Pharmacodynamics and pharmacokinetics of the HMG-CoA reductase inhibitors. Similarities and differences.
Hypercholesterolaemia plays a crucial role in the development of atherosclerotic diseases in general and coronary heart disease in particular. The risk of progression of the atherosclerotic process to coronary heart disease increases progressively with increasing levels of total serum cholesterol or low density lipoprotein (LDL) cholesterol at both the individual and the population level. The statins are reversible inhibitors of the microsomal enzyme HMG-CoA reductase, which converts HMG-CoA to mevalonate. This is an early rate-limiting step in cholesterol biosynthesis. Inhibition of HMG-CoA reductase by statins decreases intracellular cholesterol biosynthesis, which then leads to transcriptionally upregulated production of microsomal HMG-CoA reductase and cell surface LDL receptors. Subsequently, additional cholesterol is provided to the cell by de novo synthesis and by receptor-mediated uptake of LDL-cholesterol from the blood. This resets intracellular cholesterol homeostasis in extrahepatic tissues, but has little effect on the overall cholesterol balance. There are no simple methods to investigate the concentration-dependent inhibition of HMG-CoA reductase in human pharmacodynamic studies. The main clinical variable is plasma LDL-cholesterol, which takes 4 to 6 weeks to show a reduction after the start of statin treatment. Consequently, a dose-effect rather than a concentration-effect relationship is more appropriate to use in describing the pharmacodynamics. Fluvastatin, lovastatin, pravastatin and simvastatin have similar pharmacodynamic properties; all can reduce LDL-cholesterol by 20 to 35%, a reduction which has been shown to achieve decreases of 30 to 35% in major cardiovascular outcomes. Simvastatin has this effect at doses of about half those of the other 3 statins. The liver is the target organ for the statins, since it is the major site of cholesterol biosynthesis, lipoprotein production and LDL catabolism. However, cholesterol biosynthesis in extrahepatic tissues is necessary for normal cell function. The adverse effects of HMG-reductase inhibitors during long term treatment may depend in part upon the degree to which they act in extrahepatic tissues. Therefore, pharmacokinetic factors such as hepatic extraction and systemic exposure to active compound(s) may be clinically important when comparing the statins. Different degrees of liver selectivity have been claimed for the HMG-CoA reductase inhibitors. However, the literature contains confusing data concerning the degree of liver versus tissue selectivity. Human pharmacokinetic data are poor and incomplete, especially for lovastatin and simvastatin, and it is clear that any conclusion on tissue selectivity is dependent upon the choice of experimental model. However, the drugs do differ in some important aspects concerning the degree of metabolism and the number of active and inactive metabolites. The rather extensive metabolism by different cytochrome P450 isoforms also makes it difficult to characterise these drugs regarding tissue selectivity unless all metabolites are well characterised. The effective elimination half-lives of the hydroxy acid forms of the 4 statins are 0.7 to 3.0 hours. Protein binding is similar (> 90%) for fluvastatin, lovastatin and simvastatin, but it is only 50% for pravastatin. The best characterised statins from a clinical pharmacokinetic standpoint are fluvastatin and pravastatin. The major difference between these 2 compounds is the higher liver extraction of fluvastatin during the absorption phase compared with pravastatin (67 versus 45%, respectively, in the same dose range). Estimates of liver extraction in humans for lovastatin and simvastatin are poorly reported, which makes a direct comparison difficult.


Dental Decay and Oral Findings in Children and Adolescents Affected by Different Types of Cerebral Palsy: A Comparative Study.
To compare dental caries and oral findings in patients affected by different types of Cerebral Palsy (CP). This cross-sectional study involved 120 children and adolescents with a diagnosis of CP. WHO diagnostic criteria were used to determine DMFT (caries diagnosis), the pocket depth and attachment level (periodontitis diagnosis). Additionally, the study evaluated dental erosion, traumatic dental injuries, treatment needs index (TNI), oral habits, malocclusions, gingival overgrowth, and dental fluorosis. The most frequent CP type was spastic (62.5%), followed by mixed (18.3%), ataxic (10%), and athetoid (9.1). Patients affected by mixed CP showed a higher prevalence in decayed, DMFT index and TNI compared with the other types of CP (p<0.05). The frequency of malocclusion in the clinical evaluation was 87.5% and in plaster models was 49.2%. Dental caries was an important issue in mixed and athetoid CP groups. Oral habits and malocclusions were the most significant oral health problems in individuals with CP.


[Treatment of hepatitis C virus--2012: a real breakthrough].
For almost a decade the standard of care (SOC) therapy in patients with chronic hepatitis C virus (HCV) infection has consisted of a 24-48 week course of pegylated interferon-alpha in combination with ribavirin. This therapy is associated with significant adverse effects and leads to sustained virological response (SVR) in only 50% of patients with genotype 1. The development of compounds with direct antiviral activity (DAAs) against HCV genotype 1 during the past 10 years has led to the most significant breakthrough since the virus was first identified in 1989, Leading to a real revolution in the treatment of chronic HCV infection. The combination of the new DAAs with the SOC therapy has led to a significant improvement in achieving SVR in treatment-naïve (30%), as well as in treatment-experienced patients with genotype 1 (24-64%, depending on the response to previous antiviral treatment). In addition, treatment with DAAs enables shortening therapy in certain subgroups of patients, without compromising the SVR rate. However, the new treatment is challenging as it is associated with more severe adverse effects, complicated treatment regimens, need for frequent monitoring, drug-drug interaction, tolerance problems and development of selected resistant strains. This review updates the current information regarding DAAs, the new challenges that we will have to face and the therapeutic horizon in the near future.


A new approach to health research in Canada's North.
Over the past four years, despite low resource allocations to the North, northern residents and community organizations have taken significant initiatives towards the development of health research. In this commentary, we present a model for the development of northern health research based on our experiences in establishing the Institute for Circumpolar Health Research (ICHR) in the Northwest Territories. It is hoped that the lessons we have learned will inform decision-makers and encourage them to make strategic investments to support further health research capacity and institutional development within the North. Factors that have enabled the development of a health research institute in the North include leadership, a vision for health research, and the engagement of key partners and stakeholders. Challenges arise in the development of appropriate governance and policy for health research. There is an urgency to target resources to support the development of policies and governance for health research in northern jurisdictions. Both academic and community-based research need to be strengthened.


Windkessel Measures Derived From Pressure Waveforms Only: The Framingham Heart Study.
Background Waveform parameters derived from pressure-only Windkessel models are related to cardiovascular disease risk and could be useful for understanding arterial system function. However, prior reports varied in their adjustment for potential confounders. Methods and Results Carotid tonometry waveform data from 2539 participants (mean age 63±11 years, 58% women) of the Framingham Heart Study were used to derive Windkessel measures using pressure and assuming a linear model with fixed diastolic time constant (τdias) and variable asymptotic pressure (Pinf, median 54.5; 25th, 75th percentiles: 38.4, 64.9 mm Hg) or nonlinear model with inverse pressure-dependent τdias and fixed Pinf (20 mm Hg). During follow-up (median 15.1 years), 459 (18%) participants had a first cardiovascular disease event. In proportional hazards models adjusted for age, sex, total cholesterol, high-density lipoprotein cholesterol, smoking, antihypertensive medication use, diabetes mellitus, and physician-acquired systolic blood pressure, only the systolic time constant (τsys) derived from the nonlinear model was related to risk for cardiovascular disease events (hazard ratio=0.91 per 1 SD, 95% CI=0.84-0.99, P=0.04). When heart rate was added to the model, τsys (hazard ratio=0.92, CI=0.84-1.00, P=0.04) and reservoir pressure amplitude (hazard ratio=1.14, CI=1.01-1.28, P=0.04) were related to events. In contrast, measures derived from the linear model were not related to events in models that adjusted for risk factors including systolic blood pressure ( P>0.31) and heart rate ( P>0.19). Conclusions Our results suggest that pressure-only Windkessel measures derived by using a nonlinear model may provide incremental risk stratification, although associations were modest and further validation is required.


An Occupational Health Education Program for Thai Farmers Exposed to Chlorpyrifos.
The majority of the farmers in this sample of Thai farmers did not use sufficient self-protective behaviors when using the organophosphate insecticide chlorpyrifos. Most were directly exposed to chlorpyrifos, potentially leading to illnesses. The aim of this study was to improve safety behaviors when using chlorpyrifos by an occupational health education program. A controlled trial (n = 70) of an occupational health education program was undertaken in rural Thailand prior to the occupational health education program. There were no differences in behavior between experimental and control groups. Completion of the program led to a significant improvement in safe working practices and in the amount of the metabolite. However, significant differences were noticed after participating in the occupational health education program on both safety behaviors and the amount of the metabolite 3,5,6-trichloro-2-pyridinol present in urine.


Gout mimicking spondyloarthritis: case report and literature review.
Gout is clinically characterized by episodes of monoarthritis, which not only typically affects the peripheral joints but also occasionally affect the axial joint, such as the sacroiliac joint (SIJ), and often mimics spondyloarthritis (SpA). Two cases of gout mimicking SpA are presented in the current paper. One patient was a 32-year-old man with a history of asymmetrical oligoarthritis of ankle and metatarsophalangeal joints (MTPJ). He had left gluteal pain for 2 weeks. Computed tomography (CT) and magnetic resonance imaging (MRI) revealed the bone erosion of the left SIJ. T1-weighted MRI showed hypointense T1 and hyperintense T2 signals of the left SIJ. The other patient was a 24-year-old man with left back pain and hip pain for 4 months and intermittent fever for 3 months. He had a history of gout for 3 years. Both patients underwent CT-guided sacroiliac biopsy, and monosodium urate (MSU) crystals were shown by polarized microscopy. Gout can often mimic SpA and seldomly affects the SIJ. Thus, its correct diagnosis and adequate therapy can halt the development of such damaging complications.


Secondary metabolites from the endophytic fungus Talaromyces pinophilus.
Endophytic fungi have a great influence on plant health and growth, and are an important source of bioactive natural compounds. Organic extracts obtained from the culture filtrate of an endophytic strain of Talaromyces pinophilus isolated from strawberry tree (Arbutus unedo) were studied. Metabolomic analysis revealed the presence of three bioactive metabolites, the siderophore ferrirubin, the platelet-aggregation inhibitor herquline B and the antibiotic 3-O-methylfunicone. The latter was the major metabolite produced by this strain and displayed toxic effects against the pea aphid Acyrthosiphon pisum (Homoptera Aphidiidae). This toxicity represents an additional indication that the widespread endophytic occurrence of T. pinophilus may be related to a possible role in defensive mutualism. Moreover, the toxic activity on aphids could promote further study on 3-O-methylfunicone, or its derivatives, as an alternative to synthetic chemicals in agriculture.


NICHD research initiative in newborn screening.
Recent changes in genetics research have created new opportunities to improve the scope and quality of newborn screening services. Changes in newborn screening should be supported and directed by an organized program of research. The NICHD Research Initiative in Newborn Screening includes the development of systematic methods to identify additional conditions appropriate for newborn screening; development and testing innovative interventions and treatments to improve outcomes; education of the provider workforce; development and implementation of appropriate information and communication systems for parents and providers; and, sponsoring an ongoing program of research and research training. Future needs will include the development of a national translational research infrastructure, prevention research and research into behavioral and social sciences issues. The NICHD Research Initiative in Newborn Screening is expected to be an ongoing and vital initiative that adapts itself to new scientific findings, technological developments, changes in the public and personal health care system, and our evolving understanding of the needs of affected individuals, families and the community.


Milk Fat Globule-EGF Factor 8 Alleviates Pancreatic Fibrosis by Inhibiting ER Stress-Induced Chaperone-Mediated Autophagy in Mice.
Pancreatic fibrosis is an important pathophysiological feature of chronic pancreatitis (CP). Our recent study has shown that milk fat globule-EGF factor 8 (MFG-E8) is beneficial in acute pancreatitis. However, its role in CP remained unknown. To study this, CP was induced in male adult Mfge8-knockout (Mfge8-KO) mice and wild type (WT) mice by six intraperitoneal injections of cerulein (50 μg/kg/body weight) twice a week for 10 weeks. The results showed that knockout of mfge8 gene aggravated pancreatic fibrosis after repeated cerulein injection. In WT mice, pancreatic levels of MFG-E8 were reduced after induction of CP and administration of recombinant MFG-E8 alleviated cerulein-induced pancreatic fibrosis. The protective effect of MFG-E8 in CP was associated with reduced autophagy and oxidative stress. In human pancreatic stellate cells (PSCs), MFG-E8 inhibited TGF-β1-induced ER stress and autophagy. MFG-E8 downregulated the expression of lysosomal associated membrane protein 2A (LAMP2A), a key factor in ER stress-induced chaperone-mediated autophagy (CMA). QX77, an activator of CMA, eliminated the effects of MFG-E8 on TGF-β1-induced PSC activation. In conclusion, MFG-E8 appears to mitigate pancreatic fibrosis via inhibiting ER stress-induced chaperone-mediated autophagy. Recombinant MFG-E8 may be developed as a novel treatment for pancreatic fibrosis in CP.


Methionine synthase exists in two distinct conformations that differ in reactivity toward methyltetrahydrofolate, adenosylmethionine, and flavodoxin.
Methionine synthase (MetH) from Escherichia coli catalyzes the synthesis of methionine from homocysteine and methyltetrahydrofolate via two methyl transfer reactions that are mediated by the endogenous cobalamin cofactor. After binding both substrates in a ternary complex, the enzyme transfers a methyl group from the methylcobalamin cofactor to homocysteine, generating cob(I)alamin enzyme and methionine. The enzyme then catalyzes methyl transfer from methyltetrahydrofolate to the cob(I)alamin cofactor, forming methylcobalamin cofactor and tetrahydrofolate prior to the release of both products. The cob(I)alamin form of the enzyme occasionally undergoes oxidation to an inactive cob(II)alamin species; the enzyme also catalyzes its own reactivation. Electron transfer from reduced flavodoxin to the cob(II)alamin cofactor is thought to generate cob(I)alamin enzyme, which is then trapped by methyl transfer from adenosylmethionine to the cobalt, restoring the enzyme to the active methylcobalamin form. Thus the enzyme is potentially able to catalyze two methyl transfers to the cob(I)alamin cofactor: methyl transfer from methyltetrahydrofolate during primary turnover and methyl transfer from adenosylmethionine during activation. It has recently been shown that methionine synthase is constructed from at least four separable regions that are responsible for binding each of the three substrates and the cobalamin cofactor, and it has been proposed that changes in positioning of the substrate binding regions vis-à-vis the cobalamin binding region could allow the enzyme to control which substrate has access to the cofactor. In this paper, we offer evidence that methionine synthase exists in two different conformations that interconvert in the cob(II)alamin oxidation state. In the primary turnover conformation, the enzyme reacts with homocysteine and methyltetrahydrofolate but is unreactive toward adenosylmethionine and flavodoxin. In the reactivation conformation, the enzyme is active toward adenosylmethionine and flavodoxin but unreactive toward methyltetrahydrofolate. The two conformations differ in the susceptibility of the substrate-binding regions to tryptic proteolysis. We propose a model in which conformational changes control access to the cobalamin cofactor and are the primary means of controlling cobalamin reactivity in methionine synthase.


The Northwestern University multihospital twin study. IV. Duration of gestation according to fetal sex.
Recently MacGillivray has observed that the average duration of male twin gestations is shorter than that of either female twin or male/female twin gestations. The data from 562 twin gestations from the Northwestern University multihospital twin study were used to test this observation. Male twin gestations were slightly but significantly shorter than other twin gestations as measured by pediatric examination (p less than 0.005). Approaching significance at the 0.05 level were findings that male twin gestations were shorter than other twin gestations when measured by dates, and that the male twins were slightly shorter and lighter than other twins. No significant differences were found between male/female twin gestations and female twin gestations. No relationship could be found between twin sex combinations and a variety of maternal and obstetric factors. Taken together, the results suggest that male twin gestations differ in some distinctive biologic sense from other twin gestations.


A multi-institutional study of short-term mortality in COVID-positive patients undergoing hip fracture surgery: is survival better than expected?
Early reports of 30-day mortality in COVID-positive patients with hip fracture were often over 30% and were higher than historical rates of 10% in pre-COVID studies. We conducted a multi-institutional retrospective cohort study to determine whether the incidence of 30-day mortality and complications in COVID-positive patients undergoing hip fracture surgery is as high as initially reported. A retrospective chart review was performed at 11 level I trauma centers from January 1, 2020 to May 1, 2022. Patients 50 years or older undergoing hip fracture surgery with a positive COVID test at the time of surgery were included. The primary outcome measurements were the incidence of 30-day mortality and complications. Post-operative outcomes were reported using proportions with 95% confidence interval (C.I.). Forty patients with a median age of 71.5 years (interquartile range, 50-87 years) met the criteria. Within 30-days, four patients (10%; 95% C.I. 3-24%) died, four developed pneumonia, three developed thromboembolism, and three remained intubated post-operatively. Increased age was a statistically significant predictor of 30-day mortality (p = 0.01), with all deaths occurring in patients over 80 years. In this multi-institutional analysis of COVID-positive patients undergoing hip fracture surgery, 30-day mortality was 10%. The 95% C.I. did not include 30%, suggesting that survival may be better than initially reported. While COVID-positive patients with hip fractures have high short-term mortality, the clinical situation may not be as dire as initially described, which may reflect initial publication bias, selection bias introduced by testing, or other issues. Therapeutic Level III.


Structure of the zeta chain of human embryonic hemoglobin.
The complete amino acid sequence of the zeta chain of human embryonic hemoglobin has been determined. It differs from human alpha globin at 57 of the 141 residues and several of the replacements are at positions of structural or functional importance, particularly in relationship to the Bohr effect and high intrinsic oxygen affinity which are characteristic of embryonic hemoglobins. The zeta-globin sequence is more closely related to other mammalian embryonic alpha-like globins than to human alpha, suggesting that there have been strong selective pressures to maintain these embryo-specific globins since their emergence several hundred million years ago.


Shedding of escherichia coli O157:H7 by cattle fed diets containing monensin or tylosin.
Monensin and tylosin have activity against gram-positive bacteria, and it has been theorized that their effects on the intestinal environment may promote proliferation of gram-negative bacteria such as Escherichia coli. Effects of these antibiotics on the shedding of E. coli O157:H7 were studied in a feedlot environment, using 32 finishing steers. A diet containing 85% barley grain, 10% barley silage, and 5% supplement was amended with 33 ppm monensin, 11 ppm tylosin, both of these additives, or no additives (control). All steers were orally inoculated with 10(10) CFU of a mixture of four strains of nalidixic acid-resistant E. coli O157:H7. Fecal (grab), oral (mouth swab) and water, water-water bowl interface, feed, and pen floor fecal pat samples were collected weekly for 12 weeks. Prevalence of E. coli O157:H7-positive fecal grab samples did not differ (P = 0.26) among treatments, nor did the rate (P = 0.81) or duration (P = 0.85) of shedding of the organism. Fecal grab samples were positive for E. coli O157:H7 more frequently (P < 0.001) than were oral swabs. More (P = 0.02) E. coli O157:H7-positive oral swabs were recovered from the tylosin group than from controls. E. coli O157:H7 was not detected in any of 47 water samples, but was present in 1 of 47 water bowl swabs, 7 of 48 feed samples, and 36 of 48 fecal pats. Pulsed-field gel electrophoresis suggested that differences existed among inoculated strains in their ability to persist in animals and in the environment. However, this study revealed no evidence that dietary inclusion of monensin or tylosin, alone or in combination, increased fecal shedding of E. coli O157:H7 or its persistence in the environment.


Streptolysin O inhibition of neutrophil chemotaxis and mobility: nonimmune phenomenon with species specificity.
The effects of streptolysin O (SO) (1 to 4 hemolytic units) on the mobility of neutrophilic leukocytes from humans, baboons, sheep, and rabbits were compared. After SO treatment, chemotaxis and random mobility of human neutrophils were markedly suppressed, baboon and sheep neutrophils were partially suppressed, and rabbit neutrophils were unaffected and demonstrated normal chemotaxis and mobility. The amounts of SO used in the mobility studies caused no leukocyte lysis or trypan blue uptake by human, baboon, or sheep cells, and minimal lysis or trypan blue uptake by rabbit cells. The possible involvement of immune mediators in the observed inhibition of human neutrophils was considered and excluded by the following studies. White blood cells from humans with humoral or cellular immune deficiencies responded in a manner similar to normal human cells; supernatant solutions from SO-treated human white blood cells did not contain a chemotactic suppressor; preincubation of SO with cholesterol (an inhibitor of SO hemolytic activity) caused loss of the chemotactic suppressive effect of the toxin on human leukocytes; and leukocytes from rabbits preimmunized with SO remained refractory to chemotactic suppression.


Using biomarkers to predict clinical outcomes in multiple sclerosis.
Long-term outcomes in multiple sclerosis (MS) are highly varied and treatment with disease-modifying therapies carries significant risks. Finding tissue biomarkers that can predict clinical outcomes would be valuable in individualising treatment decisions for people with MS. Several candidate biomarkers-reflecting inflammation, neurodegeneration and glial pathophysiology-show promise for predicting outcomes. However, many candidates still require validation in cohorts with long-term follow-up and evaluation for their independent contribution in predicting outcome when models are adjusted for known demographic, clinical and radiological predictors. Given the complexity of MS pathophysiology, heterogeneous panels comprising a combination of biomarkers that encompass the various aspects of neurodegenerative, glial and immune pathology seen in MS, may enhance future predictions of outcome.


How Swallow Pressures and Dysphagia Affect Malnutrition and Mealtime Outcomes in Long-Term Care.
Malnutrition is a major cause of hospitalization for residents of long-term care facilities (LTC). Dysphagia is thought to contribute to malnutrition. Tongue weakness is suggested to predict poor food intake, longer meals, and dysphagia. We explored the relationships between tongue strength, dysphagia, malnutrition and mealtime outcomes in LTC residents. Data were collected from 639 LTC residents (199 male), aged 62-102 (mean 87). Maximum isometric tongue pressures (MIPs) and saliva swallow pressures (MSPs) were measured using the Iowa Oral Performance Instrument. Participants also completed the Screening Tool for Acute Neuro Dysphagia. Nutrition status was assessed using the Patient-Generated Subjective Global Assessment. A series of repeated meal observations provided measures of meal duration and calories consumed. Mean MIPs were 33 kPa (95% CI 29-37) and MSPs were 26 kPa (95% CI 23-29). The odds of showing signs of dysphagia were 3.7 times greater in those with MSPs less than 26 kPa (p < 0.05). The odds of being malnourished were almost double in those showing signs of dysphagia. Co-occurrence of dysphagia and malnutrition was seen in 29%. Residents with low MSPs also had significantly longer mealtime durations (MTD) (p < 0.05). Moreover, those with both low swallowing pressures and suspected dysphagia consumed fewer calories/minute (p < 0.05) and had significantly longer MTDs (p < 0.05). This study confirms associations between tongue weakness, signs of dysphagia, mealtime outcomes and malnutrition among LTC residents. These findings suggest that saliva swallow pressure measures may be helpful for early identification of dysphagia and nutritional risk in this population.


"Activated" keratinocyte phenotype is unifying feature in conditions which predispose to squamous cell carcinoma of the skin.
While some cutaneous squamous cell carcinomas (SCC) arise from predisposing conditions such as burn scars, draining sinuses, and chronic, nonhealing wounds, the vast majority of these tumors arise from actinically damaged epidermis. It has been shown previously that keratinocytes within healing wounds show an "activated" immunophenotype when stained with antibodies to psi-3, involucrin, filaggrin, and cytokeratins. A similar pattern has been seen in keratinocytes from patients with recessive dystrophic epidermolysis bullosa (RDEB), in whom the incidence of cutaneous SCC is markedly increased. We tested the hypothesis that actinic keratoses (AK), recognized as precursors in the development of the majority of SCC, would show a similar activated immunophenotype when stained with the antibody panel described above. We examined 10 AK, biopsied from the facies and extremities of ten patients, ages 60 to 80, with antibodies to psi-3, involucrin, filaggrin, and AE1. All lesions examined had an immunostaining pattern indistinguishable from that seen in keratinocytes from patients with RDEB or within healing wounds. There was suprabasilar staining of keratinocytes with antibodies to psi-3 and AE1. Involucrin and filaggrin was expressed by all keratinocytes above the midstratum spinosum. Within the acrosyringia and acrotrichia, the staining pattern was that of the normal epidermis, i.e., AE1 staining of basal keratinocytes, granular layer staining of involucrin and filaggrin, and absence of psi-3 expression. These data suggest that an activated keratinocyte phenotype is a unifying feature in conditions which predispose to development of cutaneous SCC.


Examining the general practitioner's role in health education: a critical review.
Recent international and national policy documents have placed great emphasis on health promotion programmes and one of the key figures in these programmes has been the general practitioner and the primary health care team. This review, drawing mainly on evidence from the United Kingdom, critically reviews the role of the general practitioner in health promotion and disease prevention. The first part of the paper examines the assumptions in contemporary policy and outlines alternative roles for the general practitioner in health education. The second part focuses on the social organization of the doctor-patient relationship and its influence on health education, specifically examining the structure of the doctor-patient relationship, the uncertainties in scientific health knowledge and the lay perspective on health.


Psychoeducational intervention focused on healthy living improves psychopathological severity and lifestyle quality in psychiatric patients: preliminary findings from a controlled study.
Individuals with psychiatric disorders incur an increased risk of morbidity and mortality, with higher prevalence of cardio-metabolic risk factors s largely contributing to a significant reduction in life expectancy. The aim of the present study was at evaluating the clinical effectiveness of an educational intervention targeting lifestyle habits in patients with mood and psychotic disorders. Patients (n = 32) were randomly assigned to receive, in addition to the pharmacological treatment, either five sessions of group psychoeducation focused on healthy lifestyle or five sessions of a control group therapy. Both psychopathological severity (i.e. the brief psychiatric rating scale) and lifestyle quality (i.e. physical activity, sleep quality and adherence to the Mediterranean diet) improved significantly over time in patients who underwent specific psychoeducational sessions but not in the controls. These findings add to the accumulating evidence that educational interventions focused on lifestyle habits can ameliorate general and mental health in patients with psychiatric disorders and suggest that educational programs represent an effective non-pharmacological intervention to manage drug-induced cardiometabolic disturbances.


Comparison of heat stress measuring techniques in a steel mill.
Three heat stress measurement devices, currently used to assess heat exposure in the workplace, were compared in indoor and outdoor environments at a steel mill in Orem, Utah, during the month of July, 1982. Sixty sets of environmental data from a total of fourteen different test locations were collected and analyzed. Significance tests, linear regression equations and correlation coefficients were calculated to determine comparability and relationships between standard WBGT Index and Botsball (WGT) and also between standard WBGT Index and an electronic WBGT Index Meter. The results of the significance testing between the standard WBGT, Botsball, and electronically generated WBGT showed that the electronically generated WBGT means were statistically much closer to the standard WBGT values than were the Botsball (WGT) results. The statistical analysis performed shows that a high correlation of variation exists between the standard WBGT and both the Botsball and the electronically generated WBGT.


Organized Disassembly of Photosynthesis During Programmed Cell Death Mediated By Long Chain Bases.
In plants, pathogen triggered programmed cell death (PCD) is frequently mediated by polar lipid molecules referred as long chain bases (LCBs) or ceramides. PCD interceded by LCBs is a well-organized process where several cell organelles play important roles. In fact, light-dependent reactions in the chloroplast have been proposed as major players during PCD, however, the functional aspects of the chloroplast during PCD are largely unknown. For this reason, we investigated events that lead to disassembly of the chloroplast during PCD mediated by LCBs. To do so, LCB elevation was induced with Pseudomonas syringae pv. tomato (a non-host pathogen) or Fumonisin B1 in Phaseolus vulgaris. Then, we performed biochemical tests to detect PCD triggering events (phytosphingosine rises, MPK activation and H2O2 generation) followed by chloroplast structural and functional tests. Observations of the chloroplast, via optical phenotyping methods combined with microscopy, indicated that the loss of photosynthetic linear electron transport coincides with the organized ultrastructure disassembly. In addition, structural changes occurred in parallel with accumulation of H2O2 inside the chloroplast. These features revealed the collapse of chloroplast integrity and function as a mechanism leading to the irreversible execution of the PCD promoted by LCBs.


C-terminal loop of Streptomyces phospholipase D has multiple functional roles.
We have recently shown that two flexible loops of Streptomyces phospholipase D (PLD) affect the catalytic reaction of the enzyme by a comparative study of chimeric PLDs. Gly188 and Asp191 of PLD from Streptomyces septatus TH-2 (TH-2PLD) were identified as the key amino acid residues involved in the recognition of phospholipids. In the present study, we further investigated the relationship between a C-terminal loop of TH-2PLD and PLD activities to elucidate the reaction mechanism and the recognition of the substrate. By analyzing chimeras and mutants in terms of hydrolytic and transphosphatidylation activities, Ala426 and Lys438 of TH-2PLD were identified as the residues associated with the activities. We found that Gly188 and Asp191 recognized substrate forms, whereas residues Ala426 and Lys438 enhanced transphosphatidylation and hydrolysis activities regardless of the substrate form. By substituting Ala426 and Lys438 with Phe and His, respectively, the mutant showed not only higher activities but also higher thermostability and tolerance against organic solvents. Furthermore, the mutant also improved the selectivity of the transphosphatidylation activity. The residues Ala426 and Lys438 were located in the C-terminal flexible loop of Streptomyces PLD separate from the highly conserved catalytic HxKxxxxD motifs. We demonstrated that this C-terminal loop, which formed the entrance of the active well, has multiple functional roles in Streptomyces PLD.


Competitive yeast fermentation with selective flocculation and recycle.
Continuous fermentations were carried out involving competition between two strains of Saccharomyces cerevisiae. One of the strains has a lower specific growth rate and is very flocculent, whereas the faster-growing strain is nonflocculent. The product stream from the chemostat was fed into an inclined settler where the flocculent strain was partially separated from the nonflocculent strain as a result of the higher sedimentation rate of the flocculent cells. The underflow from the inclined settler, which was concentrated and enriched with flocculent cells, was recycled to the chemostat. When no recycle was used, the faster-growing, nonflocculent yeast rapidly overtook the culture. With selective recycle, however, the experiments demonstrated that the slower-growing flocculent yeast could be maintained as the dominant species. A theoretical development is also presented in order to describe the competition between two strains in the bioreactor-settler system. The concept of selective recycle via selective flocculation and sedimentation offers a possible means of maintaining unstable recombinant microorganisms in continuous fermentations.


Comparative analysis of big five personality traits in obese and normal weight type 2 diabetes mellitus patients.
Type 2 diabetes has multifactorial causation, with obesity and metabolic dysregulation being two of them. Personality traits are also known to influence many metabolic processes and have been associated with the pathogenesis of diabetes as well as obesity. The objective of the study was to analyze the differences in the big five personality traits of normal-weight type 2 diabetes mellitus, obese type 2 diabetes mellitus patients, and healthy controls. A total of 70 subjects were included in the study after outpatient-based screening, of which 40 were type 2 diabetes patients (20 obese and 20 normal weight) and 30 were healthy controls. After the anthropometric screening, the personality assessment of the subjects was done using the Neuroticism, Extraversion, Openness, Agreeableness, and Conscientiousness-Five Factor Inventory (NEO-FFI). The differences in the scores of each trait for every group were analyzed by analysis of variance (ANOVA) with Tukey's honest significant difference (HSD) post hoc corrections. The difference in the scores between controls and diabetes patients was also compared by independent samples t-test. The neuroticism score was significantly higher in both the normal-weight diabetes group (P = 0.01) and obese diabetes group (P = 0.02) as compared to the control group. All diabetes patients when compared with healthy controls had a significantly higher neuroticism score (P = 0.00) while their score of openness was significantly lower (P = 0.035) than healthy controls. This study identifies the association of personality with type 2 diabetes mellitus. The diabetes patients have higher neuroticism and lesser openness to experience as traits of personality. Importantly, this association is present irrespective of the obesity status of the patients.


Body composition, food intake, and brown fat thermogenesis in pregnant Djungarian hamsters.
Strategies for balancing energy storage and expenditure during pregnancy were examined in the Djungarian hamster. In expt 1, pregnant hamsters lost nearly 50% of their body lipid stores, even though they showed significant increases in body weight and food intake during the latter half of pregnancy. The increase in body weight was accounted for by the growth of the uteri, fetuses, and placentas. The water and fat-free dry contents of the maternal carcasses did not differ from those of the unmated controls. In expt 2, brown fat cytochrome-c oxidase activity (mitochondrial content) was significantly lower in the late- but not early-pregnant females relative to the nonpregnant controls. Specific GDP-binding levels did not differ significantly among these groups. Thus an overall decrease in total thermogenic activity in brown fat would be expected during late pregnancy. The loss of carcass lipid, despite decreased brown fat thermogenesis and increased food intake, suggests that substantial increases in energy expenditure occur in pregnant females that are not related to heat production in brown fat. The present results are not consistent with traditional models of energy balance during pregnancy. Some of the inconsistencies may be related to differences between hoarding and nonhoarding families of rodents, whereas others may be due to the fact that the traditional model is based on a possibly exceptional species, the laboratory rat.


It takes a village.
In this issue of Blood, Bhatia et al demonstrate the critical importance of an adherence to oral chemotherapy regimens in attaining cure for children with acute lymphoblastic leukemia (ALL) and identify race-specific determinants of adherence.


Current achievements in the mechanically pretreated conversion of plant biomass.
At present, "mechanochemistry" is synonymous with "grinding," according to the views of a significant number of scientists and technologists. Often, one comes across the opinion that "the less the particle size, the better." The cases of considering chemical reactions occurring during pretreatment, as well as considering changes in the ultrastructure of cell walls are extremely rare. Also, the wrong choice of the type of mechanical impact and the equipment used in most cases leads to excessive consumption of electrical energy and reduce economic efficiency. The review presents the currently available published data on mechanically activated processes for the pretreatment of plant materials and shows that when using mechanical treatment, it is necessary to look more closely at the phenomena occurring, rather than reducing everything to the production of fine and ultrafine powders. As a result of mechanical action, active surface radicals can form, hydrothermal chemical processes can occur, and mechanocomposites can form. The role of interphase processes, changes in surface chemistry, related dimensional effects, and the disordering of the crystal structure and amorphization should be taken into account. In addition, the physicochemical insights in mechanical pretreatment make it possible to more efficiently use the energy delivered to the material, and, consequently, increase the economic efficiency of the activation process.


Evidence-based macro practice: addressing the challenges and opportunities.
Steps involved in the process of evidence-based practice are reviewed in terms of their applicability to macro-level social work. These steps include (1) posing answerable questions; (2) locating credible research studies, (3) critically evaluating this research and its applicability to a practice situation; 4. selecting an intervention(s) by integrating research evidence with professional expertise, ethical standards, and the situation's unique circumstance; and (5) evaluating outcomes. This process has clear and compelling applications to macro-practice. A substantial body of research applicable to macro-level social work currently exists. Widespread adoption of EBP has great potential to improve social work programs and policies.


Tailoring treatment duration to 12 to 16 weeks in hepatitis C genotype 2 or 3 with rapid virologic response: systematic review and meta-analysis of randomized controlled trials.
Current treatment for genotype (GT) 2 or 3 hepatitis C virus infection is pegylated interferon and ribavirin (RBV) 800 mg/d for 24 weeks. This meta-analysis was carried out to assess whether the treatment duration can be reduced in patients with rapid virologic response (RVR) METHODS: Literature was searched for studies comparing short-term (12 to 16 wk) and 24 weeks treatment in GT 2 or 3 with RVR. Six studies (n=2434) were included and data on end-of-treatment response (ETR), sustained virologic response (SVR), and relapse rates (RR) were obtained. Pooled odds ratio (95% CI) for SVR and RR were 0.54 (0.35-0.85; P=0.008) and 3.12 (1.99-4.91; P<0.00001) favoring 24 weeks of treatment. Reducing treatment duration to 12 to 16 weeks and retreating relapses for 24 weeks was cost-effective. Reducing treatment duration to 12 to 16 weeks for GT 2 or 3 HCV patients with RVR is associated with a lower SVR and a higher RR. Advantages of short-term treatment include better patient compliance, lower rate of adverse effects, and cost. Short-term treatment may be an option for patients unable to tolerate treatment. Further studies are needed to identify factors predicting relapse with short-term treatment in GT 2 or 3 patients with RVR.


BiP is feed-back regulated by control of protein translation efficiency.
The lumenal endoplasmic reticulum (ER) protein BiP, among its other functions, is believed to serve as an ER stress sensor, triggering the so-called 'unfolded protein response' or UPR. For this role, BiP levels are critical. Indeed, here we show that BiP expression is tightly controlled at a post-transcriptional level. Thus, an artificial increase in cellular BiP mRNA does not lead to increased synthesis of BiP in unstressed cells, and, consequently, protein levels remain constant. Under ER stress conditions, however, this homeostatic restriction is alleviated, and independent of transcript levels, the translation efficiency of BiP transcripts is enhanced, allowing the cells to produce more protein. We additionally show that this regulation is independent of elements in the 5' and 3' UTR of BiP mRNA, which rather points to a novel type of translational feedback control. BiP is the first example of a lumenal protein whose expression is controlled at a translational level. The implications of these findings with respect to cellular stress are discussed.


An Arabidopsis thaliana pectin acetylesterase gene is upregulated in nematode feeding sites induced by root-knot and cyst nematodes.
By using differential display, gene expression was investigated in Arabidopsis thaliana roots shortly after nematode infection, and a putative pectin acetylesterase (PAE) homolog (DiDi 9C-12) was found to be upregulated. PAEs catalyze the deacetylation of pectin, a major compound of primary cell walls. mRNA in situ hybridization experiments showed that the expression of DiDi 9C-12 was enhanced very early after infection in initiating giant-cells and in cells surrounding the nematodes. Later on, the level of DiDi 9C-12 mRNA was lower in giant-cells and transcripts were mainly found in parenchyma, endodermis, and pericycle cells of the root gall. Twenty days after infection, DiDi 9C-12 transcripts could no longer be detected. DiDi 9C-12 transcripts were also found in young syncytia and in the cells surrounding the expanding syncytium. Our results suggest that plant parasitic nematodes can modulate the rapid growth of the feeding cells and the expansion of the root gall by triggering the expression of DiDi 9C-12. PAEs, which probably act together with a range of other pectin-degrading enzymes, could be involved in softening and loosening the primary cell wall in nematode-infected plant roots.


A transition metal- and photosensitizer-free approach for site-selective (hetero)arylation of polychlorinated heteroarenes.
We have developed an effective photochemical method for site-selective (hetero)arylation of polychlorinated heteroarenes. This approach eliminates the need for transition metal catalysts and photosensitizers by relying on in situ formation of unconventional electron donor-acceptor (EDA) complexes between two substrates and a basic additive. Our protocol yields chlorine-containing biaryl heterocyclic compounds with high levels of site-selectivity, which are of significant importance in both synthetic and medicinal chemistry.


Is glycemic control in patients with type-2 diabetes in Rawalpindi improving?
Glycaemic control is critical for managing diabetes and related complications. Considering high prevalence of Diabetes in Pakistan, our study aimed to assess the status of glycaemic control in Type-II Diabetics by measurement of HbA1c from 2005-2007 at Rawalpindi. We also evaluated changes in its trends in relation with sex and age. It was a retrospective analysis of data from Clinical Pathology Laboratory, Army Medical College, Rawalpindi during 2005-2007. A total of 2875 patients, aged 24-70 years, taking oral hypoglycaemic agents, were included. HbA1c was measured by using Human kit. International Diabetes Federation guidelines, < or = 6.5%, 6.6%-8.4% and > or = 8.5% were used to classify patients into good, fair and poor control categories. The number of patients (n = 2875) tested for HbA1c increased from 904,974 to 997 during 2005-2007. The patients had an age of 48 +/- 13 years and comprised of 54% males and 46% females. Improvement in patient's glycaemic control among the three categories during 2005 to 2007 was as follows: good (41% vs 47%), fair (38% vs 40%) and poor (21% vs 13%) respectively. The average HbA1c values improved from 7.25 % in 2005 to 6.69% in 2007 (p < 0.05). Overall, males (45%) and youngest age group (53%) patients had good diabetic control. Glycaemic control improved in diabetic patients from 41% to 47% during 2005-2007 at Rawalpindi. Males, especially the youngest patients comprised majority of good control population. For effective disease management and optimal HbA1c values, a combined effort by the patient and physician is required.


Telomerase Inhibition and Human Telomeric G-Quadruplex DNA Stabilization by a β-Carboline-Benzimidazole Derivative at Low Concentrations.
Guanine rich regions in DNA, which can form highly stable secondary structures, namely, G-quadruplex or G4 DNA structures, affect DNA replication and transcription. Molecules that stabilize G4 DNA have become important in recent years. In this study, G4 DNA stabilization, inhibition of telomerase, and anticancer activity of synthetic β-carboline-benzimidazole derivatives (5a, 5d, 5h, and 5r) were studied. Among them, derivatives containing a 4-methoxyphenyl ring at C1 and a 6-methoxy-substituted benzimidazole at C3 (5a) were found to stabilize telomeric G-quadruplex DNA efficiently. The stoichiometry and interaction of a synthetic, β-carboline-benzimidazole derivative, namely, 3-(6-methoxy-1H-benzo[d]imidazol-2-yl)-1-(4-methoxyphenyl)-9H-pyrido[3,4-b]indole (5a), with human intermolecular G-quadruplex DNA at low concentrations were examined using electrospray ionization mass spectrometry. Spectroscopy techniques indicate that 5a may intercalate between the two stacks of G-quadruplex DNA. This model is supported by docking studies. When cancer cells are treated with 5a, the cell cycle arrest occurs at the sub-G1 phase. In addition, an apoptosis assay and fluorescence microscopy studies using cancer cells indicate that 5a can induce apoptosis. Results of biochemical assays such as the polymerase chain reaction stop assay and telomerase activity assay indicate that 5a has the potential to stabilize G-quadruplex DNA, and thereby, it may interfere with in vitro DNA synthesis and decrease telomerase activity. The results of this study reveal that the β-carboline-benzimidazole derivative (5a) is efficient in G-quadruplex DNA stabilization over double-stranded DNA, inhibits telomerase activity, and induces apoptosis in cancer cells.


Comparative Proteomic Analysis of Toxoplasma gondii RH Wild-Type and Four SRS29B (SAG1) Knock-Out Clones Reveals Significant Differences between Individual Strains.
In T. gondii, as well as in other model organisms, gene knock-out using CRISPR-Cas9 is a suitable tool to identify the role of specific genes. The general consensus implies that only the gene of interest is affected by the knock-out. Is this really the case? In a previous study, we generated knock-out (KO) clones of TgRH88_077450 (SRS29B; SAG1) which differed in the numbers of the integrated dihydrofolate-reductase-thymidylate-synthase (MDHFR-TS) drug-selectable marker. Clones 18 and 33 had a single insertion of MDHFR-TS within SRS29B. Clone 6 was disrupted by the insertion of a short unrelated DNA-sequence, but the marker was integrated elsewhere. In clone 30, the marker was inserted into SRS29B, and several other MDHFR-TS copies were found in the genome. KO and wild-type (WT) tachyzoites had similar shapes, dimensions, and vitality. This prompted us to investigate the impact of genetic engineering on the overall proteome patterns of the four clones as compared to the respective WT. Comparative shotgun proteomics of the five strains was performed. Overall, 3236 proteins were identified. Principal component analysis of the proteomes revealed five distinct clusters corresponding to the five strains by both iTop3 and iLFQ algorithms. Detailed analysis of the differentially expressed proteins revealed that the target of the KO, srs29B, was lacking in all KO clones. In addition to this protein, 20 other proteins were differentially expressed between KO clones and WT or between different KO clones. The protein exhibiting the highest variation between the five strains was srs36D encoded by TgRH_016110. The deregulated expression of SRS36D was further validated by quantitative PCR. Moreover, the transcript levels of three other selected SRS genes, namely SRS36B, SRS46, and SRS57, exhibited significant differences between individual strains. These results indicate that knocking out a given gene may affect the expression of other genes. Therefore, care must be taken when specific phenotypes are regarded as a direct consequence of the KO of a given gene.


Nurses and computers. An international perspective on nurses' requirements.
This paper reports the findings from a Florence Nightingale Foundation Travel Scholarship undertaken by the author in the spring of 2006. The aim of the visit was to explore nurses' attitudes towards, and experiences of, using computers in their practice, and the requirements that they have to encourage, promote and support them in using ICT. Nurses were found to be using computers mainly for carrying out administrative tasks, such as updating records, rather than as information tools to support evidence based practice, or patient information needs. Nurses discussed the systems they used, the equipment provided, and their skills, or more often their lack of skills. The need for support was a frequent comment, most nurses feeling that it was essential that help was available at the point of need, and that it was provided by someone, preferably a nurse, who understood the work context. Three groups of nurses were identified. Engagers; Worried Willing and Resisters. The report concludes that pre-registration education has a responsibility to seek to ensure that newly qualified nurses enter practice as engagers.


Cytokines, synaptic plasticity and network dynamics: a matter of balance.
The modern view of the immune system as a sensitizing and modulating machinery of the central nervous system is now well recognized. However, the specific mechanisms underlying this fine crosstalk have yet to be fully disentangled. To control cognitive function and behavior, the two systems are engaged in a subtle interacting act. In this scenario, a dual action of pro-inflammatory cytokines in the modulation of brain network connections is emerging. Pro-inflammatory cytokines are indeed required to express physiological plasticity in the hippocampal network while being detrimental when over-expressed during uncontrolled inflammatory processes. In this dynamic equilibrium, synaptic functioning and the performance of neural networks are ensured by maintaining an appropriate balance between pro- and anti-inflammatory molecules in the central nervous system microenvironment.


Gliosarcoma: a study of four cases.
Gliosarcomas (GS) are highly malignant and rare tumors of the central nervous system with a poor prognosis. We report here on four patients with GS, the median survival for whom was 9.25 months. Prognosis of GS remains poor, and a multidisciplinary approach (surgery, radiation therapy, and chemotherapy) seems to be associated with slightly more prolonged survival times.


Induced Retro-Differentiation of Human Retinal Pigment Epithelial Cells on PolyHEMA.
Retinal pigment epithelium (RPE) cells represent a great potential to rescue degenerated cells of the damaged retina. Activation of the virtually plastic properties of RPE cells may aid in recovery of retinal degenerative disorders without the need for entire RPE sheet transplantation. Poly (2-hydroxyethyl methacrylate)(PolyHEMA) is one of the most important hydrogels in the biomaterials world. This hydrophobic polymer does not normally support attachment of mammalian cells. In the current study we investigated the effect of PolyHEMA as a cell culture substrate on the growth, differentiation, and plasticity of hRPE cells. hRPE cells were isolated from neonatal human globes and cultured on PolyHEMA and polystyrene substrates (as controls) in 24-well culture plates. DMEM/F12 was supplemented with 10% fetal bovine serum (FBS) and/or 30% human amniotic fluid (HAF) for cultured cells on polystyrene and PolyHEMA coated vessels. Morphology, rate of cell proliferation and cell death, MTT assay, immunocytochemistry and Real-Time RT-PCR were performed to investigate the effects of PolyHEMA on the growth and differentiation of cultured hRPE cells. Proliferation rate of the cells that had been cultured on PolyHEMA was reduced; PolyHEMA did not induce cell death in the hRPE cultures. hRPE cells cultured on PolyHEMA formed many giant spheroid colonies. The giant colonies were re-cultured and the presence of retinal progenitor markers and markers of hRPE cells were detected in cell cultures on PolyHEMA. PolyHEMA seems to be promising for both maintenance and de-differentiation of hRPE cells and expansion of the retinal progenitor cells from the cultures that are originated from hRPE cells. J. Cell. Biochem. 118: 3080-3089, 2017. © 2017 Wiley Periodicals, Inc.


Micro-Raman characterization of high- and low-spin heme moieties within single living erythrocytes.
Raman microspectroscopy was applied to monitor porphyrin perturbation associated with the tense-relaxed (T --> R) state transition of hemoglobin (Hb) within a single red blood cell. The spectra exhibited dramatic changes in the spin state region (1650-1500 cm(-1)) and the methine C-H deformation region (1250-1200 cm(-1)) between the 27- and 54-min interval following reoxygenation. Principal components analysis revealed a sigmoidal curve when the PC1 scores versus time were plotted. The inflection point on the curve corresponded to the T --> R transition point spectrum, indicating the cell is composed of Hb in a mixture of spin states. The results of this work illustrate the dynamics of porphyrin perturbation during erythrocyte respiration and may have applications in the diagnosis and treatment of red blood cell disorders including thalassemia and sickle cell anemia.


Ganglioside glycosyltransferases and newly synthesized gangliosides are excluded from detergent-insoluble complexes of Golgi membranes.
GEM (glycosphingolipid-enriched microdomains) are specialized detergent-resistant domains of the plasma membrane in which some gangliosides concentrate. Although genesis of GEM is considered to occur in the Golgi complex, where the synthesis of gangliosides also occurs, the issue concerning the incorporation of ganglioside species into GEM is still poorly understood. In this work, using Chinese hamster ovary K1 cell clones with different glycolipid compositions, we compared the behaviour with cold Triton X-100 solubilization of plasma membrane ganglioside species with the same species newly synthesized in Golgi membranes. We also investigated whether three ganglioside glycosyltransferases (a sialyl-, a N-acetylgalactosaminyl- and a galactosyl-transferase) are included or excluded from GEM in Golgi membranes. Our data show that an important fraction of plasma membrane G(M3), and most G(D3) and G(T3), reside in GEM. Immunocytochemical examination of G(D3)-expressing cells showed G(D3) to be distributed as cold-detergent-resistant patches in the plasma membrane. These patches did not co-localize with a glycosylphosphatidylinositol-anchored protein used as GEM marker, indicating a heterogeneous composition of plasma membrane GEM. In Golgi membranes we were unable to find evidence for GEM localization of either ganglioside glycosyltransferases or newly synthesized gangliosides. Since the same ganglioside species appear in plasma membrane GEM, it was concluded that in vivo nascent G(D3), G(T3) and G(M3) segregate from their synthesizing transferases and then enter GEM. This latter event could have taken place shortly after synthesis in the Golgi cisternae, along the secretory pathway and/or at the cell surface.


Problem Solving Training for Veterans with Complex Comorbidities: Treatment Delivery Adaptations during COVID-19.
To summarize adaptations due to COVID-19 for VA Problem Solving Training (PST) for clinicians serving medically complex patients and to compare patient mental health outcomes in the year before (2019) and during COVID-19 (2020). Clinicians attended a multi-day workshop and up to 6 months of small-group consultation for two training cases. In 2019 and 2020, 122 Veteran patients completed baseline and posttreatment measures of depression (Patient Health Questionnaire-9), anxiety (Generalized Anxiety Disorder-7 item), and negative problem-solving beliefs (Negative Problem Orientation Questionnaire). Qualitative data were collected on clinician's pandemic-related treatment implementation challenges. Program adaptations during COVID-19 addressed challenges due to delivering treatment by telephone, video, or in person; Veteran patient recruitment barriers; and privacy issues for telephone and video. Veterans in both pre-pandemic and COVID-19 cohorts had significant improvements in depression, anxiety, and negative problem-solving beliefs, with no significant differences in the amount of improvement between the two cohorts. Flexibilities afforded to clinicians delivering the PST training program during the pandemic addressed key obstacles and barriers to recruitment, and implementation did not diminish the effectiveness of the intervention. Findings support continued implementation of the PST training program with added flexibility to treatment delivery beyond the pandemic.


Control of viral infectivity by tripartite motif proteins.
It is of great interest to understand the molecular details of the pathways that constitute species barriers to viral infection. The tripartite motif protein TRIM5alpha has emerged as an important mediator of species-specific retroviral replication and innate immunity. This review considers the role of TRIM5alpha as an antiviral protein in mammals. The methods used to identify species-specific restriction to retroviral infection, and the identification of TRIM5alpha itself, are outlined. TRIM5alpha mediates an early postentry block to sensitive retroviral infection, usually before viral DNA synthesis. Results from mutational analysis of TRIM5alpha and their contribution to a mechanistic model for TRIM5alpha antiviral activity are discussed. The antiviral role of other TRIM proteins is considered, as is the role of TRIM5alpha cytoplasmic bodies.


Quantification of experimental venous thrombus resolution by longitudinal nanogold-enhanced micro-computed tomography.
The assessment of thrombus size following treatments directed at preventing thrombosis or enhancing its resolution has generally relied on physical or histological methods. This cross-sectional design imposes the need for increased numbers of animals for experiments. Micro-computed tomography (microCT) has been used to detect the presence of venous thrombus in experimental models but has yet to be used in a quantitative manner. In this study, we investigate the use of contrast-enhanced microCT for the longitudinal assessment of experimental venous thrombus resolution. Thrombi induced by stenosis of the inferior vena cava in mice were imaged by contrast-enhanced microCT at 1, 7 and 14 days post-induction (n=18). Thrombus volumes were determined longitudinally by segmentation and 3D volume reconstruction of microCT scans and by standard end-point histological analysis at day 14. An additional group of thrombi were analysed solely by histology at 1, 7 and 14 days post-induction (n=15). IVC resident thrombus was readily detectable by contrast-enhanced microCT. MicroCT-derived measurements of thrombus volume correlated well with time-matched histological analyses (ICC=0.75, P<0.01). Thrombus volumes measured by microCT were significantly greater than those derived from histological analysis (P<0.001). Intra- and inter-observer analyses were highly correlated (ICC=0.99 and 0.91 respectively, P<0.0001). Further histological analysis revealed noticeable levels of contrast agent extravasation into the thrombus that was associated with the presence of neovascular channels, macrophages and intracellular iron deposits. Contrast-enhanced microCT represents a reliable and reproducible method for the longitudinal assessment of venous thrombus resolution providing powerful paired data.


Conformational deviation of Thrombin binding G-quadruplex aptamer (TBA) in presence of divalent cation Sr2+: A classical molecular dynamics simulation study.
Thrombin binding TBA-G-quadruplex aptamer (TBA) plays a major role in blood coagulation cascade. The 15-mer TBA sequence tends to form four-stranded TBA-G-quadruplex structure. In this research work, a series of explicit solvent classical MD simulations of the TBA is carried out using different salt (SrCl2) concentrations (0, 50, 100 and 200 mM). Here we have also testified the effect of salt concentration of divalent cation Sr2+ on the conformational change of quadruplex DNA. The structural deviations, fluctuations, torsional angles and the affinity of the ion are explored at different salt concentrations. It is found that the conformation of TBA-G-quadruplex at 0 mM and 50 mM salt concentrations, is very much different than the other salt concentrations (100 mM and 200 mM). Also observed are as follows: (i) no exchange of Sr2+ ion between inside and outside of the channel, (ii) an enhancement in the Sr2+ ion density around the phosphate region of the loop residues as salt concentration increases and (iii) the stacking of T3 and T4 residues of loop-1 that appears up to 50 mM concentration, vanishes as the salt concentration is increased further.


An atypical case of optic disk drusen with nerve fiber layer thickening.
We report an atypical case of optic disk drusen (ODD). A 12-year-old girl complained of blurred vision in both eyes. However, visual acuities in both eyes were 20/20. Fundus examination revealed blurring of the optic disk margins and elevation of the optic disk in both eyes. Initially it was considered that the diagnosis would be papilledema. However, neurologic examination revealed no pathology which would cause the visual field defect and disk elevation. Optical coherence tomography (OCT) scans showed hyperreflectance lesions on the disk and shadowing areas beneath the optic nerve head in both eyes. Orbital ultrasound and orbital and cranial tomography revealed protuberances with hyperechogenicity and calcification in both eyes. It was considered that these findings were consistent with ODD. Repeated visual field tests showed constricted peripheral field loss in both eyes. Using OCT software, peripapillary nerve fiber layer thickening in both eyes corresponded to visual field defects in the superior and inferior quadrants, in which drusen was detected. Despite the extensive literature, in cases of ODD with blurred margins, elevated disks, and visual field defects, the peripapillary nerve fiber layer may be increased due to nerve layer infarct in the area which has calcification.


Conjunctive visual search in individuals with and without mental retardation.
A comprehensive understanding of the basic visual and cognitive abilities of individuals with mental retardation is critical for understanding the basis of mental retardation and for the design of remediation programs. We assessed visual search abilities in individuals with mild mental retardation and in MA- and CA-matched comparison groups. Our goal was to determine the effect of decreasing target-distracter disparities on visual search efficiency. Results showed that search rates for the group with mental retardation and the MA-matched comparisons were more negatively affected by decreasing disparities than were those of the CA-matched group. The group with mental retardation and the MA-matched group performed similarly on all tasks. Implications for theory and application are discussed.


Increased Incidence of Suspected Smoke Inhalation During the Coronavirus Disease 2019 Pandemic: A National Database Study.
The COVID-19 pandemic has forced many Americans to adapt their daily routines. In 2020, there was a significant increase in house fires according to the National Fire Prevention Association (NFPA). The objective of this study was to characterize the changes in suspected smoke inhalations (SSIs) during the first year of the pandemic in the National Emergency Medical Services Information System (NEMSIS). The NEMSIS database was queried for all EMS transports captured between 2017 and 2020. Differences in the incidences of SSIs and fire dispatches in 2020 were estimated using Poisson regression models. There was a 13.4% increase in the incidence of fire dispatches and a 15% increase in SSIs transported in 2020 compared to the previous 3 years. The incidence rate ratio of both fire dispatches (1.271; 95% CI: 1.254-1.288; P < .001) and SSI (1.152; 95% CI: 1.070-1.241; P < .001) was significantly elevated in 2020. The increases in fire dispatches and SSIs observed in the NEMSIS database are in concordance with other literature indicating the increase in fire incidence and morbidity observed during the pandemic. These results should inform fire prevention outreach efforts and resource allocation in burn centers in the event of future pandemic.


Drosophila Klp67A is required for proper chromosome congression and segregation during meiosis I.
Drosophila Klp67A belongs to the Kip3 subfamily of Kinesin-type microtubule catastrophe factors. In primary spermatocytes, loss of klp67A leads to defects in karyokinesis and cytokinesis. We show that these cells formed disorganised, bipolar spindles that contained increased numbers of microtubules. The kinetochore fibres were wavy and bent, whereas astral microtubules appeared abnormally robust and formed cortical bundles. Time-lapse studies revealed that during biorientation, the chromosomes in klp67A mutant cells continued to reorient for about twice as long as those in control cells. Metaphase plates were poorly defined in the mutants and often formed at non-equatorial positions. Consistent with the above abnormalities in chromosome congression, we found that in wild-type cells Klp67A associated with prometaphase/metaphase kinetochores before redistributing to the central spindle at anaphase onset. Although the timing of this redistribution of kinetochores argues against a role in anaphase chromosome segregation, dyads in the mutants disjoined but exhibited greatly diminished poleward velocities. They travelled on average at approximately 34% of the velocity of their wild-type counterparts and often decondensed at non-polar locations. Hypomorphic mutations of klp67A may lead to segregation defects.


Assessment of Evidence Regarding Minimally Invasive Surgery vs. Conservative Treatment on Intracerebral Hemorrhage: A Trial Sequential Analysis of Randomized Controlled Trials.
Introduction: The recent publication of a trial failed to prove the efficacy of minimally invasive surgery (MIS) in patients with intracerebral hemorrhage. The aim of this study was to answer the question: Do we need more trials to compare MIS vs. conservative treatment in these patients? Methods: Databases were searched for relevant randomized trials on MIS (endoscopic surgery or stereotactic evacuation) vs. conservative treatment. The primary outcome was significant neurological debilitation or death at the follow-up, and the secondary outcome was death. Both conventional meta-analysis and trial sequential analysis (TSA) were performed. Results: Twelve trials with 2,049 patients were included. In the conventional meta-analysis, the risk ratios of MIS vs. conservative treatment were 0.82 [95% confidence interval (CI), 0.72-0.94] and 0.74 (95% CI, 0.62-0.88) for the primary and secondary outcomes, respectively. In TSA, the cumulative z curve crossed the superiority boundary, which confirmed an 18.8% relative risk reduction of MIS vs. conservative treatment for the primary outcome. It was also highly likely that MIS would reduce mortality by 24.3%. Several sensitivity analyses suggested the robustness of our results, including different prior settings, including only trials with blind outcome assessment, and the assumption of future trials to be futile. Conclusions: Minimally invasive surgery seems to be more effective than conservative treatment in patients with intracerebral hemorrhage in reducing both morbidity and mortality. Repeating a clinical trial with similar devices, design, and outcomes is unlikely to change the current evidence.


Postoperative wound infections in a children's hospital.
A prospective study was made of postoperative wound infections at Milwaukee Children's Hospital for 1 year. Essentially all procedures requiring a skin incision were included. The clean surgical wound infection rate was 3.1% (26 infections in 849 cases). There were no significant differences in clean wound infection rates among the individual surgeons or among the four busiest surgical services. The occurrence of postoperative wound infections was associated with administration of prophylactic antibiotics, longer duration of surgical procedures and longer hospital stay before and after surgery. About 50% of patients having a clean surgical procedure were given prophylactic antibiotics. Prophylactic antibiotic were given for 4 days or more in about half the cases.


Inflammatory biomarkers as predictors of heart failure in women without obstructive coronary artery disease: A report from the NHLBI-sponsored Women's Ischemia Syndrome Evaluation (WISE).
Women with signs and symptoms of ischemia, no obstructive coronary artery disease (CAD) and preserved left ventricular ejection fraction (EF) often have diastolic dysfunction and experience elevated rates of major adverse cardiac events (MACE), including heart failure (HF) hospitalization with preserved ejection fraction (HFpEF). We evaluated the predictive value of inflammatory biomarkers for long-term HF hospitalization and all-cause mortality in these women. We performed a cross-sectional analysis to investigate the relationships between inflammatory biomarkers [serum interleukin-6 (IL-6), C-reactive protein (hs-CRP) and serum amyloid A (SAA)] and median of 6 years follow-up for all-cause mortality and HF hospitalization among women with signs and symptoms of ischemia, non-obstructive CAD and preserved EF. Multivariable Cox regression analysis tested associations between biomarker levels and adverse outcomes. Among 390 women, mean age 56 ± 11 years, median follow up of 6 years, we observed that there is continuous association between IL-6 level and HF hospitalization (adjusted hazard ratio [AHR] 2.5 [1.2-5.0], p = 0.02). In addition, we found significant association between IL-6, SAA levels and all-cause mortality AHR (1.8 [1.1-3.0], p = 0.01) (1.5 [1.0-2.1], p = 0.04), respectively. In women with signs and symptoms of ischemia, non-obstructive CAD and preserved EF, elevated IL-6 predicted HF hospitalization and all-cause mortality, while SAA level was only associated with all-cause mortality. These results suggest that inflammation plays a role in the pathogenesis of development of HFpEF, as well all-cause mortality.


Ia alloantigen(s) detected on thymocytes by use of a fluorescence-activated cell sorter.
With the increased sensitivity of detection of fluorescence made possible by a fluorescence-activated cell sorter (FACS), Ia antigen(s) have been demonstrated, although very small amounts, on murine thymocytes by using an indirect immunofluorescent technique. Absorption studies indicate that the Ia antigens detected on thymocytes are also present on spleen B cells, however, they do not rule out the possibility that certain Ia antigens may exist only on B cells. These studies suggest that the surface distribution and/or the decreased density of Ia antigens on thymocytes relative to peripheral B cells may preclude their demonstration by more conventional assays. Although these studies demonstrate Ia antigens on less than 50% of thymocytes, the percentage may in fact be much higher since current methods do not allow an upper limit to be assigned.


The TN Visa: The Future of Foreign Workers in Livestock Production.
Agricultural employers have faced extreme challenges in recruiting and retaining an adequate workforce. Various societal changes have made hiring local workers into agricultural jobs difficult. Therefore, there is a growing reliance on foreign workers and visa programs to meet labor demands. One such program, the TN visa, can be an effective and useful tool for recruiting professional labor for livestock operations, and many agricultural employers have already seen its value. It is likely that the use of the TN program will continue to grow in the future. However, there is opportunity for misuse and abuse of the TN program because there are few administrative rules and limited oversight. We offer recommendations to improve the TN program and the well-being of TN professionals including additional oversight of the program, transparency in recruiting and contracting workers, educating TN workers about U.S. labor rights, ensuring fair pay, and allowing a path to work authorization for TN workers' spouses and children who accompany them in the U.S. Clearly, sustainable solutions to the farm labor shortage are needed. As a field, we need to better understand workforce recruitment and retention concerns as well as mechanisms being used to address such concerns and their impact on workers' health, safety, and well-being.


Selective breeding for a multivariate index of ethanol dependence in mice: results from the first five generations.
Starting with a population of genetically heterogeneous mice (HS/lbg), selection for a multivariate index of the ethanol withdrawal syndrome has been initiated. The study uses within-litter selection to minimize inbreeding and includes replicate high, low, and control lines. After five generations, results indicate that selection is proceeding successfully. There is evidence of asymmetry in the selection, i.e., selection is proceeding more rapidly for signs of severe withdrawal than for mild withdrawal signs. The realized heritability after five generations of within-family selection is approximately 0.15. These selected lines should eventually prove useful in determining some of the underlying genetic, physiological, and biochemical mechanisms involved in ethanol dependence.


[Differential diagnosis of fever of unknown origin. A case of adult onset Still disease].
A case of Still's disease in the adult, an uncommon seronegative rheumatoid arthritis-like disease with prominent systemic features is reported. This case did not show the typical clinical features and appeared like a fever of unknown origin. A 60 year-old female was admitted to the hospital for high fever occurred two months before without other important clinical symptoms and signs. Laboratory tests and morphologic images were negative for infectious diseases, tumours and immunological disorders. The course of the disease worsened and an hepatic failure threatened the patient life. The onset of many other typical clinical features, i.e. joints pain, characteristic skin rash, splenomegaly, throat pain, serositis and weight loss, led us to make a sure diagnosis and to save the patient with steroid therapy.


Genetic changes in human fetuses from spontaneous abortion after in vitro fertilization detected by comparative genomic hybridization.
The in vitro fertilization (IVF) technique is becoming a very important approach for infertile disease therapy, but approximately 30% of pregnancies are spontaneously aborted in the first trimester. It is believed that chromosomal abnormality is the major reason for early spontaneous abortion. Although some reports have mentioned cytogenetic changes in spontaneously aborted embryos after IVF, little is known about the comprehensive cytogenetic alterations in these aborted embryos. Here we use the comparative genomic hybridization (CGH) technique to analyze the genetic alterations in 41 spontaneously aborted human specimens after IVF. In this study, 25 of 41 cases (61%) showed chromosomal changes. Among them, autosomes and sex chromosomes were involved in 16 and 11 cases, respectively. Several nonrandom chromosomal changes were identified, including loss of one sex chromosome (six cases) and gains of 22 (four cases), Y (four cases), 21 (three cases), 4 (two cases), and 13 (two cases). Our data support the opinion that chromosome abnormality is one of the major causes of early spontaneous abortion after IVF. The association between chromosome changes in these spontaneously aborted fetuses and maternal age, infertility patterns, infertility causes, and IVF patterns (routine IVF and other methods, including intracytoplasmic sperm injection, egg donation, and embryo donation) were also studied. No significant correlation was found.


The impact of DO and salinity on microbial community in poly(butylene succinate) denitrification reactors for recirculating aquaculture system wastewater treatment.
The interactions between environmental factors and bacterial community shift in solid-phase denitrification are crucial for optimum operation of a reactor and to achieve maximum treatment efficiency. In this study, Illumina high-throughput sequencing was applied to reveal the effects of different operational conditions on bacterial community distribution of three continuous operated poly(butylene succinate) biological denitrification reactors used for recirculating aquaculture system (RAS) wastewater treatment. The results indicated that salinity decreased OTU numbers and diversity while dissolved oxygen (DO) had no obvious influence on OTU numbers. Significant microbial community composition differences were observed among and between three denitrification reactors under varied operation conditions. This result was also demonstrated by cluster analysis (CA) and detrended correspondence analysis (DCA). Hierarchical clustering and redundancy analysis (RDA) was performed to test the relationship between environmental factors and bacterial community compositions and result indicated that salinity, DO and hydraulic retention time (HRT) were the three key factors in microbial community formation. Besides, Simplicispira was detected under all operational conditions, which worth drawing more attention for nitrate removal. Moreover, the abundance of nosZ gene and 16S rRNA were analyzed by real-time PCR, which suggested that salinity decreased the proportion of denitrifiers among whole bacterial community while DO had little influence on marine reactors. This study provides an overview of microbial community shift dynamics in solid-phase denitrification reactors when operation parameters changed and proved the feasibility to apply interval aeration for denitrification process based on microbial level, which may shed light on improving the performance of RAS treatment units.


A comparison of hospice and hospital care for people who die: views of the surviving spouse.
To compare the quality of inpatient care for dying people in St Christopher's Hospice, London and nearby hospitals in 1994 and make comparisons with earlier studies of the same setting, interviews were undertaken with spouses of people who had died from cancer in these settings, matched by age and sex. The subjects comprised 66 people who had died in 1994, 33 of whom had died in the hospice, 33 in local hospitals. The mean age was 70.2, 61% were male. The hospice group were more likely to know that they were dying and less likely to be admitted as emergencies. Treatment for pain, breathlessness and nausea from both sources provided relief in almost all cases. Most information about the illness was given by hospital doctors before hospice care occurred. Where it occurred, communication by hospice staff was judged better than that by hospital doctors. Staff in hospitals were more likely to be judged 'very busy'. Hospice respondents were less likely to want improvements, and more likely to judge the institution as being 'like a family'. Earlier studies had shown a trend for symptom control to have improved in hospitals but for difference in the psychosocial climate to favour the hospice, By 1994, this latter difference was still obtained. We stress the role of hospital staff and general practitioners in helping patients accept a terminal prognosis, so that better-planned care can proceed. The busy public atmosphere of some hospital wards may not be conducive to the good care of dying people.


Impact of continuous quality improvement on selection of pacing mode and rate of complications in permanent pacing.
To improve pacing mode selection and to reduce complications of pacing using continuous quality improvement. Criterion standard study. Comparison of implantations from 1992-94 with preset standards. Implementation of corrections in 1994 and re-evaluation in 1995, with one year follow up of all patients. Tertiary hospital. Consecutive patients implanted with a pacemaker from January 1992 to October 1993, 361 patients; October 1993 to June 1994, 115 patients; and January 1995 to October 1995, 140 patients. Reasons for not choosing physiological pacing and complications of pacemaker implantation. Most frequent reasons for not selecting physiological pacing for patients in sinus node disease were age (12.8%, 5 of 39) and technical problems (12.8%, 5 of 39); and for patients in atrioventricular block, age (31.4%, 16 of 51), and disability due to other diseases (13.7%, 7 of 51). To improve the standards, age as a sole reason for not selecting physiological pacing was disregarded and VDD pacing was introduced. Follow up showed fulfillment of standards. Cost analysis indicated minimally increased expenses of pacing hardware and no additional costs of procedures. A high rate of complications (16.2%, 77 of 476) was found related to atrial lead displacement (10.2%, 19 of 186), and to subclavian puncture from January 92-June 94. To reduce complications use of atrial screw-in leads and cephalic cut down were encouraged. Follow up showed significant reduction of complications from January 92-June 94 (77 of 476) compared with January 95-October 95 (12 of 140) (P = 0.03). Better compliance with international pacing guidelines was obtained by registration of reasons for deviations followed by corrections of procedures. By using screw-in leads and by using cephalic cut down the set standards were met.


Alcohol-induced alterations in serum immunoglobulin e (IgE) levels in human subjects.
The association of alcohol intake with total serum IgE concentrations in humans is discussed in the present review. The possible relationship of regular alcohol intake with both the risk of allergic sensitization and serum allergen-specific IgE values is also reviewed. Several studies consistently show that total serum IgE concentrations are increased in alcoholics when compared with healthy controls. Total serum IgE levels decrease after ethanol abstinence in alcoholics. Total serum IgE is increased in moderate alcohol consumers with respect to abstainers. Alcohol consumption in mothers may be associated with increased cord blood IgE levels in their offspring. IgE elevation in alcohol consumers is independent of potential confounders such as age, sex, liver disease, cigarette smoking or atopic status. Experimental studies in animals further support that ethanol administration is followed by an increase in serum IgE concentrations. In atopic patients, regular alcohol consumption is associated with increased serum specific IgE levels against some aeroallergens. Preliminary reports suggest that alcohol intake is associated to variable risk of sensitization to some aeroallergens. The possible mechanisms of alcohol-induced alterations in IgE levels and IgE-mediated diseases are discussed.


Hydrophobic DES Based on Menthol and Natural Organic Acids for Use in Antifouling Marine Coatings.
Marine biofouling negatively impacts industries with off-shore infrastructures, such as naval, oil, and aquaculture. To date, there are no ideal sustainable, economic, and environmentally benign solutions to deal with this phenomenon. The advances achieved in green solvents, as well as its application in different industries, such as pharmaceutical and biotechnology, have promoted the emergence of deep eutectic systems (DES). These eutectic systems have applications in various fields and can be revolutionary in the marine-based industrial sector. In this study, the main objective was to investigate the potential use of hydrophobic DES (HDES) based on menthol and natural organic acids for their use as marine antifouling coatings. Our strategy encompassed the physicochemical characterization of different formulations, which allowed us to identify the most appropriate molar ratio and intermolecular interactions for HDES formations. The miscibility of the resulting HDES with the marine coating has been evaluated and proven to be successful. The Men/OL (1:1) system proved to be the most promising in terms of cost-production and thus was the one used in subsequent antifouling tests. The cytotoxicity of this HDES was evaluated using an in vitro cell model (HaCat cells) showing no significant toxicity. Furthermore, the application of this system incorporated into coatings that are used in marine structures was also studied using marine species (Mytilus edulis mussels and Patella vulgata limpets) to evaluate both their antifouling and ecotoxicity effects. HDES Men/OL (1:1) incorporated in marine coatings was promising in reducing marine macrofouling and also proved to be effective at the level of microfouling without viability impairment of the tested marine species. It was revealed to be more efficient than using copper oxide, metallic copper, or ivermectin as antifouling agents. Biochemical assays performed on marine species showed that this HDES does not induce oxidative stress in the tested species. These results are a strong indication of the potential of this HDES to be sustainable and efficiently used in marine fouling control technologies.


Comparison the effects of topical application of olive and calendula ointments on Children's diaper dermatitis: A triple-blind randomized clinical trial.
This study compares the effective of of topical application of olive and calendula ointments on childrens' diaper dermatitis (DD). This triple-blind clinical trial was conducted on 73 healthy children under the age of 2 years with non-severe and not infected DD, referred to a pediatric healthcare center in Tabriz, Iran. The children were assigned to 1.5% olive ointment (n = 37) and 1.5% calendula ointment (n = 39) using a random block method with the ratio of 2:2. The severity of DD in both groups was measured and compared on a six-point scale on days 0 (before the intervention) and 3, 5, and 7 after interventions. The findings releaved there was not significant stastistical difference between the olive oil and calendula groups in terms of severity of DD in the third, fifth and seventh days. No adverse effect was reported from either of the medications in this study. The external validity and consequently the ability to generalize the findings may be diminished as this study was conducted at a single site. Owing to olive ointment and calendula ointment providing the same results in the healing of DD, olive ointment can be used as an alternative case to DD.


Two androsterone derivatives as inhibitors of androgen biosynthesis.
The title compounds, (3R,5S,5'R,8R,9S,10S,13S,14S)-10,13-dimethyl-5'-(2-methylpropyl)tetradecahydro-6'H-spiro[cyclopenta[a]phenanthrene-3,2'-[1,4]oxazinane]-6',17(2H)-dione, C(26)H(41)NO(3), (I), and methyl (2R)-2-[(3R,5S,8R,9S,10S,13S,14S)-10,13-dimethyl-2',17-dioxohexadecahydro-3'H-spiro[cyclopenta[a]phenanthrene-3,5'-[1,3]oxazolidin-3'-yl]]-4-methylpentanoate, C(28)H(43)NO(5), (II), possess the typical steroid shape (A-D rings), but they differ in their extra E ring. The azalactone E ring in (I) shows a half-chair conformation, while the carbamate E ring of (II) is planar. The orientation of the E-ring substituent is clearly established and allows a rationalization of the biological results obtained with such androsterone derivatives.


Inspiratory muscle training: integrative review.
This article provides a critical review of inspiratory muscle training (IMT) in chronic obstructive pulmonary disease (COPD). Although extensive research on IMT has accumulated, its benefits have been debated, primarily because of methodological limitations of studies. Using relevant key words, multiple databases were searched from 1966. Selected studies used PImax (maximal inspiratory pressure) as an outcome variable. Overall, research demonstrated that a standard protocol of 30% or higher for a duration of 20 to 30 minutes per day for 10 to 12 weeks improves dyspnea and inspiratory strength and endurance with either inspiratory resistive or inspiratory threshold training. Regardless of method, IMT protocols for people with COPD and inspiratory muscle weakness and dyspnea are generally safe, feasible, and effective. Patient selectivity and study of subgroups are recommended.


The virtual asthma guideline e-learning program: learning effectiveness and user satisfaction.
Effective educational tools are important for increasing adherence to asthma guidelines and clinical improvement of asthma patients. We developed a computer-based interactive education program for asthma guideline named the Virtual Learning Center for Asthma Management (VLCAM). We evaluated the usefulness of program in terms of its effects on user awareness of asthma guideline and level of satisfaction. Physicians-in-training at tertiary hospitals in Korea were enrolled in a cross-sectional questionnaire survey. The e-learning program on asthma guideline was conducted over a 2-week period. We investigated changes in the awareness of asthma guideline using 35-item self-administered questionnaire aiming at assessing physicians' knowledge, attitude, and practice. Satisfaction with the program was scored on 4-point Likert scales. A total of 158 physicians-in-training at six tertiary hospitals completed the survey. Compared with baseline, the overall awareness obtained from the scores of knowledge, attitude, and practice was improved significantly. Participants were satisfied with the VLCAM program in the following aspects: helpfulness, convenience, motivation, effectiveness, physicians' confidence, improvement of asthma management, and willingness to recommend. All items in user satisfaction questionnaires received high scores over 3 points. Moreover, the problem-based learning with a virtual patient received the highest user satisfaction among all parts of the program. Our computer-based e-learning program is useful for improving awareness of asthma management. It could improve adherence to asthma guidelines and enhance the quality of asthma care.


Clinical management of crown fractures.
Contemporary treatment of uncomplicated and complicated crown fractures is presented in this article. New concepts and approaches are discussed in relation to modern research and new restorative materials. Practical suggestions for the recognition and clinical management of various types of crown fractures are described.


Equivalent cross-relaxation rate imaging for sentinel lymph node biopsy in breast carcinoma.
Sentinel lymph node biopsy (SLNB) is an important technique for detecting axillary lymph node metastasis in breast carcinoma patients. However, false-negative results are a problem. Equivalent cross-relaxation rate (ECR) imaging (ECRI) is a measurement method that can be used to quantitatively evaluate a change in the structural organization of lymph nodes by magnetic resonance imaging (MRI). We performed axillary ECRI in an attempt to decrease the false-negative results of SLNB. Regions without metastases showed a higher ECR value. On the other hand, regions with metastases showed a lower ECR value. The ECR images were compared with macroscopic histology images in which the presence or absence of axillary lymph node metastasis could be evaluated. ECRI is a potentially useful method for evaluating the efficacy of SLNB.


Pharmacokinetics and pharmacodynamics of Da-Cheng-Qi decoction in the liver of rats with severe acute pancreatitis.
To explore the pharmacokinetics and pharmacodynamics of Da-Cheng-Qi decoction (DCQD) in the liver of rats with severe acute pancreatitis (SAP) based on an herbal recipe tissue pharmacology hypothesis. Healthy male Sprague-Dawley rats were randomly divided into a sham operation group (SOG); a model group (MG); and low-, median- and high-dose treatment groups (LDG, MDG, and HDG, respectively). Different dosages (6, 12 and 24 g/kg for the LDG, MDG, and HDG, respectively) of DCQD were administered to the rats with SAP. The tissue concentrations of aloe-emodin, rhein, emodin, chrysophanol, honokiol, rheo chrysophanol, magnolol, hesperidin, naringenin and naringin in the liver of the treated rats were detected by high-performance liquid chromatography tandem mass spectrometry. Alanine transaminase (ALT) and aspartate transaminase (AST) in serum, inflammatory mediators in the liver and pathological scores were evaluated. The major components of DCQD were detected in the liver, and their concentrations increased dose-dependently. The high dose of DCQD showed a maximal effect in ameliorating the pathological damages, decreasing the pro-inflammatory mediators tumor necrosis factor-α and interleukin (IL)-6 and increasing anti-inflammatory mediators IL-4 and IL-10 in the liver. The pathological scores in the pancreas for the MG were significantly higher than those for the SOG (P < 0.05). DCQD could reduce the pathological scores in the pancreas and liver of the rats with SAP, especially in the HDG. Compared to the SOG, the ALT and AST levels in serum were higher in the MG (P < 0.05), while there was no statistical difference in the MG and HDG. DCQD could alleviate liver damage by altering the inflammatory response in rats with SAP based on the liver distribution of its components.