The role of HDAC2 in cigarette smoke-induced airway inflammation in a murine model of asthma and the effect of intervention with roxithromycin.
Cigarette smoke is well known to worsen asthma symptoms in asthmatic patients and to make them refractory to treatment, but the underling molecular mechanism is unclear. We hypothesized that cigarette smoke can reduce the expression of HDAC2 in asthma and the process was achieved by activating the PI3K-δ/Akt signaling pathway. We further hypothesized that roxithromycin (RXM) can alleviate the impacts by cigarette smoke. A murine model of asthma induced by ovalbumin (OVA) and cigarette smoke has been established. The infiltration of inflammatory cells and inflammatory factors was examined in this model. Finally, we evaluated the expression of HDAC2, Akt phosphorylation levels, and the effects of RXM treatment on the model described earlier. Cigarette smoke exposure reduced HDAC2 protein expression by enhancing the phosphorylation of Akt in PI3K-δ/Akt signaling pathway. Furthermore, RMX reduced the airway inflammation and improved the level of expression of HDAC2 in the cigarette smoke-exposed asthma mice. This study provides a novel insight into the mechanism of cigarette smoke exposure in asthma and the effects of RXM treatment on this condition. These results may be helpful for treating refractory asthma and emphasizing the need for a smoke-free environment for asthmatic patients.


Bio-electricity Generation using Jatropha Oil Seed Cake.
The review of patents reveals that Handling of Jatropha seed cake after extraction of oil is essential as it contains toxic materials which create environmental pollution. The goal of this work is complete utilisation of Jatropha seeds. For this purpose, Jatropha oil was used for producing biodiesel and the byproduct Jatropha seed cake was gasified to obtain producer gas. Both biodiesel and producer gas were used to generate electricity. To achieve this, a system comprising gasifier, briquetting machine, diesel engine and generator was developed. Biodiesel was produced successfully using the method patented for biodiesel production and briquettes of Jatropha seed cake were made using a vertical extruding machine. Producer gas was obtained by gasifying these briquettes in a downdraft gasifier. A diesel engine was then run in dual fuel mode with biodiesel and producer gas instead of only diesel. Electricity was generated by coupling it to a generator. The cost of producing kilowatthour of electricity with biodiesel and diesel in dual fuel mode with producer gas was found to be 0.84 $ and 0.75 $, respectively as compared to 0.69 $ and 0.5 $ for the same fuels in single fuel mode resulting in up to 48 % saving of pilot fuel. Compared to singlefuel mode, there was 25-32 % reduction in system and brake thermal efficiency along with significantly lower NOx, higher CO and CO2 emissions when the bio-electricity generating system was operated in dual fuel mode. Overall, the developed system could produce electricity successfully by completely uti- lising Jatropha seeds without leaving any seed cake to cause environmental pollution.


Effect of caffeine on myocardial perfusion imaging using single photon emission computed tomography during adenosine pharmacologic stress.
Approximately 6 million cardiac stress tests are performed annually in the United States, of which 2.4 million are pharmacologic stress tests using agents such as adenosine. Adenosine induces differential coronary hyperemia in normal coronary arteries versus coronary arteries with atherosclerosis, allowing single photon emission computed tomography (SPECT) imaging to identify reduced coronary flow in segments subtended by diseased coronary arteries. The potential attenuation of pharmacologic effects of adenosine in the presence of caffeine is why patients are routinely instructed to abstain from caffeine for 12 to 24 hours prior to administration of an adenosine stress test. Failure to abstain from caffeine results in cancellation or delaying of cardiac stress testing, resulting in procedural delays and its impact on patient throughput. Recent studies have evaluated such interaction and suggested a lack of clinically significant effect of caffeine on adenosine-induced hyperemia during myocardial SPECT imaging. This article reviews the clinical pharmacology of caffeine, adenosine, and dipyridamole and effect of caffeine on myocardial stress testing using adenosine and dipyridamole in clinical cardiovascular medicine. The limited published data are conflicting, but some recent publications suggest that myocardial perfusion SPECT imaging using adenosine may not be clinically significantly altered by routine consumption of caffeine, such as a cup of coffee. Although prospective randomized studies would be required to obtain a definitive answer to this question, it appears on the basis of some of the studies reviewed in this article that caffeine consumption prior to myocardial perfusion imaging may not necessitate cancellation or rescheduling of adenosine stress testing.


[Metabolic features of the liver and spleen and antibody formation in animals following hyperimmunization with viral antigens].
Hyperimmunization with the tick encephalitis and Western horse encephalomyelitis viruses reproduced in the brain of albino mice, intensified the protein synthesis in the splenic tissue during the productive phase of the immunogenesis (the 7th day). An accumalation of protein, activation of aniuno-acyl-t-RNA-ligases, a reduction of the concehtration of some amino acids was noted, An analogous reaction was distinct in the tissue of the liver only when an intact brain suspension was used as an antigen. Formation of specific antibodies coursed more intensively after the administration of a more pathogenic virusof Western equine encephalomyelitis.


Uptake of microemulsion components into the stratum corneum and their molecular effects on skin barrier function.
This research determined the uptake of individual components of topically applied microemulsions into the stratum corneum (SC) and assessed their molecular effects on skin barrier function. The microemulsions comprised oleic acid, Tween20, Transcutol and water. The effects of selected formulations, and of the individual components, on the conformational order of the SC intercellular lipids, and on SC hydration, were assessed by infrared spectroscopy. Measurements were made as a function of SC depth by progressively tape-stripping the membrane in the normal way. SC uptake of microemulsion components was quantified via extraction and analysis of the collected tape strips. SC hydration increased in proportion to the water content of the microemulsion. Each of the microemulsion components penetrated into the SC, but to different extents. Oleic acid decreased the conformational order of the SC lipids, and induced some phase separation, as revealed by the frequency shifts and peak areas of the absorbances associated with -CH(2) symmetric and asymmetric stretching vibrations. Tween20 extracted some of the SC intercellular lipids. In summary, SC structure was perturbed by all components of the microemulsions, and the degree of the effects detected was proportional to the level of the respective component present in the skin.


Unravelling the pathophysiology of delirium: a focus on the role of aberrant stress responses.
Delirium is a common and serious acute neuropsychiatric syndrome with core features of inattention and cognitive impairment, and associated features including changes in arousal, altered sleep-wake cycle, and other changes in mental status. The main risk factors are old age, cognitive impairment, and other comorbidities. Though delirium has consistent core clinical features, it has a very wide range of precipitating factors, including acute illness, surgery, trauma, and drugs. The molecular mechanisms by which these precipitating factors lead to delirium are largely obscure. In this article, we attempt to narrow down some specific causal pathways. We propose a basic classification for the etiological factors: (a) direct brain insults and (b) aberrant stress responses. Direct brain insults are largely indiscriminate and include general and regional energy deprivation (e.g., hypoxia, hypoglycaemia, stroke), metabolic abnormalities (e.g., hyponatraemia, hypercalcaemia), and the effects of drugs. Aberrant stress responses are conceptually and mechanistically distinct in that they constitute adverse effects of stress-response pathways, which, in health, are adaptive. Ageing and central nervous system disease, two major predisposing factors for delirium, are associated with alterations in the magnitude or duration of stress and sickness behavior responses and increased vulnerability to the effects of these responses. We discuss in detail two stress response systems that are likely to be involved in the pathophysiology of delirium: inflammation and the sickness behavior response, and activity of the limbic-hypothalamic-pituitary-adrenal axis. We conclude by discussing the implications for future research and the development of new therapies for delirium.


Structural connectivity from DTI to predict mild cognitive impairment in de novo Parkinson's disease.
Early detection of Parkinson's disease (PD) patients at high risk for mild cognitive impairment (MCI) can help with timely intervention. White matter structural connectivity is considered an early and sensitive indicator of neurodegenerative disease. To investigate whether baseline white matter structural connectivity features from diffusion tensor imaging (DTI) of de novo PD patients can help predict PD-MCI conversion at an individual level using machine learning methods. We included 90 de novo PD patients who underwent DTI and 3D T1-weighted imaging. Elastic net-based feature consensus ranking (ENFCR) was used with 1000 random training sets to select clinical and structural connectivity features. Linear discrimination analysis (LDA), support vector machine (SVM), K-nearest neighbor (KNN) and naïve Bayes (NB) classifiers were trained based on features selected more than 500 times. The area under the ROC curve (AUC), accuracy (ACC), sensitivity (SEN) and specificity (SPE) were used to evaluate model performance. A total of 57 PD patients were classified as PD-MCI nonconverters, and 33 PD patients were classified as PD-MCI converters. The models trained with clinical data showed moderate performance (AUC range: 0.62-0.68; ACC range: 0.63-0.77; SEN range: 0.45-0.66; SPE range: 0.64-0.84). Models trained with structural connectivity (AUC range, 0.81-0.84; ACC range, 0.75-0.86; SEN range, 0.77-0.91; SPE range, 0.71-0.88) performed similar to models that were trained with both clinical and structural connectivity data (AUC range, 0.81-0.85; ACC range, 0.74-0.85; SEN range, 0.79-0.91; SPE range, 0.70-0.89). Baseline white matter structural connectivity from DTI is helpful in predicting future MCI conversion in de novo PD patients.


Simultaneous monitoring of gaseous CO(2) and ethanol above champagne glasses via micro-gas chromatography (μGC).
In champagne tasting, gaseous CO(2) and volatile organic compounds progressively invade the headspace above glasses, thus progressively modifying the chemical space perceived by the consumer. In this study, a novel, rapid, and nonintrusive method aimed to simultaneously determine the content in gaseous CO(2) and ethanol above a glass poured with champagne, using a micro-gas chromatography technique coupled with a thermal conductivity detector, was presented. The simultaneous quantification of CO(2) and ethanol in the headspace of a champagne glass was monitored, in real tasting conditions, all along the first 15 min following pouring, depending on whether or not the glass shows effervescence. Both CO(2) and ethanol were found to be enhanced by the presence of ascending bubbles, thus confirming the close link between rising bubbles and the release of gaseous CO(2) and volatile organic compounds.


2-(Adamantan-1-yl)-1,3-bis-(4-methyl-phen-yl)propan-2-ol.
The conformation of the title compound, C27H34O, is stabilized by a weak intra-molecular C-H⋯π inter-action. The dihedral angle between the benzene rings is 54.79 (4)°. The adamantane cage consists of three fused cyclo-hexane rings in classical chair conformations, with C-C-C angles in the range 107.75 (10)-111.35 (9)°. Although the mol-ecule contains a hy-droxy group as a conceivable hydrogen-bond donor, this group is sterically hindered by bulky substituents and no hydrogen bonds are observed in the crystal structure.


Novel high-efficiency crystalline-silicon-based compound heterojunction solar cells: HCT (heterojunction with compound thin-layer).
With an amorphous silicon (a-Si:H)/crystalline silicon (c-Si) heterojunction structure, the heterojunction with intrinsic thin-layer (HIT) solar cell has become one of the most promising technologies for c-Si based solar cells. By replacing a-Si:H thin films with appropriate compound semiconductors, we propose novel heterojunction structures which allow c-Si heterojunction solar cells to possess higher power conversion efficiencies than HIT solar cells. Several promising heterojunction candidates and hetero-structures have been proposed in this work, and this kind of novel c-Si compound heterojunction solar cell is denominated HCT (heterojunction with a compound thin-layer). The feasibilities of these novel HCT structures are further investigated by theoretical approaches, and the modeling results demonstrate the device performance improvement. Finally, this paper proclaims the compound selection standards and essentials of achieving high-efficiency HCT solar cells, which are guidelines for the real device implementation.


Growth retardation, reduced invasiveness, and impaired colistin-mediated cell death associated with colistin resistance development in Acinetobacter baumannii.
Two colistin-susceptible/colistin-resistant (Col(s)/Col(r)) pairs of Acinetobacter baumannii strains assigned to international clone 2, which is prevalent worldwide, were sequentially recovered from two patients after prolonged colistin administration. Compared with the respective Col(s) isolates (Ab248 and Ab299, both having a colistin MIC of 0.5 μg/ml), both Col(r) isolates (Ab249 and Ab347, with colistin MICs of 128 and 32 μg/ml, respectively) significantly overexpressed pmrCAB genes, had single-amino-acid shifts in the PmrB protein, and exhibited significantly slower growth. The Col(r) isolate Ab347, tested by proteomic analysis in comparison with its Col(s) counterpart Ab299, underexpressed the proteins CsuA/B and C from the csu operon (which is necessary for biofilm formation). This isolate also underexpressed aconitase B and different enzymes involved in the oxidative stress response (KatE catalase, superoxide dismutase, and alkyl hydroperoxide reductase), suggesting a reduced response to reactive oxygen species (ROS) and, consequently, impaired colistin-mediated cell death through hydroxyl radical production. Col(s) isolates that were indistinguishable by macrorestriction analysis from Ab299 caused six sequential bloodstream infections, and isolates indistinguishable from Ab248 caused severe soft tissue infection, while Col(r) isolates indistinguishable from Ab347 and Ab249 were mainly colonizers. In particular, a Col(s) isolate identical to Ab299 was still invading the bloodstream 90 days after the colonization of this patient by Col(r) isolates. These observations indicate considerably lower invasiveness of A. baumannii clinical isolates following the development of colistin resistance.


Genealogical structure changes as range expansions transition from pushed to pulled.
Range expansions accelerate evolution through multiple mechanisms, including gene surfing and genetic drift. The inference and control of these evolutionary processes ultimately rely on the information contained in genealogical trees. Currently, there are two opposing views on how range expansions shape genealogies. In invasion biology, expansions are typically approximated by a series of population bottlenecks producing genealogies with only pairwise mergers between lineages-a process known as the Kingman coalescent. Conversely, traveling wave models predict a coalescent with multiple mergers, known as the Bolthausen-Sznitman coalescent. Here, we unify these two approaches and show that expansions can generate an entire spectrum of coalescent topologies. Specifically, we show that tree topology is controlled by growth dynamics at the front and exhibits large differences between pulled and pushed expansions. These differences are explained by the fluctuations in the total number of descendants left by the early founders. High growth cooperativity leads to a narrow distribution of reproductive values and the Kingman coalescent. Conversely, low growth cooperativity results in a broad distribution, whose exponent controls the merger sizes in the genealogies. These broad distribution and non-Kingman tree topologies emerge due to the fluctuations in the front shape and position and do not occur in quasi-deterministic simulations. Overall, our results show that range expansions provide a robust mechanism for generating different types of multiple mergers, which could be similar to those observed in populations with strong selection or high fecundity. Thus, caution should be exercised in making inferences about the origin of non-Kingman genealogies.


Dynamics of capillary electrochromatography experimental study on the electrosmotic flow and conductance in open and packed capillaries.
For capillary electrochromatography (CEC) to become an analytical separation technique of high speed and resolution the factors determining the conductivity of the column as well as the generation and control of electrosmotic flow (EOF) in porous media have to be understood. In the present study the conductance of capillaries packed with a variety of stationary phases was evaluated with respect to the conductance of the open capillary and the data were interpreted in the light of the Tobias equation. However, the consistently observed reduction of the EOF when a capillary having a charged inner wall is packed with particles having charges of the same sign and the dependence of the EOF velocity on the particle size needs further explanation. The data suggests that, due to the employment of relatively long columns packed with small particles, CEC may offer peak capacities much higher than HPLC or micro-HPLC. The CEC columns are unique as they consist of a packed and an open capillary segment having different conductances and consequently different voltage gradients and electrical field strengths. Therefore, any sufficiently detailed study on CEC systems requires also the characterization of the individual column segments. EOF velocities of 6-7 mm/s could be realized at 60 kV applied voltage with a 23/32 cm x 50 microns raw fused-silica capillary packed with 6-micron Zorbax ODS particles. The current was a linear function of the field strength up to 1.8 kV/cm, but at high field strengths the EOF increased with squared field strength. Data on band spreading indicate that with a given column the plate height at high EOF velocities is smaller in CEC than in micro-HPLC and it is weakly dependent on the velocity.


Vitamin C requirements in postoperative patients.
The postoperative ascorbic acid requirements of 63 surgical patients were assessed by measurement of buffy layer leucocyte ascorbic acid and the ascorbic acid content of white blood cells. There was a significant reduction in ascorbic acid levels following surgery. The postoperative changes were unrelated to the extent of surgical trauma or the volume of blood transfused during surgery but there was a significant correlation between postoperative ascorbic acid measurements and white blood cell counts. It appears that postoperative leucocytosis and release by the bone marrow of white blood cells with a low ascorbic acid content may partly account for the postoperative changes in buffy layer and white blood cell ascorbic acid measurements. However, surgical operations were followed by an authentic increase in ascorbic acid requirements, and there was a 42 per cent reduction in circulating white blood cell ascorbic acid levels on the third postoperative day. The findings of this study create an argument for the use of ascorbic acid supplements in surgical patients although it is unlikely that postoperative changes in leucocyte ascorbic acid have pathologic significance in wound repair.


Use of Primary Care and Emergency Departments for Substance Use Treatment: The Rural and Urban Divide.
Background: Alcohol and illicit substance use remain significant public health issues in the United States. In this analysis, we assessed differences in the use of primary care and emergency departments (EDs) for treatment of substance use among rural and urban sexual minorities (SMs).Methods: Data come from the National Survey on Drug Use and Health (NSDUH, 2015-2019). Survey-weighted multivariable linear and logistic regression analyses were used to assess the relationship between sexual identity and the use of primary care settings or EDs for treatment of substance use, stratified by urbanicity of residence.Results: Among the entire sample, 7.9% reported residing in rural environments with slightly more SMs living in urban (7.3%) relative to rural (5.4%) locales. Both rural (β=-0.20; 95% CI: -0.29, -0.10) and urban SMs (β=-0.13; 95% CI: -0.16, -0.11) self-reported worse overall health. Urban SMs, but not rural SMs, had significantly higher odds of reporting use of primary care treatment for substance use (aOR 2.80; 95% CI: 2.13, 3.68). ED treatment for substance use was greater among both rural (aOR = 2.99; 95% CI: 1.01, 8.87) and urban SMs (aOR = 3.02; 95% CI: 2.12, 4.30) as was overall number of ED visits among both rural (β = 0.48; 95% CI: 0.24, 0.72) and urban SMs (β = 0.23; 95% CI: 0.19, 0.28) .Conclusion: These findings suggest increased reliance on EDs for treatment of alcohol or substance use among rural SMs. Future research should examine whether increasing culturally competent primary care services for SMs in rural areas may be a key intervention point for reducing health disparities.


Pembrolizumab plus chemotherapy versus chemotherapy in untreated advanced pleural mesothelioma in Canada, Italy, and France: a phase 3, open-label, randomised controlled trial.
Pleural mesothelioma usually presents at an advanced, incurable stage. Chemotherapy with platinum-pemetrexed is a standard treatment. We hypothesised that the addition of pembrolizumab to platinum-pemetrexed would improve overall survival in patients with pleural mesothelioma. We did this open-label, international, randomised phase 3 trial at 51 hospitals in Canada, Italy, and France. Eligible participants were aged 18 years or older, with previously untreated advanced pleural mesothelioma, with an Eastern Cooperative Oncology Group performance status score of 0 or 1. Patients were randomly assigned (1:1) to intravenous chemotherapy (cisplatin [75 mg/m2] or carboplatin [area under the concentration-time curve 5-6 mg/mL per min] with pemetrexed 500 mg/m2, every 3 weeks for up to 6 cycles), with or without intravenous pembrolizumab 200 mg every 3 weeks (up to 2 years). The primary endpoint was overall survival in all randomly assigned patients; safety was assessed in all randomly assigned patients who received at least one dose of study therapy. This trial is registered with ClinicalTrials.gov, NCT02784171, and is closed to accrual. Between Jan 31, 2017, and Sept 4, 2020, 440 patients were enrolled and randomly assigned to chemotherapy alone (n=218) or chemotherapy with pembrolizumab (n=222). 333 (76 %) of patients were male, 347 (79%) were White, and median age was 71 years (IQR 66-75). At final analysis (database lock Dec 15, 2022), with a median follow-up of 16·2 months (IQR 8·3-27·8), overall survival was significantly longer with pembrolizumab (median overall survival 17·3 months [95% CI 14·4-21·3] with pembrolizumab vs 16·1 months [13·1-18·2] with chemotherapy alone, hazard ratio for death 0·79; 95% CI 0·64-0·98, two-sided p=0·0324). 3-year overall survival rate was 25% (95% CI 20-33%) with pembrolizumab and 17% (13-24%) with chemotherapy alone. Adverse events related to study treatment of grade 3 or 4 occurred in 60 (27%) of 222 patients in the pembrolizumab group and 32 (15%) of 211 patients in the chemotherapy alone group. Hospital admissions for serious adverse events related to one or more study drugs were reported in 40 (18%) of 222 patients in the pembrolizumab group and 12 (6%) of 211 patients in the chemotherapy alone group. Grade 5 adverse events related to one or more drugs occurred in two patients on the pembrolizumab group and one patient in the chemotherapy alone group. In patients with advanced pleural mesothelioma, the addition of pembrolizumab to standard platinum-pemetrexed chemotherapy was tolerable and resulted in a significant improvement in overall survival. This regimen is a new treatment option for previously untreated advanced pleural mesothelioma. The Canadian Cancer Society and Merck & Co.


Evidence-based implementation of evidence-based guidelines.
There is evidence that some strategies for guideline implementation are more successful than others. This paper aims to describe the process of developing an evidence-based guideline implementation strategy for use in rural emergency departments. Participation in a nationally funded, research fellowship program involved attendance at workshops run by internationally renowned experts in the field of knowledge translation. Attendance at these workshops, associated reading and a literature review allowed those implementation strategies with the most supportive evidence of effectiveness to be determined. A multi-faceted implementation strategy was developed. This strategy involved the use of an implementation team as well as addressing issues surrounding individual clinicians, the "emergency department team", the physical structure and processes of the ED and the culture of the department as a whole. Reminders, audit and feedback, education, the use of opinion leaders, and evidence-based formatting of guidelines were all integral to the process. It is postulated that an evidence-based implementation strategy will lead to greater changes in clinician behaviour than other strategies used in quality improvement projects. This is an important article as it describes the concept and development of evidence-based interventions, which, if tailored to the individual hospital (as evidence-based medicine is tailored to the individual patient), has the potential to improve compliance with clinical guidelines beyond that achieved with most QI projects.


Contributions of different modes of TRPV1 activation to TRPV1 antagonist-induced hyperthermia.
Transient receptor potential vanilloid-1 (TRPV1) antagonists are widely viewed as next-generation pain therapeutics. However, these compounds cause hyperthermia, a serious side effect. TRPV1 antagonists differentially block three modes of TRPV1 activation: by heat, protons, and chemical ligands (e.g., capsaicin). We asked what combination of potencies in these three modes of TRPV1 activation corresponds to the lowest potency of a TRPV1 antagonist to cause hyperthermia. We studied hyperthermic responses of rats, mice, and guinea pigs to eight TRPV1 antagonists with different pharmacological profiles and used mathematical modeling to find a relative contribution of the blockade of each activation mode to the development of hyperthermia. We found that the hyperthermic effect has the highest sensitivity to the extent of TRPV1 blockade in the proton mode (0.43 to 0.65) with no to moderate sensitivity in the capsaicin mode (-0.01 to 0.34) and no sensitivity in the heat mode (0.00 to 0.01). We conclude that hyperthermia-free TRPV1 antagonists do not block TRPV1 activation by protons, even if they are potent blockers of the heat mode, and that decreasing the potency to block the capsaicin mode may further decrease the potency to cause hyperthermia.


Effect of Activity at Time of Injury and Concomitant Ligament Injuries on Patient-Reported Outcome After Posterior Cruciate Ligament Reconstruction.
The outcomes after posterior cruciate ligament reconstruction (PCLR) have been shown to be inferior to those of anterior cruciate ligament reconstruction. There is a lack of knowledge regarding prognostic factors of PCLR outcomes. To explore the effect of injury mechanism and concomitant ligament injuries on patient-reported outcomes at 2-year follow-up after PCLR. Cohort study; Level of evidence, 2. A total of 373 patients who underwent primary PCLR and who were registered in the Norwegian Knee Ligament Registry were included. The Knee injury and Osteoarthritis Outcome Score (KOOS) was used as the patient-reported outcome measure. At 2-year follow-up, 252 patients (68%) had completed the KOOS. Multiple regression analysis was used to evaluate the effects of injury activity and multiligament injuries on the KOOS outcomes. In the adjusted and unadjusted regression analyses, patients injured during sports reported significantly better outcome at 2-year follow-up after PCLR than patients injured during other activities (P < .001) according to all KOOS subscales. Adjusted analysis was as follows for the KOOS subscales: Symptoms (regression coefficient [β], 7.0; 95% CI, 1.9-12.2), Pain (β, 13.4; 95% CI, 8.0-18.9), Activities of Daily Living (β, 12.6; 95% CI, 7.1-18.1), Sport/Recreation (β, 15.3; 95% CI, 8.0-22.5), and Quality of Life (β, 13.5; 95% CI, 7.1-20.0). In the unadjusted analysis, patients with isolated PCL injuries reported higher scores in the Sport/Recreation subscale (β, -7.9; 95% CI, -15.5 to -0.3). The difference was not significant in the adjusted analysis. No other significant differences in KOOS outcomes were found between isolated and multiligament injuries. Patients injured in sports reported better outcomes at 2 years after PCLR as compared with patients injured in other activities. Multiligament injuries involving the PCL do not seem to predict a worse outcome than for isolated PCL injuries.


[Singultus - Diagnostic Workup and Therapy].
A hiccup is a reflex movement with diffusely distributed afferents and efferents in the thorax; its functional relevance is controversial. In its physiological form, it is mostly a minor complaint that stops spontaneously and rarely leads to medical consultation. However, prolonged agonizing hiccups represent serious deterioration of quality of life. Chronic hiccups by definition last for more than 48 h, with gastroesophageal reflux being the frequent underlying disease. Various other causes affect multiple organ systems, some with serious underlying diseases. A hiccup may be the only symptom at the first manifestation of some neurological disorders. In neuroimaging a lesion of the medulla oblongata is often seen. A NMO and an ischemic stroke with Wallenberg syndrome are 2 frequently underlying neurological diseases, but other inflammatory and vascular diseases and tumors of the central nervous system may be present. No optimal evidencebased recommendations for diagnosis and management of chronic hiccups are available. The search for the underlying disease often requires an interdisciplinary approach by internists, neurologists, and otolaryngologists. Symptomatic treatment may be necessary even before diagnosis. Persistent hiccups, a common problem in oncological palliative care, are often challenging. Proton pump inhibitor or prokinetics are used for treating underlying gastroesophageal reflux and baclofen with or without gabapentin in other cases. Anticonvulsants, antipsychotics, antidepressants, and calcium channel blockers represent other alternative treatment possibilities. In therapy-refractory cases, invasive procedures such as the selective phrenic nerve block are available. More studies are needed to help deal with the diagnostic and therapeutic challenge that hiccups present for neurologists.


[Phenomenon of inverted rotation in spastic torticollis].
The article describes a rare clinical case where a patient with right-side spastic torticollis developed stable left-side spastic torticollis following discontinuation of nacom. On the basis of clinico-physiological analysis of the given phenomenon and having compared their findings with the literature data the authors substantiate the involvement of the nigrostriatal systems of both hemispheres in the pathogenesis of torticollis and in the mechanisms of rotation inversion reported in the given disease for the first time.


Impact of perioperative decreased serum albumin level on anastomotic leakage in esophageal squamous cell carcinoma patients treated with neoadjuvant chemotherapy followed by minimally invasive esophagectomy.
Anastomotic leakage (AL) is a severe complication following esophagectomy with high mortality. Perioperative decreased serum albumin level is considered a predictive of AL, however, its impact on AL incidence in patients treated with neoadjuvant chemotherapy (NCT) followed by minimally invasive esophagectomy (MIE) is not well defined. The data of 318 consecutive esophageal cancer patients who underwent MIE were collected retrospectively from January 2021 to December 2021. The perioperative level of albumin was detected and the baseline of altering levels for albumin was established. The incidence of postoperative complications and survival rate were analyzed between groups. After exclusion, 137 patients were enrolled and assigned to more decreased albumin (MA) and less decreased albumin (LA) groups. The levels of albumin descended significantly after MIE (p < 0.0001). There was no significant difference in the clinicopathologic characteristics or surgical outcomes between groups. The incidence of postoperative AL was 10.2% in MA group and 1.4% in LA group (p = 0.033). Three patients died due to AL in MA group, while no mortality was observed in LA group (p = 0.120). The rate of other postoperative complications was similar between groups. Progression-free survival (PFS) in LA group was a little higher than that in MA group, but it was no significant difference (p = 0.853). Similarly, no difference was observed in overall survival (OS) between groups (p = 0.277). Severely deficient serum albumin after MIE was an indicator of AL in esophageal cancer patients treated with NCT. Chinese clinical trial registry: ChiCTR2200066694, registered December14th,2022. https://www.chictr.org.cn/edit.aspx?pid=185067&htm=4 .


Evaluation of the potential aphrodisiac activity of sesquiterpenoids from roots of Ferula huber-morathii Peşmen in male rats.
Several species of Ferula L. genus have been used in traditional Turkish medicine as aphrodisiac to treat male sexual dysfunction. Especially, roots and oleo gum resin of F. elaeochytris Korovin, F. communis L., F. assa-foetida L. and F. gummosa Boiss. were claimed to be used for aphrodisiac activity, menstrual regulation and treatment of gastric pain in Anatolia. Ferula L. is represented by 23 taxa in Turkey, 13 of which are endemic species. F. huber-morathii Peşmen (FHM), an endemic plant, is popularly known as ''helizan, çağşır''. This study aimed to isolate sesquiterpenoids from the roots of Ferula huber-morathii (FHM) and to confirm their aphrodisiac potential in male rats. In a preliminary experiment, the effects of aqueous (H2O) and chloroform (CHCl3) extracts of FHM were tested for their potential aphrodisiac activities in male rats. Then, sesquiterpene derivatives were isolated from the active chloroform extract of FHM roots (FHM-R) and characterized (TLC, 1D, 2D NMR, HR-MS and CD). Moreover, some of the isolates with adequate quantities were evaluated for their possible aphrodisiac effects on male rats. Single doses (10 mg/kg BW) of sildenafil citrate (SC, positive control), gummosin, mogoltavidin, deacetylkellerin, ferukrin acetate with kellerin, elaeochytrin-A and ferutinin were administered orally by gavages to male Wistar albino rats. Mount latency (ML), mount frequency (MF), intromission latency (IL), intromission frequency (IF), ejaculation latency (EL) and postejaculatory interval (PEI) were studied. In addition, copulatory efficiency (CE) and intercopulatory efficiency (ICE) were calculated. The preliminary experiment revealed that the chloroform extract was the main source of the active compounds as it showed the higher aphrodisiac activity while the aqueous extract was found to be inactive. Eleven sesquiterpene derivatives, viz. gummosin, mogoltavidin, farnesiferol A, deacetylkellerin, ferukrin acetate, kellerin, teuclatriol, feruhermonin C, ferutinin, elaeochytrin A and teferidin, were isolated from the FHM-CHCl3 extract. Oral administration of deacetylkellerin, elaeochytrin-A and ferutinin significantly increased MF and IF. The ML and IL were significantly reduced, and ejaculation latencies were prolonged. Administration of these sesquiterpenoids also reduced the PEI. The present results revealed that ferutinin was the most effective aphrodisiac compound compared to other sesquiterpenoids. The results of 10 mg/kg of ferutinin are comparable to SC, the positive control. The results revealed that gummosin, mogoltavidin and ferukrin acetate with kellerin did not significantly alter the aphrodisiac parameters. This study has established that the CHCl3 extract of FHM root contains sesquiterpene derivatives, especially coumarin ethers and benzoic esters. Findings of the present study demonstrate that the chloroform extract and some of the sesquiterpene derivatives significantly stimulates sexual behavior in male rats, thus suggesting that F. huber-morathii possesses an aphrodisiac activity.


Immunoglobulin E (IgE)-Mediated Food Allergy in Children: Epidemiology, Pathogenesis, Diagnosis, Prevention, and Management.
A food allergy is an immunoglobulin E (IgE)-mediated hypersensitive reaction to food, which consists in the appearance of allergic symptoms; it can vary from common urticaria to even fatal anaphylaxis. The prevalence of food allergies has been increasing in the past twenty years and it represents a major public health problem in industrialized countries. The mechanism that leads to food allergies is the lack of immunologic and clinical tolerance to food allergens. The diagnosis of IgE-mediated food allergies is based on the combined use of a detailed medical history, in-vivo, and in-vitro research of specific IgE, the elimination diet, and the double-blind placebo-controlled food challenge. The only currently available treatment for allergies is the strict elimination diet. This type of attitude, which we could define as "passive", does not overcome the risk of accidental reactions due to involuntary intake of the culprit food. For food allergy management, an "active" approach is urgently needed, such as specific allergen immunotherapy, which is currently under development and only used for research purposes. This article aims to give an updated review of IgE-mediated food allergies in pediatric populations in terms of epidemiology, pathogenesis, prevention, diagnosis, and management.


Pentose conversions support the tumorigenesis of pancreatic cancer distant metastases.
Pancreatic ductal adenocarcinoma (PDAC) adopts several unique metabolic strategies to support primary tumor growth. Whether additional metabolic strategies are adopted to support metastatic tumorigenesis is less clear. This could be particularly relevant for distant metastasis, which often follows a rapidly progressive clinical course. Here we report that PDAC distant metastases evolve a unique series of metabolic reactions to maintain activation of the anabolic glucose enzyme phosphogluconate dehydrogenase (PGD). PGD catalytic activity was recurrently elevated across distant metastases, and modulating PGD activity levels dictated tumorigenic capacity. Metabolomics data raised the possibility that distant metastases evolved a core pentose conversion pathway (PCP) that converted glucose-derived metabolites into PGD substrate, thereby hyperactivating the enzyme. Consistent with this, each individual metabolite in the PCP stimulated PGD catalysis in distant metastases, and knockdown of each individual PCP enzyme selectively impaired tumorigenesis. We propose that the PCP manufactures PGD substrate outside of the rate-limiting oxidative pentose phosphate pathway (oxPPP). This enables PGD-dependent tumorigenesis by providing adequate substrate to fuel high catalytic activity, and raises the possibility that PDAC distant metastases adopt their own unique metabolic strategies to support tumor growth.


Episode-based payment: evaluating the impact on chronic conditions.
Policy makers are interested in aggregating fee-for-service reimbursement into episode-based bundle payments, hoping it will lead to greater efficiency in the provision of care. The focus of bundled payment initiatives has been upon surgical or discrete procedures. Relatively little is known about calculating and implementing episode-based payments for chronic conditions. Compare the differences in two different episode-creation algorithms for two common chronic conditions: diabetes and coronary artery disease (CAD). We conducted a retrospective evaluation using enrollees with continuous coverage in a self-funded plan from 2003 to 2006, meeting Healthcare Effectiveness Data and Information Set (HEDIS) criteria for diabetes or CAD. For each condition, an annual episode-based payment was assessed using two algorithms: Episode Treatment Groups (ETGs) and the Prometheus model. We began with 1,580 diabetes patients with a 4-year total payment mean of $67,280. ETGs identified 1,447 (92%) as having diabetes with 4-year episode-based mean payments of $12,731; while the Prometheus model identified 1,512 (96%) as having diabetes, but included only 1,195 of them in the Prometheus model with mean diabetes payments of $23,250. Beginning with 1,644 CAD patients with a 4-year total payment mean of $65,661, ETGs identified 983 patients (60%) with a 4-year episode-based mean of $24,362. The Prometheus model identified 1,135 (69%) as CAD patients with 948 CAD patients having a mean of $26,536. The two episode-based methods identify different patients with these two chronic conditions. In addition, there are significant differences in the episode-based payment estimates for diabetes, but similar estimates for CAD. Implementing episode-based payments for chronic conditions is challenging, and thoughtful discussions are needed to determine appropriate payments.


Advanced colorectal neoplasia risk stratification by penalized logistic regression.
Colorectal cancer is the second leading cause of death from cancer in the United States. To facilitate the efficiency of colorectal cancer screening, there is a need to stratify risk for colorectal cancer among the 90% of US residents who are considered "average risk." In this article, we investigate such risk stratification rules for advanced colorectal neoplasia (colorectal cancer and advanced, precancerous polyps). We use a recently completed large cohort study of subjects who underwent a first screening colonoscopy. Logistic regression models have been used in the literature to estimate the risk of advanced colorectal neoplasia based on quantifiable risk factors. However, logistic regression may be prone to overfitting and instability in variable selection. Since most of the risk factors in our study have several categories, it was tempting to collapse these categories into fewer risk groups. We propose a penalized logistic regression method that automatically and simultaneously selects variables, groups categories, and estimates their coefficients by penalizing the [Formula: see text]-norm of both the coefficients and their differences. Hence, it encourages sparsity in the categories, i.e. grouping of the categories, and sparsity in the variables, i.e. variable selection. We apply the penalized logistic regression method to our data. The important variables are selected, with close categories simultaneously grouped, by penalized regression models with and without the interactions terms. The models are validated with 10-fold cross-validation. The receiver operating characteristic curves of the penalized regression models dominate the receiver operating characteristic curve of naive logistic regressions, indicating a superior discriminative performance.


Resting glutamate levels and rapid glutamate transients in the prefrontal cortex of the Flinders Sensitive Line rat: a genetic rodent model of depression.
Despite the numerous drugs targeting biogenic amines for major depressive disorder (depression), the search for novel therapeutics continues because of their poor response rates (~30%) and slow onset of action (2-4 weeks). To better understand role of glutamate in depression, we used an enzyme-based microelectrode array (MEA) that was selective for glutamate measures with fast temporal (2 Hz) and high spatial (15 × 333 μm) resolution. These MEAs were chronically implanted into the prefrontal cortex of 3- to 6-month-old and 12- to 15-month-old Flinders Sensitive Line (FSL) and control Flinders Resistant Line (FRL) rats, a validated genetic rodent model of depression. Although no changes in glutamate dynamics were observed between 3 and 6 months FRL and FSL rats, a significant increase in resting glutamate levels was observed in the 12- to 15-month-old FSL rats compared with the 3- to 6-month-old FSL and age-matched FRL rats on days 3-5 post-implantation. Our MEA also recorded, for the first time, a unique phenomenon in all the four rat groups of fluctuations in resting glutamate, which we have termed glutamate transients. Although these events lasted only for seconds, they did occur throughout the testing paradigm. The average concentration of these glutamate-burst events was significantly increased in the 12- to 15-month-old FSL rats compared with 3- to 6-month-old FSL and age-matched FRL rats. These studies lay the foundation for future studies of both tonic and phasic glutamate signaling in rat models of depression to better understand the potential role of glutamate signaling in depression.


Financial Impact of Complex Cancer Surgery in India: A Study of Pancreatic Cancer.
The rapidly increasing burden of cancer in India has profound impacts on health care costs for patients and their families. High out-of-pocket (OOP) expenditure, lack of insurance, and low government expenditure create a vicious cycle, leading to household impoverishment. Complex cancer surgery is now increasingly important for emerging countries; however, little is understood about the macro- and microeconomics of these procedures. After the Lancet Oncology Commission on Global Cancer Surgery, we evaluated the OOP expenditure for patients undergoing pancreatico-duodenectomy (PD) at a government tertiary cancer center in India. Prospective data from 98 patients who underwent PD between January 2014 and June 2015 were collected and analyzed. The time frame for consideration of expenses, including all preoperative investigations, was from the first hospital visit to the day of discharge. Catastrophic expenditure was calculated by assessing the percentage of households in which OOP health payments exceeded 10% of the total household income. The mean expenditure for PD by patients was Rs.295,679.57 (US$74,420, purchasing power parity corrected). This amount was significantly higher among those admitted to a private ward and those with complications. Only 29.6% of the patients had insurance coverage. A total of 76.5% of the sample incurred catastrophic expenditure, and 38% of those with insurance underwent financial catastrophe compared with 93% of those without insurance. The percentage of patients facing catastrophic impact was highest among those in semiprivate wards, at 86.7%, followed by those in public and private wards. The cost of PD is high and is often unaffordable for a majority of India's population. A review of insurance coverage policies for better coverage must be considered.


[Memory clinic in the day hospital].
Our Memory Clinic at the Day Hospital has developed from years of existing services offered for the outpatient diagnosis of memory disorders. This article presents how such two- to three-day outpatient diagnostic programs are held. After an initial consultation, the patient is admitted to the day clinic. Then a survey of the patient's daily activities is taken, a semi-standardized interview is conducted with patients and the caregivers; neuropsychological tests and a somatic examination including a functional assessment are carried out. In the following, we will discuss how the diagnosis is subsequently rendered on the basis of these findings. Frequently asked questions, common problems and diagnostic difficulties will be elucidated, while focusing on diagnostic and therapeutic discussions and the contents of the consultations.


Cognitive Deficits after Cerebral Ischemia and Underlying Dysfunctional Plasticity: Potential Targets for Recovery of Cognition.
Cerebral ischemia affects millions of people worldwide and survivors suffer from long-term functional and cognitive deficits. While stroke and cardiac arrest are typically considered when discussing ischemic brain injuries, there is much evidence that smaller ischemic insults underlie neurodegenerative diseases, including Alzheimer's disease. The "regenerative" capacity of the brain relies on several aspects of plasticity that are crucial for normal functioning; less affected brain areas may take over function previously performed by irreversibly damaged tissue. To harness the endogenous plasticity mechanisms of the brain to provide recovery of cognitive function, we must first understand how these mechanisms are altered after damage, such as cerebral ischemia. In this review, we discuss the long-term cognitive changes that result after cerebral ischemia and how ischemia alters several plasticity processes. We conclude with a discussion of how current and prospective therapies may restore brain plasticity and allow for recovery of cognitive function, which may be applicable to several disorders that have a disruption of cognitive processing, including traumatic brain injury and Alzheimer's disease.


Cilioplasm is a cellular compartment for calcium signaling in response to mechanical and chemical stimuli.
Primary cilia with a diameter of ~200 nm have been implicated in development and disease. Calcium signaling within a primary cilium has never been directly visualized and has therefore remained a speculation. Fluid-shear stress and dopamine receptor type-5 (DR5) agonist are among the few stimuli that require cilia for intracellular calcium signal transduction. However, it is not known if these stimuli initiate calcium signaling within the cilium or if the calcium signal originates in the cytoplasm. Using an integrated single-cell imaging technique, we demonstrate for the first time that calcium signaling triggered by fluid-shear stress initiates in the primary cilium and can be distinguished from the subsequent cytosolic calcium response through the ryanodine receptor. Importantly, this flow-induced calcium signaling depends on the ciliary polycystin-2 calcium channel. While DR5-specific agonist induces calcium signaling mainly in the cilioplasm via ciliary CaV1.2, thrombin specifically induces cytosolic calcium signaling through the IP3 receptor. Furthermore, a non-specific calcium ionophore triggers both ciliary and cytosolic calcium responses. We suggest that cilia not only act as sensory organelles but also function as calcium signaling compartments. Cilium-dependent signaling can spread to the cytoplasm or be contained within the cilioplasm. Our study thus provides the first model to understand signaling within the cilioplasm of a living cell.


Increased aortic impedance precedes peripheral vasoconstriction at the early stage of ventricular failure in the paced canine model.
Aortic input impedance is altered in patients with congestive heart failure. However, little is known about whether this vascular response is an early change or a late manifestation of left ventricular dysfunction. This investigation used a paced canine model of congestive heart failure to demonstrate that abnormal aortic input impedance does evolve in the setting of ventricular systolic dysfunction and to prospectively define the time course of change in aortic input impedance and conduit vessel compliance. Studies were performed in closed-chest conditioned beagles aged 1 to 2 years that underwent hemodynamic evaluation at baseline and after induction of left ventricular dysfunction by rapid ventricular pacing. Within 48 hours of the onset of rapid ventricular pacing, we observed mild left ventricular systolic dysfunction with an echocardiographically derived left ventricular ejection fraction of 37% (p < .001 compared with baseline) measured during interruption of rapid ventricular pacing. Concomitant with this reduction in left ventricular systolic function, the aortic input impedance spectrum was shifted above baseline in all dogs studied. Characteristic impedance of the aorta significantly increased from 121 +/- 65 dynes.s/cm5 to 186 +/- 114 dynes.s/cm5 (P < .02), and a significant increase in the first modulus of impedance from 137 +/- 43 dynes.s/cm5 to 228 +/- 139 dynes.s/cm5 was observed (P < .05). Although characteristic aortic impedance increased by 50%, there was at this point no change in peripheral vascular resistance. Therefore, these abnormalities in aortic input impedance are representative of an early vascular change that evolves in response to ventricular systolic dysfunction. Considering the early appearance of these findings, the resultant impaired power transfer and reduced conduit vessel compliance likely contribute to the progression of abnormal myocardial energetics and systolic dysfunction characteristic of ventricular failure.


White matter hyperintensities in the forties: their prevalence and topography in an epidemiological sample aged 44-48.
White matter hyperintensities (WMHs) are a frequent finding on T2-weighted MRI of the brain in elderly individuals, but their prevalence and severity in younger asymptomatic populations is less well studied. We report the topography of WMHs on T2-weighted fluid inversion recovery (FLAIR) MRI in 428 individuals aged 44-48 years recruited randomly from a healthy community sample. WMHs were delineated from FLAIR and T1-weighted scans by using a computer algorithm, further verified and then classified using k-nearest neighbor (kNN) algorithm into deep WMH (DWMH), and periventricular WMH (PVWMH), which included extended periventricular "rims" and frontal and occipital "caps". Small caps and pencil-thin rims were not taken as WMHs for this analysis. The new computer algorithm was validated and compared with the scores of visual rating, and the correspondence between the two methods was high. We found that 218 (50.9%) subjects had WMHs. 146 of the 218 (34.1% of whole sample population of 428) subjects had deep white matter hyperintensities (DWMHs). The average number of WMH clusters (occurrences) per brain was 1.37 (0.94 for DWMH and 0.43 for pathological PVWMH) and the mean WMH tissue volume was 0.278 ml. There was no significant sex difference in the severity and distribution of WMHs. The study suggests that small punctate or focal WMHs are common in the brains of individuals in their 40s, and may represent an early stage of development of these lesions.


Formation of 11 beta-hydroxysteroids requires the integrity of the microfilament network in adrenocortical cells.
In order to determine the role of microfilaments in adrenal steroidogenesis, we have studied the effect of cytochalasin B, a microfilament-disrupting agent, on the kinetics of [3H] pregnenolone conversion to labelled metabolites by frog interrenal tissue in vitro. Cytochalasin B (5 x 10(-5)M) induced a 50 to 70% decrease in corticosterone, 18-hydroxycorticosterone and aldosterone biosynthesis while the formation of progesterone and 11-desoxycorticosterone was not affected. These results suggest that microfilaments interfere in the conversion of 11-desoxycorticosterone to corticosterone probably by controlling the movement of 11-desoxycorticosterone from the reticulum to the mitochondria.


Development of craniofacial and dental arch morphology in relation to sleep disordered breathing from 4 to 12 years. Effects of adenotonsillar surgery.
To study the development of craniofacial and dental arch morphology in children with sleep disordered breathing in relation to adenotonsillar surgery. From a community-based cohort of 644 children, 393 answered questionnaires at age 4, 6 and 12 years. Out of this group, 25 children who were snoring regularly at age 4 could be followed up to age 12 together with 24 controls not snoring at age 4, 6 and 12 years. Study casts were obtained from cases and controls and lateral cephalograms from the cases. Analysis regarding facial features and dento-alveolar development was performed. Children snoring regularly at age 4 showed reduced transversal width of the maxilla and more frequently had anterior open bite and lateral cross-bite than the controls. These conditions persisted for most cases at age 6, by which time 18/25 had been operated for snoring. In most of the cases, surgery cured the snoring temporarily, but their width of the maxilla was still smaller by age 12-even when nasal breathing was attained. At age 12, the frequency of lateral cross-bite was much reduced and anterior open bite was resolved, both in cases and controls. The children who snored regularly at age 12 operated or not operated, showed a long face anatomy and were oral breathers (this applied even to those who were operated). The seven cases who were not operated and the five who were still snoring in spite of surgery at age 12, did not have reduced maxillary width as compared to the controls. Dento-facial development in snoring children is not changed by adenotonsillar surgery regardless of symptom relief. If snoring persists or relapses orthodontic maxillar widening and/or functional training should be considered. Collaboration between otorhinolaryngologist, orthodontists and speech and language pathologists is strongly recommended.


Distinctive ligand-binding specificities of tandem PA14 biomass-sensory elements from Clostridium thermocellum and Clostridium clariflavum.
Cellulolytic clostridia use a highly efficient cellulosome system to degrade polysaccharides. To regulate genes encoding enzymes of the multi-enzyme cellulosome complex, certain clostridia contain alternative sigma I (σI ) factors that have cognate membrane-associated anti-σI factors (RsgIs) which act as polysaccharide sensors. In this work, we analyzed the structure-function relationship of the extracellular sensory elements of Clostridium (Ruminiclostridium) thermocellum and Clostridium clariflavum (RsgI3 and RsgI4, respectively). These elements were selected for comparison, as each comprised two tandem PA14-superfamily motifs. The X-ray structures of the PA14 modular dyads from the two bacterial species were determined, both of which showed a high degree of structural and sequence similarity, although their binding preferences differed. Bioinformatic approaches indicated that the DNA sequence of promoter of sigI/rsgI operons represents a strong signature, which helps to differentiate binding specificity of the structurally similar modules. The σI4 -dependent C. clariflavum promoter sequence correlates with binding of RsgI4_PA14 to xylan and was identified in genes encoding xylanases, whereas the σI3 -dependent C. thermocellum promoter sequence correlates with RsgI3_PA14 binding to pectin and regulates pectin degradation-related genes. Structural similarity between clostridial PA14 dyads to PA14-containing proteins in yeast helped identify another crucial signature element: the calcium-binding loop 2 (CBL2), which governs binding specificity. Variations in the five amino acids that constitute this loop distinguish the pectin vs xylan specificities. We propose that the first module (PA14A ) is dominant in directing the binding to the ligand in both bacteria. The two X-ray structures of the different PA14 dyads represent the first reported structures of tandem PA14 modules.


The prognosis of myofascial pain syndrome (MPS) during a fixed orthodontic treatment.
Among treatments in the literature for myofascial pain syndrome (MPS), the most reliable therapies in dentistry are spray and stretch, and, although less frequently used, anesthetic injection. Adult MPS subjects are often treated using fixed orthodontic therapy for resolution of malocclusion. There is no clarity in the literature on the prognosis of MPS during orthodontic therapy. The purpose of this study was to analyze the prognosis of MPS during orthodontic treatment of subjects with malocclusion, initially diagnosed as having MPS. The analysis covered the medical records of 91 young adult Caucasians scheduled for orthodontic treatment for various malocclusions. Thirty-seven of the patients were initially diagnosed as also having MPS (T0). Thirty patients began the orthodontic treatment and were recalled for a re-evaluation of MPS after dental alignment and dental class correction was achieved (T1). A wait-and-see strategy was applied in seven subjects who were included as the control subjects. They received no treatment for MPS. At T1, a statistically significant decrease was observed in the study group in the presence of any clicking or creaking noises from the jaw joint, a significant jaw joint and jaw muscle pain reduction, and a quality of life improvement. Among patients who were depressed at the beginning of treatment, the majority felt better at the follow-up evaluation. On muscular palpation, a statistically significant decrease was found on the visual analogic scale value of the middle fibers of the temporalis muscle, temporalis tendon, clavicular and sternal division of the sternocleidomastoid muscle, masseter muscles, and posterior cervical muscles. The temporalis and the masseter muscles showed a significant decrease in the number of subjects with trigger points (TrPs) in all areas in the study group, after treatment. The digastric and sternocleidomastoid muscles also showed a significant reduction in the number of subjects with TrPs. Subjects with MPS and malocclusion were treated using a fixed orthodontic treatment. They showed improvement, although no resolution, in the signs and symptoms of MPS, compared with the untreated control group.


Diminished synthesis of an alpha chain mutant, hemoglobin I (alpha-16 lys leads to glu).
In patients heterozygous for abnormal hemoglobins there is usually less than 50% of the mutant hemoglobin present in peripheral blood. The synthetic rates of alpha-chain mutants compared to alpha(A) have not been reported to date. In this study the production of alpha(A)- and alpha(I)-chains has been measured in peripheral blood and bone marrow of two patients with approximately 30% hemoglobin I, an alpha-chain abnormality (alpha(16 lys --> glu)). The results suggest that the decreased amount of alpha(I) compared to alpha(A) is due solely to diminished biosynthesis of the alpha(I)-chains. The relative rates of synthesis of alpha(I)- and alpha(A)-chains are similar in both nucleated red cells and reticulocytes indicating that no change occurs during erythroid cell maturation which preferentially affects either alpha(I) or alpha(A) production.


Long-term treatment of N-3 PUFAS on plasma lipoprotein levels and fatty acid composition of total serum and erythrocyte lipids in hypertriglyceridemic patients.
The low incidence of coronary heart disease in Greenland Eskimos and Japanese fishermen who have high consumption of fish and seafood has called the attention in the role of eicosapentaenoic (EPA = 20:5n-3) and docosahexaenoic (DHA = 22: 6n-3) acids, the major n-3 polyunsaturated fatty acids (PUFAs) in fish oils, in reducing cardiovascular risk. N-3 PUFAs may reduce serum lipids by promoting fatty acid oxidation and decrease VLDL producing from the liver, depress tissue arachidonate synthesis and alter the composition and tissue PUFAs. Plasma lipoprotein and fatty acid composition of total serum and erythrocyte lipids in 9 hypertriglyceridemic patients consisting of 4 males and 5 females aged 39-72 yr who attended the Nutrition Clinic, Ramathibodi Hospital were investigated. The study period consisted of 4 wks of dietary advice only followed by 48 wks of dietary advice with a daily intake of 6 g of fish oil capsules (FOC). Six grams of FOC provided 1080 mg of 2:5n-3 and 720 mg of 22:6n-3. Their plasma triglyceride (TG) levels at wk 0, 12, 24, 36, 48 were 356.7, 230.1, 209.7, 192.9, 22 7.4 mg/dL and M-particle (equivalent to very low density lipoprotein, VLDL) were 484.4, 354.8, 383.1, 349.7, 453.2 mg/dL respectively that decreased significantly, whereas their plasma low density lipoprotein cholesterol (LDL-C) levels at the same periods were 139.4, 164.9, 171.0, 157.1, 158.3 mg/dL that increased significantly. Serum and erythrocyte 20:5n-3 and 22:6n-3 in these subjects were significantly higher than those at wk 0 throughout the study. These findings indicate the bioavailability of 20: 5n-3 and 22:6n-3 in TG lowering effect of FOC. Fatty acids from fish oil have a remarkable effect on the synthesis and clearance of TG-rich lipoproteins, especially VLDL and chylomicrons. Though daily treatment with 6 g of FOC has a striking effect in increasing plasma LDL-C levels.


Characterization of apolipoprotein E-containing lipoproteins in cerebrospinal fluid: effect of phenotype on the distribution of apolipoprotein E.
Apolipoprotein (apo) E, one of the main apolipoproteins in the central nervous system, may play an important role in lipid metabolism; however, the details of its function are poorly understood. In this study, we characterized apoE-containing lipoproteins in cerebrospinal fluid (CSF) and examined the effect of apoE phenotype on the distribution of apoE among the lipoprotein fractions. CSF lipoproteins were fractionated by gel filtration and ultracentrifugation, and then characterized by electrophoresis, immunoblot, electron microscopy, and analysis of apoE, total cholesterol, and phospholipid concentrations. The ratio of sialylated to nonsialylated apoE was higher in CSF than in serum. However, the fundamental forms containing apoE homodimers or heterodimers [such as apo(E-AII) and apo(AII-E2-AII) complexes] were similar in CSF and serum. apoE-containing lipoproteins were fractionated at densities of <1.006, 1.063-1.125, and 1.125-1.21 kg/L. Neither apoE nor apoAI was detected in the fraction with a density range of 1.006-1.063 kg/L. The diameters of the lipoprotein particles with densities of <1.006, 1.063-1.125, and 1.125-1.21 kg/L were 16.7 +/- 3.1, 14.0 +/- 3.2, and 11.6 +/- 2.8 nm (mean +/- SD, n = 200), respectively. All of these lipoproteins exhibited a spherical structure. The distribution profile of apoE-containing lipoproteins was affected by the apoE phenotype. A relatively large amount of apoE-containing lipoproteins was isolated from the fraction with a density >1.125 kg/L obtained from CSF associated with apoE2 or apoE3. This tendency was more obvious in CSF associated with apoE2 than in CSF without apoE2. apoE-containing lipoproteins were predominantly observed in the fraction with a density of <1.006 kg/L obtained from CSF associated with apoE4. The lipoproteins in CSF have a unique composition that is different from that of the lipoproteins in plasma. However, the differences in diameter between the CSF fractions were not as large as for the serum fractions. Our data suggest that the apoE phenotype may affect the distribution profile of apoE-containing lipoproteins in the CSF. This would mean that the metabolism of apoE-containing lipoproteins depends on the apoE isoform present.


How language and inhibition influence analogical reasoning in children with or without developmental language disorder?
Introduction: Analogical reasoning is a human ability of crucial importance in several domains of cognition, such as numerical abilities, social cognition, and language, and which is impaired in children with developmental language disorder (DLD). This impairment might be caused by their weaknesses in inhibition or by the inefficient use of phonological recoding.Method: We compared children with DLD and age-matched children without language disorders in an A:B::C:D analogical task. We manipulated two variables: interference (versus no interference) was used to evaluate the impact of articulatory suppression on analogical performance, and distraction (versus no distractor) was used to test whether perceptual distractors (which compete with relational responses) diminish children's performance.Results: Contrary to expectations, articulatory suppression does not have a negative effect on analogical reasoning. In contrast, perceptual distractors have a detrimental impact on performance, and children with DLD are more impacted by perceptual distraction than their peers. Moreover, inhibition, as measured by a classical inhibition task, influences performance, but only for children with DLD.Conclusion: The analogical reasoning impairment observed in DLD, therefore, seems to be related to perceptual distraction and inhibition rather than to phonological recoding. To conclude, this study investigates the analogical reasoning impairment observed in DLD and contributes to our understanding of the relationships between language, analogical reasoning, and executive functions.


Misato Controls Mitotic Microtubule Generation by Stabilizing the TCP-1 Tubulin Chaperone Complex [corrected].
Mitotic spindles are primarily composed of microtubules (MTs), generated by polymerization of α- and β-Tubulin hetero-dimers. Tubulins undergo a series of protein folding and post-translational modifications in order to fulfill their functions. Defects in Tubulin polymerization dramatically affect spindle formation and disrupt chromosome segregation. We recently described a role for the product of the conserved misato (mst) gene in regulating mitotic MT generation in flies, but the molecular function of Mst remains unknown. Here, we use affinity purification mass spectrometry (AP-MS) to identify interacting partners of Mst in the Drosophila embryo. We demonstrate that Mst associates stoichiometrically with the hetero-octameric Tubulin Chaperone Protein-1 (TCP-1) complex, with the hetero-hexameric Tubulin Prefoldin complex, and with proteins having conserved roles in generating MT-competent Tubulin. We show that RNAi-mediated in vivo depletion of any TCP-1 subunit phenocopies the effects of mutations in mst or the Prefoldin-encoding gene merry-go-round (mgr), leading to monopolar and disorganized mitotic spindles containing few MTs. Crucially, we demonstrate that Mst, but not Mgr, is required for TCP-1 complex stability and that both the efficiency of Tubulin polymerization and Tubulin stability are drastically compromised in mst mutants. Moreover, our structural bioinformatic analyses indicate that Mst resembles the three-dimensional structure of Tubulin monomers and might therefore occupy the TCP-1 complex central cavity. Collectively, our results suggest that Mst acts as a co-factor of the TCP-1 complex, playing an essential role in the Tubulin-folding processes required for proper assembly of spindle MTs.


Decreased numeric density of succinic dehydrogenase-positive mitochondria in CA1 pyramidal neurons of 3xTg-AD mice.
Alzheimer disease (AD) is associated with mitochondrial dysfunction. In this study, we investigated succinic dehydrogenase (SDH) activity in mitochondria of hippocampal CA1 pyramidal neurons obtained from 10-month-old 3xTg-AD mice, an animal model of AD, as well as from age-matched control mice PS1-KI. In SDH-positive mitochondria, we measured numeric density (Nv, number of mitochondria/microm(3) of cytoplasm), average organelle volume (V), volume density (Vv, volume fraction of mitochondria/microm(3) of cytoplasm), average length (Fmax), and the ratio (R) between the total area of the cytochemical precipitate due to SDH activity and the total mitochondrial area. Our results indicate that 3xTg-AD mitochondria show a significant decrease of Nv, increase in V and Fmax, as well as a trend toward a reduction of R, whereas Vv is unchanged. Our findings further support the idea that mitochondrial dysfunction is involved in AD and are in line with studies indicating that both amyloid precursor protein (APP) and amyloid-beta (Abeta) localize to mitochondria.


In vivo burn scar assessment with speckle decorrelation and joint spectral and time domain optical coherence tomography.
Post-burn scars and scar contractures present significant challenges in burn injury management, necessitating accurate evaluation of the wound healing process to prevent or minimize complications. Non-invasive and accurate assessment of burn scar vascularity can offer valuable insights for evaluations of wound healing. Optical coherence tomography (OCT) and OCT angiography (OCTA) are promising imaging techniques that may enhance patient-centered care and satisfaction by providing detailed analyses of the healing process. Our study investigates the capabilities of OCT and OCTA for acquiring information on blood vessels in burn scars and evaluates the feasibility of utilizing this information to assess burn scars. Healthy skin and neighboring scar data from nine burn patients were obtained using OCT and processed with speckle decorrelation, Doppler OCT, and an enhanced technique based on joint spectral and time domain OCT. These methods facilitated the assessment of vascular structure and blood flow velocity in both healthy skin and scar tissues. Analyzing these parameters allowed for objective comparisons between normal skin and burn scars. Our study found that blood vessel distribution in burn scars significantly differs from that in healthy skin. Burn scars exhibit increased vascularization, featuring less uniformity and lacking the intricate branching network found in healthy tissue. Specifically, the density of the vessels in burn scars is 67% higher than in healthy tissue, while axial flow velocity in burn scar vessels is 25% faster than in healthy tissue. Our research demonstrates the feasibility of OCT and OCTA as burn scar assessment tools. By implementing these technologies, we can distinguish between scar and healthy tissue based on its vascular structure, providing evidence of their practicality in evaluating burn scar severity and progression.


Immune-directed therapy for type 1 diabetes at the clinical level: the Immune Tolerance Network (ITN) experience.
Reestablishing immune tolerance in type 1 diabetes (T1D), a chronic autoimmune disease, is a major goal. The Immune Tolerance Network (ITN) has initiated eight clinical trials of immunomodulatory therapies in recent-onset T1D over the past decade. Results have been mixed in terms of clinical efficacy, but the studies have provided valuable mechanistic insight that are enhancing our understanding of the disease and guiding the design of future trials. Trials of non-Fc-binding anti-CD3 mAbs have revealed that modulation of this target leads to partial responses, and ITN's AbATE trial led to identification of a robust responder group that could be distinguished from non-responders by baseline metabolic and immunologic features. A pilot study of the combination of IL-2 and rapamycin gave the first demonstration that frequency and function of regulatory T cells (Tregs) can be enhanced in T1D subjects, although the therapy triggered the activation of effectors with transient β-cell dysfunction. Similarly, therapy with anti-thymocyte globulin led to substantial lymphocyte depletion, but also to the activation of the acute-phase response with no clinical benefit during preliminary analyses. These and other results provide mechanistic tools that can be used as biomarkers for safety and efficacy in future trials. Furthermore, our results, together with those of other organizations, notably TrialNet, delineate the roles of the major components of the immune response in T1D. This information is setting the stage for future combination therapy trials. The development of disease-relevant biomarkers will also enable the implementation of innovative trial designs, notably adaptive trials, which will increase efficiencies in terms of study duration and sample size, and which will expedite the conduct of trials in which there are uncertainties about dose response and effect size.


An umbrella review on the association between factors of oral health and cognitive dysfunction.
An increasing number of systematic reviews and meta-analyses have been published on the association between oral health and cognitive dysfunction, also known as oral-cognitive links. However, there is great diversity in the oral and cognitive factors included in these studies, with different opinions for clinical practice drawn from the evidence. To understand which oral and cognitive factors are involved in those associations, we conducted an umbrella review of 28 systematic reviews, including 12 meta-analyses, on oral-cognitive links. We found that (a) periodontal diseases, oral microbiome, and dementia were frequently studied, while other factors, such as mastication and mild cognitive impairment, were less commonly investigated, and (b) severe deterioration of oral health, such as severe periodontitis or extensive tooth loss, rather than the presence of oral diseases alone, was strongly associated with cognitive dysfunction. In conclusion, the diversity of oral and cognitive factors included in the review studies reflects the complexity of oral-cognitive links. Clarifying the factors helps to form evidence-based clinical advice for healthcare.


Intrauterine growth retardation in Iowa communities with herbicide-contaminated drinking water supplies.
In a statewide survey of 856 Iowa municipal drinking water supplies in 1986-1987 the Rathbun rural water system was found to contain elevated levels of triazine herbicides. Rates of low birth weight, prematurity, and intrauterine growth retardation (IUGR) in live singleton births during the period 1984-1990 by women living in 13 communities served by the Rathbun water system were compared to other communities of similar size in the same Iowa counties. The Rathbun communities had a greater risk of IUGR than southern Iowa communities with other surface sources of drinking water (relative risk = 1.8; 95% CI = 1.3, 2.7). Multiple linear regression analyses revealed that levels of the herbicides atrazine, metolachlor, and cyanzinc were each significant predictors of community IUGR rates in southern Iowa after controlling for several potentially confounding factors including maternal smoking and socioeconomic variables. The association with IUGR was strongest for atrazine, but all three herbicides were intercorrelated and the independent contributions of each to IUGR risk could not be determined. We conclude that communities in southern Iowa with drinking water supplies contaminated with herbicides have elevated rates of IUGR compared to neighboring communities with different water supplies. Because of the limitations of the ecologic design of this study, including aggregate rather than individual measures of exposure and limited ability to control for confounding factors related to source of drinking water and risk of IUGR, a strong causal relationship between any specific water contaminant and risk of IUGR cannot yet be inferred. The association between the water supplied to the Rathbun communities and the increased risk of IUGR should be considered a preliminary finding that needs to be verified by more detailed epidemiologic studies.


What do we learn from high-throughput protein interaction data?
The biological significance of protein interactions, their method of generation and reliability is briefly reviewed. Protein interaction networks adopt a scale-free topology that explains their error tolerance or vulnerability, depending on whether hubs or peripheral proteins are attacked. Networks also allow the prediction of protein function from their interaction partners and therefore, the formulation of analytical hypotheses. Comparative network analysis predicts interactions for distantly related species based on conserved interactions, even if sequences are only weakly conserved. Finally, the medical relevance of protein interaction analysis is discussed and the necessity for data integration is emphasized.


Imaging Strategy that Achieves Ultrahigh Contrast by Utilizing Differential Esterase Activity in Organs: Application in Early Detection of Pancreatic Cancer.
Most nanoparticles show much higher uptake in mononuclear phagocyte system (MPS) organs than in tumors, which has been a long-lasting dilemma in nanomedicine. Here, we report an imaging strategy that selectively decreases MPS organ uptakes by utilizing the differential esterase activity in tumors and other organs. When an esterase-labile radiotracer loaded liposome was injected into the body, radioactivity was rapidly excreted from the liver and spleen after breakage of the ester bond by esterase. However, the lipophilic radiotracer delivered to the tumor remained in the tumor with minimal bond cleavage. The underlying mechanism was fully characterized in vitro and in vivo in colon tumor models. As a proof of concept, the liposomal radiotracer was further optimized for the early detection of pancreatic cancer. The folate-coated liposomal radiotracer showed highly selective tumor uptake. At 4 h postinjection, a pancreatic tumor a few millimeters in size was unambiguously visualized in orthotopic tumor models by PET imaging. At 24 h, an exceptionally high tumor-to-background ratio was achieved, enabling the visualization of tumors alone with minimal background noise. More than 9% of the total radioactivity was found in the tumor. Utilizing our imaging strategy, various tumor imaging agents can be developed for sensitive detection with ultrahigh contrast.


Exploring folding patterns of infant cerebral cortex based on multi-view curvature features: Methods and applications.
The highly convoluted cortical folding of the human brain is intriguingly complex and variable across individuals. Exploring the underlying representative patterns of cortical folding is of great importance for many neuroimaging studies. At term birth, all major cortical folds are established and are minimally affected by the complicated postnatal environments; hence, neonates are the ideal candidates for exploring early postnatal cortical folding patterns, which yet remain largely unexplored. In this paper, we propose a novel method for exploring the representative regional folding patterns of infant brains. Specifically, first, multi-view curvature features are constructed to comprehensively characterize the complex characteristics of cortical folding. Second, for each view of curvature features, a similarity matrix is computed to measure the similarity of cortical folding in a specific region between any pair of subjects. Next, a similarity network fusion method is adopted to nonlinearly and adaptively fuse all the similarity matrices into a single one for retaining both shared and complementary similarity information of the multiple characteristics of cortical folding. Finally, based on the fused similarity matrix and a hierarchical affinity propagation clustering approach, all subjects are automatically grouped into several clusters to obtain the representative folding patterns. To show the applications, we have applied the proposed method to a large-scale dataset with 595 normal neonates and discovered representative folding patterns in several cortical regions, i.e., the superior temporal gyrus (STG), inferior frontal gyrus (IFG), precuneus, and cingulate cortex. Meanwhile, we have revealed sex difference in STG, IFG, and cingulate cortex, as well as hemispheric asymmetries in STG and cingulate cortex in terms of cortical folding patterns. Moreover, we have also validated the proposed method on a public adult dataset, i.e., the Human Connectome Project (HCP), and revealed that certain major cortical folding patterns of adults are largely established at term birth.


Hepatitis B vaccine responsiveness and clinical outcomes in HIV controllers.
Hepatitis B virus (HBV) vaccine responsiveness is associated with reduced risk of AIDS or death in HIV-infected individuals. Although HIV controllers (HIC) typically have favorable immunologic and clinical characteristics compared to non-controllers, vaccine responsiveness has not been studied. In the U.S. Military HIV Natural History Study, HBV vaccine response was defined as antibody to hepatitis B surface antigen (anti-HBs) ≥ 10 IU/L after last vaccination. For determination of vaccine responsiveness, HIC (n = 44) and treatment-naïve non-controllers (n = 476) were not on highly active antiretroviral therapy (HAART) when vaccinated while treated non-controllers (n = 284) received all HBV vaccine doses during viral load (VL)-suppressive HAART. Progression to AIDS or death was also compared for all HIC (n = 143) and non-controllers (n = 1566) with documented anti-HBs regardless of the timing of HBV vaccination. Positive vaccine responses were more common in HIC (65.9%) compared to HAART-naïve non-controllers (36.6%; P<0.001), but similar to non-controllers on HAART (59.9%; P = 0.549). Factors associated with vaccine response for HIC compared to HAART-naïve non-controllers include HIC status (OR 2.65, 95% CI 1.23-5.89; P = 0.014), CD4 count at last vaccination (OR 1.28, 1.15-1.45 for every 100 cells/uL; P<0.001), and number of vaccine doses administered (OR 0.56, 0.35-0.88; P = 0.011). When HIC were compared to non-controllers on HAART, only CD4 count at last vaccination was significant (OR 1.23, 1.1-1.38 for every 100 cells/uL; P<0.001). The rate of AIDS or death per 100 person/years for HIC compared to non-controllers was 0.14 (95% CI 0-0.76) versus 0.98 (95% CI 0.74-1.28) for vaccine responders and 0 (95% CI 0-2.22) versus 4.11 (95% CI 3.38-4.96) for non-responders, respectively. HIC have improved HBV vaccine responsiveness compared to treatment-naïve non-controllers, but similar to those on VL-suppressive HAART. Progression to AIDS or death can be predicted by HBV vaccine responder status for non-controllers, however these events are rarely observed in HIC.


Geographical distribution of perfluorinated compounds in fish from Minnesota lakes and rivers.
In response to growing interest in human exposure to perfluorinated compounds (PFCs), the state of Minnesota measured and reported PFC concentrations in fish collected from the Minneapolis-St. Paul area. To better determine the geographical distribution of PFC contamination throughout Minnesota, fish were collected from 59 lakes throughout the state and several areas along the Mississippi River. Composite fish samples were analyzed for 10 PFC analytes by solid-phase extraction (SPE) and liquid chromatography-tandem mass spectrometry (LC/MS/MS). PFOS (perfluorooctanesulfonate) was the most commonly detected PFC, occurring in 73% of fish from the Mississippi River but only 22% of fish from lakes. Fish from Mississippi River Pool 2 near the Minneapolis-St. Paul area had the highest levels of PFOS, whereas locations upstream had PFOS concentrations below 40 ng/g, the concentration at which Minnesota issues "one meal per week" fish consumption advice. Fish from most Minnesota lakes tested (88%) had PFOS concentrations below 3 ng/g. Two lakes, McCarrons and Zumbro, contained fish with PFOS levels above 40 ng/g. The results reported here will help researchers to better understand the extent of PFC contamination in Minnesota fish and evaluate potential sources of contamination and will provide a basis for comprehensive fish consumption advice.


Health promoting properties and sensory characteristics of phytochemicals in berries and leaves of sea buckthorn (Hippophaë rhamnoides).
Sea buckthorn (Hippophaë rhamnoides L., SB), as a multi-functional plant, is widely grown in Asia, Europe and Canada. The berries and leaves of SB contain a diverse array of health-supporting phytochemicals, which are also related to the sensory qualities of berry and berry products. This review summarizes the biologically active key-compounds of the berries and leaves of SB, their health-promoting effects, as well as the contributions to the sensory quality of the berries. The target compounds consist of sugars, sugar derivatives, organic acids, phenolic compounds and lipophilic compounds (mainly carotenoids and tocopherols), which play an important role in anti-inflammatory and antioxidant functions, as well as in metabolic health. In addition, these compounds contribute to the orosensory qualities of SB berries, which are closely related to consumer acceptance and preference of the products. Studies regarding the bioavailability of the compounds and the influence of the processing conditions are also part of this review. Finally, the role of the sensory properties is emphasized in the development of SB products to increase utilization of the berry as a common meal component and to obtain value-added products to support human health.


Perfectionism and attitudes towards doping in junior athletes.
Recent theory and research suggest that perfectionism is a personal factor contributing to athletes' vulnerability to doping (using banned substances/drugs to enhance sporting performance). So far, however, no study has examined what aspects of perfectionism suggest a vulnerability in junior athletes. Employing a cross-sectional design, this study examined perfectionism and attitudes towards doping in 129 male junior athletes (mean age 17.3 years) differentiating four aspects of perfectionism: perfectionistic strivings, perfectionistic concerns, parental pressure to be perfect, and coach pressure to be perfect. In the bivariate correlations, only parental pressure showed a positive relationship with positive doping attitudes. In a multiple regression analysis controlling for the overlap between the four aspects, perfectionistic strivings additionally showed a negative relationship. Moreover, a structural equation model examining the relationships between all variables suggested that coach pressure had a negative indirect effect on attitudes towards doping via perfectionistic strivings. The findings indicate that perceived parental pressure to be perfect may be a factor contributing to junior athletes' vulnerability to doping, whereas perfectionistic strivings may be a protective factor.


Alteration of the microRNA expression profile during the activation of pancreatic stellate cells.
OBJECTIVE. Pancreatic stellate cells (PSCs) play a pivotal role in the pancreatic fibrosis associated with chronic pancreatitis and pancreatic cancer. In response to pancreatic injury or inflammation, PSCs are activated to myofibroblast-like cells. MicroRNA (miRNA) is a small RNA, consisting of 17-25 nucleotides, which targets 3'-untranslated region sequences of mRNA. miRNAs regulate a variety of cell functions such as cell proliferation, differentiation, and carcinogenesis. We examined here whether the miRNA expression profiles are altered during the activation of PSCs. MATERIALS AND METHODS. Rat PSCs were isolated from the pancreas tissue of male Wistar rats. PSCs were activated in vitro by culture in serum-containing medium. miRNAs were prepared from quiescent (day 1) PSCs and culture-activated (day 14) PSCs. Agilent's miRNA microarray containing probes for 680 miRNAs was used to identify differentially expressed miRNAs. Ingenuity Pathway Analysis (IPA) was used for the integrated analysis of altered miRNAs. RESULTS. Upon activation, 42 miRNAs were upregulated (>2.0-fold) and 42 miRNAs were downregulated (<0.5-fold). Upregulated miRNAs included miR-31, miR-143, and miR-221. Downregulated miRNAs included miR-126, miR-146a, and miR-150. IPA revealed the most impacted biological processes including cellular development, cellular growth, and cell movement. Interestingly, IPA identified 22 miRNAs affected both in pancreatic cancer and PSC activation. The top network generated by IPA revealed the interactions of altered miRNAs with signaling pathways such as p38 mitogen-activated protein kinase, extracellular-signal-regulated kinase, and Smad2/3. CONCLUSIONS. Our results suggest a novel role of miRNAs in the activation of PSCs.


[Method of evaluating the acoustic properties of devices for auscultation].
It is suggested that the appraisal of acoustic properties of auscultation instruments should be done by an expert-physician by following the most outstanding auscultative characteristics. A procedure for medical appraisal of acoustic properties is proposed. The BF-1 sthetophonendoscope manufactured by the Nizhny-Tagil medical instruments plant is recommended to serve as a model one.


An eight-mRNA signature predicts the prognosis of patients with bladder urothelial carcinoma.
Bladder cancer is one of the most common cancers, and its histopathological type is mainly bladder urothelial carcinoma, accounting for about 90%. The prognostic biomarkers of bladder cancer are classified into clinical features biomarkers and molecular biomarkers. Nevertheless, due to the existence of individual specificity, patients with similar pathological characteristics still have great differences in the risk of disease recurrence. Therefore, it is often inaccurate to predict the survival status of patients based on clinical characteristic biomarkers, and a prognostic molecular biomarker that can grade the risk of bladder cancer patients is needed. A total of three bladder urothelial carcinoma datasets were used in this study from the Cancer Genome Atlas database and Gene Expression Omnibus database. In order to avoid overfitting, all samples were randomly divided into one training set and three validation sets, which were used to construct and test the prognostic biomarker model of bladder urothelial carcinoma. Univariate and multivariate Cox regression were used to screen candidate mRNAs and construct prognostic biomarkers model. Kaplan-Meier survival analysis and the receiver operating characteristic (ROC) curve were used to evaluate the predictive performance of the model. A prognostic biomarker model of bladder urothelial carcinoma combining with eight mRNA was constructed. Kaplan-Meier analyses indicated that a significant difference in the survival time of patients between the high-risk and the low-risk group. The area under the ROC curve were 0.632 (95% confidence interval (CI) [0.541-0.723]), 0.693 (95% CI [0.601-0.784]) and 0.686 (95% CI [0.540-0.831]) when the model was used to predict the patient's survival time in three validation datasets. The model showed high accuracy and applicability.


Quantitative analysis of the relationship between maxillary incisors and the incisive canal by cone-beam computed tomography in an adult Japanese population.
In setting goals for orthodontic treatment, determining the morphologies of the alveolar bone and maxillary incisor root is important for avoiding root resorption, dehiscence, and fenestration. This study aimed to analyze the configurational relationships among maxillary incisors, the alveolar border, and the incisive canal by cone-beam computed tomography (CBCT). Cone-beam CT images of 93 orthodontic patients were evaluated for length of the incisive canal (L); angles between the palatal plane and the maxillary alveolar border (θ1), the incisive canal (θ2), and maxillary incisor (θ3); distance from the left maxillary incisor to the incisive canal (D); and cross-sectional areas of the incisive canal (CSAs) at three vertical levels. Comparison of variables between male and female patients was performed with the two-sample t test. Correlations between parameters were examined by Pearson's correlation analysis and Bonferroni correction for multiple comparisons. Male patients exhibited significantly greater values of L than female patients. There were significant positive correlations between θ1 and θ2, θ2 and θ3, and θ3 and θ1. While the value of D was the lowest at the oral opening, that of the cross-sectional area of the incisive canal (CSA) was the greatest at the incisal root apex. This study demonstrated that the incisive canal had large inter-individual variability, and the proximity between the incisive canal and the incisal root could not be precisely predicted by the conventional cephalograms. Therefore, pre-treatment CBCT examination should be recommended when a large amount of maxillary anterior retraction and/or intrusion is planned in orthodontic diagnosis.


Interpretation of airborne oceanic lidar: effects of multiple scattering.
The effects of multiple scattering on the interpretation of the time dependence of elastic backscattering of laser pulses from the ocean (lidar) are investigated through solving the radiative transfer equation by Monte Carlo techniques. In particular, after removal of the geometric loss factors, it is found that the backscat-tered power is a decaying exponential function of time, over the time interval required for photons to travel four attenuation lengths through the water. The effective attenuation coefficient of this exponential decay is found to be strongly dependent on the parameters of the lidar system and on the optical properties of the water. The significant parameter is the ratio of the radius of the spot on the sea surface viewed by the lidar receiver optics to the mean free path of photons in the water. For values of this parameter near zero, the decay is determined by the beam attenuation coefficient, while for values greater than ~5-6, the decay is given by the attenuation coefficient for downwelling irradiance, often referred to as the diffuse attenuation coefficient. Between these two extremes the interpretation of the effective attenuation coefficient requires, essentially, complete knowledge of the inherent optical properties of the water: the beam attenuation coefficient and the volume scattering function.