Application of a trigger tool in near real time to inform quality improvement activities: a prospective study in a general medicine ward.
Retrospective record review using trigger tools remains the most widely used method for measuring adverse events (AEs) to identify targets for improvement and measure temporal trends. However, medical records often contain limited information about factors contributing to AEs. We implemented an augmented trigger tool that supplemented record review with debriefing front-line staff to obtain details not included in the medical record. We hypothesised that this would foster the identification of factors contributing to AEs that could inform improvement initiatives. A trained observer prospectively identified events in consecutive patients admitted to a general medical ward in a tertiary care academic medical centre (November 2010 to February 2011 inclusive), gathering information from record review and debriefing front-line staff in near real time. An interprofessional team reviewed events to identify preventable and potential AEs and characterised contributing factors using a previously published taxonomy. Among 141 patients, 14 (10%; 95% CI 5% to 15%) experienced at least one preventable AE; 32 patients (23%; 95% CI 16% to 30%) experienced at least one potential AE. The most common contributing factors included policy and procedural problems (eg, routine protocol violations, conflicting policies; 37%), communication and teamwork problems (34%), and medication process problems (23%). However, these broad categories each included distinct subcategories that seemed to require different interventions. For instance, the 32 identified communication and teamwork problems comprised 7 distinct subcategories (eg, ineffective intraprofessional handovers, poor interprofessional communication, lacking a shared patient care, paging problems). Thus, even the major categories of contributing factors consisted of subcategories that individually related to a much smaller subset of AEs. Prospective application of an augmented trigger tool identified a wide range of factors contributing to AEs. However, the majority of contributing factors accounted for a small number of AEs, and more general categories were too heterogeneous to inform specific interventions. Successfully using trigger tools to stimulate quality improvement activities may require development of a framework that better classifies events that share contributing factors amenable to the same intervention.


Deciphering anaerobic ethanol metabolic pathways shaped by operational modes.
Efficient anaerobic digestion requires the syntrophic cooperation among diverse microorganisms with various metabolic pathways. In this study, two operational modes, i.e., the sequencing batch reactor (SBR) and the continuous-flow reactor (CFR), were adopted in ethanol-fed systems with or without the supplement of powdered activated carbon (PAC) to examine their effects on ethanol metabolic pathways. Notably, the operational mode of SBR and the presence of CO2 facilitated ethanol metabolism towards propionate production. This was further evidenced by the dominance of Desulfobulbus, and the increased relative abundances of enzymes (EC: 188.8.131.52 and 220.127.116.11) involved in CO2 metabolism in SBRs. Moreover, SBRs exhibited superior biomass-based rates of ethanol degradation and methanogenesis, surpassing those in CFRs by 53.1% and 22.3%, respectively. Remarkably, CFRs with the extended solids retention time enriched high relative abundances of Geobacter of 71.7% and 70.4% under conditions with and without the addition of PAC, respectively. Although both long-term and short-term PAC additions led to the increased sludge conductivity and a reduced methanogenic lag phase, only the long-term PAC addition resulted in enhanced rates of ethanol degradation and propionate production/degradation. The strategies by adjusting operational mode and PAC addition could be adopted for modulating the anaerobic ethanol metabolic pathway and enriching Geobacter.


[The opinions of Turkish physicians about the tasks of tuberculosis central dispensary].
Department of tuberculosis control is the main tuberculosis branch of Minister of Health, with coordinators in cities as intermediate departments and Tuberculosis Central Dispensaries (TCD) as peripheral branches. This study was performed through January-May 2007 in seven different geographical regions to figure out opinions of physicians on tuberculosis dispensaries. A specific questionnaire was distributed to doctors in two cities in each geographical region. A number of 1250 doctor participated in the study as at least fifty doctors in each city. Mean age of the subjects was 32.58 +/- 6.63 (22-65), 52.1% (651) of whom had diagnosed tuberculosis before. It was found in the study that two important functions of tuberculosis central dispensaries for the doctors were the treatment of patients regularly and freely, and scanning the persons who have very close contact with active tuberculosis patient. A number of 157 doctors accepted all seven functions of dispensary as important. Female doctors, pediatricians and chest physicians had better knowledge on the tasks of tuberculosis central dispensaries (p< 0.005). This study showed that Turkish physicians did not have enough knowledge about tuberculosis and its tasks. We believe that practical training procedures for the physicians on the goals and functions of TCD will help to treat tuberculosis.


How effective were Australian Quarantine Stations in mitigating transmission aboard ships during the influenza pandemic of 1918-19?
The influenza pandemic of 1918-19 was the most devastating pandemic of the 20th century. It killed an estimated 50-100 million people worldwide. In late 1918, when the severity of the disease was apparent, the Australian Quarantine Service was established. Vessels returning from overseas and inter-state were intercepted, and people were examined for signs of illness and quarantined. Some of these vessels carried the infection throughout their voyage and cases were prevalent by the time the ship arrived at a Quarantine Station. We study four outbreaks that took place on board the Medic, Boonah, Devon, and Manuka in late 1918. These ships had returned from overseas and some of them were carrying troops that served in the First World War. By analysing these outbreaks under a stochastic Bayesian hierarchical modeling framework, we estimate the transmission rates among crew and passengers aboard these ships. Furthermore, we ask whether the removal of infectious, convalescent, and healthy individuals after arriving at a Quarantine Station in Australia was an effective public health response.


Predictors of health care use in Australian cancer patients.
The purpose of this study is to measure health care utilization in Australian cancer patients based on their demographic, geographic and socioeconomic backgrounds. A total of 13,609 participants (aged 15 and over) from 7,230 households were interviewed as part of Wave 13 of the national Household, Income and Labour Dynamics in Australia (HILDA) survey. Five hundred and seventeen participants indicated a current cancer diagnosis with 90% of those receiving active treatment at the time of interview. Independent sample t-tests, Pearson Chi-sq tests, Kruskal‒Wallis H test, binary logistic regression and a zero-inflated Poisson regression were used to examine inequality in health care use. Demographic and sociocultural factors such as advancing age, gender, low income, low education status, rurality, no private health insurance, increased psychological distress and less access to specialist care are associated with lower health care utilization among cancer patients. However, models of care such as general practitioner-led cancer care is preferable in younger individuals with cancer, while accessing specialist care is associated with lower rates of hospitalization and higher levels of psychological distress increases hospital length of stay. The findings of lower health care utilization by those cancer patients with characteristics of disadvantage have implications for policy development and intervention design. Broadly, policies targeting structural social inequities are likely to increase health care utilization among the most affected/disadvantaged populations. Further investigation is needed to identify potential links between health care utilization and cancer outcomes as a step toward targeted interventions for improving outcomes in the adversely affected groups.


European position paper on drug-induced sedation endoscopy (DISE).
Although drug-induced sedation endoscopy (DISE) represents the most widespread diagnostic tool for upper airway endoscopic evaluation of snoring and obstructive sleep apnea hypopnea syndrome (OSAHS), many controversies exist about how to perform the sedation, the indications for DISE, and how to report DISE findings. The present position paper reports on a consensus as proposed by a group of European experts in the field of DISE after discussion during a recent dedicated meeting. The authors have evaluated all the available evidence reported in the literature and have compared experience among various departments in leading European centers in order to provide a standardization of the DISE procedure and an in-depth insight in the main aspects of this technique. A proposal of the DISE procedure standardization has been achieved with a general agreement concerning the terminology, indications, contraindications, required preliminary examinations, setting, technical equipment required, staffing, local anesthesia and nasal decongestion, patient positioning, basis and special diagnostic maneuvers, and the applied sedation drugs and observation windows. Otherwise, no consensus has been reached on a scoring and classification system. Although consensus has been reached on several aspects of the DISE procedure, some topics remain open to future research, such as a better analysis of the importance of positional aspects during DISE and a further comparison of the differences in degree, level and pattern of upper airway collapse observed during DISE versus during natural sleep and awake endoscopy. Finally, a universally accepted scoring and classification system is lacking.


Mercury determination in various environmental, food and material complex matrices using unified operating conditions for a cold vapor generation high-resolution continuum source quartz tube atomic absorption spectrometry method.
An analytical method with broad applicability based on cold vapor generation high-resolution continuum source quartz tube atomic absorption spectrometry was developed and evaluated for the determination of total mercury in matrices with various complexities and compositions. Sample preparation for different matrices of food, environmental samples and (bio)polymeric materials and unified operating conditions for derivatization and measurement were evaluated. The method was validated according to established requirements (Eurachem Guide 2014, EC Decisions 657/2002; 333/2007; 836/2011 and Association of Official Analytical Chemists Guide - AOAC). Analytical versatility was checked on various samples of fish fillets, mushrooms, soil, water and water sediment, sludge from a wastewater treatment unit, and (bio)polymeric materials from waste recycled from food packaging, computers and garden tools. Under optimal conditions for cold vapor generation in a batch system, namely 3% (v/v) HCl as reaction medium for 5 mL aliquot samples and a volume of 3.5 mL 0.3% (m/v) NaBH4 stabilized in 0.2% (m/v) NaOH as derivatization reagent, the detection limit for Hg in terms of peak height measurement (n = 7 days) was in the range 0.064 ± 0.004 μg L-1 in water, 0.014 ± 0.001 mg kg-1 in environmental samples and 0.009 ± 0.001 mg kg-1 in (bio)polymeric materials. Overall recovery of Hg by analysis of certified reference materials was 102 ± 20% (k = 2) in food, soil, wastewater and water sediment, and polyethylene. Precision for the measurement of various real samples ranged between 4.2 and 15.0%. A performance study highlighted that the method was sensitive, free of non-spectral interference coming from the multielemental matrix and that it complied with the requirements for Hg determination set in EC Decisions and AOAC Guidelines at least for the more common matrices analyzed for social impact.


Mutations in TMEM231 cause Meckel-Gruber syndrome.
Meckel-Gruber syndrome (MKS) is a genetically heterogeneous severe ciliopathy characterised by early lethality, occipital encephalocele, polydactyly, and polycystic kidney disease. To report genetic analysis results in two families in which all known MKS diseases genes have been excluded. In two consanguineous families with classical MKS in which autozygome-guided sequencing of previously reported MKS genes was negative, we performed exome sequencing followed by autozygome filtration. We identified one novel splicing mutation in TMEM231, which led to complete degradation of the mutant transcript in one family, and a novel missense mutation in the other, both in the homozygous state. TMEM231 represents a novel MKS locus. The very recent identification of TMEM231 mutations in Joubert syndrome supports the growing appreciation of the overlap in the molecular pathogenesis between these two ciliopathies.


Actinomycetoma caused by Nocardiopsis dassonvillei.
We report a case of mycetoma caused by Nocardiopsis dassonvillei in a 39-year-old man. He had multiple nodules and draining sinuses on the anterior aspect of his right leg just below the knee. Few cream-colored granules were seen in the exudate. The biopsy specimen showed gram-positive, non-acid-fast granules with distinct borders. An aerobic actinomycete isolated from the lesion was identified as N dassonvillei. We think that this is the first reported case of mycetoma caused by N dassonvillei.


Model-Based Control of Soft Actuators Using Learned Non-linear Discrete-Time Models.
Soft robots have the potential to significantly change the way that robots interact with the environment and with humans. However, accurately modeling soft robot and soft actuator dynamics in order to perform model-based control can be extremely difficult. Deep neural networks are a powerful tool for modeling systems with complex dynamics such as the pneumatic, continuum joint, six degree-of-freedom robot shown in this paper. Unfortunately it is also difficult to apply standard model-based control techniques using a neural net. In this work, we show that the gradients used within a neural net to relate system states and inputs to outputs can be used to formulate a linearized discrete state space representation of the system. Using the state space representation, model predictive control (MPC) was developed with a six degree of freedom pneumatic robot with compliant plastic joints and rigid links. Using this neural net model, we were able to achieve an average steady state error across all joints of approximately 1 and 2° with and without integral control respectively. We also implemented a first-principles based model for MPC and the learned model performed better in terms of steady state error, rise time, and overshoot. Overall, our results show the potential of combining empirical modeling approaches with model-based control for soft robots and soft actuators.


Melatonin prevents methotrexate-induced hepatorenal oxidative injury in rats.
Regarding the mechanisms of methotrexate (MTX) hepatotoxicity and nephrotoxicity, several hypotheses have been put forward, among which oxidative stress (including depletion of glutathione) is likely. This investigation elucidates the role of free radicals in MTX-induced toxicity and the protection by melatonin. Wistar albino rats were injected with MTX intraperitoneally. Following a single dose of MTX (20 mg/kg), either saline (MTX group) or melatonin (10 mg/kg, MTX + Mel group) was administered for 5 days. In other rats, physiologic saline (control group) or melatonin (10 mg/kg, Mel group) was injected for 5 days, following a single injection of saline. On the sixth day, rats were killed to obtain blood, liver, and kidney tissue samples. Malondialdehyde (MDA), an end product of lipid peroxidation, and glutathione (GSH), a key antioxidant, levels were evaluated in blood and tissue homogenates. Reactive oxygen metabolite-induced inflammatory changes in kidney and liver tissues were evaluated by measuring myeloperoxidase (MPO) activity, an index of neutrophil infiltration. MTX administration resulted in increased MDA levels and MPO activity and decreased GSH levels in the blood, liver, and kidney whereas melatonin reversed these effects. When melatonin was administered alone, no significant changes in biochemical parameters were noted. In conclusion, the present study suggests that melatonin may be of therapeutic benefit when used with MTX.


Temporal Changes in Periprocedural Events in the Carotid Revascularization Endarterectomy Versus Stenting Trial.
Post-hoc, we hypothesized that over the recruitment period of the Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST), increasing experience and improved patient selection with carotid stenting, and to a lesser extent, carotid endarterectomy would contribute to lower periprocedural event rates. Three study periods with approximately the same number of patients were defined to span recruitment. Composite and individual rates of periprocedural stroke, myocardial infarction, and death rate were calculated separately by treatment assignment (carotid stenting/carotid endarterectomy). Temporal changes in unadjusted event rates, and rates after adjustment for temporal changes in patient characteristics, were assessed. For patients randomized to carotid stenting, there was no significant temporal change in the unadjusted composite rates that declined from 6.2% in the first period, to 4.9% in the second, and 4.6% in the third (P=0.28). Adjustment for patient characteristics attenuated the rates to 6.0%, 5.9%, and 5.6% (P=0.85). For carotid endarterectomy-randomized patients, both the composite and the combined stroke and death outcome decreased between periods 1 and 2 and then increased in period 3. The hypothesized temporal reduction of stroke+death events for carotid stenting-treated patients was not observed. Further adjustment for changes in patient characteristics between periods, including the addition of asymptomatic patients and a >50% decrease in proportion of octogenarians enrolled, resulted in practically identical rates. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00004732.


Anaplastic thyroid cancer with transient thyrotoxicosis: case report and literature review.
A 55-year-old woman with anaplastic thyroid carcinoma presented with hyperthyroidism and neck swelling, hoarseness, and cervical lymphadenopathy. On physical examination, she was found to be clinically hyperthyroid with an enlarged, nontender multinodular goitre. Her serum thyroid hormone levels confirmed hyperthyroidism and technetium-99m pertechnetate scan failed to visualize the thyroid gland. Open biopsy showed an invasion of the thyroid gland by anaplastic thyroid carcinoma. The thyrotoxic phase lasted 60 days with predominantly increased thyroxine level and triiodothyronine/thyroxine (T3/T4) ratio decreased below 15. The thyrotoxic period was followed by subclinical hyperthyroidism and hypothyroidism which continued until she died of lung metastasis.


Induction of ovulation and ovarian cancer: a critical review of the literature.
To critically examine the possible association between ovulation-inducing drugs and ovarian cancer. Medline literature review and cross-reference of published data. The studies that have adjusted for the effects of confounding factors such as duration of oral contraceptive use and number of pregnancies have noted an increased risk of ovarian cancer among infertile women who remain childless despite long periods of unprotected intercourse. Whether such women are at risk due to the primary basis for their infertility or factors such as ovulation-inducing drugs, has been the subject of several studies. Overall, the findings on ovarian cancer (especially invasive epithelial and non-epithelial) risk associated with fertility drug treatment are reassuring. However, a stronger association between fertility drug use and borderline tumors of the ovary has been observed. Despite the overall reassuring findings of the available studies, there is a need for well-designed clinical trials to understand the possible carcinogenic effects of the ovulation-inducing drugs.


[Evaluation of technics used to define type 'A' pattern, in the Belgian Prevention Project of cardiovascular diseases (author's transl)].
In order to define the Rosenman and Friedman type A pattern three technics where used: the Bortner scale, the Jenkins Acitivity Survey (J.A.S.) and the interview. These are part of the base-line data recorded during the screening of a belgian male population aged 40 to 59 at entry of a controlled trial for the multifactorial prevention of cardiovascular diseases. The J.A.S. and the Bortner scale are evaluated in relation to the interview. Extremes of type A and B are less prevalent in our study compared to the Western Collaborative Group Study. Both the J.A.S. and the Bortner scale are very satisfactory in predicting type A and B pattern. The Bortner scale predicts the pattern in 78% of the subjects, by the method of weighted scores. The validation of this classification method, on a second sample, gives an accurate classification in 75% of the subjects. The J.A.S. predicts, the pattern in relation to the interview in 78% of the subjects; again the validation of the classification method, on a second sample, gives a correct classification in 70% of the subjects.


Genomic and clinical characterization of B/T mixed phenotype acute leukemia reveals recurrent features and T-ALL like mutations.
The B/T subtype of mixed phenotype acute leukemia (B/T MPAL) is defined by co-expression of antigens of both B- and T-cell lineages on leukemic blasts. Although it has been suggested that multilineage antigen expression portends poor response to chemotherapy, the clinical characteristics and driver mutations that underlie the pathogenesis of this rare subtype of acute leukemia are scarcely known. We identified nine cases of B/T MPAL from multiple institutions and correlated clinical and immunophenotypic findings with next-generation sequencing data. We report that B/T MPAL commonly presents with lymphadenopathy in adolescence and young adulthood. While the tumors have diverse cytogenetic and genomic perturbations, recurrent acquired aberrations include mutations in the putative transcriptional regulator PHF6 and the JAK-STAT and Ras signaling pathways. Alterations were also identified in genes encoding hematopoietic transcription factors, cell cycle regulators/tumor suppressors, and chromatin modifying enzymes. The genomic landscape of B/T MPAL strongly resembles that of T-ALL subgroups associated with early developmental arrest, while genetic alterations that are common in B-ALL were rarely seen. Two-thirds of the patients responded to ALL-based chemotherapy with or without stem cell transplantation. Our observations lay the groundwork for further study of the unique biology and clinical trajectory of B/T MPAL.


Synthesis of Jacaranone-Derived Nitrogenous Cyclohexadienones and Their Antiproliferative and Antiprotozoal Activities.
The cytotoxic and antiprotozoal activities of the phytoquinoide, jacaranone, and related compounds have been an ongoing topic in recent drug discovery. Starting from the natural product-derived cyclohexadienone scaffold, a series of nitrogen-containing derivatives were synthesized and subsequently evaluated for their antiproliferative and antiprotozoal activity. Anticancer potency was analyzed using different types of cancer cell lines: MDA-MB-231 breast cancer, CCRF-CEM leukemia, HCT-116 colon cancer, U251 glioblastoma, and, in addition, non-tumorigenic MRC-5 lung fibroblasts. Antiproliferative activities at micromolar concentrations could be shown. Antiprotozoal activity was assessed against Plasmodium falciparum NF54 and Trypanosoma brucei rhodesiense STIB900. For all compounds, selectivity indices (SI) were calculated based on assessed cytotoxicity towards L6 cells. In addition, the structure-activity-relationships and physicochemical parameters of these compounds are discussed.


Mitigating Lower Urinary Tract Symptoms Secondary to Benign Prostatic Hyperplasia: Ameliorating Sexual Function and Psychological Well-Being in Older Men.
This study aimed to investigate the prevalence of lower urinary tract symptoms (LUTS) in older men (N= 3056) with benign prostatic hyperplasia (BPH) and its effects on their sexual function and mental health. Descriptive, correlation, and regression analyses were used to explore the relationships between prostate and lower urinary tract health and psychological well-being. Better prostate and lower urinary tract health positively affected psychological well-being, and sexual function also had a positive influence. LUTS have an adverse impact on sexual function and mental health. Early intervention is crucial for mitigating the negative impact of LUTS on the quality of life in older men. Addressing prostate and lower urinary tract health issues through appropriate interventions may improve psychological well-being. Health care professionals must consider the adverse effects of BPH and LUTS on sexual function and mental health, and implement interventions to enhance the overall quality of life in older men.


Chemical composition analysis, antioxidant, antiglycating activities and neuroprotective effects of S. choloroleuca, S. mirzayanii and S. santolinifolia from Iran.
This study was designed to examine antioxidant activities, antiglycating abilities and neuroprotective effects of methanolic extracts of Salvia choloroleuca, Salvia santolinifolia and Salvia mirzayanii from Iran. The extracts were screened for their possible antioxidant activities by several biochemical assays such as DPPH, FRAP, β-carotene bleaching and TEAC assays. HPLC analysis of these extracts led to the separation of a number of components such as catechine and rosmarinic acid. Based on our results, all these plants had antioxidant and antiglycating activities, among them S. choloroleuca seems to be the most effective one. Furthermore, these species not only showed no cytotoxic effects in neuron-like PC12 cells, but also protected them against oxidative stress-induced cell death, exerted by H(2)O(2). We further showed that these plants increase superoxide dismutase and catalase levels, reduce lipid peroxidation and up regulate hemeoxygenase-1 and glutamylcysteine synthetase proteins. This study raised the possibility of developing these plants as potential neuroprotective agents.


Reactions between chlorine atom and acetylene in solid para-hydrogen: infrared spectrum of the 1-chloroethyl radical.
We applied infrared matrix isolation spectroscopy to investigate the reactions between Cl atom and acetylene (C₂H₂) in a para-hydrogen (p-H₂) matrix at 3.2 K; Cl was produced via photodissociation at 365 nm of matrix-isolated Cl₂ in situ. The 1-chloroethyl radical (·CHClCH₃) and chloroethene (C₂H₃Cl) are identified as the main products of the reaction Cl + C₂H₂ in solid p-H₂. IR absorption lines at 738.2, 1027.6, 1283.4, 1377.1, 1426.6, 1442.6, and 2861.2 cm⁻¹ are assigned to the 1-chloroethyl radical. For the reaction of Cl + C₂D₂, lines due to the ·CDClCH₂D radical and trans-CHDCDCl are observed; the former likely has a syn-conformation. These assignments are based on comparison of observed vibrational wavenumbers and ¹³C- and D-isotopic shifts with those predicted with the B3LYP/aug-cc-pVDZ and MP2/aug-cc-pVDZ methods. Our observation indicates that the primary addition product of Cl + C₂H₂, 2-chlorovinyl (·CHCHCl) reacts readily with a neighboring p-H2 molecule to form ·CHClCH₃ and C₂H₃Cl. Observation of ·CDClCH₂D and trans-CHDCDCl from Cl + C₂D₂ further supports this conclusion. Although the reactivity of p-H₂ appears to be a disadvantage for making highly reactive free radicals in solid p-H₂, the formation of 1-chloroethyl radical indicates that this secondary reaction might be advantageous in producing radicals that are difficult to prepare from simple photolysis or bimolecular reactions in situ.


Ongoing Healthcare Disparities in neuroHIV: Addressing Gaps in the Care Continuum.
We aim to review the neurological complications of HIV and the social, cultural, and economic inequalities that contribute to disparities in neuroHIV care. Disparities in diagnostics and care of patients with neurological infections and non-infectious conditions associated with HIV in both high-income and low-to-middle-income countries (LMIC) are common. The COVID-19 pandemic has exacerbated these disparities. Factors, such as HIV-related stigma, may deter people from accessing HIV treatment. First-line recommended treatments for neurological infections are not available in many LMICs, leading to inadequate treatment and exposure to agents with more harmful side effect profiles. Access-related factors, such as lack of transportation, lack of health insurance, and inadequate telehealth access, may increase the risk of HIV-related neurological complications. Further research is needed to increase awareness of neurological complications among providers and PWH, and regional guidelines should be considered to better address these complications.


Are CSF neopterin levels a marker of disease activity in multiple sclerosis?
The study aimed to evaluate neopterin levels in cerebro-spinal fluid (CSF) as a marker of disease activation and progression of multiple sclerosis (MS). Neopterin, a substance known to be released from macrophages and monocytes at increased rates in cellular immune reactions, was investigated by radioimmunoassay, in the CSF of 19 patients with MS during exacerbations of the disease, in 34 patients with other neurological diseases (OND) and in 20 normal subjects used as controls. Poser's criteria were used for the diagnosis of MS. Although elevated neopterin levels in the CSF of patients with MS during exacerbations have been reported by other investigators, we found such elevation in only 4 out of 19 patients with MS (21%), in 5 out of 34 patients with OND (14.7%), and in none of the control group. Student's t-test was used for statistical analysis. There was no significant difference in the CSF values of the MS patients, the patients with OND (p > 0.05) or the controls. These results indicate that neopterin levels in CSF may not be considered a marker of disease activity in MS.


Amputation and reamputation of the diabetic foot.
The authors compare the level of foot amputation by age, prevalence of arterial disease as a precipitating factor, gender, and ethnicity in persons with diabetes mellitus. Medical records were abstracted for each hospitalization for a lower extremity amputation from January 1 to December 31, 1993, in six metropolitan statistical areas in south Texas. Amputation level was defined by ICD-9-CM codes and were categorized as foot, leg, and thigh amputations. Foot-level amputations were further subcategorized as hallux or first ray, middle, fifth, multiple digit or ray, and midfoot amputations. Only the highest amputation level for each individual was used in the analysis. Of 1,043 subjects undergoing a lower extremity amputation in south Texas in the year 1993, 477 received their amputation at the level of the foot. African-Americans requiring a foot-level amputation were at significantly higher risk to undergo a midfoot-level amputation than was the rest of the population. Nearly 40% of all subjects undergoing a foot-level amputation had a previous history of amputation. However, nearly 40% of subjects undergoing foot amputations had not been diagnosed either before or during admission with peripheral arterial occlusive disease, suggesting a causal pathway dependent primarily on neuropathy. This implies that better screening of diabetic patients with appropriate risk-directed treatment at the primary care level may significantly impact the large number of preventable diabetes-related lower extremity amputations.


Examining the impact of 11 long-standing health conditions on health-related quality of life using the EQ-5D in a general population sample.
Health-related quality of life (HRQoL) measures have been increasingly used in economic evaluations for policy guidance. We investigate the impact of 11 self-reported long-standing health conditions on HRQoL using the EQ-5D in a UK sample. We used data from 13,955 patients in the South Yorkshire Cohort study collected between 2010 and 2012 containing the EQ-5D, a preference-based measure. Ordinary least squares (OLS), Tobit and two-part regression analyses were undertaken to estimate the impact of 11 long-standing health conditions on HRQoL at the individual level. The results varied significantly with the regression models employed. In the OLS and Tobit models, pain had the largest negative impact on HRQoL, followed by depression, osteoarthritis and anxiety/nerves, after controlling for all other conditions and sociodemographic characteristics. The magnitude of coefficients was higher in the Tobit model than in the OLS model. In the two-part model, these four long-standing health conditions were statistically significant, but the magnitude of coefficients decreased significantly compared to that in the OLS and Tobit models and was ranked from pain followed by depression, anxiety/nerves and osteoarthritis. Pain, depression, osteoarthritis and anxiety/nerves are associated with the greatest losses of HRQoL in the UK population. The estimates presented in this article should be used to inform economic evaluations when assessing health care interventions, though improvements can be made in terms of diagnostic information and obtaining longitudinal data.


6-Perfluoroalkylated phenanthridines via radical perfluoroalkylation of isonitriles.
A simple and efficient approach to 6-perfluoroalkylated phenanthridines starting with readily prepared isonitriles and commercially available cheap perfluoroalkyl iodides as perfluoroalkyl radical precursors is described. Various 6-perfluoroalkylated phenanthridines are obtained in moderate to excellent yields. The sequence comprises a perfluoroalkylation with concomitant arene formation.


Endoscopic Gluteus Medius Repair With Concomitant Arthroscopy for Labral Tears: A Case Series With Minimum 5-Year Outcomes.
To report the minimum 5-year outcomes of endoscopic gluteus medius repair for partial- and full-thickness tears with concomitant hip arthroscopy. Data for all patients who underwent hip arthroscopy between February 2009 and September 2011 were prospectively collected. We included patients who underwent endoscopic gluteus medius repair with concomitant arthroscopic labral treatment and for whom the following measures were obtained preoperatively and at a minimum of 5 years' follow-up: modified Harris Hip Score, Non-Arthritic Hip Score, Hip Outcome Score-Sports Specific Subscale, and visual analog scale score for pain. For included patients, the International Hip Outcome Tool-12 (iHOT-12) score and satisfaction rating were also available at latest follow-up. Patients with at least 1 of the following criteria were excluded: preoperative Tönnis osteoarthritis grade of 2 or greater, previous hip conditions, severe dysplasia, and Workers' Compensation claims. There were 16 patients eligible for inclusion, 14 (87.5%) of whom had minimum 5-year follow-up, with a mean of 68.8 months (range, 60.1-79.6 months). The study group consisted of 13 women (92.9%) and 1 man (7.1%) with a mean age at surgery of 57.4 years (range, 46.3-74.8 years). Outcome scores improved as follows: modified Harris Hip Score, from 52.4 to 81.2 (P = .004); Non-Arthritic Hip Score, from 48.0 to 82.5 (P = .002); Hip Outcome Score-Sports Specific Subscale, from 30.1 to 66.4 (P < .001); and visual analog scale score, from 6.2 to 2.6 (P = .001). At minimum 5-year follow-up, the mean iHOT-12 score was 73.8 and the mean patient satisfaction rating was 8.4. Survivorship was 92.9%, with 1 patient who underwent conversion to total hip arthroplasty. There was no deterioration in patient outcomes and satisfaction between 2 and 5 years postoperatively. There were no clinical failures of gluteus medius repair and no complications. Endoscopic gluteus medius repair with concomitant hip arthroscopy for labral tears is safe and shows favorable outcomes at minimum 5-year follow-up. Patient outcomes were as favorable at 5 years as they were at 2 years postoperatively. Level IV, therapeutic case series.


Cntnap2 Knockout Rats and Mice Exhibit Epileptiform Activity and Abnormal Sleep-Wake Physiology.
Although recent innovations have enabled modification of the rat genome, it is unclear whether enhanced utility of rodents as human disease models will result. We compared electroencephalogram (EEG) and behavioral phenotypes of rats and mice with homozygous deletion of Cntnap2, a gene associated with cortical dysplasia-focal epilepsy (CDFE) and autism spectrum disorders (ASD). Male contactin-associated protein-like 2 (Cntnap2) knockout (KO) and wild-type (WT) rats and male Cntnap2 KO and WT mice were implanted with telemeters to record EEG, electromyogram, body temperature, and locomotor activity. Animals were subjected to a test battery for ASD-related behaviors, followed by 24-hr EEG recordings that were analyzed for sleep-wake parameters and subjected to spectral analysis. Cntnap2 KO rats exhibited severe motor seizures, hyperactivity, and increased consolidation of wakefulness and REM sleep. By contrast, Cntnap2 KO mice demonstrated absence seizure-like events, hypoactivity, and wake fragmentation. Although seizures observed in Cntnap2 KO rats were more similar to those in CDFE patients than in KO mice, neither model fully recapitulated the full spectrum of disease symptoms. However, KOs in both species had reduced spectral power in the alpha (9-12 Hz) range during wake, suggesting a conserved EEG biomarker. Deletion of Cntnap2 impacts similar behaviors and EEG measures in rats and mice, but with profound differences in nature and phenotypic severity. These observations highlight the importance of cross-species comparisons to understand conserved gene functions and the limitations of single- species models to provide translational insights relevant to human diseases.


Differential thermal and thermogravimetric analyses of bound water content in cellulosic substrates and its significance during cellulose hydrolysis by alkaline active fungal cellulases.
Various cellulosic substrates were examined for bound water content by differential thermal analysis (DTA) and thermogravimetry (TG). Samples were heated in the range of 30-100 degrees C at a rate of 3 degrees C/min. DTA vaporization curves for different cellulose samples indicated that the bound water (Wf) was vaporized at higher temperature than free water (Wf) at the surface. Weight loss was observed in two stages, corresponding to Wf and Wb in TG curves. The bound water content was dependent on the degree of crystallinity of cellulose. Among different cellulosic substrates, Walseth cellulose showed the highest bound water content, and it also was found to be the least crystalline. The alkaline-active, alkali-stable cellulase was obtained from the alkalotolerant Fusarium sp. The substrate specificity and viscometric characteristics confirmed the enzyme to be an endoglucanase. The Wb content of Walseth cellulose was lowered during the enzymatic hydrolysis. The possible application of bound water analysis in understanding the hydrolysis of cellulosic substrates of different crystallinity is discussed.


Regulated actin cytoskeleton assembly at filopodium tips controls their extension and retraction.
The extension and retraction of filopodia in response to extracellular cues is thought to be an important initial step that determines the direction of growth cone advance. We sought to understand how the dynamic behavior of the actin cytoskeleton is regulated to produce extension or retraction. By observing the movement of fiduciary marks on actin filaments in growth cones of a neuroblastoma cell line, we found that filopodium extension and retraction are governed by a balance between the rate of actin cytoskeleton assembly at the tip and retrograde flow. Both assembly and flow rate can vary with time in a single filopodium and between filopodia in a single growth cone. Regulation of assembly rate is the dominant factor in controlling filopodia behavior in our system.


Thirty-day mortality in traumatically brain-injured patients undergoing decompressive craniectomy.
Decompressive craniectomy is a life-saving measure for patients who have sustained traumatic brain injury (TBI), but patients undergoing this procedure may still die during an early phase of head injury. The aim of this study was to investigate the incidence, causes, and risk factors of 30-day mortality in traumatically brain-injured patients undergoing decompressive craniectomy. The authors included 201 head-injured patients undergoing decompressive craniectomy in this 3-year retrospective study. The main outcome evaluated was 30-day mortality in patients who had undergone craniectomy after TBI. Demographic and clinical data, including information on death, were obtained for subsequent analysis. The authors identified differences between survivors and nonsurvivors in terms of clinical parameters; multivariate logistic regression was used to adjust for independent risk factors of short-term death. The 30-day mortality rate was 26.4% in traumatically brain-injured patients undergoing decompressive craniectomy. The majority of deaths following decompression resulted from uncontrollable brain swelling and extensive brain infarction, which accounted for 79.2% of mortality. In the multivariate logistic regression mode, the 2 independent risk factors for 30-day mortality were age (OR 1.035 [95% CI 1.006-1.064]; p = 0.018) and Glasgow Coma Scale (GCS) score before decompressive craniectomy (OR 0.769 [95% CI 0.597-0.990]; p = 0.041). There is a high 30-day mortality rate in traumatically brain-injured patients undergoing decompressive craniectomy. Most of the deaths are attributed to ongoing brain damage, even after decompression. Risk factors of short-term death, including age and preoperative GCS score, are important in patient selection for decompressive craniectomy, and these factors should be considered together to ensure the highest chance of surviving TBI.


Novel biomarkers for prostate cancer: An evidence-based review for use in clinical practice.
Prostate cancer is a heterogeneous disease with disparate outcomes. Traditional clinical parameters are limited in their ability to differentiate between these cases, and there is uncertainty regarding management strategies. A number of novel biomarkers have emerged, but how best to use them at the point of care remains confusing. In the present review, we describe the most common novel biomarkers, their key supporting literature, and propose a meaningful algorithm for their use in clinical practice. To identify commercially available prostate cancer diagnostic tests, we carried out a PubMed literature search (through May 2016). Only English-language studies were included. We restricted our search to studies published within the past 10 years in order to focus our review on novel data. Secondary sources were also examined. We identified 12 novel biomarkers and categorized them into broad areas of clinical practice: (i) early diagnosis and screening; (ii) staging and primary treatment selection; (iii) post-treatment risk stratification; (iv) advanced disease prognosis and treatment response; and (v) emerging tests. Most validation studies rely on small retrospective cohorts and carry a high risk of bias; furthermore, most cohorts are restricted to Caucasians, with little to no representation of other geographic, racial or ethnic populations. Novel biomarkers for prostate cancer management, while potentially helpful, should not replace standard clinical information and physician judgment. They are currently best suited to serve as an adjunct to existing management tools. Clinicians should have a sound grasp of each biomarker-based test's indications and limitations.


Dose-escalated accelerated hypofractionation for elderly or frail patients with a newly diagnosed glioblastoma.
The standard of care for elderly glioblastoma patients is 40 Gy in 15 fraction radiotherapy with temozolomide (TMZ). However, this regimen has a lower biologic equivalent dose (BED) compared to the Stupp regimen of 60 Gy in 30 fractions. We hypothesize that accelerated hypofractionated radiation of 52.5 Gy in 15 fractions (BED equivalent to Stupp) will have superior survival compared to 40 Gy in 15 fractions. Elderly patients (≥ 65 years old) who received hypofractionated radiation with TMZ from 2010 to 2020 were included in this analysis. Overall survival (OS) and progression free survival were defined as the time elapsed between surgery/biopsy and death from any cause or progression. Baseline characteristics were compared between patients who received 40 and 52.5 Gy. Univariable and multivariable analyses were performed. Sixty-six newly diagnosed patients were eligible for analysis. Thirty-nine patients were treated with 40 Gy in 15 fractions while twenty-seven were treated with 52.5 Gy in 15 fractions. Patients had no significant differences in age, sex, methylation status, or performance status. OS was superior in the 52.5 Gy group (14.1 months) when compared to the 40 Gy group (7.9 months, p = 0.011). Isoeffective dosing to 52.5 Gy was shown to be an independent prognostic factor for improved OS on multivariable analysis. Isoeffective dosing to 52.5 Gy in 15 fractions was associated with superior OS compared to standard of care 40 Gy in 15 fractions. These hypothesis generating data support accelerated hypofractionation in future prospective trials.


Amplifying TLR-MyD88 signals within tumor-specific T cells enhances antitumor activity to suboptimal levels of weakly immunogenic tumor antigens.
The efficacy of T cell-based immunotherapy to treat cancer patients remains a challenge partly because of the weak activity toward subdominant tumor antigens (TAg) and to tumors expressing suboptimal TAg levels. Recent reports indicate that Toll-like receptor (TLR) stimulation on T cells can lower the activation threshold. In this study, we examined the antitumor activity and survival of TLR2-MyD88-stimulated CD8 T cells derived from melanoma patients and T-cell receptor transgenic pmel mice. TLR2-stimulated pmel CD8 T cells, but not TLR2(-/-)pmel or MyD88(-/-)pmel T cells, responded to significantly lower TAg levels and resulted in increased production of effector molecules and cytotoxicity. Wild-type or MyD88(-/-) mice treated with TLR2 ligand and pmel T cells, but not TLR2(-/-)pmel or MyD88(-/-)pmel T cells, showed tumor regression of an established melanoma tumor. Overexpressing TLR2 in TAg-specific T cells eradicated tumors; four times fewer cells were needed to generate antitumor responses. The enhanced antitumor activity of TLR2-MyD88-stimulated T cells was associated with increased effector function but perhaps more importantly with improved survival of T cells. Activating TLR-MyD88 signals in patient-derived T cells also reduced the activation threshold to several weakly immunogenic TAgs, resulting in increased cytokine production, expansion, and cytotoxicity. These data highlight a previously unappreciated role for activating TLR-MyD88 signals in tumor-reactive T lymphocytes.


Entanglement as a signature of quantum chaos.
We explore the dynamics of entanglement in classically chaotic systems by considering a multiqubit system that behaves collectively as a spin system obeying the dynamics of the quantum kicked top. In the classical limit, the kicked top exhibits both regular and chaotic dynamics depending on the strength of the chaoticity parameter kappa in the Hamiltonian. We show that the entanglement of the multiqubit system, considered for both the bipartite and the pairwise entanglement, yields a signature of quantum chaos. Whereas bipartite entanglement is enhanced in the chaotic region, pairwise entanglement is suppressed. Furthermore, we define a time-averaged entangling power and show that this entangling power changes markedly as kappa moves the system from being predominantly regular to being predominantly chaotic, thus sharply identifying the edge of chaos. When this entangling power is averaged over all states, it yields a signature of global chaos. The qualitative behavior of this global entangling power is similar to that of the classical Lyapunov exponent.


Dynamics of the stratification process in drying colloidal dispersions studied by terahertz time-domain spectroscopy.
We present an optical study that reveals the bulk dynamics of the stratification process in drying colloidal dispersions. Terahertz time-domain spectroscopy has been used to measure in situ solventborne and waterborne paint layers as a function of drying time. The dynamic behavior of the dry top layer and wet bottom layer thickness, as well as the bulk thickness, reflect the principal processes of the established drying mechanism. In addition, the results demonstrate stratification only when the drying process is in the evaporation controlled regime, whereas the coating is shown to remain a single layer for diffusion controlled drying.


Uptake and reversibility of uptake of nickel by human macrophages.
The use of nickel-containing alloys in dentistry has been questioned because of the biological liabilities of nickel and the release of nickel ions from dental appliances into the oral cavity. The uptake of nickel by cells in the oral tissues is a critical factor in assessing the biological liabilities of nickel. Nickel uptake by macrophages may be particularly important because of the central role of macrophages in the inflammatory process and the known role of the macrophage in orchestrating the response to biomaterials. The aims of the current study were to assess the reversibility of the uptake of nickel from human macrophages and determine the portion of the nickel which reaches the nuclei as a function of time. Cellular nickel content was measured by means of atomic absorption spectrometry. Nuclear nickel content was assessed after fractionating cells. The results showed that nickel was rapidly taken up by macrophages and that the nickel accumulated in the nucleus in as little as 8 h. After 48 h, over 60% of the cellular nickel was in the nucleus. Once taken up, the nickel was lost at a lower rate. The rate of loss decreased as the initial exposure time to the nickel increased. Thus, the results indicated that macrophages may accumulate nickel if the time between exposures is insufficient to reverse the uptake. Further studies are necessary to correlate the retention of nickel with impaired function of macrophages and to further define the biological risks of using nickel in dental alloys.


Microbiome alteration via fecal microbiota transplantation is effective for refractory immune checkpoint inhibitor-induced colitis.
Immune checkpoint inhibitors (ICIs) target advanced malignancies with high efficacy but also predispose patients to immune-related adverse events like immune-mediated colitis (IMC). Given the association between gut bacteria with response to ICI therapy and subsequent IMC, fecal microbiota transplantation (FMT) represents a feasible way to manipulate microbial composition in patients, with a potential benefit for IMC. Here, we present a large case series of 12 patients with refractory IMC who underwent FMT from healthy donors as salvage therapy. All 12 patients had grade 3 or 4 ICI-related diarrhea or colitis that failed to respond to standard first-line (corticosteroids) and second-line immunosuppression (infliximab or vedolizumab). Ten patients (83%) achieved symptom improvement after FMT, and three patients (25%) required repeat FMT, two of whom had no subsequent response. At the end of the study, 92% achieved IMC clinical remission. 16S rRNA sequencing of patient stool samples revealed that compositional differences between FMT donors and patients with IMC before FMT were associated with a complete response after FMT. Comparison of pre- and post-FMT stool samples in patients with complete responses showed significant increases in alpha diversity and increases in the abundances of Collinsella and Bifidobacterium, which were depleted in FMT responders before FMT. Histologically evaluable complete response patients also had decreases in select immune cells , including CD8+ T cells, in the colon after FMT when compared with non-complete response patients (n = 4). This study validates FMT as an effective treatment strategy for IMC and gives insights into the microbial signatures that may play a critical role in FMT response.


The aromatic "trapping" of the catalytic histidine is essential for efficient catalysis in acetylcholinesterase.
While substitution of the aromatic residues (Phe295, Phe338), located in the vicinity of the catalytic His447 in human acetylcholinesterase (HuAChE) had little effect on catalytic activity, simultaneous replacement of both residues by aliphatic amino acids resulted in a 680-fold decrease in catalytic activity. Molecular simulations suggested that the activity decline is related to conformational destabilization of His447, similar to that observed for the hexamutant HuAChE which mimics the active center of butyrylcholinesterase. On the basis of model structures of other cholinesterases (ChEs), we predicted that catalytically nonproductive mobility of His447 could be restricted by introduction of aromatic residue in a different location adjacent to this histidine (Val407). Indeed, the F295A/F338A/V407F enzyme is 170-fold more reactive than the corresponding double mutant and only 3-fold less reactive than the wild-type HuAChE. However, analogous substitution of Val407 in the hexamutant HuAChE (generating the heptamutant Y72N/Y124Q/W286A/F295L/F297V/Y337A/V407F) did not enhance catalytic activity. Reactivity of these double, triple, hexa, and hepta mutant HuAChEs was monitored toward covalent ligands such as organophosphates and the transition state analogue TMFTA, which probe, respectively, the facility of the enzymes to accommodate Michaelis complexes and to undergo the acylation process. The findings suggest that in the F295A/F338A mutant the two His447 conformational states, which are essential for the different stages of the catalytic process, seem to be destabilized. On the other hand, in the F295A/F338A/V407F mutant only the state involved in acylation is impaired. Such differential effects on the His447 conformational properties demonstrate the general role of aromatic residues in cholinesterases, and probably in other serine hydrolases, in "trapping" of the catalytic histidine and thereby in optimization of catalytic activity.


Distribution of insulin-dependent diabetes mellitus (IDDM)-related HLA alleles correlates with the difference in IDDM incidence in four populations of the Eastern Baltic region.
The high incidence of insulin-dependent diabetes mellitus (IDDM) in Finland contrasts strikingly with the low rates in the neighbouring populations of countries in the Eastern Baltic region: Estonia, Latvia and Russia. To evaluate the possible contribution of genetic factors to these differences, the frequencies of HLA-DQB1 alleles and relevant DQB1-DQA1 or DQB1-DRB1 haplotypes associated with IDDM risk or protection were analysed among IDDM patients and control subjects from these four populations. An increased frequency of HLA-DQB1*0302, DQB1*02-DQA1*05 and DQB1*0302-DRB1*0401 was observed in subjects with IDDM in all studied populations, whereas the prevalence of DQB1*0301 and DQB1*0602 and/or *0603 was decreased among patients. The degree of IDDM risk associated with HLA alleles analysed here did not differ significantly between the populations. Comparisons of the distribution of IDDM-related HLA alleles and haplotypes in the background populations revealed its consonance with IDDM incidence. The combined frequency of high risk genotypes was significantly higher among Finns than in other populations studied. Our data support the hypothesis that variance in the dispersion of HLA alleles is the genetic basis of variation of IDDM incidence observed in the Eastern Baltic region.


Lack of a significant legacy effect of baseline blood pressure 'treatment naivety' on all-cause and cardiovascular mortality in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial.
To investigate legacy effects at 14-year follow-up of all-cause and cardiovascular disease (CVD) mortality in 'treatment-naive' or 'previous treatment' groups based on blood pressure (BP)-lowering treatment status at baseline. A post-hoc observational study of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. We excluded participants with a previous history of CVD events. Cox proportional hazard model and 95% confidence interval were used to estimate the effects of treatment naive on mortality outcomes. Moreover, a subgroup analysis by estimated 10-year Framingham risk score was performed. In multivariable models adjusting for baseline and in-trial characteristics (BP values and number of BP medications as time-dependent variables), there was no statistically significant difference in 5 and 14-year all-cause mortality with a hazard ratio of 0.93 (95% confidence interval 0.80-1.09) and hazard ratio 0.95 (0.88-1.03) and in 5 and 14-year CVD mortality hazard ratio 0.94 (0.72-1.23) and hazard ratio 0.93 (0.80-1.08). In subgroup by absolute CVD risk, no heterogeneity of the association between treatment naive and short-term or long-term all-cause or CVD mortality were found. All comparisons are between the treatment-naive and previous treatment groups. Physicians are concerned about 'legacy effects' of not treating individuals with a BP of 140 mmHg or over and low absolute risk. When treatment intensification was taken into consideration in the primary prevention population in this study, no adverse legacy effect as a result of baseline BP 'treatment naivety' was evident in 14 years of follow-up. The nonsignificant associations were consistent across the CVD risk subgroups. However, the results may be biased due to unobserved residual confounding and therefore should be interpreted with caution.


Role for growth factors and extracellular matrix in controlling differentiation of prospectively isolated hepatic stem cells.
In liver development, a number of growth factors (GFs) and components of the extracellular matrix (ECMs) lead to differentiation of liver parenchymal cells. As the liver contains many cell types, specifically investigating their functional effects on hepatic stem cell populations is difficult. Prospective isolation and clonal assays for hepatic stem cells enable the examination of direct effects of GFs and ECMs on this rare cell fraction. Using previously purified cells that fulfill the criteria for hepatic stem cells, we examined how GFs and ECMs regulate differentiation in the developing liver. We show here that hepatocyte growth factor (HGF) induced early transition of albumin (ALB)-negative stem cells to ALB-positive hepatic precursors resembling hepatoblasts and then oncostatin M (OSM) promoted their differentiation to tryptophan-2, 3-dioxygenase (TO)-positive mature hepatocytes. During this transition, ECMs were necessary for the differentiation of stem cells and precursors, but their effects were only supportive. In the first step of stem cell differentiation induced by HGF, the expression of CCAAT/enhancer binding protein (C/EBP), a basic leucine zipper transcription factor, changed dramatically. When C/EBP function was inhibited in stem cells, they stopped differentiating to hepatocyte-lineage cells and proliferated actively. These are the first findings to illustrate the mechanism of hepatic stem cell differentiation in liver development.


Reaction of 5-halo-1,2,3-thiadiazoles with aliphatic diamines. Synthesis and intramolecular cyclization of bis(1,2,3-triazolyl-1,2,3-thiadiazolyl)sulfides.
Bis[1,2,3]triazolo[1,5-f:5',1'-b][1,3,6]thiadiazepine and [1,5-g:5',1'-b][1,3,7]thiadiazocine ring systems have been synthesized from 5-halo-1,2,3-thiadiazoles and aliphatic diamines. We have found that the last step of the process is the cyclization of initially formed bis(1,2,3-triazolyl-1,2,3-thiadiazolyl)sulfides. The structures of the intermediates and products were supported by different NMR spectroscopic methods (1H coupled 13C NMR, 2D HETCOR, HMBC and 1D INADEQUATE experiments) and mass spectrometry. Differences in the reaction pathway for aliphatic and less nucleophilic aromatic diamines were determined.


Improved localization of phosphorylation sites in simian virus 40 large T antigen.
The location of phosphorylation sites in the large T antigen of simian virus 40 has been studied both by partial chemical cleavage and by partial proteolysis of various forms of large T. These included the full-size wild-type molecule with an apparent molecular weight of 88,000, deleted molecules coded for by the mutants dl1265 and dl1263, and several shortened derivatives generated by the action of a cellular protease. These molecules differed from each other by variations in the carboxy-terminal end. In contrast, a ubiquitous but minor large T form with a molecular weight of 91,000 was found to be modified in the amino-terminal half of the molecule. In addition to the phosphorylation of threonine at position 701 (K.-H. Scheidtmann et al., J. Virol. 38:59-69, 1981), two other discrete domains of phosphorylation were recognized, one at either side of the molecule. The amino-terminal region was located between positions 81 and 124 and contained both phosphothreonine and phosphoserine residues. The carboxy-terminal region was located between approximate positions 500 and 640 and contained at least one phosphoserine residue but no phosphothreonine. The presence in the phosphorylated domains of large T of known recognition sequences for different types of protein kinases is discussed, together with possible functions of large T associated with these domains.


[Immunomorphological study of plasmorrhagia in experimental hypertension in rats].
Plasmorrhagia of the arterial wall of various organs in rats with ischemic renal, DOCA-saline, and genetic spontaneous hypertension was studied by the method of fluorescent antibodies according to Coombs with the use of pure antibodies to yamma-globudin of a rabbit. The most pronounced plasmorrhagia was observed in rats with DOCA-saline hypertension in the arterial vessels of the kidneys. In rats with genetic hypertension lesions of the heart vessels were noted.


Monteggia lesion in an Asian small-clawed otter (Aonyx cinerea).
A 10-yr-old female Asian small-clawed otter (Aonyx cinerea) presented with a history of right forelimb lameness. Antebrachial radiographs revealed a Monteggia lesion, classified by cranial radial head luxation and distal diaphyseal ulnar fracture. Open reduction with placement of an ulnar-radial positional screw was performed. The lateral collateral ligament was reconstructed using suture anchored by a condylar screw and bone tunnel in the radius. Reduction and proper implant placement was confirmed on postoperative radiographs. The ulnar-radial positional screw was removed 6 wk postoperatively to allow proper supination and pronation. Limb function was greatly improved at this time; however, a mild lameness was still observed. At 7 mo postoperatively, the otter was ambulating lameness-free. Radiographs documented proper joint reduction and stable condylar screw. At 32 mo postoperatively, the otter continued to exhibit normal ambulation.


Receptor occupancy with digoxin vs receptor occupancy with a putative endogenous digitalislike factor.
The possibility that an endogenous ligand for the digitalis receptor might exist has been a source of speculation resulting in efforts over the past decades to identify such a hormone. In the current context it is of interest that prolonged wash of myocardial and skeletal muscular samples from subjects who were not in digoxin treatment generally resulted in small tendencies to increase 3H-ouabain binding ranging from 2 to 9% and from -2 to 7%, respectively. It may be appreciated that neither wet weight nor water content of left ventricular or skeletal muscular samples have been found to change as a result of the prolonged wash. Although these tendencies most likely are a mere play of chance, it may be argued that the studies did not entirely rule out the possibility of the existence of a quantitatively small amount of endogenous digitalislike factor. However, based on the evaluations of receptor occupancy with digoxin during treatment of 24-34% in the left ventricle and 9-13% in skeletal muscle, it would seem reasonable to expect that a comparatively larger fraction of digitalis receptors should be occupied by a putative endogenous digitalislike factor, if such a factor were to be of any physiological significance.


Effect of endocrine therapy on quality of life and cognitive functions in patients with breast cancer.
The use of endocrine therapy (ET) in postmenopausal breast cancer patients may affect their cognitive status. This study aims to assess the effects of tamoxifen and aromatase inhibitors (Als) on quality of life (QoL) and cognitive functions in breast cancer patients. The study included 101 patients receiving tamoxifen, 97 patients receiving Als, and 95 patients without any ET. All patients completed both the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and the Short Form-12 (SF-12) questionnaires. The patients' characteristics were similar between the groups. The mean duration of ET was 2.6 years for tamoxifen and 2.5 years for Als. EORTC QLQ-C30 global scores and cognitive functioning scores as well as SF-12 mental scorings (mcs) were found not significantly different between patients without any ET and those receiving tamoxifen or Als (p = 0.529, p = 0.333, and p = 0.452, respectively). SF-12 mcs correlated moderately with EORTC QLQ-C30 global scores for the 3 treatment groups (all p values < 0.001). Our study suggests that QoL and cognitive functions are similar in patients receiving Als or tamoxifen. Moreover, it appears that these parameters also do not differ in patients with respect to the use of ET.


Electrofluorescence switching of tetrazine-modified TiO2 nanoparticles.
Highly fluorescent tetrazine-modified TiO2 nanoparticles were prepared by the reaction of triethoxysilane-appended chloroalkoxy tetrazine (ESTZ) with TiO2 nanoparticles through a condensation reaction between the surface hydroxyl groups of an electrode and the silane anchor group of ESTZ. The prepared electrodes were used as robust fluorescent layers for electrochemical fluorescence switching (electrofluorochromism) applications in the presence of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) as a charge balancing mediator. The stable charge balancing mediator, TEMPO, in the electrolyte was found to be essential to reduce the intrinsic electron transport resistance of TiO2 in order to achieve reversible electrofluorescence switching. Furthermore it facilitated a fully reversible electrochemical reaction and provided a sufficient charge balance, which allowed us to realize semiconductor-based electrofluorescence switching with an on/off ratio of 4.0 and cyclability greater than 100 cycles.


Identification and quantification of in vivo metabolites of 9,10-phenanthrenequinone in human urine associated with producing reactive oxygen species.
Polycyclic aromatic hydrocarbon quinones (PAHQs) are components in airborne particulate matter (PM) and generate reactive oxygen species (ROS) in a redox cycling process. 9,10-Phenanthrenequinone (9,10-PQ) is a PAHQ found in diesel exhaust particulates and PM. When inhaled, it produces much more ROS than other PAHQs. We hypothesized that urinary metabolites of 9,10-PQ could serve as biomarkers of PAHQ exposure. Here, we describe methods for pretreating urine samples and analyzing 9,10-PQ metabolites by liquid chromatography with tandem mass spectrometry (LC-MS/MS). In urine from rats intraperitoneally injected with 9,10-PQ, the monoglucuronide of 9,10-dihydroxyphenanthrene (9,10-PQHG) was found to be a major metabolite of 9,10-PQ. 9,10-PQHG was also identified in the urine of a nonoccupationally exposed human by its retention time and MS/MS spectra. Furthermore, the urine contained hardly any free (unmetabolized) 9,10-PQ, but treating it with hydrolytic enzymes released 9,10-PQ from conjugated metabolites such as 9,10-PQHG. The concentrations of 9,10-PQHG in urine samples from nonoccupationally exposed subjects who lived in a suburban area were 2.04-19.08 nmol/mol creatinine. This study is the first to demonstrate the presence of 9,10-PQHG in human urine. Determination of urinary 9,10-PQHG should be useful for determining 9,10-PQ exposure.


Immunocytochemical studies on co-localization of alpha-granule membrane alphaIIbbeta3 integrin and intragranular fibrinogen of human platelets and their cell-surface expression during the thrombin-induced release reaction.
We employed a double-staining method to immunocytochemically study the role of alpha-granule membrane alphaIIbbeta3 integrin in the expression of intragranular fibrinogen (Fbg) and albumin on the surface of thrombin-activated human platelets. In unstimulated platelets, alphaIIbbeta3 was distributed along the alpha-granule membrane as well as on the cell-surface membrane, including the open canalicular system (OCS), while Fbg and albumin were exclusively and evenly detected in the granules. At 30 s after activation by 0.1 U ml(-1) thrombin under non-stirred conditions, a small amount of Fbg in the granules was redistributed in association with alpha-granule membrane alphaIIbbeta3, suggesting that co-localization between alphaIIbbeta3and Fbg occurs at this period during platelet activation. At 1-5 min, the shape of the platelets changed from discoid to spheroid with pseudopodia and intact alpha-granules were no longer observed in these cells. Fibrinogen associated with alphaIIbbeta3 became increasingly expressed on the membranes of both the swollen OCS and the cell surface. Nevertheless, abundant Fbg still remained in the lumen of the swollen OCS, the membrane of which had already been depleted of alphaIIbbeta3. By western blot analysis using anti-human Fbg antibody, we detected no Fbg in the surrounding medium of the thrombin-stimulated platelets for 5 min. Unlike Fbg, abundant albumin in the alpha-granules was released into the surrounding medium without association with the membrane of either the alpha-granules or the cell surface. These results suggest that a small portion of the intragranular Fbg may bind to an Fbg binding site expressed on the activated aIIbbeta3 on the alpha-granule membrane, resulting in the formation of an alphaIIbbeta3-Fbg complex, which is then moved through the OCS membrane and expressed on the cell-surface membrane. Thus, alpha-granule membrane aIIbbeta3 may act as a carrier of intragranular Fbg.


[Diet and health behaviour in Danish children aged 11-15 years].
A total of 1,671 school children aged 11, 13 and 15 years answered a questionnaire on diet, other health behaviour, social background, social network, health and life satisfaction. The proportions who ate fruit, vegetables, and rye bread every day were 77%, 64% and 94%. Moreover, 78% had fibre-containing breakfast every day and 79% had a regular lunch meal every day. 26% of the children received an optimal diet containing all of these five components every day, and 19% received less than three of these components every day. The proportions who consumed five unhealthy diet components every day (candy, chips, French fries, sausages/hamburgers, and sweet long-drinks) were 32%, 12%, 5%, 5% and 18%. 39% received at least one of these unhealthy diet components every day. There was no association between intake of healthy and intake of unhealthy diet components. We found no age differences among boys regarding the healthy diet components but an increasing consumption of unhealthy components with increasing age. Among girls we found a decreasing consumption of both healthy and unhealthy components with increasing age. Healthy diet was associated with high social class, good health, positive life satisfaction, positive school assimilation, and positive health behaviour.


Development and applications of new technology for two-dimensional space-time characterization and correlation analysis of ultraweak biophoton information.
We describe the spatial distribution and temporal correlation analysis of ultraweak biophoton emission based on photoelectron pulse time series and position measurement techniques. Experimental results on the spatio-temporal variation of biophoton emission from soybean seedlings after physical and chemical stimulation to the root tip are analyzed. Our results suggest the potential usefulness of this technique to quantify the transmission mechanisms of biological signals in the living system by measuring the biophoton emission.


[New unifying diagnosis of functional diseases].
Functional somatic symptoms are prevalent in all medical settings, but their management is hampered by an obsolete theoretical framework and inadequate classification systems. Epidemiological and neurobiological studies suggest that the functional somatic syndromes, e.g. fibromyalgia, chronic fatigue syndrome, irritable bowel syndrome and somatoform disorders belong to the same family of disorders. An empirically based diagnosis including different subtypes and severities is proposed as a unifying diagnostic construct: bodily distress syndrome. This construct provides a common language for functional disorders across medical specialties.


Structure-activity relationship study of some triazolinone based compounds with antagonistic balanced activity on angiotensin II receptor subtypes AT1 and AT2. A three-dimensional quantitative structure-activity relationship investigation.
Angiotensin II (AII) receptor antagonists have attracted much attention as anti-hypertensive agents in recent times following the discovery of side effects associated with angiotensin converting enzyme (ACE) inhibitors. Various lead structures of the compounds of this category are reported in the literature. Studying the structure-activity relationships (SAR) for such compounds has been a fascination for scientists and efforts have been made to identify the essential physico-chemical requirements for the angiotensin type 1 (AT1) receptor selective, angiotensin type 2 (AT2) receptor selective and some AT,/ AT2 balanced antagonistic activity compounds. With an aim to identify the structural requirements for balanced activity and differentiate between the features individually responsible for AT1 and AT2 antagonistic activities, a quantitative SAR (QSAR) analysis was carried out on a series of triazolinone based balanced AII receptor antagonists. The statistically significant equations with r > 0.88, chance < 0.01, q2 > 0.60 and F values at least three times greater than those reported were obtained for both AT1 and AT2 receptor subtypes antagonistic activities. A comparative study of the parameters responsible for AT1 and AT2 receptor antagonistic activities is carried out in order to identify the features that can be modulated to obtain balanced compounds. It has been observed that the most reliable equations obtained in the study show the contribution of hydrophobic parameters: logarithm of partition coefficient (logP), thermodynamic parameters: bend energy (Eb), and electronic parameters: electronic energy (Eelec) parameters towards AT1 anatgonistic activity, and thermodynamic parameters: total energy (E), steric parameters: principal moment of inertia along the Y-axis (PMIY) and electronic parameters: electronic energy (Eelec) parameters towards AT2 antagonistic activity. The parameter Eelec is common but its effect towards the two activities is opposite, negative for AT1 and positive for AT2.


Lipopeptides from Bacillus and Paenibacillus spp.: A Gold Mine of Antibiotic Candidates.
The emergence of multidrug-resistant bacteria has placed a strain on health care systems and highlighted the need for new classes of antibiotics. Bacterial lipopeptides are secondary metabolites, generally produced by nonribosomal peptide synthetases that often exhibit broad-spectrum antimicrobial activity. Only two new structural types of antibiotics have entered the market in the last 40 years, linezolid and the bacterial lipopeptide daptomycin. A wide variety of bacteria produce lipopeptides, however Bacillus and Paenibacillus spp. in particular have yielded several potent antimicrobial lipopeptides. Many of the lipopeptides produced by these bacteria have been known for decades and represent a potential gold mine of antibiotic candidates. This list includes the polymyxins, octapeptins, polypeptins, iturins, surfactins, fengycins, fusaricidins, and tridecaptins, as well as some novel examples, including the kurstakins. These lipopeptides have a wide variety of activities, ranging from antibacterial and antifungal, to anticancer and antiviral. This review presents a reasonably comprehensive list of each class of lipopeptide and their known homologues. Emphasis has been placed on their antimicrobial activities, as well other potential applications for this interesting class of substances.


Carbonless copy paper and workplace safety: a review.
Carbonless copy paper (CCP), introduced in 1954, is ubiquitous in the U.S. marketplace, and because of this, many workers come into contact with it. Its safety to workers who handle large amounts of CCP has been addressed in numerous studies and reports; and the National Institute for Occupational Safety and Health (NIOSH) on two occasions has sought to determine what, if any, hazards to health CCP might pose. This review encompasses the world's literature on CCP and provides a weight-of-evidence analysis of the safety of CCP to workers in the United States. CCP is systematically studied on large groups of humans using repeat insult patch tests. Consistently, CCP in U.S. commerce since 1987 (the focus of this review) has produced neither primary skin irritation nor skin sensitization under exaggerated test conditions, demonstrating that no irritation or sensitization is expected on contact with CCP under normal conditions of manufacture and use. Years after the introduction of CCP, the first case reports appeared in 1974 suggesting an association between CCP use and various generic symptoms. Most of the earliest reports occurred in Sweden in response to negative publicity concerning the product, and to date approximately half of all published articles originate in Scandinavia. Many early reports were questionnaire/interview studies which suffered from suggestive questions, biases, and lack of control for confounding factors. Few studies included a comparison group (i.e., people not exposed to CCP) making it impossible to estimate risk values. Later, sick building syndrome studies, accounting for many relevant factors in the office environment, found no association between CCP exposure and symptoms unexplained by other factors. Animal studies showed that compounds used to manufacture CCP do not have acute toxic potential and are not genotoxic. Finally, very few published complaints have come from the manufacturing sector where the closest and most voluminous contact occurs. A few reports of symptoms have emanated from printing facilities (with a multiplicity of other chemical exposures), but generally most symptoms are reported in the office setting where the exposure is lower than in the manufacturing or printing settings. Based on the weight of the evidence, CCP currently in commerce in the United States is shown not to be the causative agent for the reported general symptoms sometimes associated with it over the years. Recently NIOSH evaluated the literature as to possible hazards to health posed by CCP, and NIOSH is anticipated to conclude that CCP is not a hazard to workers and has only a small possibility of producing mild and transient skin irritation.


Confronting racism in family planning: a critical ethnography of Roma health mediation.
Roma health mediators are part of a government funded, community-led health intervention. One of the programme's central aims is to improve access to reproductive care for Roma women, often said to be one of the most disadvantaged population groups in Europe. This paper is a critical analysis of mediation in Romania, focusing on how social determinants shape access to family planning and how mediators are employed to address inequalities. It is based on ethnographic observations of mediators at work, as well as in-depth interviews with community members, health professionals, and mediators. Health professionals tended to see Roma families as wanting and having an unreasonably large number of children and tried to curtail this through the promotion of contraception. This contrasted with the perspective of community members, who appeared not to choose having many children but who instead struggled to access contraception for financial reasons. Roma health mediators generally seemed aware of multiple and intersecting pressures that women were facing, but ultimately tended to frame family planning as a matter of choice, culture, and knowledge. I set these perspectives against the background of anti-Roma racism and eugenic sentiments, reflected in popular discourses about Roma reproduction. I explore how an intervention that nominally aims to promote the emancipation of Roma communities, in fact entrenches some of the racially fused assumptions that are connected to inequalities of access to reproductive health care in the first place. The discussion has implications for Roma reproductive health interventions across Europe, and for participatory interventions more globally.


Plasticity in foraging strategies of inshore birds: how Little Penguins maintain body reserves while feeding offspring.
Breeding animals face important time and energy constraints when caring for themselves and their offspring. For long-lived species, life-history theory predicts that parents should favor survival over current reproductive attempts, thus investing more into their own maintenance than the provisioning of their young. In seabirds, provisioning strategies may additionally be influenced by the distance between breeding sites and foraging areas, and offshore and inshore species should thus exhibit different strategies. Here, we examine the provisioning strategies of an inshore seabird using a long-term data set on more than 200 Little Penguins, Eudyptula minor. They alternated between two consecutive long and several short foraging trips all along chick rearing, a strategy almost never observed for inshore animals. Short trips allowed for regular provisioning of the chicks (high feeding frequency and larger meals), whereas long trips were performed when parent body mass was low and enabled them to rebuild their reserves, suggesting that adult body condition may be a key factor in initiating long trips. Inshore seabirds do use dual strategies of alternating short and long trips, but from our data, on a simpler and less flexible way than for offshore birds.


Revisiting Pt/TiO2 photocatalysts for thermally assisted photocatalytic reduction of CO2.
Artificial photosynthesis by a semiconductor-oxide-based photocatalysis is presently challenging due to low CO2 conversion rates and poor product selectivity. To promote CO2 reduction, Pt/TiO2 has been deemed as a classic photocatalyst. In this study, we restudy Pt/TiO2 for the thermally assisted photocatalytic reduction of CO2 and reveal a different story between photocatalysis and photothermal catalysis. For example, when using disordered Pt/TiO2-x, the CO2 conversion via photocatalysis at 298 K is not impressive. However, when the system temperature is increased to 393 K, the CO2 conversion rate is significantly enhanced by a factor of 155 as compared to that obtainable from pristine TiO2; further, surprisingly high selectivity of CH4 (87.5%) could be achieved. Thermally coupled photocatalysis yields the enhanced evolution of H2 side products over Pt (4.06 nm)/TiO2 and promoted H2 splitting over Pt (2.33 nm)/TiO2, which is seldom observed in conventional Pt/TiO2 photocatalysis. The synergy of improved charge separation at the Pt/TiO2-x interface induced by surface disordering and accelerated H2 consumption near smaller Pt nanoparticles by thermal assistance are believed to be critically important for the simultaneous enhancement of CO2 conversion rates and CH4 product selectivity. This study inspires revisiting not only Pt/TiO2 but also reactivating other semiconductor-oxide-based photocatalysts for use in thermally assisted photocatalysis.


Macrophage polarisation: an immunohistochemical approach for identifying M1 and M2 macrophages.
Macrophage polarization is increasingly recognised as an important pathogenetic factor in inflammatory and neoplastic diseases. Proinflammatory M1 macrophages promote T helper (Th) 1 responses and show tumoricidal activity. M2 macrophages contribute to tissue repair and promote Th2 responses. CD68 and CD163 are used to identify macrophages in tissue sections. However, characterisation of polarised macrophages in situ has remained difficult. Macrophage polarisation is regulated by transcription factors, pSTAT1 and RBP-J for M1, and CMAF for M2. We reasoned that double-labelling immunohistochemistry for the detection of macrophage markers together with transcription factors may be suitable to characterise macrophage polarisation in situ. To test this hypothesis, we have studied conditions associated with Th1- and Th2-predominant immune responses: infectious mononucleosis and Crohn's disease for Th1 and allergic nasal polyps, oxyuriasis, wound healing and foreign body granulomas for predominant Th2 response. In all situations, CD163+ cells usually outnumbered CD68+ cells. Moreover, CD163+ cells, usually considered as M2 macrophages, co-expressing pSTAT1 and RBP-J were found in all conditions examined. The numbers of putative M1 macrophages were higher in Th1- than in Th2-associated diseases, while more M2 macrophages were seen in Th2- than in Th1 related disorders. In most Th1-related diseases, the balance of M1 over M2 cells was shifted towards M1 cells, while the reverse was observed for Th2-related conditions. Hierarchical cluster analysis revealed two distinct clusters: cluster I included Th1 diseases together with cases with high numbers of CD163+pSTAT1+, CD68+pSTAT1+, CD163+RBP-J+ and CD68+RBP-J+ macrophages; cluster II comprised Th2 conditions together with cases displaying high numbers of CD163+CMAF+ and CD68+CMAF+ macrophages. These results suggest that the detection of pSTAT1, RBP-J, and CMAF in the context of CD68 or CD163 expression is a suitable tool for the characterisation of macrophage polarisation in situ. Furthermore, CD163 cannot be considered a reliable M2 marker when used on its own.


Influence of the superior colliculus on the primate blink reflex.
In this study we used microstimulation to investigate the influence of the superior colliculus on the trigeminal blink reflex. We report that stimulation in the intermediate to deep layers of the tectum produced inhibition of reflex blinks at a latency of approximately 26 ms. We considered the hypothesis that the blink inhibition was mediated via the omnipause neurons (OPNs) of the eye movement control system in the brainstem. Our results show that the least effective sites for suppression were in the rostral colliculus. This is inconsistent with the prediction that OPNs should be maximally recruited from the rostral tectum near the "fixation zone." From these points and other considerations, we conclude that the reflex blink suppression from the superior colliculus is not directly mediated by the OPNs or the saccadic eye movement circuits.


[Arrhythmias in the pulmonary exeresis postoperative period].
To determine the frequency of episodes of cardiac arrhythmia during the period following elective exeresis of the pulmonary parenchyma (pneumonectomies, double and single lobectomies), and to study the temporal patterns of occurrence and the association of arrhythmia and certain risk factors. Retrospective analysis of data recorded in the case histories of 100 patients admitted to the postoperative intensive care unit (PICU) between November 1991 and March 1995. We monitored changes in heart rate after surgery by continuous electrocardiography in 38 of the 100 patients (38%). Changes were more common in certain subgroups: older patients, those with preoperative cardiovascular and electrocardiographic abnormalities, and those who needed prolonged postoperative mechanical ventilation. Most arrhythmias were supraventricular (97.3%), the most common being atrial fibrillation (55.3%). Most diagnoses of arrhythmia (87%) were made within the first three days after surgery. Several drugs were used for treatment, based on the diagnosing anesthesiologist's criteria. Digitalis was the drug most often prescribed. Seven patients (7%) died in the PICU. Three were discharged with atrial fibrillation with ventricular response of less than 100 beats per minute. Postoperative cardiac arrhythmia was a direct cause of death of only one patient, who had ventricular fibrillation upon admission to the PICU.


Population characteristics, habitat and diet of a recently discovered stingray Dasyatis marianae: implications for conservation.
This study examined population density, habitat and diet of Dasyatis marianae, a recently discovered species, in the reef complex of Maracajaú in Rio Grande do Norte state, Brazil. The highest concentration of D. marianae occurred in seagrass beds. Habitat use differed significantly between sex and age classes, with females and juveniles using areas other than reefs. Females utilized primarily seagrass beds and juveniles occurred mainly along the sandy bottom near the beach, highlighting the importance of protecting these areas. Dasyatis marianae diet was characterized primarily by crustaceans (91·9% index of relative importance, IRI ), including shrimp, crabs and lobsters. The availability of prey in different habitat types influences occupation by D. marianae, but the prey selectivity of D. marianae, among other factors, may affect this relationship. Intense shrimp and lobster fishing in the region probably has an effect on preferred prey resources of this ray. Information on feeding habits of this species contributes to a better understanding of trophic dynamics and food webs, which is critical if ecosystem principles are to be integrated into fisheries management.


The Role of Systemic Inflammation in Acquired Nasolacrimal Duct Obstruction.
This study aims to investigate the influence of systemic inflammation on adult patients with acquired nasolacrimal duct obstruction (ANLDO). Peripheral venous blood analysis was performed on adult patients who underwent dacryocystorhinostomy for ANLDO between June 2020 and December 2022, during their remission period just before the surgery. Platelet, Neutrophil, Lymphocyte, Monocyte, White Blood Cell (WBC) count, Platelet/Lymphocyte ratio (PLR), Neutrophil/Lymphocyte ratio (NLR), Monocyte/Lymphocyte ratio (MLR), and systemic inflammatory index (SII) (calculated as platelet × (neutrophil/lymphocyte)) were compared with a volunteer control group. The study included 54 adult patients with ANLDO and 54 individuals in the control group. The mean age was 42.5±14.4 years in the ANLDO group and 37.8±12.3 years in the volunteer control group. There was no significant difference in age between the groups (p=0.064). Platelet value (295.9±70.9→254.7±43.9), PLR value (143.8±77.7→119.0±36.1), and SII value (534.7±192.0→442.6±212.2) in the ANLDO group were significantly higher compared to the Control group (p=0.000, p=0.023, p=0.020, respectively). Neutrophil, lymphocyte, monocyte, NLR, MLR, and WBC values did not exhibit significant differences between the case and control groups (p=0.299, p=0.469, p=0.125, p=0.419, p=0.143, and p=0.465, respectively). The study revealed elevated systemic platelet counts in ANLDO patients, resulting in higher PLR and SII values. The authors suggest that a histopathological examination to assess the local impact of platelets or other inflammatory processes in nasolacrimal duct obstruction could offer valuable insights into the etiopathology of ANLDO.


Tunable photoluminescence and an enhanced photoelectric response of Mn2+-doped CsPbCl3 perovskite nanocrystals via pressure-induced structure evolution.
Mn2+:CsPbCl3 nanocrystals (NCs) were synthesized using a modified one-pot injection method, which exhibits significantly improved thermal stability. For the first time, the pressure-treated optical and structural properties of synthetic Mn2+:CsPbCl3 NCs were further investigated, and their associated intriguing electrical and photoelectric properties were revealed from impedance spectra and photocurrent measurements under compression. The pressure-dependent photoluminescence experienced an initial redshift before 1.7 GPa followed by a continuous blueshift, as evidenced by the bandgap shifts. High-pressure XRD spectra uncovered a cubic-to-orthorhombic structural transition at about 1.1 GPa and subsequent amorphization upon further compression, which was fully reversible. Furthermore, the sample annealing from 340 K drove grain growth and decreased grain boundary resistance at ambient pressure. The compression further decreased the grain boundary barrier and improved the electrical conductivity (up to ∼10-2Ω-1 cm-1) of the thermally annealed Mn2+:CsPbCl3 NC surface. Simultaneous photocurrent enhancement of thermally annealed NCs was also achieved as expected, and reached optimal performance at 0.7 GPa. Strikingly, after the pressure cycling (loading-releasing), the results show that thermally annealed Mn2+:CsPbCl3 NCs gained preservable higher electrical conductivity (∼10 times increase) and an improved photoelectric response compared to the ambient state before compression. This work proves that high pressure is useful for opening the versatility in the structure and properties of metal-halide perovskite nanocrystals leading to a promising way for superior optoelectronic materials-by-design.


Richer gut microbiota with distinct metabolic profile in HIV infected Elite Controllers.
Gut microbiota dysbiosis features progressive HIV infection and is a potential target for intervention. Herein, we explored the microbiome of 16 elite controllers (EC), 32 antiretroviral therapy naive progressors and 16 HIV negative controls. We found that the number of observed genera and richness indices in fecal microbiota were significantly higher in EC versus naive. Genera Succinivibrio, Sutterella, Rhizobium, Delftia, Anaerofilum and Oscillospira were more abundant in EC, whereas Blautia and Anaerostipes were depleted. Additionally, carbohydrate metabolism and secondary bile acid synthesis pathway related genes were less represented in EC. Conversely, fatty acid metabolism, PPAR-signalling and lipid biosynthesis proteins pathways were enriched in EC vs naive. The kynurenine pathway of tryptophan metabolism was altered during progressive HIV infection, and inversely associated with microbiota richness. In conclusion, EC have richer gut microbiota than untreated HIV patients, with unique bacterial signatures and a distinct metabolic profile which may contribute to control of HIV.


Pharmacotherapy of dual substance abuse and dependence.
The US FDA has approved a limited number of treatments for alcohol, nicotine and opioid dependence; however, no treatments for other abused drugs such as marijuana, cocaine or methamphetamine are approved. This review focuses on research into drug pharmacotherapies, particularly single-drug therapies, for substance abuse and dependence contributing to the most important dual substance use disorders (SUDs). Given the implications of poly-substance abuse, it is essential that clinicians and researchers be aware of potential pharmacotherapies for the treatment of dual SUDs.A substantial number of patients abuse more than one drug concurrently, complicating the treatment of SUD and leaving clinicians with few FDA-approved drug options for their patients. In this era of evidence-based medicine, such patients are typically treated with therapeutically proven medications, but in ways that are outside the scope of a drug's original indication by the FDA. Such 'off-label' prescribing has become an important therapeutic strategy for practitioners seeking treatments for other diseases in subpopulations such as paediatrics and gerontology or for medical conditions such as oncology or mental illness. Similarly, the information that most clinicians use to make their decisions for treating patients abusing multiple drugs stems from trials treating a single SUD, anecdotal experiences from their own practice or that of their colleagues, or single-case studies reported in the literature. The existing evidence suggests there are few treatments for SUDs that confer significant reductions in substance use across a broad patient population. Moreover, even fewer clinical efficacy trials have been conducted that provide evidence of therapeutic benefit for these drugs. Recognising the difficulty in making the proper drug choice for facilitating maximum treatment success, this review highlights the single drugs or drug combinations that show some potential for treating dual SUDs. This review finds strongest support for the use of disulfiram for treatment of alcohol and cocaine dependence (with or without concomitant methadone maintenance), baclofen for alcohol and cocaine dependence (but not opioid-dependent cocaine users), tiagabine for cocaine dependence in methadone-maintained patients, and topiramate for alcohol, nicotine and cocaine dependence. While ondansetron and olanzapine show some efficacy in treating alcohol and cocaine dependence, more research is needed to better delineate the subpopulation in which these drugs may provide their maximum effect.