytes, natural killer cells, or several cell lines of epithelial, endothelial, or fibroblast origin. High expression was also detected in normal thymus and less expression in lung and spleen. Unlike most other CC chemokines, MDC is encoded on human chromosome 16. MDC is thus a unique member of the CC chemokine family that may play a fundamental role in the function of dendritic cells, natural killer cells, and monocytes.


Associations between brain microstructures, metabolites, and cognitive deficits during chronic HIV-1 infection of humanized mice.
Host-species specificity of the human immunodeficiency virus (HIV) limits pathobiologic, diagnostic and therapeutic research investigations to humans and non-human primates. The emergence of humanized mice as a model for viral infection of the nervous system has overcome such restrictions enabling research for HIV-associated end organ disease including behavioral, cognitive and neuropathologic deficits reflective of neuroAIDS. Chronic HIV-1 infection of NOD/scid-IL-2Rgcnull mice transplanted with human CD34+ hematopoietic stem cells (CD34-NSG) leads to persistent viremia, profound CD4+ T lymphocyte loss and infection of human monocyte-macrophages in the meninges and perivascular spaces. Murine cells are not infected with virus. Changes in mouse behavior were measured, starting at 8 weeks after viral infection. These were recorded coordinate with magnetic resonance spectroscopy metabolites including N-acetylaspartate (NAA), creatine and choline. Diffusion tensor magnetic resonance imaging (DTI) was recorded against multispectral immunohistochemical staining for neuronal markers that included microtubule associated protein-2 (MAP2), neurofilament (NF) and synaptophysin (SYN); for astrocyte glial fibrillary acidic protein (GFAP); and for microglial ionized calcium binding adaptor molecule 1 (Iba-1). Oligodendrocyte numbers and integrity were measured for myelin associated glycoprotein (MAG) and myelin oligodendrocyte glycoprotein (MOG) antigens. Behavioral abnormalities were readily observed in HIV-1 infected mice. Longitudinal open field activity tests demonstrated lack of habituation indicating potential for memory loss and persistent anxiety in HIV-1 infected mice compared to uninfected controls. End-point NAA and creatine in the cerebral cortex increased with decreased MAG. NAA and glutamate decreased with decreased SYN and MAG. Robust inflammation reflected GFAP and Iba-1 staining intensities. DTI metrics were coordinate with deregulation of NF, Iba-1, MOG and MAG levels in the whisker barrel and MAP2, NF, MAG, MOG and SYN in the corpus callosum. The findings are consistent with some of the clinical, biochemical and pathobiologic features of human HIV-1 nervous system infections. This model will prove useful towards investigating the mechanisms of HIV-1 induced neuropathology and in developing novel biomarkers and therapeutic strategies for disease.


Effect of insulin on glucose uptake by the maternal hindlimb and uterus, and by the fetus in conscious pregnant sheep.
Previous studies have demonstrated the presence of insulin receptors on the maternal surface of the placenta in several species and the specific binding of insulin to the placenta in sheep. However, both in-vitro and in-vivo studies have produced conflicting evidence concerning the effect of insulin on placental glucose uptake. To clarify this problem, we measured maternal hindlimb, uterine and fetal glucose and oxygen extractions and glucose/oxygen quotients in chronically catheterized, non-stressed, late-gestation pregnant sheep over 1 h at a constant concentration of arterial plasma glucose, and again during the next 2 h at the same glucose level but at a higher insulin concentration using glucose 'clamp' methodology. Insulin produced a 4.9-fold increase in glucose extraction and a 3.5-fold increase in glucose/oxygen quotient across the hindlimb; in contrast, insulin did not significantly affect uterine or fetal glucose extraction or glucose/oxygen quotient. We conclude that in contrast to other tissues of the pregnant ewe, placental glucose uptake and transfer are insensitive to variations in maternal insulin concentration.


Buprenorphine reduces methamphetamine intake and drug seeking behavior via activating nociceptin/orphanin FQ peptide receptor in rats.
Buprenorphine, which has been approved for the treatment of opioid dependence, reduces cocaine consumption by co-activating μ-opioid receptors and nociceptin/orphanin FQ peptide (NOP) receptors. However, the role of buprenorphine in methamphetamine (METH) reinforcement and drug-seeking behavior remains unclear. This study investigated the effects of buprenorphine on METH self-administration and reinstatement of METH-seeking behavior in rats. We found that buprenorphine pretreatment had an inhibitory effect on METH self-administration behavior, and that buprenorphine at a dose of 0.3 mg/kg could inhibit motivation to respond for METH. Pretreatment with the NOP receptor antagonist thienorphine (0.5 mg/kg) or SB-612111 (1 mg/kg) could reverse the inhibitory effect of buprenorphine (0.1 mg/kg) on the METH self-administration. Moreover, treatment with buprenorphine (0.1 mg/kg and 0.3 mg/kg) significantly reduced the drug-seeking behavior induced by context or by METH priming but failed to reduce the drug-seeking behavior induced by conditional cues. Additionally, the NOP receptor antagonist SB-612111 reversed the inhibitory action of buprenorphine on the drug-seeking behavior induced by METH priming. The results demonstrated that buprenorphine reduced either METH intake or the drug-seeking behavior by activating NOP receptors, providing empirical evidence for the clinical use of buprenorphine in the treatment of METH relapse and addiction.


Central projections of the lateral line and eighth nerves in the bowfin, Amia calva.
The first-order connections of the anterior and posterior lateral line nerves and of the eighth nerve were determined in the bowfin, Amia calva, using experimental degeneration and anterograde HRP transport techniques. The termination sites of these nerves define a dorsal lateralis cell column and a ventral octavus cell column. The anterior and posterior lateralis nerves distribute ipsilaterally to two medullary nuclei-nucleus medialis and nucleus caudalis. Nucleus medialis comprises the rostral two-thirds of the lateralis column and contains large, Purkinje-like cells dorsally and polygonal, granule, and fusiform cells ventrally. Nucleus caudalis is located posterior to nucleus medialis and consists of small, granule cells. Anterior lateralis fibers terminate ventrally to ventromedially in both nucleus medialis and nucleus caudalis. Posterior lateralis fibers terminate dorsally to dorsolaterally within these two nuclei. A sparse anterior lateralis input may also be present on the dendrites of one of the nuclei within the octavus cell column, nucleus magnocellularis. In contrast, the anterior and posterior rami of the eighth nerve each terminate within four medullary nuclei which comprise the octavus cell column: the anterior, magnocellular, descending, and posterior octavus nuclei. An eighth nerve projection to the medial reticular formation is also present. Some fibers of the lateralis and eighth nerves terminate within the ipsilateral eminentia granularis of the cerebellum. Lateralis fibers distribute to approximately the lateral half of this structure with posterior lateral line fibers terminating laterally and anterior lateral line fibers terminating medially. Eighth nerve fibers distribute to the medial half of the eminentia granularis.


A Weighted Two-Level Bregman Method with Dictionary Updating for Nonconvex MR Image Reconstruction.
Nonconvex optimization has shown that it needs substantially fewer measurements than l 1 minimization for exact recovery under fixed transform/overcomplete dictionary. In this work, two efficient numerical algorithms which are unified by the method named weighted two-level Bregman method with dictionary updating (WTBMDU) are proposed for solving lp optimization under the dictionary learning model and subjecting the fidelity to the partial measurements. By incorporating the iteratively reweighted norm into the two-level Bregman iteration method with dictionary updating scheme (TBMDU), the modified alternating direction method (ADM) solves the model of pursuing the approximated lp -norm penalty efficiently. Specifically, the algorithms converge after a relatively small number of iterations, under the formulation of iteratively reweighted l 1 and l 2 minimization. Experimental results on MR image simulations and real MR data, under a variety of sampling trajectories and acceleration factors, consistently demonstrate that the proposed method can efficiently reconstruct MR images from highly undersampled k-space data and presents advantages over the current state-of-the-art reconstruction approaches, in terms of higher PSNR and lower HFEN values.


A novel black tea pigment and two new oxidation products of epigallocatechin-3-O-gallate.
During tea fermentation, oxidation-reduction dismutation of a number of quinone metabolites of tea catechins yields numerous minor products, which make it difficult to separate and purify black tea polyphenols. In this study, epigallocatechin-3-O-gallate was enzymatically oxidized and then the unstable quinone metabolites in the oxidation mixture were hydrogenated with 2-mercaptoethanol to reduce production of inseparable minor dismutation products. As a result, three new oxidation products including a new black tea pigment were isolated, and their structures were determined based on chemical and spectroscopic data. Dehydrotheasinensin AQ is a new reddish-orange pigment with a 1,2-diketone structure, and its presence in commercial black tea was confirmed. In addition, a new quinone dimer with a complex caged structure and a trimer of epigallocatechin-3-O-gallate were also isolated and their production mechanisms are proposed. The presence of this trimer suggested participation of galloyl quinones in production of minor polyphenols in black tea.


Amelogenesis imperfecta with growth hormone deficiency in a 12 year-old boy.
Amelogenesis imperfecta (AI) is a diverse group of hereditary disorders that are characterized by a defect in the formation of the tooth enamel and a high degree of clinical diversity. X-linked, autosomal dominant and recessive inheritance have been demonstrated. Growth hormone (GH) has an effect on bone and soft tissue development. Dental and facial abnormalities associated with pituitary dwarfism have been reported, but GH deficiency with AI is very rare. We describe a 12 year-old pre-pubertal boy who was referred to our hospital with teeth deformities and growth retardation. His teeth had brown-yellow pigmented surfaces, and dental examination showed extensive enamel deficiency in his permanent teeth. He also had severe growth retardation; height SDS was -3.6. Laboratory examinations showed reduced GH levels, and he was diagnosed as having idiopathic isolated GH deficiency and AI.


Charge-transport anisotropy in black phosphorus: critical dependence on the number of layers.
Phosphorene is a promising candidate for modern electronics because of the anisotropy associated with high electron-hole mobility. Additionally, superior mechanical flexibility allows the strain-engineering of various properties including the transport of charge carriers in phosphorene. In this work, we have shown the criticality of the number of layers to dictate the transport properties of black phosphorus. Trilayer black phosphorus (TBP) has been proposed as an excellent anisotropic material, based on the transport parameters using Boltzmann transport formalisms coupled with density functional theory. The mobilities of both the electron and the hole are found to be higher along the zigzag direction (∼10(4) cm(2) V(-1) s(-1) at 300 K) compared to the armchair direction (∼10(2) cm(2) V(-1) s(-1)), resulting in the intrinsic directional anisotropy. Application of strain leads to additional electron-hole anisotropy with 10(3) fold higher mobility for the electron compared to the hole. Critical strain for maximum anisotropic response has also been determined. Whether the transport anisotropy is due to the spatial or charge-carrier has been determined through analyses of the scattering process of electrons and holes, and their recombination as well as relaxation dynamics. In this context, we have derived two descriptors (S and F(k)), which are general enough for any 2D or quasi-2D systems. Information on the scattering involving purely the carrier states also helps to understand the layer-dependent photoluminescence and electron (hole) relaxation in black phosphorus. Finally, we justify trilayer black phosphorus (TBP) as the material of interest with excellent transport properties.


The transcriptional response to oxidative stress is part of, but not sufficient for, insulin resistance in adipocytes.
Insulin resistance is a major risk factor for metabolic diseases such as Type 2 diabetes. Although the underlying mechanisms of insulin resistance remain elusive, oxidative stress is a unifying driver by which numerous extrinsic signals and cellular stresses trigger insulin resistance. Consequently, we sought to understand the cellular response to oxidative stress and its role in insulin resistance. Using cultured 3T3-L1 adipocytes, we established a model of physiologically-derived oxidative stress by inhibiting the cycling of glutathione and thioredoxin, which induced insulin resistance as measured by impaired insulin-stimulated 2-deoxyglucose uptake. Using time-resolved transcriptomics, we found > 2000 genes differentially-expressed over 24 hours, with specific metabolic and signalling pathways enriched at different times. We explored this coordination using a knowledge-based hierarchical-clustering approach to generate a temporal transcriptional cascade and identify key transcription factors responding to oxidative stress. This response shared many similarities with changes observed in distinct insulin resistance models. However, an anti-oxidant reversed insulin resistance phenotypically but not transcriptionally, implying that the transcriptional response to oxidative stress is insufficient for insulin resistance. This suggests that the primary site by which oxidative stress impairs insulin action occurs post-transcriptionally, warranting a multi-level 'trans-omic' approach when studying time-resolved responses to cellular perturbations.


Sweet Mitochondria: A Shortcut to Alzheimer's Disease.
A growing body of evidence supports a clear association between Alzheimer's disease and diabetes and several mechanistic links have been revealed. This paper is mainly devoted to the discussion of the role of diabetes-associated mitochondrial defects in the pathogenesis of Alzheimer's disease. The research experience and views of the author on this subject will be highlighted.


Selective thromboxane synthetase inhibitors. 2. 3-(1H-imidazol-1-ylmethyl)-2-methyl-1H-indole-1-propanoic acid and analogues.
The preparation of a series of 3-(1H-imidazol-1-ylmethyl)-1H-indole-1-alkanoic acids is described. Several compounds were found to be more potent thromboxane synthetase inhibitors than the corresponding analogues lacking an acidic substituent. In the cases examined, compounds had no significant activity against PGI2 synthetase or cyclooxygenase, and introduction of the carboxylic acid substituent led to a reduction in activity against adrenal steroid 11 beta-hydroxylase. Compound 21 strongly inhibited thromboxane formation after iv administration to anesthetized rabbits and oral administration to conscious dogs. The compound had a long duration of action, and marked inhibition of thromboxane production was observed 15 h after oral administration of 1 mg/kg to conscious dogs.


Computing Mixture Adsorption in Porous Materials through Flat Histogram Monte Carlo Methods.
Mixture adsorption properties of porous materials are critical to determine their potential as adsorbents in separation applications. Toward the discovery of optimal adsorbents, in silico screening studies typically employ the grand canonical Monte Carlo (GCMC) technique to compute adsorption properties of gas mixtures in materials of interest at a given condition (i.e., composition, total pressure, and temperature) or to compute their adsorption properties for each component, followed by utilizing methods to predict mixture adsorption isotherms. However, the former approach results in the need for repeated calculations when different conditions such as compositions are considered. For the latter, the predictions may involve uncertainties, sometimes originating from the fitting quality to the pure component isotherms, and repeated simulations may also be needed for different temperatures. To this end, this study demonstrates the potential of flat histogram Monte Carlo methods in addressing the abovementioned shortfalls. Specifically, the so-called NVT + W method, first reported by Smit and co-workers, is extended herein to determine the macrostate probability distribution (MPD) of binary mixtures in porous materials. The obtained MPD can be reweighted to any conditions, yielding accurate adsorption isotherms of any desired compositions and temperatures. This approach, denoted as 2D NVT + W, is also compared with the widely adopted ideal adsorbed solution theory (IAST) method, and the former is found to offer more reliable predictions. Overall, the 2D NVT + W approach represents an efficient and effective alternative to compute mixture adsorption isotherms for porous materials, and the obtained MPD can be conveniently reused by peer researchers. A user-friendly Python code is also provided along with this article to employ this method.


Severe upper gastrointestinal bleeding determined by a gastric lymphoma associated with Helicobacter pylori-positive atrophic gastritis.
The pathogenesis of gastric cancer regardless of histological structure is a classic example of gene-environment interaction, and an important epidemiological aspect was the recognized association with Helicobacter pylori infection. This paper describes a case of gastric mucosa-associated lymphoid tissue (MALT) lymphoma in a young patient whose first sign of the disease was upper gastrointestinal bleeding and associated hemorrhagic shock. The patient is a 31-year-old man, diagnosed by endoscopy 10 years ago with H. pylori-positive chronic atrophic gastritis, who refused treatment to eradicate the bacterium and presents currently in the emergency room for serious upper gastrointestinal bleeding. Emergency upper gastrointestinal tract endoscopy highlights the presence of bleeding gastric tumors. It was a surgical emergency and intra-operatively the presence of invasive gastric cancer into the left hepatic lobe was noted which required total gastrectomy with the purpose of hemostasis. Immediate and remote postoperative evolution was favorable and post-operative follow-up at six months, 12 months, and 24 months showed no signs of local or distance occurrence.


Mucopolysaccharidosis type VII associated with hydrops fetalis: histopathological and ultrastructural features with genetic implications.
A case of mucopolysaccharidosis type VII (MPS VII, beta glucuronidase deficiency) causing fatal hydrops fetalis in the third trimester is presented. The diagnosis was suspected on histopathological examination by the presence of foam cells in many of the viscera and foamy change in the placental Hofbauer cells. Electron microscopy showed empty cytoplasmic inclusion bodies within macrophages and in the Hofbauer cells. Enzyme assay of cultured fibroblasts showed markedly deficient beta glucuronidase activity, thus confirming the diagnosis. A detailed and thorough histopathological examination of hydrops fetalis cases is important to detect subtle features of inherited metabolic disorders. Use of a structured necropsy protocol is recommended for cases of non-immune hydrops. Electron microscopy is a useful adjunct to light microscopy in cases where an inherited metabolic disorder is suspected. Precise necropsy diagnosis is important as there are implications for genetic counselling and possible prenatal diagnosis in subsequent pregnancies.


The effect of functional insulin therapy on glycaemic parameters in children with diabetes mellitus type 1.
Aim The aim of the study is to evaluate the effect of a prospectively conducted interactive 5-day education programme based on Düsseldorf model on glycated haemoglobin (A1C), and total daily dose of insulin in type 1 diabetes patients. Methods A total of 67 type 1 diabetes patients was analysed; mean age of 11±0.68 years, 43 females and 24 males. The programme was led by a trained team of diabetes specialist doctors and nurses. All subjects and their parents completed a knowledge test about diabetes at beginning, and at the end of education, and after 12 months (30 questions). Subjects were evaluated for total daily insulin, and HbA1c at baseline, as well as 3, 6, 9 and 12 months after the end of the education programme. Results Results of the knowledge test after the education have shown higher knowledge at baseline. At the end of the education programme an average of total daily insulin dose was significantly lower. There was a 3.17% reduction in HbA1c values over 9 months, and 1.8% over 12 months in the comparison to the baseline values (p<0.001). Conclusions Structured education programme of functional insulin therapy was associated with improved glycaemic control in type 1 diabetes patients and their parents. It motivated patients and parents to improve glycaemic control. One year after the follow up, glycaemic control was worsening, due to lack of patients' motivation, therefore, there is a need for yearly re-education.


Influence of the spatial organization of the perimysium on beef tenderness.
The spatial distribution of the intramuscular connective tissue (IMCT) in four types of beef muscle (Biceps femoris, Infraspinatus, Longissimus thoracis, and Pectoralis profundus) was examined using histology and magnetic resonance imaging (MRI). The surface and the length of the IMCT and the surface of the myofiber bundles were evaluated by image analysis. The texture of the cooked meat from these muscles was measured both instrumentally by a compression test and by sensory analysis. The relationship between muscle structure and meat texture was studied by general discriminant analysis. The models obtained could assign correctly up to 87% of the samples to two tenderness classes. Histology and MRI provided complementary information about the microscopic and macroscopic IMCT structures, respectively. Both were necessary to predict sensory tenderness whereas only the MRI measurements were necessary to predict instrumental toughness. Tough muscles had smaller MRI myofiber bundles (0.7-1 mm radius) than tender muscles.


Mechanical properties of the passive pharynx in Vietnamese pot-bellied pigs. II. Dynamics.
We described the dynamic mechanical properties of the passive pharynx in Vietnamese pot-bellied pigs and the effects of caudal tracheal displacement. During general anesthesia and neuromuscular blockade, airflow through the upper airway (V) and pharyngeal cross-sectional area were measured during ramp decreases in pressure downstream from the pharynx (Pdown). Measurements were made with 0, 1, and 2 cm of caudal tracheal displacement. Airflow limitation and/or negative pressure dependence (NPD) were observed in all animals. Tracheal displacement (2 cm) increased maximal V (V(max)) by 205.1 +/- 105.1% (P < 0.05) relative to the value with no displacement and increased the magnitude of NPD, expressed as percent decrease in V from V(max), from 22.9 +/- 27.4 to 56.6 +/- 37.5% (P < 0.05). Initial decreases in Pdown narrowed all levels of the pharynx, but, once V(max) was reached, further decreases in Pdown narrowed the hypopharynx but not the nasopharynx and oropharynx. We conclude that the hypopharynx is the flow-limiting site in the pig pharynx. Tracheal displacement not only improved airflow dynamics as V(max) increased but also resulted in pronounced NPD.


Early molecular signatures of responses of wheat to Zymoseptoria tritici in compatible and incompatible interactions.
Zymoseptoria tritici, the causal agent of septoria tritici blotch, a serious foliar disease of wheat, is a necrotrophic pathogen that undergoes a long latent period. Emergence of insensitivity to fungicides, and pesticide reduction policies, mean there is a pressing need to understand septoria and control it through greater varietal resistance. Stb6 and Stb15, the most common qualitative resistance genes in modern wheat cultivars, determine specific resistance to avirulent fungal genotypes following a gene-for-gene relationship. This study investigated compatible and incompatible interactions of wheat with Z. tritici using eight combinations of cultivars and isolates, with the aim of identifying molecular responses that could be used as markers for disease resistance during the early, symptomless phase of colonization. The accumulation of TaMPK3 was estimated using western blotting, and the expression of genes implicated in gene-for-gene interactions of plants with a wide range of other pathogens was measured by qRT-PCR during the presymptomatic stages of infection. Production of TaMPK3 and expression of most of the genes responded to inoculation with Z. tritici but varied considerably between experimental replicates. However, there was no significant difference between compatible and incompatible interactions in any of the responses tested. These results demonstrate that the molecular biology of the gene-for-gene interaction between wheat and Zymoseptoria is unlike that in many other plant diseases, indicate that environmental conditions may strongly influence early responses of wheat to infection by Z. tritici, and emphasize the importance of including both compatible and incompatible interactions when investigating the biology of this complex pathosystem.


Evaluation of renal tubular damage in liver cirrhosis by urinary enzymes and beta-2-microglobulin excretions.
To assess the renal tubular damage in liver cirrhosis the fractional clearances of beta-2-microglobulin (B2m-fr.cl) and malate-dehydrogenase (MDH-fr.cl) were measured respectively in sixty-four and in forty-six out of seventy-nine patients with liver cirrhosis of different aetiology; furthermore the fractional excretions of gammaglutamyl-transpeptidase (fr-GGT) and of alpha-glucosidase (fr-AGL) were determined in fifty-three and in forty of them respectively. In all patients glomerular filtration rate (GFR) and renal plasma flow (RPF) were also measured. Twenty-five subjects were studied as a control group for the enzyme excretions, sixteen for B2m-fr.cl. B2m-fr.cl and MDH-fr.cl--indexes of tubular functions--on the average were normal and only slightly increased respectively in cirrhotics compared to controls. Nevertheless fr-GGT and fr-AGL--indexes of cytolysis of tubular cells--on the average were massively increased in cirrhosis compared to controls, particularly in those with reduced RPF and/or GFR. No clear relationship between the indexes of tubular damage studied and the indexes of liver function was found. Our results show that (1) A renal tubular anatomical damage was found by means of an increase in the release of enzyme from tubular cells in patients with liver cirrhosis, particularly in those with a significant reduction of RPF and/or GFR; even so renal reabsorption of low molecular weight proteins is generally maintained. (2) The tubular damage does not seem to be related to the degree of liver impairment.


Alcohol abuse-duration dependent decrease in plasma testosterone and antioxidants in males.
Ethanol is a testicular toxin and it causes fertility abnormalities with low sperm count and impaired sperm motility in men. The present study was designed to investigate plasma testosterone level and hypothalamic pituitary gonadal (HPG) axis function in alcoholic men and also effect of ethanol on systemic oxidative stress. Forty six male alcohol abusers in the age group 20-40 years were selected. Fifty five, males in the same age group served as control. Alcohol abusers had significantly low plasma testosterone with low luteinizing hormone and follicle stimulating hormone. In addition they had significantly high thiobarbituric acid reactive substances (TBARS), superoxide dismutase and glutathione S-transferase, and low glutathione, ascorbic acid, catalase, glutathione reductase and glutathione peroxidase. Moreover, serum testosterone level in alcoholics negatively correlated with duration of alcohol abuse, and TBARS. Duration dependent decreased serum testosterone level in alcohol abusers might be due to 1) increased oxidative stress which can damage Leydig and supporting Sertoli cells and 2) impaired HPG axis.


Meridional analysis of with-the-rule astigmatism in Oklahoma Indians.
Refraction and keratometry records were obtained for 142 consecutive with-the-rule astigmats and for 100 consecutive nonastigmats from W. W. Hastings Indian Health Service Hospital in Tahlequah, Oklahoma. Patients were 5 to 40 years of age. Patients with higher degrees of Indian ancestry were more common in the astigmatic group than in the spherical refraction group. An analysis of refractive error and keratometry by principal meridian was performed. The horizontal meridian refractive error in astigmats was most often near emmetropia. Compound myopic astigmatism and mixed astigmatism accounted for over 3/4 of the cases. The astigmats as a group had flatter corneas in the horizontal and steeper corneas in the vertical than the nonastigmats. Horizontal refractive errors and horizontal keratometry readings showed a weak but significant correlation in astigmats but not in nonastigmats.


Levothyroxine sodium tablets: chemical equivalence and bioequivalence.
Two brands of levothyroxine sodium tablets were compared in vivo for bioequivalence in a double-blind, randomized study. The tablets were identical in levothyroxine content. Evaluation was by means of triiodothyronine (uptake), tetraiodothyronine, free thyroxine index, total triiodothyronine by radioimmunoassay, and thyroid-stimulating hormone measurements. No differences in clinical response were found in a study with a high statistical power. It was concluded that the two brands were bioequivalent because of chemical equivalence, use of micronized levothyroxine powder in tablet production with at least one of the brands, and scrupulous attention to quality control during the manufacturing process, all of which contributed to assurance of homogeneity of the products and close adherence (+/- five percent) to the claimed potency.