Dissociation of blood volume and flow in regulation of salt and water balance in burn patients.
The relationship between effective blood volume and related hormones in burn patients following resuscitation is not well understood. Previous reports have suggested that hormone secretion is altered by a resetting of neural control mechanisms. Serum and urine sodium, plasma renin activity, serum ADH, cardiac index, effective renal plasma flow, and total blood volume were measured in seven burn patients (mean age, total burn size, and postburn day: 32 years, 56%, and 9 days, respectively). The same values (with the exception of cardiac index and blood volume) were measured in 10 control patients (mean age, 24 years). The blood volume of patients was measured by 51chromium red blood cell (RBC) labeling and compared to normal predicted values based on body surface area and sex. Mean serum sodium and osmolality were 138 mmol/L (millimolar) and 286 mosm/kg, respectively, in both patients and control subjects. Mean +/- standard error of the mean total blood volume in the patients was low, 81% +/- 4% of predicted values. Cardiac index and renal plasma flow were significantly elevated. Plasma renin activity and antidiuretic hormone (ADH) levels were elevated and altered in the direction expected from blood volume measurements despite the findings of increased blood flow. Dissociation of organ flow and hormonal response suggests that simultaneous direct blood volume measurements are necessary to elucidate factors other than altered neural control settings to explain hormonal changes in the flow phase of injury. Depressed total blood volume appears to promote elevated ADH levels in burn patients following resuscitation. Whether there is an additional role of altered neural control settings remains to be established.


GFR in Healthy Aging: an Individual Participant Data Meta-Analysis of Iohexol Clearance in European Population-Based Cohorts.
Population mean GFR is lower in older age, but it is unknown whether healthy aging is associated with preserved rather than lower GFR in some individuals. We investigated the cross-sectional association between measured GFR, age, and health in persons aged 50-97 years in the general population through a meta-analysis of iohexol clearance measurements in three large European population-based cohorts. We defined a healthy person as having no major chronic disease or risk factors for CKD and all others as unhealthy. We used a generalized additive model to study GFR distribution by age according to health status. There were 935 (22%) GFR measurements in persons who were healthy and 3274 (78%) in persons who were unhealthy. The mean GFR was lower in older age by -0.72 ml/min per 1.73 m2 per year (95% confidence interval [95% CI], -0.96 to -0.48) for men who were healthy versus -1.03 ml/min per 1.73 m2 per year (95% CI, -1.25 to -0.80) for men who were unhealthy, and by -0.92 ml/min per 1.73 m2 per year (95% CI, -1.14 to -0.70) for women who were healthy versus -1.22 ml/min per 1.73 m2 per year (95% CI, -1.43 to -1.02) for women who were unhealthy. For healthy and unhealthy people of both sexes, both the 97.5th and 2.5th GFR percentiles exhibited a negative linear association with age. Healthy aging is associated with a higher mean GFR compared with unhealthy aging. However, both the mean and 97.5 percentiles of the GFR distribution are lower in older persons who are healthy than in middle-aged persons who are healthy. This suggests that healthy aging is not associated with preserved GFR in old age.


Social recognition, participation, and the dynamic between the environment and personal factors of students with deafblindness.
The study describes environmental and personal factors that, from the student perspective, impede participation in education in secondary upper schools by students with postlingual deafblindness. The discussion is framed by the International Classification of Functioning, Disability, and Health. The researchers use the theory of social recognition as a theoretical tool in understanding the dynamics between personal factors and environment in the context of secondary upper-school education. Thirty-four students with deafblindness responded to a questionnaire; the survey's findings indicate experiences of barriers in the natural and social environments that restrict participation. Experience of considerateness--such as concern for the special requirements of students with deafblindness--and experience of the lack of considerateness are the most important factors. Negative roles adapted by some students for themselves may be interpreted as resulting from a lack of recognition, in the form of denigration or insults.


Abdominoplasty with Lymphatic Microsurgery for Patients with Secondary Lower Extremity Lymphedema.
Patients with secondary lower extremity lymphedema often develop suprapubic lymphedema. The authors developed a novel surgical method of shaping the lower abdomen and debulking suprapubic lymphedema with simultaneous reconstruction of lymphatic flow in case of lower extremity lymphedema. A fleur-de-lis skin incision pattern was performed for horizontal and vertical abdominal skin and fat resection. A caudally based isosceles triangular flap was created on the central suprapubic region to reduce wound tension at the intersection of the horizontal and vertical incisions. After resection and debulking of the suprapubic region, a lymphaticovenular anastomosis between the efferent lymphatic vessel of the groin node and the superficial inferior epigastric vein was created or vascularized lymph node transfer to the groin region was performed to restore lymphatic flow. Lymphaticovenular anastomosis and lymph node transfer were also performed at the lower extremities to improve lower extremity lymphedema. Perioperative change in limb volume was evaluated using the lower extremity lymphedema index, and lymphatic function was evaluated by lymphoscintigraphy. Simultaneous abdominoplasty and reconstructive lymphatic microsurgery were performed in 11 patients. The lower extremity lymphedema index improved perioperatively, with a significant difference (p < 0.01). In eight patients who underwent lymphoscintigraphy before and after surgery, the lymphatic function was found to have not deteriorated in any limb. When simultaneous lymphatic microsurgical procedures and careful observation for complications were performed, abdominoplasty resulted in good outcomes in patients with lower extremity lymphedema and suprapubic lymphedema without worsening of lymphedema. Therapeutic, V.


Difference in determinants of ICU admission and death among COVID-19 hospitalized patients in two epidemic waves in Portugal: possible impact of healthcare burden and hospital bed occupancy on clinical management and outcomes, March-December 2020.
Identify factors associated with COVID-19 intensive care unit (ICU) admission and death among hospitalized cases in Portugal, and variations from the first to the second wave in Portugal, March-December 2020. Determinants of ICU admission and death for COVID-19 need further understanding and may change over time. We used hospital discharge data (ICD-10 diagnosis-related groups) to identify factors associated with COVID-19 outcomes in two epidemic periods with different hospital burdens to inform policy and practice. We conducted a retrospective cohort study including all hospitalized cases of laboratory-confirmed COVID-19 in the Portuguese NHS hospitals, discharged from March to December 2020. We calculated sex, age, comorbidities, attack rates by period, and calculated adjusted relative risks (aRR) for the outcomes of admission to ICU and death, using Poisson regressions. We tested effect modification between two distinct pandemic periods (March-September/October-December) with lower and higher hospital burden, in other determinants. Of 18,105 COVID-19 hospitalized cases, 10.22% were admitted to the ICU and 20.28% died in hospital before discharge. Being aged 60-69 years (when compared with those aged 0-49) was the strongest independent risk factor for ICU admission (aRR 1.91, 95%CI 1.62-2.26). Unlike ICU admission, risk of death increased continuously with age and in the presence of specific comorbidities. Overall, the probability of ICU admission was reduced in the second period but the risk of death did not change. Risk factors for ICU admission and death differed by epidemic period. Testing interactions, in the period with high hospital burden, those aged 80-89, women, and those with specific comorbidities had a significantly lower aRR for ICU admission. Risk of death increased in the second period for those with dementia and diabetes. The probability of ICU admission was reduced in the second period. Different patient profiles were identified for ICU and deaths among COVID-19-hospitalized patients in different pandemic periods with lower and higher hospital burden, possibly implying changes in clinical practice, priority setting, or clinical presentation that should be further investigated and discussed considering impacts of higher burden on services in health outcomes, to inform preparedness, healthcare workforce planning, and pandemic prevention measures.


Prenatal cocaine and/or nicotine exposure in rats: preliminary findings on long-term cognitive outcome and genital development at birth.
Prenatal cocaine or nicotine exposure is associated with a variety of teratogenic effects. The current study was conducted to determine their effects alone and in combination on cognitive function and sexual differentiation. Pregnant Long-Evans rats (N = 19) were exposed to either cocaine (15 mg/kg/dose b.i.d. SC on GD 8-20); nicotine (4 mg/kg/day continuous SC infusion on GD 4-20); both nicotine + cocaine; or vehicle only. Birth weight and anogenital distance (AGD) were measured in all pups at birth. Learning and memory were tested in the Morris water maze (MWM) during prepubertal and pubertal ages in five daily consecutive sessions and a sixth session 1 week later and in the radial-arm maze (RAM) during adulthood. In the RAM, a drug challenge of the beta-noradrenergic antagonist propranolol (10-20 mg/kg) was given after acquisition training. Maternal weight gain was reduced 13-42% and offspring birth weight was reduced by 7-12% in all three exposure groups compared to controls. Cocaine decreased the AGD of males (2.68 mm) compared to 2.88 mm in noncocaine-exposed male pups (p < 0.025). A sex-selective cocaine effect was also seen after adjustment of AGD measurements for body weight. With this measure cocaine-treated females showed significantly (p < 0.05) greater AGD than those not exposed to cocaine. In the MWM, there were two types of trials: cued reference memory trials and uncued spatial working memory trials. On cued reference memory trials significant cocaine-induced latency deficits were seen on only the first session. On spatial working memory trials cocaine-induced latency deficits were seen throughout daily training on sessions 1-5, but not the retention session 6, 1 week later. During RAM acquisition, there were no significant differences in choice accuracy between exposure groups. Following propranolol challenge, deficits in choice accuracy were demonstrated in rats prenatally exposed to cocaine or nicotine. These rats did not show any response to propranolol, whereas the controls slightly improved their choice accuracy. The results of this study indicated that prenatal cocaine exposure altered long-term cognitive function under basal conditions in the MWM and drug challenge in the RAM, birth weight, and genital development. Cocaine-induced cognitive deficits were predominately in working memory rather than reference memory or long-term retention. Prenatal nicotine exposure was only observed to alter birth weight and cognitive function in response to propranolol challenge in the RAM.


The significance of the enlargement of the aortic shadow in adult Nigerians.
A study of the width of the aortic shadow and of the cardiothoracic ratios in 183 chest radiographs, of persons over the age of 35 years, shows that hypertension produces a constant enlargment of the aortic shadow. The study suggests that gross enlargement, in the absence of disease of the aorta or of the aortic valves, is a result of hypertension. The authors suggest that this enlargement is valuable in delineating a sub-group of cases of myocardial failure in which the primary cause of failure may be hypertension. Cases with gross aortic arch dilation and no detectable cardiovascular disease often have cardiomegaly. The question of the possibility of remission of untreated hypertension is raised.


Methylation analysis of SFRP genes family in cervical adenocarcinoma.
Aberrant activation of the Wnt/beta-catenin signaling pathway is common in human cancers. Recently, we have shown that secreted frizzled-related proteins (SFRPs) are frequently methylated in cervical squamous cell carcinoma (SCC). Furthermore, reexpression of SFRP1 and SFRP2 could suppress tumor cell transformation and invasion. Here, we want to further investigate the methylation status and function of SFRPs in adenocarcinoma of uterine cervix. The methylation status of SFRPs was assessed in 23 adenocarcinomas (AC), and 45 normal control swabs by methylation-specific polymerase chain reaction and bisulfite sequencing. Then, we used reexpression of SFRP5 in cervical cancer cell lines, HeLa3rd and CaSki, to study the role of SFRP5 in cervical adenocarcinoma by colony formation and invasion assays. Finally, we checked whether SFRP5 could repress the expression of Wnt/beta-catenin downstream genes by quantitative reverse transcription-polymerase chain reaction. The frequency of SFRP genes promoter hypermethylation in adenocarcinoma of cervix samples was 52.2% (12/23), 82.6% (19/23), 65.2% (15/23), and 73.9% (17/23), for SFRP1, SFRP2, SFRP4, and SFRP5, respectively. The frequency of SFRP1, SFRP2, SFRP4, and SFRP5 promoter methylation in adenocarcinoma was significantly higher than in normal control samples (P < 0.001). Restoration of SFRP5 suppressed colony formation and invasive ability and inhibited expression of Wnt/beta-catenin downstream genes. Our data suggest that promoter hypermethylation of SFRPs is associated with cervical adenocarcinoma, which could be used for molecular screening of cervical adenocarcinoma in the future. Moreover, SFRP5 inhibits cervical tumorigenesis through interfering Wnt pathway in vitro.


Cross-validation of an instrument for measuring professionalism behaviors.
To cross-validate an instrument to measure behavioral aspects of professionalism in pharmacy students using a rating scale that minimizes ceiling effects. Seven institutions collaborated to create a 33-item assessment tool that included 5 domains of professionalism: (1) Reliability, Responsibility and Accountability; (2) Lifelong Learning and Adaptability; (3) Relationships with Others; (4) Upholding Principles of Integrity and Respect; and (5) Citizenship and Professional Engagement. Each item was rated based on 5 levels of competency which were aligned with a modified Miller's Taxonomy (Knows, Knows How, Shows, Shows How and Does, and Teaches). Factor analyses confirmed the presence of 5 domains for professionalism. The factor analyses from the 7-school pilot study demonstrated that professionalism items were good fits within each of the 5 domains. Based on a multi-institutional pilot study, data from the Professionalism Assessment Tool (PAT), provide evidence for internal validity and reliability. Use of the tool by external evaluators should be explored in future research.


[Gastroenterology in Germany: results of a survey in hospitals and practices].
In future, the profile of gastroenterology in Germany - as in other countries - will change. New achievements such as capsule endoscopy, aero-scopes and advanced CT and MRI technology and others will become alternatives to conventional endoscopy. Additional emphasis in clinical and outpatient gastroenterology is shifted towards gastrointestinal oncology, dietetics, nutrition and metabolism and in the clinical setting onto infectious diseases, endocrinology/diabetology, intensive care medicine, emergency service and geriatric medicine. The German Confederation of Gastroenterology (BVGD) initiated two Germany-wide surveys on the current diagnostic and therapeutic spectrum in hospitals and out-patient facilities to achieve a base for future discussions regarding the development of gastroenterology. The number of gastroenterologists working in hospitals and in out-patient facilities has been analysed as well as the number of examinations passed successfully during the last few years in the speciality "gastroenterology". The results of this survey offer a valid basis for continuing discussions as to how gastroenterology should develop in Germany.


Barriers to genome editing with CRISPR in bacteria.
Genome editing is essential for probing genotype-phenotype relationships and for enhancing chemical production and phenotypic robustness in industrial bacteria. Currently, the most popular tools for genome editing couple recombineering with DNA cleavage by the CRISPR nuclease Cas9 from Streptococcus pyogenes. Although successful in some model strains, CRISPR-based genome editing has been slow to extend to the multitude of industrially relevant bacteria. In this review, we analyze existing barriers to implementing CRISPR-based editing across diverse bacterial species. We first compare the efficacy of current CRISPR-based editing strategies. Next, we discuss alternatives when the S. pyogenes Cas9 does not yield colonies. Finally, we describe different ways bacteria can evade editing and how elucidating these failure modes can improve CRISPR-based genome editing across strains. Together, this review highlights existing obstacles to CRISPR-based editing in bacteria and offers guidelines to help achieve and enhance editing in a wider range of bacterial species, including non-model strains.


Anatomy and histology of the lacrimal fluid drainage system.
Five human specimens of the lacrimal canaliculus and sac were examined by light and scanning electron microscopy. The superior and inferior lacrimal canaliculi are lined with stratified squamous epithelium that is non-keratinized and non-mucin-producing. The common canaliculus is also lined with stratified squamous epithelium, but its lumen is much narrower than the lumen of the superior and inferior canaliculi. The common canaliculus opens into an ample space called the vestibule, where the epithelium changes to high pseudostratified columnar and then low pseudostratified columnar. The vestibule continues to the infundibulum of the lacrimal sac. The infundibulum is formed by several epithelial folds that radiate from the vestibular opening to the lacrimal sac. The vestibule and infundibulum are consistent transitional structures from the common canaliculus to the lacrimal sac. The connective tissue of the lamina propria from the common canaliculus to the lacrimal sac has two histological characteristics: numerous free cell aggregates (= lymphoid structure) and numerous venules and capillaries (= cavernous structure).


Impact of partial urethral obstruction on bladder function: time-dependent changes and functional correlates of altered expression of Ca²⁺ signaling regulators.
In animal models of partial urethral obstruction (PUO), altered smooth muscle function/contractility may be linked to changes in molecules that regulate calcium signaling/sensitization. PUO was created in male rats, and urodynamic studies were conducted 2 and 6 wk post-PUO. Cystometric recordings were analyzed for the presence or absence of nonvoiding contractions [i.e., detrusor overactivity (DO)]. RT-PCR and Western blots were performed on a subpopulation of rats to study the relationship between the expression of RhoA, L-type Ca(2+) channels, Rho kinase-1, Rho kinase-2, inositol 1,4,5-trisphosphate, ryanodine receptor, sarco(endo)plasmic reticulum Ca(2+)-ATPase 2 and protein kinase C (PKC)-potentiated phosphatase inhibitor of 17 kDa, and urodynamic findings in the same animal. Animals displayed DO at 2 (38%) and 6 wk (43%) post-PUO, increases were seen in in vivo pressures at 2 wk, and residual volume at 6 wk. Statistical analysis of RT-PCR and Western blot data at 2 wk, during the compensatory phase of detrusor hypertrophy, documented that expression of molecules that regulate calcium signaling and sensitization was consistently lower in obstructed rats without DO than those with DO or control rats. Among rats with DO at 2 wk, linear regression analysis revealed positive correlations between in vivo pressures and protein and mRNA expression of several regulatory molecules. At 6 wk, in the presence of overt signs of bladder decompensation, no clear or consistent alterations in expression of these same targets were observed at the protein level. These data extend prior work to suggest that molecular profiling of key regulatory molecules during the progression of PUO-mediated bladder dysfunction may shed new light on potential biomarkers and/or therapeutic targets.


DNA synthesis and multinucleation in embryonic stem cell-derived cardiomyocytes.
The proliferative capacity of embryonic stem (ES) cell-derived cardiomyocytes was assessed. Enriched preparations of cardiomyocytes were isolated by microdissection of the cardiogenic regions of cultured embryoid bodies. The identity of the isolated cells was established by immunocytology, and mitotic activity was monitored by [3H]thymidine incorporation and pulse-chase experiments. ES-derived cardiomyocytes were mitotically active and predominantly mononucleated at 11 days after cardiogenic induction. By 21 days postinduction, cardiomyocyte DNA synthesis was markedly decreased, with a concomitant increase in the percentage of multinucleated cells. Interestingly, the duration of active cardiomyocyte reduplication in the ES system appeared to be roughly similar to that observed during normal murine cardiogenesis. Given these observations, as well as the genetic tractability of ES cells, ES-derived cardiogenesis might provide a useful in vitro system with which to assess the molecular regulation of the cardiomyocyte cell cycle.


Mortality Amenable to Health Care in European Union Countries and Its Limitations.
The concept of amenable mortality is intended to assess health care system performance. It is defined as "premature deaths that should not occur in the presence of timely and effective health care". The purpose of paper is to analyse differences in amenable mortality across European Union countries and to determine the associations between amenable mortality and life expectancy at birth. This is a cross-country and time trend analysis. Data on deaths by cause, and five-year age groups were obtained from the World Health Organization database for the 20 European Union countries, throughout the period from 2002 to 2013. The rates of amenable mortality were expressed by the age-standardised death rates per 100,000 inhabitants. We applied the method of direct standardisation using the European Standard Population. Throughout the explored period, the statistically significant variations of the age-standardised death rates in a relation to the European Union average fluctuated from 78.7 per 100,000 inhabitants (95% CI 72.4-84.9) in France to 374.3 per 100,000 inhabitants (95% CI 350.8-397.7) in Latvia. The leading causes of amenable mortality were ischaemic heart disease, cerebrovascular diseases, and colorectal cancer that accounted for, respectively, 42.2%, 19.5%, and 11.3% of overall amenable mortality. As expected, statistically significant strong negative relationship (R2=0.95; ρ=-0.98) between amenable mortality and life expectancy at birth was proved by linear regression. The concept has several limitations relating to the selection of causes of death and setting age threshold over time, not consideration actually available health care resources in each country, as well as differences in the prevalence of diseases among countries. We found an explicit divide in amenable mortality rates between more developed countries of Western, Northern and Southern Europe, and less developed countries of Central and Eastern Europe. Increasing of amenable mortality may suggest deterioration in health care system performance.


High resistance and control of biological risks in transgenic plants expressing modified plum pox virus coat protein.
Transgenic plums transformed with the plum pox virus coat protein (PPV CP) gene displayed a resistance to the sharka disease (Ravelonandro et al., 1997). However, the expression of PPV CP in transgenic plants may lead to complementation of deficient characteristic of an incoming potyvirus. Indeed, an aphid-intransmissible strain of zucchini yellow mosaic virus (ZYMV-NAT) could be transmitted when encapsidated by the engineered PPV CP (Lecoq et al., 1993). To control such a risk, new PPV CP constructs were designed and introduced into Nicotiana benthamiana genome. In the first construct, the DAG amino acid triplet involved in the potyvirus aphid-transmission was deleted. The second construct encoded a truncated PPV CP lacking its first 140 amino acids. In the last construct, the nucleotides encoding the charged amino-acids R220, Q221 and D264 localized in the core of the PPV CP were removed. A bacterial expression system was developed to show that these deletions prevent the assembly of the PPV CP subunits. For each construct, several transgenic lines were produced and first challenged with several strains of PPV. Two phenotypes of resistance were observed: recovery and immunity. Their biochemical characterization showed that the resistance was RNA-mediated and therefore can be classified as homology-dependent (Jacquet et al., 1998a). Resistant lines producing high level of wild type or modified PPV CP were then inoculated with ZYMV-NAT to perform an aphid-transmission assay. Results of these experiments demonstrated that the use of modified forms of PPV CP genes in transgenic plants provide a good way to control the biological risks associated with heteroencapsidation (Jacquet et al., 1998b).


Optimal selection on two quantitative trait loci with linkage.
A mathematical approach to optimize selection on multiple quantitative trait loci (QTL) and an estimate of residual polygenic effects was applied to selection on two linked or unlinked additive QTL. Strategies to maximize total or cumulative discounted response over ten generations were compared to standard QTL selection on the sum of breeding values for the QTL and an estimated breeding value for polygenes, and to phenotypic selection. Optimal selection resulted in greater response to selection than standard QTL or phenotypic selection. Tight linkage between the QTL (recombination rate 0.05) resulted in a slightly lower response for standard QTL and phenotypic selection but in a greater response for optimal selection. Optimal selection capitalized on linkage by emphasizing selection on favorable haplotypes. When the objective was to maximize total response after ten generations and QTL were unlinked, optimal selection increased QTL frequencies to fixation in a near linear manner. When starting frequencies were equal for the two QTL, equal emphasis was given to each QTL, regardless of the difference in effects of the QTL and regardless of the linkage, but the emphasis given to each of the two QTL was not additive. These results demonstrate the ability of optimal selection to capitalize on information on the complex genetic basis of quantitative traits that is forthcoming.


Multiple protein-protein interactions by RNA polymerase I-associated factor PAF49 and role of PAF49 in rRNA transcription.
We previously demonstrated the critical role of RNA polymerase I (Pol I)-associated factor PAF53 in mammalian rRNA transcription. Here, we report the isolation and characterization of another Pol I-associated factor, PAF49. Mouse PAF49 shows striking homology to the human nucleolar protein ASE-1, so that they are considered orthologues. PAF49 and PAF53 were copurified with a subpopulation of Pol I during purification from cell extracts. Physical association of PAF49 with Pol I was confirmed by a coimmunoprecipitation assay. PAF49 was shown to interact with PAF53 through its N-terminal segment. This region of PAF49 also served as the target for TAF(I)48, the 48-kDa subunit of selectivity factor SL1. Concomitant with this interaction, the other components of SL1 also coimmunoprecipitated with PAF49. Specific transcription from the mouse rRNA promoter in vitro was severely impaired by anti-PAF49 antibody, which was overcome by addition of recombinant PAF49 protein. Moreover, overexpression of a deletion mutant of PAF49 significantly reduced pre-rRNA synthesis in vivo. Immunolocalization analysis revealed that PAF49 accumulated in the nucleolus of growing cells but dispersed to nucleoplasm in growth-arrested cells. These results strongly suggest that PAF49/ASE-1 plays an important role in rRNA transcription.


Medical marijuana use for pediatric oncology patients: single institution experience.
Medical marijuana (MM) is widespread in many medical fields, including oncology, with limited use in pediatric oncology where research is scarce and often shows conflicting results. This research focuses on alleviating side effects of anticancer treatment as an integral part of supportive and palliative care of children with cancer. We report our experience with MM treatment in 50 children, adolescents, and young adults with different types of cancer during 2010-2017. The main indications for prescriptions were nausea and vomiting, decreased mood, disturbed sleep, and pain. The medication was supplied to 30 patients via oil drops (60%) and 11 via smoking (22%), followed by vaporization, capsules, or combinations of various routes. Positive effects were reported by verbal children and parents in 80% of cases. MM was generally well tolerated with few patients reporting toxicity, with the most common adverse reactions being burning in the throat and anxiety attacks in subjects who chose to smoke the product. We conclude that MM may serve as a potentially useful complementary therapy to conventional supportive treatment of children suffering from cancer at the end of life. Further research is needed on the safety and efficacy and the consequences of prolonged use in pediatric populations.


Beyond the basics. Effects of the Eden Alternative model on quality of life issues.
In Life Worth Living, Thomas (1996) proposed that in long-term care facilities for elderly individuals, loneliness, helplessness, and boredom are out of control and are steadily decaying the residents' spirits, adversely affecting quality of life. While Thomas' contention appeals to common sense, no empirical evidence is offered in its support. The purpose of this quasi-experimental study was to assess the impact of implementation of the Eden Alternative model on levels of loneliness, boredom, and helplessness of older residents of a long-term care facility. The model was introduced into the experimental facility on May 1, 1998. The final sample for the experimental group included 21 cognitively intact older adults from a state veterans home (13 men, 8 women, mean age = 76.1). The final control group was composed of 13 residents in a private long-term care facility (11 women, 2 men, mean age = 85.7). A Background Data Sheet, the Geriatric Depression Scale (includes yes or no questions related to helplessness and boredom), and the UCLA Loneliness Scale (Version 3) were administered by an interviewer at baseline and 1-year post-implementation of the Eden Alternative model. Data analysis from the post-implementation phase revealed significant differences between the groups on levels of boredom (z = -2.6, p = .01) and helplessness (z = -2.2, p = .03). Lower levels of distress were found in the experimental group on both boredom and helplessness, but not loneliness. Findings suggest health care professionals and researchers have an opportunity to take a leading role in impacting services related to quality-of-life issues for this important, but often overlooked, population.


Phase II study of erlotinib (OSI-774) in patients with metastatic colorectal cancer.
Erlotinib (Tarceva, OSI-774), a potent epidermal growth factor receptor tyrosine kinase inhibitor (EGFR), was evaluated in a phase II study to assess its activity in patients with metastatic colorectal cancer. In all, 38 patients with metastatic colorectal cancer were treated with erlotinib at a continuous daily oral dose of 150 mg. Radiological evaluation was carried out every 8 weeks and tumour biopsies were performed before treatment and on day 8. Of 31 evaluable patients, 19 (61%) had progressive disease and 12 (39%) had stable disease (s.d.). The median time to progression for those patients having s.d. was 123 days (range 108-329 days). The most common adverse events were rash in 34 patients and diarrhoea in 23 patients. Correlative studies were conducted to investigate the effect of erlotinib on downstream signalling. Tumour tissue correlations were based on usable tissue from eight match paired tumour samples pre- and on therapy, and showed a statistically significant decrease in the median intensity of both pEGFR (P=0.008) and phospho-extracellular signal-regulated kinase (ERK) (P=0.008) a week after commencement of treatment. No other statistically significant change in tumour markers was observed. Erlotinib was well tolerated with the most common toxicities being rash and diarrhoea. More than one-third of evaluable patients had s.d. for a minimum of 8 weeks. Correlative studies showed a reduction in phosphorylated EGFR and ERK in tumour tissue post-treatment.


Ten years results of the Canadian breast intensity modulated radiation therapy (IMRT) randomized controlled trial.
We report the long-term outcomes in patients enrolled in a multicenter randomized controlled trial comparing Intensity Modulated Radiation Therapy (IMRT) with standard wedge radiotherapy. Trial participants were assessed to compare long-term side effects between treatment arms. The primary endpoint was chronic breast pain assessed by trained observers blinded to treatment allocation. Secondary endpoints included cosmesis and quality of life measures. Median follow-up time was 9.8years and 241 patients were available for assessment. There was no significant difference in chronic pain between treatment arms (OR=0.74, range 0.432-1.271). There were also no differences for the secondary endpoints. Univariate and multivariate analyses identified young age (p=0.013) and pain during RT (p<0.001) to be associated with chronic pain. Acute moist desquamation was associated with late subcutaneous fibrosis (p=0.003) and telangiectasia (p=0.039). Pain during RT was associated with a long-term poorer self-assessed cosmetic outcome (p<0.001) and quality of life (p<0.001). Breast IMRT cannot be recommended for all patients to reduce long-term side effects. However, late toxicities were significantly correlated with acute side effects, which are increased in patients having poor dose distribution. Breast IMRT may hence be useful for selected patients.


Successful limb-sparing treatment strategy for diabetic foot osteomyelitis.
Diabetic foot osteomyelitis is common and causes substantial morbidity, including major amputations, yet the optimal treatment approach is unclear. We evaluated an approach to limb salvage that combines early surgical debridement or limited amputation with antimicrobial therapy. We conducted a retrospective cohort study of patients treated between May 1, 2005, and May 31, 2007. The primary end point was cure, defined as not requiring further treatment for osteomyelitis of the affected limb. The secondary end point was limb salvage, defined as not requiring a below-the-knee amputation or a more proximal amputation. Fifty patients with diabetic foot osteomyelitis met the study criteria. Initial surgical management included local amputation in 43 patients (86%) and debridement without amputation in seven (14%). Most infections (n = 30; 60%) were polymicrobial, and Staphylococcus aureus was the most common pathogen (n = 23; 46%). Parenteral antibiotics were used in 45 patients (90%). Patients who had pathologic evidence of osteomyelitis at the surgical margin received therapy for a median of 43 days (interquartile range [IQR], 36-56 days), whereas those without evidence of residual osteomyelitis received therapy for a median of 19 days (IQR, 13-40 days). Overall, 32 patients (64%) were considered cured after a median follow-up of 26 months (IQR, 12-38 months). Fifteen of 18 patients (83%) who failed initial therapy were treated again with limb-sparing surgery. Limb salvage was achieved in 47 patients (94%), with only three patients (6%) requiring below-the-knee amputation. In patients with diabetic foot osteomyelitis, surgical debridement or limited amputation plus antimicrobial therapy is effective at achieving clinical cure and limb salvage.


Physician Training for Electrocardiogram Interpretation: A Systematic Review and Meta-Analysis.
Using electrocardiogram (ECG) interpretation as an example of a widely taught diagnostic skill, the authors conducted a systematic review and meta-analysis to demonstrate how research evidence on instruction in diagnosis can be synthesized to facilitate improvement of educational activities (instructional modalities, instructional methods, and interpretation approaches), guide the content and specificity of such activities, and provide direction for research. The authors searched PubMed/MEDLINE, Embase, Cochrane CENTRAL, PsycInfo, CINAHL, ERIC, and Web of Science databases through February 21, 2020, for empirical investigations of ECG interpretation training enrolling medical students, residents, or practicing physicians. They appraised study quality with the Medical Education Research Study Quality Instrument and pooled standardized mean differences (SMDs) using random effects meta-analysis. Of 1,002 articles identified, 59 were included (enrolling 17,251 participants). Among 10 studies comparing instructional modalities, 8 compared computer-assisted and face-to-face instruction, with pooled SMD 0.23 (95% CI, 0.09, 0.36) indicating a small, statistically significant difference favoring computer-assisted instruction. Among 19 studies comparing instructional methods, 5 evaluated individual versus group training (pooled SMD -0.35 favoring group study [95% CI, -0.06, -0.63]), 4 evaluated peer-led versus faculty-led instruction (pooled SMD 0.38 favoring peer instruction [95% CI, 0.01, 0.74]), and 4 evaluated contrasting ECG features (e.g., QRS width) from 2 or more diagnostic categories versus routine examination of features within a single ECG or diagnosis (pooled SMD 0.23 not significantly favoring contrasting features [95% CI, -0.30, 0.76]). Eight studies compared ECG interpretation approaches, with pooled SMD 0.92 (95% CI, 0.48, 1.37) indicating a large, statistically significant effect favoring more systematic interpretation approaches. Some instructional interventions appear to improve learning in ECG interpretation; however, many evidence-based instructional strategies are insufficiently investigated. The findings may have implications for future research and design of training to improve skills in ECG interpretation and other types of visual diagnosis.


Ferromagnetic nanoparticle-embedded hybrid nanogenerator for harvesting omnidirectional vibration energy.
A new form of generator known as the triboelectric nanogenerator (TENG) has recently been suggested as a simple and low-cost solution to scavenge ambient mechanical energy. Although there have been substantial advances in TENGs over the past few years, the power efficiency of TENGs must be enhanced further before they can be practically applied. In the present study, we report a ferromagnetic nanoparticle-embedded hybrid nanogenerator (FHNG) which operates based on both triboelectricity and electromagnetic induction. A TENG and an electromagnetic generator (EMG) efficiently cooperate to generate electrical energy from the same motion, i.e., the vibration of a synthesized nanoparticle. A surface-functionalized ferric oxide nanoparticle, which has strong ferromagnetism and high triboelectricity, was produced by a simple surface-coating process. The measured electrical characteristics revealed that the output voltage of both the TENG and the EMG components increased by approximately 50 times and by twofold, respectively, after the surface functionalization step. Moreover, when constant vibration of 3 Hz is applied to the fabricated FHNG, the TENG and EMG components correspondingly generated output power of 133.2 μW at a load resistance of 100 MΩ and 6.5 μW at a load resistance of 200 Ω. The output power per unit mass from the FHNG is greater than that according to the arithmetic sum of the individual TENG and EMG components, demonstrating synergy between the two components. Furthermore, the device can generate stable output under various vibration directions, amplitudes, and frequencies due to the fluid-like characteristics of the powder. The packaged structure also securely protects the device from external humidity and dust. Connected to a rationally designed power management circuit, a digital clock was turned on solely by the fabricated FHNG.


Human lung mast cells: distribution and abundance of histochemically distinct subpopulations.
Methods originally employed to demonstrate the heterogeneity of mast cells in the rat and more recently in the human intestine were used to study mast cell heterogeneity in the human bronchial mucosa and lung parenchyma. Thus, a quantitative survey of pulmonary mast cells using different fixation and staining procedures indicated that two distinct mast cell subpopulations (formalin-sensitive and formalin-resistant) are present and have distinct patterns of distribution and abundance. The findings are of potential clinical importance because histochemical heterogeneity may be a marker of functional mast cell differences in humans including differences in responsiveness to antiallergic drugs, as occurs in rats. The findings also indicate that conventional methods of fixation are likely to lead to a gross underestimation of total mast cell numbers.


Directed fiber outgrowth from transplanted embryonic cortex-derived neurospheres in the adult mouse brain.
Neural transplantation has emerged as an attractive strategy for the replacement of neurons that have been lost in the central nervous system. Multipotent neural progenitor cells are potentially useful as donor cells to repopulate the degenerated regions. One important aspect of a transplantation strategy is whether transplanted cells are capable of fiber outgrowth with the aim of rebuilding axonal connections within the host brain. To address this issue, we expanded neuronal progenitor from the cortex of embryonic day 15 ubiquitously green fluorescent protein-expressing transgenic mice as neurospheres in vitro and grafted them into the entorhinal cortex of 8-week-old mice immediately after a perforant pathway lesion. After transplantation into a host brain with a lesion of the entorhino-hippocampal projection, the neurosphere-derived cells extended long fiber projections directed towards the dentate gyrus. Our results indicate that transplantation of neurosphere-derived cells might be a promising strategy to replace lost or damaged axonal projections.


Pepducin targeting the C-X-C chemokine receptor type 4 acts as a biased agonist favoring activation of the inhibitory G protein.
Short lipidated peptide sequences derived from various intracellular loop regions of G protein-coupled receptors (GPCRs) are named pepducins and act as allosteric modulators of a number of GPCRs. Recently, a pepducin selectively targeting the C-X-C chemokine receptor type 4 (CXCR4) was found to be an allosteric agonist, active in both cell-based assays and in vivo. However, the precise mechanism of action of this class of ligands remains poorly understood. In particular, given the diversity of signaling effectors that can be engaged by a given receptor, it is not clear whether pepducins can show biased signaling leading to functional selectivity. To explore the ligand-biased potential of pepducins, we assessed the effect of the CXCR4 selective pepducin, ATI-2341, on the ability of the receptor to engage the inhibitory G proteins (Gi1, Gi2 and Gi3), G13, and β-arrestins. Using bioluminescence resonance energy transfer-based biosensors, we found that, in contrast to the natural CXCR4 ligand, stromal cell-derived factor-1α, which promotes the engagement of the three Gi subtypes, G13 and the two β-arrestins, ATI-2341 leads to the engagement of the Gi subtypes but not G13 or the β-arrestins. Calculation of the transduction ratio for each pathway revealed a strong negative bias of ATI-2341 toward G13 and β-arrestins, revealing functional selectivity for the Gi pathways. The negative bias toward β-arrestins results from the reduced ability of the pepducin to promote GPCR kinase-mediated phosphorylation of the receptor. In addition to revealing ligand-biased signaling of pepducins, these findings shed some light on the mechanism of action of a unique class of allosteric regulators.


Guidance on selecting a translational framework for intervention development: Optimizing interventions for impact.
Intervention development frameworks offer the behavioral sciences a systematic and rigorous empirical process to guide the translation of basic science into practice in pursuit of desirable public health and clinical outcomes. The multiple frameworks that have emerged share a goal of optimization during intervention development and can increase the likelihood of arriving at an effective and disseminable intervention. Yet, the process of optimizing an intervention differs functionally and conceptually across frameworks, creating confusion and conflicting guidance on when and how to optimize. This paper seeks to facilitate the use of translational intervention development frameworks by providing a blueprint for selecting and using a framework by considering the process of optimization as conceptualized by each. First, we operationalize optimization and contextualize its role in intervention development. Next, we provide brief overviews of three translational intervention development frameworks (ORBIT, MRC, and MOST), identifying areas of overlap and divergence thereby aligning core concepts across the frameworks to improve translation. We offer considerations and concrete use cases for investigators seeking to identify and use a framework in their intervention development research. We push forward an agenda of a norm to use and specify frameworks in behavioral science to support a more rapid translational pipeline.


Tissue Doppler Imaging and Focal, Late-Onset Anthracycline-Induced Cardiovascular Disease in Long Term Survivors of Childhood Cancer: A Research Article.
In anthracycline-induced cardiomyopathy, the onset of diastolic dysfunction occurs before systolic dysfunction. Although, conventional echocardiogram is the standard method to assess cardiac function post anthracycline therapy, Tissue Doppler Imaging (TDI) may detect early onset cardiac diastolic dysfunction among anthracycline-recipient survivors of childhood cancers. There are limited data on the use of TDI in assessing anthracycline-associated cardiotoxicity in children. To evaluate the role of Tissue Doppler Imaging (TDI) in assessing late-onset cardiotoxicity in survivors of paediatric cancers. This was a single site, observational, blinded study of 11 long-term survivors of childhood cancer who had been treated with anthracyclines and 22 age-matched controls. The study group and the control group underwent conventional echo and TDI; operators were blind to study group. Conventional echo measurements were obtained. TDI was used to assess systolic and diastolic parameters at the mid-interventricular septum and lateral and medial annuli of the mitral valve; these parameters included: systolic wave (S'), early diastolic wave (E'), late diastolic wave (A'), Isovolemic Contraction Time (ICT), Isovolemic Relaxation Time (IRT) and Ejection Time (ET). Myocardial Performance Index (MPI) was also calculated. Conventional echo measurements were similar in both groups. Using TDI, cases had a lower mean E' velocity (9.7 ± 1.7 cm/s vs. 11.4 ± 1.3 cm/s, p=0.004) and a lower E'/A' (1.8 ± 0.5 vs. 2.2 ± 0.4, p=0.022) at the mid-interventricular septum than controls. The mean E' septum velocity in chemotherapy-recipients who also received chest radiotherapy was 8.5±0.5 cm/s in comparison to 10.2±1.7 cm/s in those that did not receive chest radiotherapy but this not achieve statistical significance. We did not find any additional associations between TDI parameters and patients' gender, age of diagnosis, length of follow-up and dose of anthracycline. In long-term survivors of childhood cancer who received anthracyclines, diastolic dysfunction can be detected earlier by using TDI before overt systolic dysfunction. Further large-scale multicenter studies are needed.


Concurrent BMP Signaling Maintenance and TGF-β Signaling Inhibition Is a Hallmark of Natural Resistance to Muscle Atrophy in the Hibernating Bear.
Muscle atrophy arises from a multiplicity of physio-pathological situations and has very detrimental consequences for the whole body. Although knowledge of muscle atrophy mechanisms keeps growing, there is still no proven treatment to date. This study aimed at identifying new drivers for muscle atrophy resistance. We selected an innovative approach that compares muscle transcriptome between an original model of natural resistance to muscle atrophy, the hibernating brown bear, and a classical model of induced atrophy, the unloaded mouse. Using RNA sequencing, we identified 4415 differentially expressed genes, including 1746 up- and 2369 down-regulated genes, in bear muscles between the active versus hibernating period. We focused on the Transforming Growth Factor (TGF)-β and the Bone Morphogenetic Protein (BMP) pathways, respectively, involved in muscle mass loss and maintenance. TGF-β- and BMP-related genes were overall down- and up-regulated in the non-atrophied muscles of the hibernating bear, respectively, and the opposite occurred for the atrophied muscles of the unloaded mouse. This was further substantiated at the protein level. Our data suggest TGF-β/BMP balance is crucial for muscle mass maintenance during long-term physical inactivity in the hibernating bear. Thus, concurrent activation of the BMP pathway may potentiate TGF-β inhibiting therapies already targeted to prevent muscle atrophy.


Infections, heat shock proteins, and atherosclerosis.
Recent evidence indicates that infections or a pathogen burden contribute to the development and progression of atherosclerosis. While the mechanism of infection contributing to the pathogenesis is not fully elucidated, I hypothesize that heat shock proteins may be a link between infections and atherosclerosis. Heat shock proteins are a highly conserved family of proteins expressed in most cell types and have been shown to play a general role in protecting cells in response to stress. It has been demonstrated that Chlamydia and human HSP60 coexist in atherosclerotic lesions. Bacterial and human heat shock proteins have been found in soluble form in the general circulation of patients with atherosclerosis. Both heat shock proteins can stimulate cells to express adhesion molecules and proinflammatory cytokines. Certain organisms synthesize heat shock proteins that have close structural homology with human heat shock proteins. Because of the immunologic molecular mimicry between bacterial and human HSP60, it could be an autoantigen involved in eliciting cell-mediated and humoral immune responses that cause vessel injury leading to atherosclerosis. The aim of this review is to provide an update overview on the involvement of heat shock proteins in the pathogenesis of atherosclerosis in response to infections.


The effect of a computerized visual perception and visual-motor integration training program on improving Chinese handwriting of children with handwriting difficulties.
This study aimed to investigate the effect of a computerized visual perception and visual-motor integration training program to enhance Chinese handwriting performance among children with learning difficulties, particularly those with handwriting problems. Participants were 26 primary-one children who were assessed by educational psychologists and occupational therapists to have handwriting difficulties. They were matched according to their age and then randomly assigned into either the control group or the experimental group. Subjects in the experimental group (n=13) would receive eight sessions of computerized visual perception and visual-motor integration training together with a home training program while those in the control group (n=13) would only receive conventional handwriting training by teachers, which focused mainly on remedial handwriting exercises. Results from repeated measure ANOVA revealed that children in the experimental group showed improvements in their visual perception skills as well as in their handwriting time. Both the "On Paper" time and "In Air" time of this group were improved when compared to the control group. However, no significant differences were found in visual-motor integration skill and handwriting legibility between the two groups after the intervention. This computerized training program focusing on visual perception and visual-motor integration training appeared to be effective in enhancing the handwriting time among children with handwriting difficulties. However, the training program did not seem to improve the legibility of children.


Retroviral transfer of the glucocerebrosidase gene into CD34+ cells from patients with Gaucher disease: in vivo detection of transduced cells without myeloablation.
Retroviral gene transfer of the glucocerebrosidase gene to hematopoietic progenitor and stem cells has shown promising results in animal models and corrected the enzyme deficiency in cells from Gaucher patients in vitro. Therefore, a clinical protocol was initiated to explore the safety and feasibility of retroviral transduction of peripheral blood (PB) or bone marrow (BM) CD34+ cells with the G1Gc vector. This vector uses the viral LTR promoter to express the human glucocerebrosidase cDNA. Three adult patients have been entered with follow-up of 6-15 months. Target cells were G-CSF-mobilized and CD34-enriched PB cells or CD34-enriched steady state BM cells, and were transduced ex vivo for 72 hr. Patient 1 had PB cells transduced in the presence of autologous stromal marrow cells. Patient 2 had PB cells transduced in the presence of autologous stroma, IL-3, IL-6, and SCF. Patient 3 had BM cells transduced in the presence of autologous stroma, IL-3, IL-6, and SCF. At the end of transduction, the cells were collected and infused immediately without any preparative treatment of the patients. The transduction efficiency of the CD34+ cells at the end of transduction was approximately 1, 10, and 1 for patients 1, 2, and 3, respectively, as estimated by semiquantitative PCR on bulk samples and PCR analysis of individual hematopoietic colonies. Gene marking in vivo was demonstrated in patients 2 and 3. Patient 2 had vector-positive PB granulocytes and mononuclear bone marrow cells at 1 month postinfusion and positive PB mononuclear cells at 2 and 3 months postinfusion. Patient 3 had a positive BM sample at 1 month postinfusion but was negative thereafter. These results indicate that gene-marked cells can engraft and persist for at least 3 months postinfusion, even without myeloablation. However, the level of corrected cells (<0.02%) is too low to result in any clinical benefit, and glucocerebrosidase enzyme activity did not increase in any patient following infusion of transduced cells. Modifications of vector systems and transduction conditions, along with partial myeloablation to allow higher levels of engraftment, may be necessary to achieve beneficial levels of correction in patients with Gaucher disease.


[Low-frequency electrical and magnetic fields near the beds of children with leukemia].
This pilot study points to the importance of the electric field in studies of the association between measured extremely low frequency electromagnetic fields and childhood leukaemia, and of the probe position in collecting useful data. It finds a significantly elevated extremely low frequency electric field (16.04 V/m) in the bedplace of cases of childhood leukaemia compared with healthy controls (7.76 V/m). Mean measured magnetic fields were not significantly elevated in the bedplace (74 nT, rms, against 57 nT in control' bedplaces). The study sample was large enough to detect a 5 V/m difference, but a larger study, paying particular attention to the position of the measuring instrument in the exact place where the child sleeps, is needed to confirm these results.


Creativity-the unconscious foundations of the incubation period.
Creativity is one of the most important assets we have to navigate through the fast changing world of the 21st century. Anecdotal accounts of creative individuals suggest that oftentimes, creative discoveries result from a process whereby initial conscious thought is followed by a period during which one refrains from task-related conscious thought. For example, one may spend an embarrassing amount of time thinking about a problem when the solution suddenly pops into consciousness while taking a shower. Not only creative individuals but also traditional theories of creativity have put a lot of emphasis on this incubation stage in creative thinking. The aim of the present article is twofold. First, an overview of the domain of incubation and creativity is provided by reviewing and discussing studies on incubation, mind-wandering, and sleep. Second, the causes of incubation effects are discussed. Previously, little attention has been paid to the causes of incubation effects and most findings do not really speak to whether the effects should be explained by unconscious processes or merely by consequences of a period of distraction. In the latter case, there is no need to assume active unconscious processes. The findings discussed in the current article support the idea that it is not merely the absence of conscious thought that drives incubation effects, but that during an incubation period unconscious processes contribute to creative thinking. Finally, practical implications and directions for future research will be discussed.


Enkephalin biosynthesis and enkephalin gene expression are increased in hippocampal mossy fibers following a unilateral lesion of the hilus.
The biosynthesis and posttranslational processing of proenkephalin and the level of preproenkephalin mRNA were investigated in the mossy fiber system of the granule cells of the hippocampus in the presence or absence of a unilateral lesion of the hilus, a procedure that produces an episode of recurrent bilateral hippocampal seizures lasting several hours. Both immunocytochemistry and radioimmunoassay (RIA) have demonstrated that the hilus lesion leads to large bilateral increases in enkephalin immunoreactivity in the mossy fiber system. In the present study, RIA data indicate that following an initial decline in immunoreactivity, enkephalin content within the mossy fibers first begins to increase between 18 and 24 hr after lesioning. Using the technique of in vivo radiolabeling and high-performance liquid chromatographic purification of identified radiolabeled peptides, we observed a 14-fold increase in incorporation of radiolabeled methionine into Met5-enkephalin at 24-30 hr postlesion, as compared with control animals, when Met5-enkephalin was purified from the mossy fiber terminal fields. To examine the posttranslational proteolytic processing of proenkephalin, the biosynthesis of 5 additional Met5-enkephalin-containing peptides was also examined. We determined that the posttranslational processing of proenkephalin did not yield exclusively penta-, hepta-, and octapeptides but larger opioid peptides as well in both control and lesioned animals, and that the ratio of the enkephalin peptides was not altered following the lesion. Measurement of preproenkephalin messenger RNA levels in the granule cells by Northern analysis revealed a marked increase following the lesion. Compared with the control animals, preproenkephalin mRNA was 8.5-fold higher in the contralateral dentate gyrus at 12 hr postlesion and 14- to 15-fold higher by 24 hr.(ABSTRACT TRUNCATED AT 250 WORDS)


Quality of life in relation to tamoxifen or exemestane treatment in postmenopausal breast cancer patients: a Tamoxifen Exemestane Adjuvant Multinational (TEAM) Trial side study.
Tamoxifen and aromatase inhibitors are associated with side effects which can significantly impact quality of life (QoL). We assessed QoL in the Tamoxifen Exemestane Adjuvant Multinational (TEAM) Trial and compared these data with reported adverse events in the main database. 2,754 Dutch postmenopausal early breast cancer patients were randomized between 5 years of exemestane, or tamoxifen (2.5-3 years) followed by exemestane (2.5-2 years). 742 patients were invited to participate in the QoL side study and complete questionnaires at 1 (T1) and 2 (T2) years after start of endocrine treatment. Questionnaires comprised the EORTC QLQ-C30 and BR23 questionnaires, supplemented with FACT-ES questions. 543 patients completed questionnaires at T1 and 454 patients (84%) at T2. Overall QoL and most functioning scales improved over time. The only clinically relevant and statistically significant difference between treatment types concerned insomnia; exemestane-treated patients reported more insomnia than tamoxifen-treated patients. Discrepancy was observed between QoL issue scores reported by the patients and adverse events reported by physicians. Certain QoL issues are treatment- and/or time-specific and deserve attention by health care providers. There is a need for careful inquiry into QoL issues by those prescribing endocrine treatment to optimize QoL and treatment adherence.


Hydroxylated polychlorinated biphenyl metabolites are anti-estrogenic in a stably transfected human breast adenocarcinoma (MCF7) cell line.
Hydroxylated metabolites of polychlorinated biphenyls (OHCBs) have been identified in blood of marine mammals, fish-eating birds, and humans at concentrations in some cases exceeding those of the unmetabolized polychlorinated biphenyls (PCBs). OHCBs have been associated with inhibition of vitamin A and thyroxin transport, estrogenicity in a mouse uterotrophic assay, and feminization of male turtle sexual development. OHCBs, representing both environmentally derived and laboratory exposure-derived metabolites, were tested in an in vitro bioassay utilizing an estrogen-responsive human breast adenocarcinoma cell line (MCF7-LUC) stably transfected with a luciferase reporter gene linked to estrogen responsive elements. OHCB activity was tested at three different media concentrations of 17beta-estradiol (E2), comparing the concentration-response curves using charcoal-stripped medium (0.0009 nM E2), and two physiologically relevant E2 concentrations (0.1 and 1.0 nM E2). Eleven of 13 OHCBs tested were anti-estrogenic. Evidence for an estrogen receptor mediated mechanism of action was apparent for only two OHCBs-4-OH-2',3,3',4',5,5'-Cl6-biphenyl and 4,4'-(OH)2-3,3',5,5'-Cl4-biphenyl. These two have not been identified in environmental samples. The remaining OHCBs exhibited "anti-estrogenicity" that was related to their effect on cell viability and, therefore, cannot be described as exhibiting "hormone disruption" solely by an estrogen receptor mediated mechanism. OHCB anti-estrogenic activity was eliminated in the presence of E2 concentrations normally found in humans, except for 4,4'(OH)2-3,3',5,5'-Cl4-biphenyl. 4-OH-2',3',4',5'-Cl4-biphenyl and 4-OH-2',4',6'-Cl3-biphenyl were partial estrogen agonists, exhibiting weak estrogenicity in the presence of 0.0009 nM E2 and weak anti-estrogenicity in the presence of 0.1 and 1 nM E2. Human metabolites of PCBs were not estrogenic in MCF7 cells.


Cognitive functioning of adults with Noonan syndrome: a case-control study.
Noonan syndrome (NS) is a genetic disorder characterised by short stature, facial dysmorphia, congenital heart defects and mildly lowered intellectual abilities. Research has mainly focused on genetic and somatic aspects, while intellectual and cognitive functioning has been documented scarcely. Also, to date studies have been primarily performed in children. This is the first study in which functioning within the major cognitive domains is systematically evaluated in a group of adults with NS and compared with a control group. Extensive neuropsychological assessment, including the domains intelligence, speed of information processing, memory (working memory, immediate recall and delayed recall), executive function and visuoconstruction, was performed in a sample of 42 patients with NS and 42 healthy controls, matched on age, sex and education level. In addition, subjective cognitive complaints were assessed with self-report questionnaires. On the domain speed of information processing patients performed worse than controls (P < 0.05). Furthermore, except for slightly better results on delayed recall in the patients with NS (P < 0.05), none of the other cognitive domains showed between-group differences. On the questionnaires, patients reported substantially more complaints about their own cognitive abilities than controls (P < 0.05). A lowered speed of information processing and relatively intact functioning in other cognitive domains characterises the cognitive profile of adult patients, in contrast to previous findings in children with NS, who seem to have more generalised cognitive deficits.


Novel DNA structures resulting from dTam3 excision in tobacco.
A Tam3 two-element system has been designed by combining an immobilized Tam3 element with a non-autonomous dTam3 element inserted into the HPT gene. The phenotypic assay employed, restored hygromycin resistance, indicated that trans-activation of the non-autonomous dTam3 element occurred. Molecular analyses of the excision sites revealed that the ends of the dTam3 element remain in the empty donor sites. The predominant consequence of this type of excision appears to be that excised fragments fail to re-integrate into the tobacco genome. Only one case of dTam3 re-integration could be detected. The ends of this element had been degraded upon integration into the tobacco genome. Either the altered structure of the Tam3 derivatives or tobacco host factors are influencing the trans-activation of a dTam3 element, resulting in aberrant excision.


Effect of a multifaceted intervention on use of evidence-based therapies in patients with acute coronary syndromes in Brazil: the BRIDGE-ACS randomized trial.
Studies have found that patients with acute coronary syndromes (ACS) often do not receive evidence-based therapies in community practice. This is particularly true in low- and middle-income countries. To evaluate whether a multifaceted quality improvement (QI) intervention can improve the use of evidence-based therapies and reduce the incidence of major cardiovascular events among patients with ACS in a middle-income country. The BRIDGE-ACS (Brazilian Intervention to Increase Evidence Usage in Acute Coronary Syndromes) trial, a cluster-randomized (concealed allocation) trial conducted among 34 clusters (public hospitals) in Brazil and enrolling a total of 1150 patients with ACS from March 15, 2011, through November 2, 2011, with follow-up through January 27, 2012. Multifaceted QI intervention including educational materials for clinicians, reminders, algorithms, and case manager training, vs routine practice (control). Primary end point was the percentage of eligible patients who received all evidence-based therapies (aspirin, clopidogrel, anticoagulants, and statins) during the first 24 hours in patients without contraindications. Mean age of the patients enrolled was 62 (SD, 13) years; 68.6% were men, and 40% presented with ST-segment elevation myocardial infarction, 35.6% with non-ST-segment elevation myocardial infarction, and 23.6% with unstable angina. The randomized clusters included 79.5% teaching hospitals, all from major urban areas and 41.2% with 24-hour percutaneous coronary intervention capabilities. Among eligible patients (923/1150 [80.3%]), 67.9% in the intervention vs 49.5% in the control group received all eligible acute therapies (population average odds ratio [OR(PA)], 2.64 [95% CI, 1.28-5.45]). Similarly, among eligible patients (801/1150 [69.7%]), those in the intervention group were more likely to receive all eligible acute and discharge medications (50.9% vs 31.9%; OR(PA),, 2.49 [95% CI, 1.08-5.74]). Overall composite adherence scores were higher in the intervention clusters (89% vs 81.4%; mean difference, 8.6% [95% CI, 2.2%-15.0%]). In-hospital cardiovascular event rates were 5.5% in the intervention group vs 7.0% in the control group (OR(PA), 0.72 [95% CI, 0.36-1.43]); 30-day all-cause mortality was 7.0% vs 8.4% (ORPA, 0.79 [95% CI, 0.46-1.34]). Among patients with ACS treated in Brazil, a multifaceted educational intervention resulted in significant improvement in the use of evidence-based therapies. clinicaltrials.gov Identifier: NCT00958958.


Vocal fold fixation caused by penetration of a high-velocity steel projectile.
Vocal fold fixation as a result of trauma caused by a foreign body is rare. We report a unique case of vocal fold fixation caused by traumatic penetration of a shard of steel in a 31-year-old steelworker. While the patient was at work, an airborne projectile suddenly pierced his neck and entered his larynx, causing progressive hoarseness and dyspnea. Flexible laryngoscopy detected no obvious foreign body, but it did reveal that the right vocal fold had become immobile. Computed tomography revealed that a 2.5-cm sliver of steel had become impacted in the right cricoarytenoid joint, which made the arytenoid cartilage unable to rotate. An emergency tracheostomy was performed with local anesthesia to construct a functioning airway, and then rigid laryngoscopy was performed with general anesthesia. The foreign body was removed with the assistance of a microscope and microscissors. Postoperatively, the patient immediately regained control of his right vocal fold, and he experienced no permanent injury.


The effects on cell growth of tea polyphenols acting as a strong anti-peroxidatant and an inhibitor of apoptosis in primary cultured rat skin cells.
Studies during the past few years have indicated an inhibitory effect of green tea or tea polyphenols on tumorigenesis in animal and even in human. The purpose of this study was to observe the possible effects of tea polyphenols on skin cell growth and on apoptosis in rat primary cultured keratinocytes and fibroblasts. The release of a cell plasma enzyme (LDH), lipid peroxidation products (MDA production), and GSH-Px (glutathione peroxidase) into the medium in cultured cells was determined after treatment with tea polyphenols in a primary culture of skin cells. The percentage of cells in each cell cycle phase and in apoptosis were assayed by flow cytometry (FCM). Tea polyphenols may have a beneficial effect on skin cells at concentrations from 0.05% to 0.1%, showing a dose-dependent decrease in LDH, MDA (malondialdehyde) production, and a significant dose-dependent increase in GSH-Px and cell number. These effects were more obvious after exposure for 24 h than after 12 h. The results indicate that tea polyphenols may stabilize and protect the cell membrane against the release of cell plasma enzyme LDH, and its anti-peroxidation effect is also important for cell growth. FCM analysis revealed that treatment with 0.01% to 0.1% tea polyphenols decreased the percentage of cells in the G1/G0 (quiescent) phase from 81.32% to 74.38%, and increased the percentage of cells in S and G2/M phase from 9.87% to 15.26%, and from 6.51% to 10.36%, respectively. Tea polyphenols also increased the value of PI (proliferation index) from 18.17 to 25.62. At the same time it decreased the percentage of apoptosis from 27.10% to 17.97%, which indicates that green tea stimulates cell growth and inhibits the occurrence of apoptosis. Our results indicate that tea polyphenols are effective anti-oxidants and also inhibit apoptosis, which may improve the proliferative capacity of primary skin cells in vitro.


Multidimensional scaling reveals the main evolutionary pathways of class A G-protein-coupled receptors.
Class A G-protein-coupled receptors (GPCRs) constitute the largest family of transmembrane receptors in the human genome. Understanding the mechanisms which drove the evolution of such a large family would help understand the specificity of each GPCR sub-family with applications to drug design. To gain evolutionary information on class A GPCRs, we explored their sequence space by metric multidimensional scaling analysis (MDS). Three-dimensional mapping of human sequences shows a non-uniform distribution of GPCRs, organized in clusters that lay along four privileged directions. To interpret these directions, we projected supplementary sequences from different species onto the human space used as a reference. With this technique, we can easily monitor the evolutionary drift of several GPCR sub-families from cnidarians to humans. Results support a model of radiative evolution of class A GPCRs from a central node formed by peptide receptors. The privileged directions obtained from the MDS analysis are interpretable in terms of three main evolutionary pathways related to specific sequence determinants. The first pathway was initiated by a deletion in transmembrane helix 2 (TM2) and led to three sub-families by divergent evolution. The second pathway corresponds to the differentiation of the amine receptors. The third pathway corresponds to parallel evolution of several sub-families in relation with a covarion process involving proline residues in TM2 and TM5. As exemplified with GPCRs, the MDS projection technique is an important tool to compare orthologous sequence sets and to help decipher the mutational events that drove the evolution of protein families.


Anti-photoaging effects of soy isoflavone extract (aglycone and acetylglucoside form) from soybean cake.
Soy isoflavones, found in soybean and soybean products, have been reported to possess many physiological activities such as antioxidant activity, inhibition of cancer cell proliferation, reduction of cardiovascular risk, prevention of osteoporosis and alleviation of postmenopausal syndrome. In our previous study, soy isoflavone extract ISO-1 (containing 12 soy isoflavones) from soybean cake was demonstrated to prevent skin damage caused by UVB exposure. In this study, soy isoflavone extract from soybean cake was further purified and evaluated for the protective effects on UVB-induced damage. The results revealed that Fraction 3, which contains the aglycone group (daidzein, genistein and glycitein) and acetylglucoside group (acetyldaidzin, acetylgenistin and acetylglycitin) of soy isoflavones, could inhibit UVB-induced death of human keratinocytes and reduce the level of desquamation, transepidermal water loss (TEWL), erythema and epidermal thickness in mouse skin. Furthermore, topical application of Fraction 3 increased the activity of catalase and suppressed cyclooxygenase-2 (COX-2) and proliferating cell nuclear antigen (PCNA) expression in mice exposed to UVB. In addition, in comparison with ISO-1 and genistein, the Fraction 3 possessed much greater protective effects on both UVB-induced oxidative stress and keratinocyte death than other fractions. Therefore, the soy isoflavone extract Fraction 3 from soybean cake is a desirable anti-photoaging agent for skin care.


Registered nurse scope of practice in Australia: an integrative review of the literature.
The nursing profession comprises Australia's largest regulated health workforce yet its practice boundaries are poorly understood. The ambiguity surrounding the practice scope of nurses limits the profession's ability to fully respond to Australia's current and emerging health system challenges. The aim of this review is to explore the concept of scope of practice of registered nurses (RN) in Australia, as reflected in contemporary literature. An integrative review of literature relating to the scope of practice of the Australian registered nurse published between 2007 and 2014 was conducted. Twenty primary papers and nine secondary source papers were included in the review. Themes that arose from the analysis are: Scope of practice - an elusive concept; Scope of practice and context; Scope of practice and boundaries; and Scope of practice and advanced practice. Discussion of these themes includes consideration of the professional, legal and ethical significance of scope of practice for the RN, as well as the legislative, professional and contextual influences on, and challenges to, defining scope of practice at both a professional and individual level. For the Australian registered nursing workforce to continue to be a significant and influential contributor to Australia's dynamic healthcare context, a clearly articulated scope of practice is both necessary and overdue.


Wearable MMG-Plus-One Armband: Evaluation of Normal Force on Mechanomyography (MMG) to Enhance Human-Machine Interfacing.
In this paper, we introduce a new mode of mechanomyography (MMG) signal capture for enhancing the performance of human-machine interfaces (HMIs) through modulation of normal pressure at the sensor location. Utilizing this novel approach, increased MMG signal resolution is enabled by a tunable degree of freedom normal to the sensor-skin contact area. We detail the mechatronic design, experimental validation, and user study of an armband with embedded acoustic sensors demonstrating this capacity. The design is motivated by the nonlinear viscoelasticity of the tissue, which increases with the normal surface pressure. This, in theory, results in higher conductivity of mechanical waves and hypothetically allows to interface with deeper muscle; thus, enhancing the discriminative information context of the signal space. Ten subjects (seven able-bodied and three trans-radial amputees) participated in a study consisting of the classification of hand gestures through MMG while increasing levels of contact force were administered. Four MMG channels were positioned around the forearm and placed over the flexor carpi radialis, brachioradialis, extensor digitorum communis, and flexor carpi ulnaris muscles. A total of 852 spectrotemporal features were extracted (213 features per each channel) and passed through a Neighborhood Component Analysis (NCA) technique to select the most informative neurophysiological subspace of the features for classification. A linear support vector machine (SVM) then classified the intended motion of the user. The results indicate that increasing the normal force level between the MMG sensor and the skin can improve the discriminative power of the classifier, and the corresponding pattern can be user-specific. These results have significant implications enabling embedding MMG sensors in sockets for prosthetic limb control and HMI.


Pulmonary involvement by histiocytosis X in the pediatric age group.
The lungs may be involved by histiocytosis X either as part of a generalized disease or as a separate entity, primary pulmonary histiocytosis X. The former is much more frequent in the pediatric age group, and although it occurs primarily in those who are quite sick with widely disseminated disease, the lung involvement rarely caused symptoms and almost invariably clears. By contrast, primary pulmonary histiocytosis X is mainly seen in young adult males and frequently leads to severe disability. Twelve patients less than 20 years old with lung involvement by histiocytosis X are presented.


Water vapor: observations of galactic sources.
We measured the emission of water vapor at a wavelength of 1.35 centimeters from nine sources with the 120-foot (36.5-meter) Haystack antenna. Eight sources lie within 30 seconds of arc of the hydroxyl sources of 18 centimeters but not all hydroxyl sources produced detectable emission of water vapor. All sources are smaller than 30 seconds of arc in angular diameter, but we resolved at least three separate sources in the Orion Nebula. We do not find that the known hyperfine components are present with the equilibrium intensity distribution.


MC-100093, a Novel β-Lactam Glutamate Transporter-1 Enhancer Devoid of Antimicrobial Properties, Attenuates Cocaine Relapse in Rats.
Cocaine use disorder currently lacks Food and Drug Administration-approved treatments. In rodents, the glutamate transporter-1 (GLT-1) is downregulated in the nucleus accumbens after cocaine self-administration, and increasing the expression and function of GLT-1 reduces the reinstatement of cocaine seeking. The β-lactam antibiotic ceftriaxone upregulates GLT-1 and attenuates cue- and cocaine-induced cocaine seeking without affecting motivation for natural rewards. Although ceftriaxone shows promise for treating cocaine use disorder, it possesses characteristics that limit successful translation from bench to bedside, including poor brain penetration, a lack of oral bioavailability, and a risk of bacterial resistance when used chronically. Thus, we aimed to develop novel molecules that retained the GLT-1-enhancing effects of ceftriaxone but displayed superior drug-like properties. Here, we describe a new monocyclic β-lactam, MC-100093, as a potent upregulator of GLT-1 that is orally bioavailable and devoid of antimicrobial properties. MC-100093 was synthesized and tested in vitro and in vivo to determine physiochemical, pharmacokinetic, and pharmacodynamic properties. Next, adult male rats underwent cocaine self-administration and extinction training. During extinction training, rats received one of four doses of MC-100093 for 6-8 days prior to a single cue-primed reinstatement test. Separate cohorts of rats were used to assess nucleus accumbens GLT-1 expression and MC-100093 effects on sucrose self-administration. We found that 50 mg/kg MC-100093 attenuated cue-primed reinstatement of cocaine seeking while upregulating GLT-1 expression in the nucleus accumbens core. This dose did not produce sedation, nor did it decrease sucrose consumption or body weight. Thus, MC-100093 represents a potential treatment to reduce cocaine relapse. SIGNIFICANCE STATEMENT: Increasing GLT-1 activity reliably reduces drug-seeking across classes of drugs; however, existing GLT1-enhancers have side effects and lack oral bioavailability. To address this issue, novel GLT-1 enhancers were synthesized, and the compound with the most favorable pharmacokinetic and pharmacodynamic properties, MC-100093, was selected for further testing. MC-100093 attenuated cued cocaine seeking without reducing food seeking or locomotion and upregulated GLT-1 expression in the nucleus accumbens.


Increased Iris Stiffness in Patients With a History of Angle-Closure Glaucoma: An Image-Based Inverse Modeling Analysis.
Previous studies have shown that iris mechanical properties may play a role in the pathophysiology of primary angle-closure glaucoma (PACG). Such studies, however, were not conducted in vivo and as such were limited in application and scope, especially for the development of diagnostic methods or new treatment options. The purpose of this study was to quantify in vivo iris mechanical properties both in patients with a history of angle-closure glaucoma and in healthy volunteers. We acquired optical coherence tomography scans of anterior segments under standard and dim light conditions. Using a combination of finite element simulation and an inverse fitting algorithm, we quantified the stiffness of the iris. The irides in the eyes of patients with a history of PACG were significantly stiffer when compared with healthy control irides, a result consistent with ex vivo studies. This result was independent of the compressibility assumption (incompressible: 0.97 ± 0.14 vs. 2.72 ± 0.71, P = 0.02; compressible: 0.89 ± 0.13 vs. 2.57 ± 0.69, P = 0.02) when comparing the normalized elastic modulus of the iris between patients with PACG and healthy controls. Our noninvasive, in vivo quantification is free of numerous ethical issues and potential limitations involved with ex vivo examinations. If further studies confirm that the iris stiffness is an omnipresent PACG risk factor and a mechanistic role between increased iris stiffness and angle-closure glaucoma does exist, treatment methods such as lowering the iris stiffness can be developed.


[A device for discrete information input into the Elektronika DZ-28 microcomputer].
A simple matching device destined for the connection of electrophysiological plant with micro-computer "Electronics DZ-28" has been described. The device permits to carry out straight input of information concerning neurones impulsive activity.


Light diffraction by concentrator Fresnel lenses.
Fresnel lenses are widely used in concentrating photovoltaic (CPV) systems as primary optical elements focusing sunlight onto small solar cells or onto entrance apertures of secondary optical elements attached to the solar cells. Calculations using the Young-Maggi-Rubinowicz theory of diffraction yield analytical expressions for the amount of light spilling outside these target areas due to diffraction at the edges of the concentrator Fresnel lenses. Explicit equations are given for the diffraction loss due to planar Fresnel lenses with small prisms and due to arbitrarily shaped Fresnel lenses. Furthermore, the cases of illumination by monochromatic, polychromatic, totally spatially coherent and partially spatially coherent light (e.g. from the solar disc) are treated, resulting in analytical formulae. Examples using realistic values show losses due to diffraction of up to several percent.


Role of inhaled antibiotics in children and adolescents with cystic fibrosis: Experience from the tertiary care center.
Cystic fibrosis (CF) remains under-diagnosed in Pakistan. CF population has increased tendency for Pseudomonas aeruginosa (Pa) infection and it is one of the leading causes of mortality. Utilizing inhaled antibiotics (IAs) for the treatment of Pa infection has been well established in the literature. There is limited data available on CF in Pakistan, especially regarding the efficacy of IAs. The aim of this study is to investigate the role of IAs on Pa infection in children and adolescents with CF. CF patients enrolled between January 2012 and December 2019 were selected as part of this retrospective cohort study. CF patients from 2 to 18 years of age who cultured Pa on any respiratory sample and who had never been Pa-free in at least two sputum cultures in the previous 12 months were included. Patients were divided into an IA group and a noninhaled antibiotic (NIA) group based on the treatment they received. Follow-up was done between 3 and 6 months posttherapy on Pseudomonas growth in the sputum. The number of pulmonary exacerbations were documented for 6 months follow-up. Eighty-one children with CF were enrolled during the study period, of which 39 were in the IA group and 42 were in the NIA group. There was no significant difference in their demographics and initial clinical characteristics. The mean pulmonary exacerbations after 6 months were lower in the IA group as compared to the NIA group (1.102 ± 0.50 vs. 2.45 ± 0.89: P = 0.001). Follow-up between 3 and 6 months showed greater Pseudomonas colonization in the IA group versus the NIA group (53.84% vs. 92.85%: P = 0.001). IAs in combination with airway clearance therapy and oral or IV antibiotics are an effective regimen for children with CF.


Fabrication of enrofloxacin imprinted organic-inorganic hybrid mesoporous sorbent from nanomagnetic polyhedral oligomeric silsesquioxanes for the selective extraction of fluoroquinolones in milk samples.
This paper reports a nanomagnetic polyhedral oligomeric silsesquioxanes (POSS)-directing strategy toward construction of molecularly imprinted hybrid materials for antibiotic residues determination in milk samples. The imprinted polymeric layer was facilely obtained through the copolymerization of active vinyl groups present on the nanomagnetic POSS (Fe3O4@POSS) surface and functional monomer (methacrylic acid) binding with template (enrofloxacin). Herein, the octavinyl POSS acted as not only the building blocks for hybrid rigid architectures but also the cross-linker for the formation of effective recognition sites during the imprinting process. The molecularly imprinted Fe3O4@POSS nanoparticles (Fe3O4@MI-POSS) demonstrated much higher adsorption capacity and selectivity toward enrofloxacin molecules and its analogs than the non-imprinted Fe3O4@POSS (Fe3O4@NI-POSS) materials. The imprinted particles were applied as a selective sorbent in solid-phase extraction focusing upon sample pretreatment in complex matrices prior to chromatographic analysis. The three FQs (ofloxacin, enrofloxacin, danofloxacin) could be selectively extracted from the biological matrix, while the matrix interferences were effectively eliminated simultaneously under the optimum extraction conditions. A simple, rapid and sensitive method based on the Fe3O4@MI-POSS material combined with HPLC-UV detection was then established for the simultaneous determination of three FQs from milk samples. The average recoveries of the three FQs were in the range of 75.6-108.9%. The relative standard deviations of intra- and inter-day ranging from 2.91 to 8.87% and from 3.6 to 11.5%, respectively. The limits of detections (S/N=3) were between 1.76 and 12.42 ng mL(-1). It demonstrates the effectiveness of trace analysis in complicated biological matrices utilizing magnetic separation in combination with molecularly imprinted solid-phase extraction, the rich chemistry of POSS makes it possible to be an ideal platform for generating molecular imprinted hybrid materials is also exhibited.


Metabolic Plasticity Endows Mixotrophic Organisms with High Tolerance to Cadmium and Special Potential for Recovering Cadmium-Contaminated Aquatic Environment.
Heavy metal pollution in waters causes serious stress to aquatic ecosystems. Several autotrophs with strong tolerance are extensively used to adsorb heavy metals, but their use may be limited by the specific conditions of polluted waters due to their single nutrition mode. By contrast, mixotrophs possess strong environmental adaptability due to their plastic metabolic modes. However, studies focusing on mixotroph's resistance and its underlying mechanism in response to heavy metals and their bioremediation potentials are currently lacking. In this study, we investigated the population, phytophysiological, and transcriptomic (RNA-Seq) responses of a typical and common mixotrophic organism, Ochromonas, to cadmium exposure and then evaluated their capacity to remove cadmium under mixotrophic condition. Compared with autotrophy, mixotrophic Ochromonas enhanced photosynthetic performances under short-time cadmium exposure and subsequently shifted to stronger resistance with increasing exposure time. Transcriptomic analyses suggested that the genes related to photosynthesis, ATP production, ECM components, and scavenging of reactive oxygen species and damaged organelles were upregulated to boost mixotrophic Ochromonas resistance to cadmium. Consequently, the harm of metal exposure was eventually reduced and cellular stability was maintained. Approximately, 70% of cadmium at 2.4 mg L-1 cadmium was removed by mixotrophic Ochromonas in the end, benefiting from upregulated genes associated with the transport of metal ions. Hence, mixotrophic Ochromonas tolerance to cadmium can be attributed to multiple pathways of energy metabolism and effective transport of metal ions. Collectively, this study advanced a better understanding of the unique mechanism of heavy metal resistance in mixotrophs and their potential use in recovering cadmium-contaminated aquatic ecosystems. IMPORTANCE Mixotrophs widely living in aquatic ecosystems possess unique ecological roles and strong environmental adaptability due to their plastic metabolic modes; however, little is known about their underlying resistance mechanism and bioremediation potential in response to environmental stresses. For the first time, this work investigated how mixotrophs respond to metal pollutants through physiological, population dynamics, and transcriptional regulation, and highlighted the unique underlying mechanism of mixotrophs to resist and remove heavy metal, thereby advancing our understanding of the potentials of mixotrophs in recovering metal-contaminated aquatic environments. These unique properties in mixotrophs are essential for the long-term functional stability of aquatic ecosystems.


Mandated self-reporting of ventilator-associated pneumonia bundle and catheter-related bloodstream infection bundle compliance and infection rates.
As quality measures increasingly become tied to payment, evaluating the most effective ways to provide high-quality care becomes more important. To determine whether mandated reporting for ventilator and catheter bundle compliance is correlated with decreased infection rates, and to determine whether labor-intensive audits are correlated with compliance. Multiyear retrospective review of aggregated data from all patients admitted to 15 intensive care units in a Veterans Affairs hospital setting (the Veterans Integrated Service Network 16) from 2009 to 2011. Ventilator-associated pneumonia and catheter-related bloodstream infections. Mean rates of ventilator-associated pneumonia and catheter-related bloodstream infection were analyzed by year. Relationships between infection rates, self-reported compliance, and audits were analyzed by Pearson correlation. During the study period, ventilator-associated pneumonia decreased from 2.50 to 1.60 infections per 1000 ventilator days (P = .07). The rate of pneumonia was not correlated with self-reported compliance overall (R = 0.19) or by individual year (2009, R = 0.30; 2010, R = 0.24; 2011, R = 0.46); there was a correlation in cardiac intensive care units (R = -0.70) but not other types of intensive care units (mixed, R = -0.18; medical, R = 0.42; surgical, R = 0.34). Catheter-related bloodstream infections decreased from 2.38 to 0.73 infections per 1000 catheter days (P = .04). The rate of catheter infection was not correlated with self-reported compliance overall (R = -0.18), by individual year (2009, R = -0.39; 2010, R = -0.42; 2011, R = 0.37), or by intensive care unit type (mixed, R = -0.19; cardiac, R = 0.55; medical, R = 0.17; surgical, R = -0.44). Current mandated self-reported compliance and audit measures are poorly correlated with decreased ventilator-associated pneumonia or catheter-related bloodstream infection.


Distribution of charged sites on lymphatic endothelium.
The charge distribution on the luminal and abluminal aspects of fixed and living lymphatic endothelium was examined with particular emphasis on the endocytotic vesicular system and interendothelial junctions. Native ferritin (NF; pl = 4.5), when administered abluminally to perfused lymphatics, entered endocytotic vesicles and abluminal and luminal caveolae; NF was also found in intercellular channels, in contrast, NF when applied luminally was largely excluded from both luminal caveolae and intercellular channels. Cationic ferritin (CF; pl = 8.4) bound to the discontinuous basal lamina and to the abluminal plasma membrane, clustering preferentially around the stomata of abluminal caveolae. CF did not, however, bind to the plasma membrane of, or enter, either the vesicular system or intercellular channels, when administered abluminally. When added to the perfusion fluid CF bound to the luminal membrane and to the infundibula of intercellular channels. Ruthenium red (RR) and alcian blue (AB), both cationic stains, bound intensely to the luminal membrane and much less so to the abluminal surface, thus simulating the binding pattern of CF. Unlike CF, however, RR and AB bound to the membranes of abluminal and luminal caveolae with the same level of staining as to the plasma membrane to which they were attached. These results reflect a marked asymmetry in the membrane charge characteristics of endothelial cells.


Single-day famciclovir for the treatment of genital herpes: follow-up results of time to next recurrence and assessment of antiviral resistance.
Episodic therapy of genital herpes is usually recommended for patients with infrequent symptomatic recurrences and where transmission is not a concern. While shorter courses are as effective as standard 5-day regimens, it is unknown whether abbreviated therapy has detrimental effects on natural history and the development of antiviral resistance. To assess time to next recurrence and development of antiviral resistance in patients with recurrent genital herpes treated with either single-day famciclovir (1 g twice-daily) or 3-day valacyclovir (500 mg twice-daily). Longer-term, follow-up data on the time to next recurrence and antiviral sensitivity were collected from a previously reported multicenter, multinational, double-blind, parallel group study in which 1179 immunocompetent adults were randomized 1 : 1 to receive either single-day famciclovir or 3-day valacyclovir. Treatment was self-initiated within 6 hours of a recurrence. Swabs for viral culture and sensitivity testing were collected for two sequential recurrences. The median time to next recurrence from treatment initiation was 33.5 days for famciclovir and 38.0 days for valacyclovir. No drug resistance to penciclovir, the active metabolite of famciclovir, was observed at baseline nor did any develop by the time of the next recurrence. The study had no placebo arm, typing of viral isolates was not performed and viral resistance testing was restricted to penciclovir only. Treatment with single-day famciclovir for recurrent genital herpes did not shorten the time to the next recurrence. Drug resistance to penciclovir continues to be a rare event in immunocompetent patients.